Tissue penetration device

Description

BACKGROUND

Lancing devices are known in the medical health-care products industry for piercing the skin to produce blood for analysis. Biochemical analysis of blood samples is a diagnostic tool for determining clinical information. Many point-of-care tests are performed using whole blood, the most common being monitoring diabetic blood glucose level. Other uses for this method include the analysis of oxygen and coagulation based on Prothrombin time measurement. Typically, a drop of blood for this type of analysis is obtained by making a small incision in the fingertip, creating a small wound, which generates a small blood droplet on the surface of the skin.

Early methods of lancing included piercing or slicing the skin with a needle or razor. Current methods utilize lancing devices that contain a multitude of spring, cam and mass actuators to drive the lancet. These include cantilever springs, diaphragms, coil springs, as well as gravity plumbs used to drive the lancet. Typically, the device is pre-cocked or the user cocks the device. The device is held against the skin and the user, or pressure from the users skin, mechanically triggers the ballistic launch of the lancet. The forward movement and depth of skin penetration of the lancet is determined by a mechanical stop and/or dampening, as well as a spring or cam to retract the lancet. Such devices have the possibility of multiple strikes due to recoil, in addition to vibratory stimulation of the skin as the driver impacts the end of the launcher stop, and only allow for rough control for skin thickness variation. Different skin thickness may yield different results in terms of pain perception, blood yield and success rate of obtaining blood between different users of the lancing device.

Success rate generally encompasses the probability of producing a blood sample with one lancing action, which is sufficient in volume to perform the desired analytical test. The blood may appear spontaneously at the surface of the skin, or may be “milked” from the wound. Milking generally involves pressing the side of the digit, or in proximity of the wound to express the blood to the surface. The blood droplet produced by the lancing action must reach the surface of the skin to be viable for testing. For a one-step lance and blood sample acquisition method, spontaneous blood droplet formation is requisite. Then it is possible to interface the test strip with the lancing process for metabolite testing.

When using existing methods, blood often flows from the cut blood vessels but is then trapped below the surface of the skin, forming a hematoma. In other instances, a wound is created, but no blood flows from the wound. In either case, the lancing process cannot be combined with the sample acquisition and testing step. Spontaneous blood droplet generation with current mechanical launching system varies between launcher types but on average it is about 50% of lancet strikes, which would be spontaneous. Otherwise milking is required to yield blood. Mechanical launchers are unlikely to provide the means for integrated sample acquisition and testing if one out of every two strikes does not yield a spontaneous blood sample.

Many diabetic patients (insulin dependent) are required to self-test for blood glucose levels five to six times daily. Reducing the number of steps required for testing would increase compliance with testing regimes. A one-step testing procedure where test strips are integrated with lancing and sample generation would achieve a simplified testing regimen. Improved compliance is directly correlated with long-term management of the complications arising from diabetes including retinopathies, neuropathies, renal failure and peripheral vascular degeneration resulting from large variations in glucose levels in the blood. Tight control of plasma glucose through frequent testing is therefore mandatory for disease management.

Another problem frequently encountered by patients who must use lancing equipment to obtain and analyze blood samples is the amount of manual dexterity and hand-eye coordination required to properly operate the lancing and sample testing equipment due to retinopathies and neuropathies particularly, severe in elderly diabetic patients. For those patients, operating existing lancet and sample testing equipment can be a challenge. Once a blood droplet is created, that droplet must then be guided into a receiving channel of a small test strip or the like. If the sample placement on the strip is unsuccessful, repetition of the entire procedure including re-lancing the skin to obtain a new blood droplet is necessary.

What is needed is a device, which can reliably, repeatedly and painlessly generate spontaneous blood samples. In addition, a method for performing analytical testing on a sample that does not require a high degree of manual dexterity or hand-eye coordination is required. Integrating sample generation (lancing) with sample testing (sample to test strip) will result in a simple one-step testing procedure resulting in better disease management through increased compliance with self testing regimes.

SUMMARY

Advantages can be achieved by use of a tissue penetration device that has user definable control of parameters such as lancet displacement, velocity of incision, retraction, acceleration, and tissue dwell time. A device having features of the invention can compensate for long-term changes in skin physiology, nerve function, and peripheral vascular perfusion such as occurs in diabetes, as well as diurnal variation in skin tensile properties. Alternatively, a device having features of the invention can compensate for skin differences between widely differing populations such as pediatric and geriatric patients, in addition to reducing the pain associated with lancing.

An embodiment of the invention is directed to a lancing device, which controls the advancement and retraction of a lancet by monitoring the position of the lancet in conjunction with a velocity control system in the form of a feedback loop. The feedback loop can modulate the lancet driver to follow a predetermined velocity versus position profile. The advancement and retraction profiles of the lancet through the skin govern the pain, success and spontaneous generation of the blood sample. Such a tissue penetration device can be combined with a sampling module, or sampling module cartridge, that contains a plurality of sampling modules. By integrating the tissue penetration function with the sample acquisition, and, (optionally), sample analysis, user convenience can be greatly enhanced as well as other advantages.

In another embodiment of the invention, a tissue penetration device includes a tissue penetration element coupled to a controllable driver. The controllable driver may include a magnetic source that produces a controllable magnetic field in a magnetically active region adjacent the magnetic source. A magnetic member disposed at least partially in the magnetically active region is coupled to the tissue penetration element. A position sensor is configured to measure the position of the tissue penetration element. The tissue penetration element can be a lancet.

In yet another embodiment of the invention, a controllable driver includes a magnetic source that produces a controllable magnetic field in a magnetically active region adjacent the magnetic source. A magnetic member is disposed at least partially in the magnetically active region and configured to be coupled to a lancet. A position sensor is configured to measure the position of the magnetic member. A processor is electrically coupled to the magnetic source and configured to control the magnitude of the magnetic field by controlling the amount of time the magnetic source is on in the magnetically active region based on feedback from the position sensor.

Another embodiment of the invention is directed to a tissue penetration device that includes a flat coil controllable driver having a magnetic source that produces a first magnetic field in a first magnetically active region and a second magnetic field in a second magnetically active region. A flat coil is secured to a translation substrate and has a leading segment disposed at least partially within the first magnetically active region and a trailing segment disposed at least partially within the second magnetically active region. A tissue penetration element is configured to penetrate tissue and mechanically coupled to the translation substrate. A position sensor is configured to measure the position of the tissue penetration element.

In yet another embodiment, the magnetically active regions are constructed from collections (2 or more) of solenoid coils, allowing coils to be energized such that the “slug” is always at least half (or ⅔, ¾, etc.) within the active portion of the solenoid, ensuring that the force exerted is always near optimal.

In an alternative embodiment, a tissue penetration device includes a controllable driver that has a magnetic source that produces a magnetic field in a magnetically active region. A cylindrical coil is secured to a translation substrate and disposed at least partially within the magnetically active region. A tissue penetration element configured to penetrate tissue is mechanically coupled to the translation substrate. A position sensor is configured to measure the position of the tissue penetration element directly or indirectly.

In an embodiment of a method of lancing for obtaining a sample of blood from a patient, a tissue penetration device for obtaining a blood sample from a patient is provided. The tissue penetration device has a magnetic source that produces a controllable magnetic field in a magnetically active region adjacent the magnetic source. A magnetic member is disposed at least partially in the magnetically active region and a tissue penetration element is coupled to the magnetic member. Next, the tissue penetration device is disposed adjacent tissue of the patient. The magnetic source is then activated to produce a magnetic field in the magnetically active region generating a magnetic force between the magnetic field and the magnetic member and driving the tissue penetration element into the patient's tissue.

In some embodiments, the magnetic field produced by the magnetic source is reversed after the tissue penetration element has entered the patient's tissue, reversing the force on the tissue penetration element and withdrawing the tissue penetration element from the patient's tissue. In addition, in other embodiments of the method, the magnitude of the magnetic force on the magnetic member during penetration of the patient's tissue by the tissue penetration element is greater than the magnitude of the magnetic force on the magnetic member during withdrawal of the tissue penetration element from the patient's tissue. In this way, the tissue penetration element may be withdrawn at a lower velocity from the patient's tissue than a velocity of the tissue penetration element during penetration of the patient's tissue.

Advantages can be achieved in a tissue penetration device for blood sampling by integrating a lancing and blood sample collection procedure so that the device can capture and transport the capillary blood from the wound created by the lancet or other tissue penetration element to a desired analytical area, such as a strip for analyzing glucose. This can be done in embodiments of the invention by integrating the lancet, sample flow channel and reservoir into a disposable sampling module, which can be inserted into a tissue penetration sampling device with instrumentation for analyzing the blood sample.

In the use of an embodiment of the invention, a finger is placed over an ergonomically contoured sampling area and pressure is applied with the finger so that a sensor will activate a driver, which will, in turn, lance the finger and allow the blood sample to be collected in the sample flow channel and transported to the reservoir for analysis in a single step from the patient's perspective.

Once a sample has been obtained and transported to a reservoir, advantages can be achieved by using devices and methods for easily measuring the zero or start-time of an assay and applying such a technology to kinetic assays. In addition, advantages can be achieved by using devices and methods that accurately detect successful sample introduction into a sampling module, to detect sample arrival at any predefined point or local environment in a sample flow channel, to detect sample arrival at a particular sensor or array of sensors, or to perform similar functions for fluids that are not samples containing the analyte to be measured, e.g., subsequent reagents or wash fluids. Embodiments of the invention generally relate to a method for using a thermal sensor to detect the presence or arrival of a fluid. Embodiments of the invention use the signal obtained from a thermal sensor to define the zero or start time of an assay for which knowing the rate of reaction is important or useful.

In some embodiments, a first signal from the thermal sensor is read prior to arrival of the fluid, a second signal is read as the fluid arrives, and the first signal and the second signal are related to provide an indicator that the fluid has arrived. In another embodiment, the method comprises determining the temperature of the local environment at the thermal sensor before the fluid arrives, determining the temperature of the local environment at the thermal sensor as the fluid arrives, and calculating the thermal differential, which may be used to indicate the arrival of the fluid.

Other embodiments of the invention can allow acquisition of the blood sample seamlessly, that is, without substantial contamination from ambient air, such that the blood sample may be analyzed accurately for gaseous components such as oxygen and carbon dioxide. Sampled blood can be acquired and transported to an analysis or storage device without substantial contamination by ambient air.

In one embodiment, a surface treatment of a support material is used on the target tissue to engender a difference in wetting ability. In another embodiment, an active pumping device is used in addition to capillary forces for drawing the blood into the sample reservoir and for dispensing blood from the reservoir to additional sites. Another embodiment includes the use of a device which compensates for an inadequate sample volume in the first sample reservoir by isolating the first sample reservoir and triggering a second lancing and acquisition step to fill a second “back-up” sample reservoir. Any of these three embodiments can be used alone, or in any combination of the other two embodiments.

User convenience as well as other advantages can be achieved with the use of a sampling cartridge containing a plurality of sampling modules capable of being used multiple times and obtaining multiple analytical readings before being discarded. Simplified actuation, lancing, sample acquisition, testing, and readout, can all be provided in a handheld apparatus capable of multiple uses on one sampling module cartridge. A sampling cartridge embodiment contains many individual sampling modules, each of which allows the collection and testing of a sample of blood. This allows the sampling cartridge to be used numerous times before exchange with a new cartridge and disposal of the used cartridge becomes necessary, thus reducing the need to dispose of used materials after each test. The sampling cartridge embodiment also retains used sampling materials safely, thereby reducing the problem of handling biohazardous materials.

In yet another embodiment, the sampling module can be configured to contain a hypodermic (patent) needle, and drug delivery chamber. Inherent in the position control mechanism of the electronic actuator is the ability to precisely define the position in space, allowing finite placement of a hypodermic syringe in the skin for injection of drugs, vaccines or the like. The reservoir for the drug or vaccine to be injected is the polymeric needle support module. Drug delivery can be discrete or continuous depending on the need.

A sampling cartridge embodiment provides for a simplified blood sampling and analysis process by having fewer components requiring assembly by the user and reducing the frequency that the components must be assembled for testing. A single sampling module combines the lancet and sample reservoir with analytical region, reducing the task of assembly by the user. The sampling cartridge combines a plurality of such sampling modules in a unit package that fits cassette-like into a reader device. This multi-use sampling cartridge need only be removed and replaced after all of the sampling modules are used, further reducing the task of assembly, disassembly, and disposal by the user. In one possible configuration, a separate apparatus provides a driver. In other embodiments the driver is included in the analyzer device or is integrated directly on the sampling module.

In a method, a series of blood samples may be collected and tested using a single disposable sampling cartridge which is designed to couple to an analyzer that can include a processor configured to interpret raw data from analyzed region. The sampling cartridge has a plurality of sampling modules, each sampling module adapted to be used for a single blood sampling cycle. The method starts with coupling of the sampling cartridge and analyzer and then initiating a blood sampling cycle. Upon completion of the blood sampling cycle, the sampling cartridge is advanced to bring a fresh, unused sampling module online, ready to perform another blood sampling cycle. After a series of blood sampling cycles has been performed, the sampling cartridge is decoupled from the analyzer and discarded, leaving the analyzer ready to be coupled with a new sampling cartridge.

In accordance with some embodiments of the invention, a method for lancing uses a lancet, a helix, or an elastomer to maintain the patency of the wound tract once the lancet has cut into the skin. If penetration takes place, and an appropriate number of blood vessels are cut, blood is allowed to flow up through the wound tract and onto the surface of the skin because the lancet, the helix, or the elastomer coats or braces the wound tract, keeping it open and patent. Coating or bracing is defined generally as keeping the wound open so that the blood can reach the surface of the finger. The term flow control can include any means for bracing the wound tract created by the lancet.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-3 are graphs of lancet velocity versus position for embodiments of spring driven, cam driven, and controllable force drivers.

FIG. 4 illustrates an embodiment of a controllable force driver in the form of a flat electric lancet driver that has a solenoid-type configuration.

FIG. 5 illustrates an embodiment of a controllable force driver in the form of a cylindrical electric lancet driver using a coiled solenoid-type configuration.

FIG. 6 illustrates a displacement over time profile of a lancet driven by a harmonic spring/mass system.

FIG. 7 illustrates the velocity over time profile of a lancet driver by a harmonic spring/mass system.

FIG. 8 illustrates a displacement over time profile of an embodiment of a controllable force driver.

FIG. 9 illustrates a velocity over time profile of an embodiment of a controllable force driver.

FIG. 10 illustrates the lancet needle partially retracted, after severing blood vessels; blood is shown following the needle in the wound tract.

FIG. 11 illustrates blood following the lancet needle to the skin surface, maintaining an open wound tract.

FIG. 12 is a diagrammatic view illustrating a controlled feed-back loop.

FIG. 13 is a graph of force vs. time during the advancement and retraction of a lancet showing some characteristic phases of a lancing cycle.

FIG. 14 illustrates a lancet tip showing features, which can affect lancing pain, blood volume, and success rate.

FIG. 15 illustrates an embodiment of a lancet tip.

FIG. 16 is a graph showing displacement of a lancet over time.

FIG. 17 is a graph showing an embodiment of a velocity profile, which includes the velocity of a lancet over time including reduced velocity during retraction of the lancet.

FIG. 18 illustrates the tip of an embodiment of a lancet before, during and after the creation of an incision braced with a helix.

FIG. 19 illustrates a finger wound tract braced with an elastomer embodiment.

FIG. 20 is a perspective view of a tissue penetration device having features of the invention.

FIG. 21 is an elevation view in partial longitudinal section of the tissue penetration device of FIG. 20.

FIG. 22 is an elevation view in partial section of an alternative embodiment.

FIG. 23 is a transverse cross sectional view of the tissue penetration device of FIG. 21 taken along lines 23-23 of FIG. 21.

FIG. 24 is a transverse cross sectional view of the tissue penetration device of FIG. 21 taken along lines 24-24 of FIG. 21.

FIG. 25 is a transverse cross sectional view of the tissue penetration device of FIG. 21 taken along lines 25-25 of FIG. 21.

FIG. 26 is a transverse cross sectional view of the tissue penetration device of FIG. 21 taken along lines 26-26 of FIG. 21.

FIG. 27 is a side view of the drive coupler of the tissue penetration device of FIG. 21.

FIG. 28 is a front view of the drive coupler of the tissue penetration device of FIG. 21 with the lancet not shown for purposes of illustration.

FIGS. 29A-29C show a flowchart illustrating a lancet control method.

FIG. 30 is a diagrammatic view of a patient's finger and a lancet tip moving toward the skin of the finger.

FIG. 31 is a diagrammatic view of a patient's finger and the lancet tip making contact with the skin of a patient's finger.

FIG. 32 is a diagrammatic view of the lancet tip depressing the skin of a patient's finger.

FIG. 33 is a diagrammatic view of the lancet tip further depressing the skin of a patient's finger.

FIG. 34 is a diagrammatic view of the lancet tip penetrating the skin of a patient's finger.

FIG. 35 is a diagrammatic view of the lancet tip penetrating the skin of a patient's finger to a desired depth.

FIG. 36 is a diagrammatic view of the lancet tip withdrawing from the skin of a patient's finger.

FIGS. 37-41 illustrate a method of tissue penetration that may measure elastic recoil of the skin.

FIG. 42 is a graphical representation of position and velocity vs. time for a lancing cycle.

FIG. 43 illustrates a sectional view of the layers of skin with a lancet disposed therein.

FIG. 44 is a graphical representation of velocity vs. position of a lancing cycle.

FIG. 45 is a graphical representation of velocity vs. time of a lancing cycle.

FIG. 46 is an elevation view in partial longitudinal section of an alternative embodiment of a driver coil pack and position sensor.

FIG. 47 is a perspective view of a flat coil driver having features of the invention.

FIG. 48 is an exploded view of the flat coil driver of FIG. 47.

FIG. 49 is an elevational view in partial longitudinal section of a tapered driver coil pack having features of the invention.

FIG. 50 is a transverse cross sectional view of the tapered coil driver pack of FIG. 49 taken along lines 50-50 in FIG. 49.

FIG. 51 shows an embodiment of a sampling module which houses a lancet and sample reservoir.

FIG. 52 shows a housing that includes a driver and a chamber where the module shown in FIG. 51 can be loaded.

FIG. 53 shows a tissue penetrating sampling device with the module loaded into the housing.

FIG. 54 shows an alternate embodiment of a lancet configuration.

FIG. 55 illustrates an embodiment of a sample input port, sample reservoir and ergonomically contoured finger contact area.

FIG. 56 illustrates the tissue penetration sampling device during a lancing event.

FIG. 57 illustrates a thermal sample sensor having a sample detection element near a surface over which a fluid may flow and an alternative position for a sampled detection element that would be exposed to a fluid flowing across the surface.

FIG. 58 shows a configuration of a thermal sample sensor with a sample detection element that includes a separate heating element.

FIG. 59 depicts three thermal sample detectors such as that shown in FIG. 58 with sample detection elements located near each other alongside a surface.

FIG. 60 illustrates thermal sample sensors positioned relative to a channel having an analysis site.

FIG. 61 shows thermal sample sensors with sample detection analyzers positioned relative to analysis sites arranged in an array on a surface.

FIG. 62 schematically illustrates a sampling module device including several possible configurations of thermal sample sensors including sample detection elements positioned relative to sample flow channels and analytical regions.

FIG. 63 illustrates a tissue penetration sampling device having features of the invention.

FIG. 64 is a top view in partial section of a sampling module of the tissue penetration sampling device of FIG. 63.

FIG. 65 is a cross sectional view through line 65-65 of the sampling module shown in FIG. 64.

FIG. 66 schematically depicts a sectional view of an alternative embodiment of the sampling module.

FIG. 67 depicts a portion of the sampling module surrounding a sampling port.

FIGS. 68-70 show in sectional view one implementation of a spring powered lancet driver in three different positions during use of the lancet driver.

FIG. 71 illustrates an embodiment of a tissue penetration sampling device having features of the invention.

FIG. 72 shows a top surface of a cartridge that includes multiple sampling modules.

FIG. 73 shows in partial section a sampling module of the sampling cartridge positioned in a reader device.

FIG. 74 is a perspective view in partial section of a tissue penetration sampling device with a cartridge of sampling modules.

FIG. 75 is a front view in partial section of the tissue penetration sampling device of FIG. 56.

FIG. 76 is a top view of the tissue penetration sampling device of FIG. 75.

FIG. 77 is a perspective view of a section of a sampling module belt having a plurality of sampling modules connected in series by a sheet of flexible polymer.

FIG. 78 is a perspective view of a single sampling module of the sampling module belt of FIG. 59.

FIG. 79 is a bottom view of a section of the flexible polymer sheet of the sampling module of FIG. 78 illustrating the flexible conductors and contact points deposited on the bottom surface of the flexible polymer sheet.

FIG. 80 is a perspective view of the body portion of the sampling module of FIG. 77 without the flexible polymer cover sheet or lancet.

FIG. 81 is an enlarged portion of the body portion of the sampling module of FIG. 80 illustrating the input port, sample flow channel, analytical region, lancet channel and lancet guides of the sampling module.

FIG. 82 is an enlarged elevational view of a portion of an alternative embodiment of a sampling module having a plurality of small volume analytical regions.

FIG. 83 is a perspective view of a body portion of a lancet module that can house and guide a lancet without sampling or analytical functions.

FIG. 84 is an elevational view of a drive coupler having a T-slot configured to accept a drive head of a lancet.

FIG. 85 is an elevational view of the drive coupler of FIG. 84 from the side and illustrating the guide ramps of the drive coupler.

FIG. 86 is a perspective view of the drive coupler of FIG. 84 with a lancet being loaded into the T-slot of the drive coupler.

FIG. 87 is a perspective view of the drive coupler of FIG. 86 with the drive head of the lancet completely loaded into the T-slot of the drive coupler.

FIG. 88 is a perspective view of a sampling module belt disposed within the T-slot of the drive coupler with a drive head of a lancet of one of the sampling modules loaded within the T-slot of the drive coupler.

FIG. 89 is a perspective view of a sampling module cartridge with the sampling modules arranged in a ring configuration.

FIG. 90 is a perspective view of a sampling module cartridge with the plurality of sampling modules arranged in a block matrix with lancet drive heads configured to mate with a drive coupler having adhesive coupling.

FIG. 91 is a side view of an alternative embodiment of a drive coupler having a lateral slot configured to accept the L-shaped drive head of the lancet that is disposed within a lancet module and shown with the L-shaped drive head loaded in the lateral slot.

FIG. 92 is an exploded view of the drive coupler, lancet with L-shaped drive head and lancet module of FIG. 91.

FIG. 93 is a perspective view of the front of a lancet cartridge coupled to the distal end of a controlled electromagnetic driver.

FIG. 94 is an elevational front view of the lancet cartridge of FIG. 93.

FIG. 95 is a top view of the lancet cartridge of FIG. 93.

FIG. 96 is a perspective view of the lancet cartridge of FIG. 93 with a portion of the cartridge body and lancet receptacle not shown for purposes of illustration of the internal mechanism.

FIGS. 97-101 illustrate an embodiment of an agent injection device.

FIGS. 102-106 illustrate an embodiment of a cartridge for use in sampling having a sampling cartridge body and a lancet cartridge body.

FIG. 107 illustrates a cartridge, an advancement device, and an unused penetrating member according to one embodiment of the present invention.

DETAILED DESCRIPTION

Variations in skin thickness including the stratum corneum and hydration of the epidermis can yield different results between different users with existing tissue penetration devices, such as lancing devices wherein the tissue penetrating element of the tissue penetration device is a lancet. Many current devices rely on adjustable mechanical stops or damping, to control the lancet's depth of penetration.

Displacement velocity profiles for both spring driven and cam driven tissue penetration devices are shown in FIGS. 1 and 2, respectively. Velocity is plotted against displacement X of the lancet. FIG. 1 represents a displacement/velocity profile typical of spring driven devices. The lancet exit velocity increases until the lancet hits the surface of the skin 10. Because of the tensile characteristics of the skin, it will bend or deform until the lancet tip cuts the surface 20, the lancet will then penetrate the skin until it reaches a full stop 30. At this point displacement is maximal and reaches a limit of penetration and the lancet stops. Mechanical stops absorb excess energy from the driver and transfer it to the lancet. The energy stored in the spring can cause recoil resulting in multiple piercing as seen by the coiled profile in FIG. 1. This results in unnecessary pain from the additional tissue penetration as well as from transferring vibratory energy into the skin and exciting nerve endings. Retraction of the lancet then occurs and the lancet exits the skin 40 to return into the housing. Velocity cannot be controlled in any meaningful way for this type of spring-powered driver.

FIG. 2 shows a displacement/velocity profile for a cam driven driver, which is similar to that of FIG. 1, but because the return path is specified in the cam configuration, there is no possibility of multiple tissue penetrations from one actuation. Cam based drivers can offer some level of control of lancet velocity vs. displacement, but not enough to achieve many desirable displacement/velocity profiles.

Advantages are achieved by utilizing a controllable force driver to drive a lancet, such as a driver, powered by electromagnetic energy. A controllable driver can achieve a desired velocity versus position profile, such as that shown in FIG. 3. Embodiments of the present invention allow for the ability to accurately control depth of penetration, to control lancet penetration and withdrawal velocity, and therefore reduce the pain perceived when cutting into the skin. Embodiments of the invention include a controllable driver that can be used with a feedback loop with a position sensor to control the power delivered to the lancet, which can optimize the velocity and displacement profile to compensate for variations in skin thickness

Pain reduction can be achieved by using a rapid lancet cutting speed, which is facilitated by the use of a lightweight lancet. The rapid cutting minimizes the shock waves produced when the lancet strikes the skin in addition to compressing the skin for efficient cutting. If a controllable driver is used, the need for a mechanical stop can be eliminated. Due to the very light mass of the lancet and lack of a mechanical stop, there is little or no vibrational energy transferred to the finger during cutting.

The lancing devices such as those whose velocity versus position profiles are shown in FIGS. 1 and 2 typically yield 50% spontaneous blood. In addition, some lancing events are unsuccessful and yield no blood, even on milking the finger. A spontaneous blood droplet generation is dependent on reaching the blood capillaries and venuoles, which yield the blood sample. It is therefore an issue of correct depth of penetration of the cutting device. Due to variations in skin thickness and hydration, some types of skin will deform more before cutting starts, and hence the actual depth of penetration will be less, resulting in less capillaries and venuoles cut. A controllable force driver can control the depth of penetration of a lancet and hence improve the spontaneity of blood yield. Furthermore, the use of a controllable force driver can allow for slow retraction of the lancet (slower than the cutting velocity) resulting in improved success rate due to the would channel remaining open for the free passage of blood to the surface of the skin.

Spontaneous blood yield occurs when blood from the cut vessels flow up the wound tract to the surface of the skin, where it can be collected and tested. Tissue elasticity parameters may force the wound tract to close behind the retracting lancet preventing the blood from reaching the surface. If however, the lancet were to be withdrawn slowly from the wound tract, thus keeping the wound open, blood could flow up the patent channel behind the tip of the lancet as it is being withdrawn (ref. FIGS. 10 and 11). Hence the ability to control the lancet speed into and out of the wound allows the device to compensate for changes in skin thickness and variations in skin hydration and thereby achieves spontaneous blood yield with maximum success rate while minimizing pain.

An electromagnetic driver can be coupled directly to the lancet minimizing the mass of the lancet and allowing the driver to bring the lancet to a stop at a predetermined depth without the use of a mechanical stop. Alternatively, if a mechanical stop is required for positive positioning, the energy transferred to the stop can be minimized. The electromagnetic driver allows programmable control over the velocity vs. position profile of the entire lancing process including timing the start of the lancet, tracking the lancet position, measuring the lancet velocity, controlling the distal stop acceleration, and controlling the skin penetration depth.

Referring to FIG. 4, an embodiment of a tissue penetration device is shown. The tissue penetration device includes a controllable force driver in the form of an electromagnetic driver, which can be used to drive a lancet. The term Lancet, as used herein, generally includes any sharp or blunt member, preferably having a relatively low mass, used to puncture the skin for the purpose of cutting blood vessels and allowing blood to flow to the surface of the skin. The term Electromagnetic driver, as used herein, generally includes any device that moves or drives a tissue penetrating element, such as a lancet under an electrically or magnetically induced force. FIG. 4 is a partially exploded view of an embodiment of an electromagnetic driver. The top half of the driver is shown assembled. The bottom half of the driver is shown exploded for illustrative purposes.

FIG. 4 shows the inner insulating housing 22 separated from the stationary housing or PC board 20, and the lancet 24 and flag 26 assembly separated from the inner insulating housing 22 for illustrative purposes. In addition, only four rivets 18 are shown as attached to the inner insulating housing 22 and separated from the PC board 20. In an embodiment, each coil drive field core in the PC board located in the PC Board 20 and 30 is connected to the inner insulating housing 22 and 32 with rivets.

The electromagnetic driver has a moving part comprising a lancet assembly with a lancet 24 and a magnetically permeable flag 26 attached at the proximal or drive end and a stationary part comprising a stationary housing assembly with electric field coils arranged so that they produce a balanced field at the flag to reduce or eliminate any net lateral force on the flag. The electric field coils are generally one or more metal coils, which generate a magnetic field when electric current passes through the coil. The iron flag is a flat or enlarged piece of magnetic material, which increases the surface area of the lancet assembly to enhance the magnetic forces generated between the proximal end of the lancet and a magnetic field produced by the field coils. The combined mass of the lancet and the iron flag can be minimized to facilitate rapid acceleration for introduction into the skin of a patient, to reduce the impact when the lancet stops in the skin, and to facilitate prompt velocity profile changes throughout the sampling cycle.

The stationary housing assembly consists of a PC board 20, a lower inner insulating housing 22, an upper inner insulating housing 32, an upper PC board 30, and rivets 18 assembled into a single unit. The lower and upper inner insulating housing 22 and 32 are relieved to form a slot so that lancet assembly can be slid into the driver assembly from the side perpendicular to the direction of the lancet's advancement and retraction. This allows the disposal of the lancet assembly and reuse of the stationary housing assembly with another lancet assembly while avoiding accidental lancet launches during replacement.

The electric field coils in the upper and lower stationary housing 20 and 30 are fabricated in a multi-layer printed circuit (PC) board. They may also be conventionally wound wire coils. A Teflon® material, or other low friction insulating material is used to construct the lower and upper inner insulating housing 22 and 32. Each insulating housing is mounted on the PC board to provide electrical insulation and physical protection, as well as to provide a low-friction guide for the lancet. The lower and upper inner insulating housing 22 and 32 provide a reference surface with a small gap so that the lancet assembly 24 and 26 can align with the drive field coils in the PC board for good magnetic coupling.

Rivets 18 connect the lower inner insulating housing 22 to the lower stationary housing 20 and are made of magnetically permeable material such as ferrite or steel, which serves to concentrate the magnetic field. This mirrors the construction of the upper inner insulating housing 32 and upper stationary housing 30. These rivets form the poles of the electric field coils. The PC board is fabricated with multiple layers of coils or with multiple boards. Each layer supports spiral traces around a central hole. Alternate layers spiral from the center outwards or from the edges inward. In this way each layer connects via simple feed-through holes, and the current always travels in the same direction, summing the ampere-turns.

The PC boards within the lower and upper stationary housings 20 and 30 are connected to the lower and upper inner insulating housings 22 and 32 with the rivets 18. The lower and upper inner insulating housings 22 and 32 expose the rivet heads on opposite ends of the slot where the lancet assembly 24 and 26 travels. The magnetic field lines from each rivet create magnetic poles at the rivet heads. An iron bar on the opposite side of the PC board within each of the lower and upper stationary housing 20 and 30 completes the magnetic circuit by connecting the rivets. Any fastener made of magnetically permeable material such as iron or steel can be used in place of the rivets. A single component made of magnetically permeable material and formed in a horseshoe shape can be used in place of the rivet/screw and iron bar assembly. In operation, the magnetically permeable flag 26 attached to the lancet 24 is divided into slits and bars 34. The slit patterns are staggered so that coils can drive the flag 26 in two, three or more phases.

Both lower and upper PC boards 20 and 30 contain drive coils so that there is a symmetrical magnetic field above and below the flag 26. When the pair of PC boards is turned on, a magnetic field is established around the bars between the slits of the magnetically permeable iron on the flag 26. The bars of the flag experience a force that tends to move the magnetically permeable material to a position minimizing the number and length of magnetic field lines and conducting the magnetic field lines between the magnetic poles.

When a bar of the flag 26 is centered between the rivets 18 of a magnetic pole, there is no net force on the flag, and any disturbing force is resisted by imbalance in the field. This embodiment of the device operates on a principle similar to that of a solenoid. Solenoids cannot push by repelling iron; they can only pull by attracting the iron into a minimum energy position. The slits 34 on one side of the flag 26 are offset with respect to the other side by approximately one half of the pitch of the poles. By alternately activating the coils on each side of the PC board, the lancet assembly can be moved with respect to the stationary housing assembly. The direction of travel is established by selectively energizing the coils adjacent the metal flag on the lancet assembly. Alternatively, a three phase, three-pole design or a shading coil that is offset by one-quarter pitch establishes the direction of travel. The lower and upper PC boards 20 and 30 shown in FIG. 4 contain electric field coils, which drive the lancet assembly and the circuitry for controlling the entire electromagnetic driver.

The embodiment described above generally uses the principles of a magnetic attraction drive, similar to commonly available circular stepper motors (Hurst Manufacturing BA Series motor, or “Electrical Engineering Handbook” Second edition p 1472-1474, 1997). These references are hereby incorporated by reference. Other embodiments can include a linear induction drive that uses a changing magnetic field to induce electric currents in the lancet assembly. These induced currents produce a secondary magnetic field that repels the primary field and applies a net force on the lancet assembly. The linear induction drive uses an electrical drive control that sweeps a magnetic field from pole to pole, propelling the lancet before it. Varying the rate of the sweep and the magnitude of the field by altering the driving voltage and frequency controls the force applied to the lancet assembly and its velocity.

The arrangement of the coils and rivets to concentrate the magnetic flux also applies to the induction design creating a growing magnetic field as the electric current in the field switches on. This growing magnetic field creates an opposing electric current in the conductive flag. In a linear induction motor the flag is electrically conductive, and its magnetic properties are unimportant. Copper or aluminum are materials that can be used for the conductive flags. Copper is generally used because of its good electrical conductivity. The opposing electrical field produces an opposing magnetic field that repels the field of the coils. By phasing the power of the coils, a moving field can be generated which pushes the flag along just below the synchronous speed of the coils. By controlling the rate of sweep, and by generating multiple sweeps, the flag can be moved at a desired speed.

FIG. 5 shows another embodiment of a solenoid type electromagnetic driver that is capable of driving an iron core or slug mounted to the lancet assembly using a direct current (DC) power supply. The electromagnetic driver includes a driver coil pack that is divided into three separate coils along the path of the lancet, two end coils and a middle coil. Direct current is alternated to the coils to advance and retract the lancet. Although the driver coil pack is shown with three coils, any suitable number of coils may be used, for example, 4, 5, 6, 7 or more coils may be used.

The stationary iron housing 40 contains the driver coil pack with a first coil 52 is flanked by iron spacers 50 which concentrate the magnetic flux at the inner diameter creating magnetic poles. The inner insulating housing 48 isolates the lancet 42 and iron core 46 from the coils and provides a smooth, low friction guide surface. The lancet guide 44 further centers the lancet 42 and iron core 46. The lancet 42 is protracted and retracted by alternating the current between the first coil 52, the middle coil, and the third coil to attract the iron core 46. Reversing the coil sequence and attracting the core and lancet back into the housing retracts the lancet. The lancet guide 44 also serves as a stop for the iron core 46 mounted to the lancet 42.

As discussed above, tissue penetration devices which employ spring or cam driving methods have a symmetrical or nearly symmetrical actuation displacement and velocity profiles on the advancement and retraction of the lancet as shown in FIGS. 6 and 7. In most of the available lancet devices, once the launch is initiated, the stored energy determines the velocity profile until the energy is dissipated. Controlling impact, retraction velocity, and dwell time of the lancet within the tissue can be useful in order to achieve a high success rate while accommodating variations in skin properties and minimize pain. Advantages can be achieved by taking into account that tissue dwell time is related to the amount of skin deformation as the lancet tries to puncture the surface of the skin and variance in skin deformation from patient to patient based on skin hydration.

The ability to control velocity and depth of penetration can be achieved by use of a controllable force driver where feedback is an integral part of driver control. Such drivers can control either metal or polymeric lancets or any other type of tissue penetration element. The dynamic control of such a driver is illustrated in FIG. 8 which illustrates an embodiment of a controlled displacement profile and FIG. 9 which illustrates an embodiment of a the controlled velocity profile. These are compared to FIGS. 6 and 7, which illustrate embodiments of displacement and velocity profiles, respectively, of a harmonic spring/mass powered driver.

Reduced pain can be achieved by using impact velocities of greater than 2 m/s entry of a tissue penetrating element, such as a lancet, into tissue.

Retraction of the lancet at a low velocity following the sectioning of the venuole/capillary mesh allows the blood to flood the wound tract and flow freely to the surface, thus using the lancet to keep the channel open during retraction as shown in FIGS. 10 and 11. Low-velocity retraction of the lancet near the wound flap prevents the wound flap from sealing off the channel. Thus, the ability to slow the lancet retraction directly contributes to increasing the success rate of obtaining blood. Increasing the sampling success rate to near 100% can be important to the combination of sampling and acquisition into an integrated sampling module such as an integrated glucose-sampling module, which incorporates a glucose test strip.

Referring again to FIG. 5, the lancet and lancet driver are configured so that feedback control is based on lancet displacement, velocity, or acceleration. The feedback control information relating to the actual lancet path is returned to a processor such as that illustrated in FIG. 12 that regulates the energy to the driver, thereby precisely controlling the lancet throughout its advancement and retraction. The driver may be driven by electric current, which includes direct current and alternating current.

In FIG. 5, the electromagnetic driver shown is capable of driving an iron core or slug mounted to the lancet assembly using a direct current (DC) power supply and is also capable of determining the position of the iron core by measuring magnetic coupling between the core and the coils. The coils can be used in pairs to draw the iron core into the driver coil pack. As one of the coils is switched on, the corresponding induced current in the adjacent coil can be monitored. The strength of this induced current is related to the degree of magnetic coupling provided by the iron core, and can be used to infer the position of the core and hence, the relative position of the lancet.

After a period of time, the drive voltage can be turned off, allowing the coils to relax, and then the cycle is repeated. The degree of magnetic coupling between the coils is converted electronically to a proportional DC voltage that is supplied to an analog-to-digital converter. The digitized position signal is then processed and compared to a desired “nominal” position by a central processing unit (CPU). The CPU to set the level and/or length of the next power pulse to the solenoid coils uses error between the actual and nominal positions.

In another embodiment, the driver coil pack has three coils consisting of a central driving coil flanked by balanced detection coils built into the driver assembly so that they surround an actuation or magnetically active region with the region centered on the middle coil at mid-stroke. When a current pulse is applied to the central coil, voltages are induced in the adjacent sense coils. If the sense coils are connected together so that their induced voltages oppose each other, the resulting signal will be positive for deflection from mid-stroke in one direction, negative in the other direction, and zero at mid-stroke. This measuring technique is commonly used in Linear Variable Differential Transformers (LVDT). Lancet position is determined by measuring the electrical balance between the two sensing coils.

In another embodiment, a feedback loop can use a commercially available LED/photo transducer module such as the OPB703 manufactured by Optek Technology, Inc., 1215 W. Crosby Road, Carrollton, Tex., 75006 to determine the distance from the fixed module on the stationary housing to a reflective surface or target mounted on the lancet assembly. The LED acts as a light emitter to send light beams to the reflective surface, which in turn reflects the light back to the photo transducer, which acts as a light sensor. Distances over the range of 4 mm or so are determined by measuring the intensity of the reflected light by the photo transducer. In another embodiment, a feedback loop can use a magnetically permeable region on the lancet shaft itself as the core of a Linear Variable Differential Transformer (LVDT).

A permeable region created by selectively annealing a portion of the lancet shaft, or by including a component in the lancet assembly, such as ferrite, with sufficient magnetic permeability to allow coupling between adjacent sensing coils. Coil size, number of windings, drive current, signal amplification, and air gap to the permeable region are specified in the design process. In another embodiment, the feedback control supplies a piezoelectric driver, superimposing a high frequency oscillation on the basic displacement profile. The piezoelectric driver provides improved cutting efficiency and reduces pain by allowing the lancet to “saw” its way into the tissue or to destroy cells with cavitation energy generated by the high frequency of vibration of the advancing edge of the lancet. The drive power to the piezoelectric driver is monitored for an impedance shift as the device interacts with the target tissue. The resulting force measurement, coupled with the known mass of the lancet is used to determine lancet acceleration, velocity, and position.

FIG. 12 illustrates the operation of a feedback loop using a processor. The processor 60 stores profiles 62 in non-volatile memory. A user inputs information 64 about the desired circumstances or parameters for a lancing event. The processor 60 selects a driver profile 62 from a set of alternative driver profiles that have been preprogrammed in the processor 60 based on typical or desired tissue penetration device performance determined through testing at the factory or as programmed in by the operator. The processor 60 may customize by either scaling or modifying the profile based on additional user input information 64. Once the processor has chosen and customized the profile, the processor 60 is ready to modulate the power from the power supply 66 to the lancet driver 68 through an amplifier 70. The processor 60 measures the location of the lancet 72 using a position sensing mechanism 74 through an analog to digital converter 76. Examples of position sensing mechanisms have been described in the embodiments above. The processor 60 calculates the movement of the lancet by comparing the actual profile of the lancet to the predetermined profile. The processor 60 modulates the power to the lancet driver 68 through a signal generator 78, which controls the amplifier 70 so that the actual profile of the lancet does not exceed the predetermined profile by more than a preset error limit. The error limit is the accuracy in the control of the lancet.

After the lancing event, the processor 60 can allow the user to rank the results of the lancing event. The processor 60 stores these results and constructs a database 80 for the individual user. Using the database 80, the processor 60 calculates the profile traits such as degree of painlessness, success rate, and blood volume for various profiles 62 depending on user input information 64 to optimize the profile to the individual user for subsequent lancing cycles. These profile traits depend on the characteristic phases of lancet advancement and retraction. The processor 60 uses these calculations to optimize profiles 62 for each user. In addition to user input information 64, an internal clock allows storage in the database 80 of information such as the time of day to generate a time stamp for the lancing event and the time between lancing events to anticipate the user's diurnal needs. The database stores information and statistics for each user and each profile that particular user uses.

In addition to varying the profiles, the processor 60 can be used to calculate the appropriate lancet diameter and geometry necessary to realize the blood volume required by the user. For example, if the user requires a 1-5 micro liter volume of blood, the processor selects a 200 micron diameter lancet to achieve these results. For each class of lancet, both diameter and lancet tip geometry, is stored in the processor to correspond with upper and lower limits of attainable blood volume based on the predetermined displacement and velocity profiles.

The lancing device is capable of prompting the user for information at the beginning and the end of the lancing event to more adequately suit the user. The goal is to either change to a different profile or modify an existing profile. Once the profile is set, the force driving the lancet is varied during advancement and retraction to follow the profile. The method of lancing using the lancing device comprises selecting a profile, lancing according to the selected profile, determining lancing profile traits for each characteristic phase of the lancing cycle, and optimizing profile traits for subsequent lancing events.

FIG. 13 shows an embodiment of the characteristic phases of lancet advancement and retraction on a graph of force versus time illustrating the force exerted by the lancet driver on the lancet to achieve the desired displacement and velocity profile. The characteristic phases are the lancet introduction phase A-C where the lancet is longitudinally advanced into the skin, the lancet rest phase D where the lancet terminates its longitudinal movement reaching its maximum depth and becoming relatively stationary, and the lancet retraction phase E-G where the lancet is longitudinally retracted out of the skin. The duration of the lancet retraction phase E-G is longer than the duration of the lancet introduction phase A-C, which in turn is longer than the duration of the lancet rest phase D.

The introduction phase further comprises a lancet launch phase prior to A when the lancet is longitudinally moving through air toward the skin, a tissue contact phase at the beginning of A when the distal end of the lancet makes initial contact with the skin, a tissue deformation phase A when the skin bends depending on its elastic properties which are related to hydration and thickness, a tissue lancing phase which comprises when the lancet hits the inflection point on the skin and begins to cut the skin B and the lancet continues cutting the skin C. The lancet rest phase D is the limit of the penetration of the lancet into the skin. Pain is reduced by minimizing the duration of the lancet introduction phase A-C so that there is a fast incision to a certain penetration depth regardless of the duration of the deformation phase A and inflection point cutting B which will vary from user to user. Success rate is increased by measuring the exact depth of penetration from inflection point B to the limit of penetration in the lancet rest phase D. This measurement allows the lancet to always, or at least reliably, hit the capillary beds which are a known distance underneath the surface of the skin.

The lancet retraction phase further comprises a primary retraction phase E when the skin pushes the lancet out of the wound tract, a secondary retraction phase F when the lancet starts to become dislodged and pulls in the opposite direction of the skin, and lancet exit phase G when the lancet becomes free of the skin. Primary retraction is the result of exerting a decreasing force to pull the lancet out of the skin as the lancet pulls away from the finger. Secondary retraction is the result of exerting a force in the opposite direction to dislodge the lancet. Control is necessary to keep the wound tract open as blood flows up the wound tract. Blood volume is increased by using a uniform velocity to retract the lancet during the lancet retraction phase E-G regardless of the force required for the primary retraction phase E or secondary retraction phase F, either of which may vary from user to user depending on the properties of the user's skin.

FIG. 14 shows a standard industry lancet for glucose testing which has a three-facet geometry. Taking a rod of diameter 114 and grinding 8 degrees to the plane of the primary axis to create the primary facet 110 produces the lancet 116. The secondary facets 112 are then created by rotating the shaft of the needle 15 degrees, and then rolling over 12 degrees to the plane of the primary facet. Other possible geometry's require altering the lancet's production parameters such as shaft diameter, angles, and translation distance.

FIG. 15 illustrates facet and tip geometry 120 and 122, diameter 124, and depth 126 which are significant factors in reducing pain, blood volume and success rate. It is known that additional cutting by the lancet is achieved by increasing the shear percentage or ratio of the primary to secondary facets, which when combined with reducing the lancet's diameter reduces skin tear and penetration force and gives the perception of less pain. Overall success rate of blood yield, however, also depends on a variety of factors, including the existence of facets, facet geometry, and skin anatomy.

FIG. 16 shows another embodiment of displacement versus time profile of a lancet for a controlled lancet retraction. FIG. 17 shows the velocity vs. time profile of the lancet for the controlled retraction of FIG. 16. The lancet driver controls lancet displacement and velocity at several steps in the lancing cycle, including when the lancet cuts the blood vessels to allow blood to pool 130, and as the lancet retracts, regulating the retraction rate to allow the blood to flood the wound tract while keeping the wound flap from sealing the channel 132 to permit blood to exit the wound.

In addition to slow retraction of a tissue-penetrating element in order to hold the wound open to allow blood to escape to the skin surface, other methods are contemplated. FIG. 18 shows the use of an embodiment of the invention, which includes a retractable coil on the lancet tip. A coiled helix or tube 140 is attached externally to lancet 116 with the freedom to slide such that when the lancet penetrates the skin 150, the helix or tube 140 follows the trajectory of the lancet 116. The helix begins the lancing cycle coiled around the facets and shaft of the lancet 144. As the lancet penetrates the skin, the helix braces the wound tract around the lancet 146. As the lancet retracts, the helix remains to brace open the wound tract, keeping the wound tract from collapsing and keeping the surface skin flap from closing 148. This allows blood 152 to pool and flow up the channel to the surface of the skin. The helix is then retracted as the lancet pulls the helix to the point where the helix is decompressed to the point where the diameter of the helix becomes less than the diameter of the wound tract and becomes dislodged from the skin.

The tube or helix 140 is made of wire or metal of the type commonly used in angioplasty stents such as stainless steel, nickel titanium alloy or the like. Alternatively the tube or helix 140 or a ring can be made of a biodegradable material, which braces the wound tract by becoming lodged in the skin. Biodegradation is completed within seconds or minutes of insertion, allowing adequate time for blood to pool and flow up the wound tract. Biodegradation is activated by heat, moisture, or pH from the skin.

Alternatively, the wound could be held open by coating the lancet with a powder or other granular substance. The powder coats the wound tract and keeps it open when the lancet is withdrawn. The powder or other granular substance can be a coarse bed of microspheres or capsules which hold the channel open while allowing blood to flow through the porous interstices.

In another embodiment the wound can be held open using a two-part needle, the outer part in the shape of a “U” and the inner part filling the “U.” After creating the wound the inner needle is withdrawn leaving an open channel, rather like the plugs that are commonly used for withdrawing sap from maple trees.

FIG. 19 shows a further embodiment of a method and device for facilitating blood flow utilizing an elastomer to coat the wound. This method uses an elastomer 154, such as silicon rubber, to coat or brace the wound tract 156 by covering and stretching the surface of the finger 158. The elastomer 154 is applied to the finger 158 prior to lancing. After a short delay, the lancet (not shown) then penetrates the elastomer 154 and the skin on the surface of the finger 158 as is seen in 160. Blood is allowed to pool and rise to the surface while the elastomer 154 braces the wound tract 156 as is seen in 162 and 164. Other known mechanisms for increasing the success rate of blood yield after lancing can include creating a vacuum, suctioning the wound, applying an adhesive strip, vibration while cutting, or initiating a second lance if the first is unsuccessful.

FIG. 20 illustrates an embodiment of a tissue penetration device, more specifically, a lancing device 180 that includes a controllable driver 179 coupled to a tissue penetration element. The lancing device 180 has a proximal end 181 and a distal end 182. At the distal end 182 is the tissue penetration element in the form of a lancet 183, which is coupled to an elongate coupler shaft 184 by a drive coupler 185. The elongate coupler shaft 184 has a proximal end 186 and a distal end 187. A driver coil pack 188 is disposed about the elongate coupler shaft 184 proximal of the lancet 183. A position sensor 191 is disposed about a proximal portion 192 of the elongate coupler shaft 184 and an electrical conductor 194 electrically couples a processor 193 to the position sensor 191. The elongate coupler shaft 184 driven by the driver coil pack 188 controlled by the position sensor 191 and processor 193 form the controllable driver, specifically, a controllable electromagnetic driver.

Referring to FIG. 21, the lancing device 180 can be seen in more detail, in partial longitudinal section. The lancet 183 has a proximal end 195 and a distal end 196 with a sharpened point at the distal end 196 of the lancet 183 and a drive head 198 disposed at the proximal end 195 of the lancet 183. A lancet shaft 201 is disposed between the drive head 198 and the sharpened point 197. The lancet shaft 201 may be comprised of stainless steel, or any other suitable material or alloy and have a transverse dimension of about 0.1 to about 0.4 mm. The lancet shaft may have a length of about 3 mm to about 50 mm, specifically, about 15 mm to about 20 mm. The drive head 198 of the lancet 183 is an enlarged portion having a transverse dimension greater than a transverse dimension of the lancet shaft 201 distal of the drive head 198. This configuration allows the drive head 198 to be mechanically captured by the drive coupler 185. The drive head 198 may have a transverse dimension of about 0.5 to about 2 mm.

A magnetic member 202 is secured to the elongate coupler shaft 184 proximal of the drive coupler 185 on a distal portion 203 of the elongate coupler shaft 184. The magnetic member 202 is a substantially cylindrical piece of magnetic material having an axial lumen 204 extending the length of the magnetic member 202. The magnetic member 202 has an outer transverse dimension that allows the magnetic member 202 to slide easily within an axial lumen 205 of a low friction, possibly lubricious, polymer guide tube 205′ disposed within the driver coil pack 188. The magnetic member 202 may have an outer transverse dimension of about 1.0 to about 5.0 mm, specifically, about 2.3 to about 2.5 mm. The magnetic member 202 may have a length of about 3.0 to about 5.0 mm, specifically, about 4.7 to about 4.9 mm. The magnetic member 202 can be made from a variety of magnetic materials including ferrous metals such as ferrous steel, iron, ferrite, or the like. The magnetic member 202 may be secured to the distal portion 203 of the elongate coupler shaft 184 by a variety of methods including adhesive or epoxy bonding, welding, crimping or any other suitable method.

Proximal of the magnetic member 202, an optical encoder flag 206 is secured to the elongate coupler shaft 184. The optical encoder flag 206 is configured to move within a slot 207 in the position sensor 191. The slot 207 of the position sensor 191 is formed between a first body portion 208 and a second body portion 209 of the position sensor 191. The slot 207 may have separation width of about 1.5 to about 2.0 mm. The optical encoder flag 206 can have a length of about 14 to about 18 mm, a width of about 3 to about 5 mm and a thickness of about 0.04 to about 0.06 mm.

The optical encoder flag 206 interacts with various optical beams generated by LEDs disposed on or in the position sensor body portions 208 and 209 in a predetermined manner. The interaction of the optical beams generated by the LEDs of the position sensor 191 generates a signal that indicates the longitudinal position of the optical flag 206 relative to the position sensor 191 with a substantially high degree of resolution. The resolution of the position sensor 191 may be about 200 to about 400 cycles per inch, specifically, about 350 to about 370 cycles per inch. The position sensor 191 may have a speed response time (position/time resolution) of 0 to about 120,000 Hz, where one dark and light stripe of the flag constitutes one Hertz, or cycle per second. The position of the optical encoder flag 206 relative to the magnetic member 202, driver coil pack 188 and position sensor 191 is such that the optical encoder 191 can provide precise positional information about the lancet 183 over the entire length of the lancet's power stroke.

An optical encoder that is suitable for the position sensor 191 is a linear optical incremental encoder, model HEDS 9200, manufactured by Agilent Technologies. The model HEDS 9200 may have a length of about 20 to about 30 mm, a width of about 8 to about 12 mm, and a height of about 9 to about 11 mm. Although the position sensor 191 illustrated is a linear optical incremental encoder, other suitable position sensor embodiments could be used, provided they posses the requisite positional resolution and time response. The HEDS 9200 is a two channel device where the channels are 90 degrees out of phase with each other. This results in a resolution of four times the basic cycle of the flag. These quadrature outputs make it possible for the processor to determine the direction of lancet travel. Other suitable position sensors include capacitive encoders, analog reflective sensors, such as the reflective position sensor discussed above, and the like.

A coupler shaft guide 211 is disposed towards the proximal end 181 of the lancing device 180. The guide 211 has a guide lumen 212 disposed in the guide 211 to slidingly accept the proximal portion 192 of the elongate coupler shaft 184. The guide 211 keeps the elongate coupler shaft 184 centered horizontally and vertically in the slot 202 of the optical encoder 191.

The driver coil pack 188, position sensor 191 and coupler shaft guide 211 are all secured to a base 213. The base 213 is longitudinally coextensive with the driver coil pack 188, position sensor 191 and coupler shaft guide 211. The base 213 can take the form of a rectangular piece of metal or polymer, or may be a more elaborate housing with recesses, which are configured to accept the various components of the lancing device 180.

As discussed above, the magnetic member 202 is configured to slide within an axial lumen 205 of the driver coil pack 188. The driver coil pack 188 includes a most distal first coil 214, a second coil 215, which is axially disposed between the first coil 214 and a third coil 216, and a proximal-most fourth coil 217. Each of the first coil 214, second coil 215, third coil 216 and fourth coil 217 has an axial lumen. The axial lumens of the first through fourth coils are configured to be coaxial with the axial lumens of the other coils and together form the axial lumen 205 of the driver coil pack 188 as a whole. Axially adjacent each of the coils 214-217 is a magnetic disk or washer 218 that augments completion of the magnetic circuit of the coils 214-217 during a lancing cycle of the device 180. The magnetic washers 218 of the embodiment of FIG. 21 are made of ferrous steel but could be made of any other suitable magnetic material, such as iron or ferrite. The outer shell 189 of the driver coil pack 188 is also made of iron or steel to complete the magnetic path around the coils and between the washers 218. The magnetic washers 218 have an outer diameter commensurate with an outer diameter of the driver coil pack 188 of about 4.0 to about 8.0 mm. The magnetic washers 218 have an axial thickness of about 0.05, to about 0.4 mm, specifically, about 0.15 to about 0.25 mm.

Wrapping or winding an elongate electrical conductor 221 about an axial lumen until a sufficient number of windings have been achieved forms the coils 214-217. The elongate electrical conductor 221 is generally an insulated solid copper wire with a small outer transverse dimension of about 0.06 mm to about 0.88 mm, specifically, about 0.3 mm to about 0.5 mm. In one embodiment, 32 gauge copper wire is used for the coils 214-217. The number of windings for each of the coils 214-217 of the driver pack 188 may vary with the size of the coil, but for some embodiments each coil 214-217 may have about 30 to about 80 turns, specifically, about 50 to about 60 turns. Each coil 214-217 can have an axial length of about 1.0 to about 3.0 mm, specifically, about 1.8 to about 2.0 mm. Each coil 214-217 can have an outer transverse dimension or diameter of about 4.0, to about 2.0 mm, specifically, about 9.0 to about 12.0 mm. The axial lumen 205 can have a transverse dimension of about 1.0 to about 3.0 mm.

It may be advantageous in some driver coil 188 embodiments to replace one or more of the coils with permanent magnets, which produce a magnetic field similar to that of the coils when the coils are activated. In particular, it may be desirable in some embodiments to replace the second coil 215, the third coil 216 or both with permanent magnets. In addition, it may be advantageous to position a permanent magnet at or near the proximal end of the coil driver pack in order to provide fixed magnet zeroing function for the magnetic member (Adams magnetic Products 23A0002 flexible magnet material (800) 747-7543).

FIGS. 20 and 21 show a permanent bar magnet 219 disposed on the proximal end of the driver coil pack 188. As shown in FIG. 21, the bar magnet 219 is arranged so as to have one end disposed adjacent the travel path of the magnetic member 202 and has a polarity configured so as to attract the magnetic member 202 in a centered position with respect to the bar magnet 219. Note that the polymer guide tube 205′ can be configured to extend proximally to insulate the inward radial surface of the bar magnet 219 from an outer surface of the magnetic member 202. This arrangement allows the magnetic member 219 and thus the elongate coupler shaft 184 to be attracted to and held in a zero point or rest position without the consumption of electrical energy from the power supply 225.

Having a fixed zero or start point for the elongate coupler shaft 184 and lancet 183 can be critical to properly controlling the depth of penetration of the lancet 183 as well as other lancing parameters. This can be because some methods of depth penetration control for a controllable driver measure the acceleration and displacement of the elongate coupler shaft 184 and lancet 183 from a known start position. If the distance of the lancet tip 196 from the target tissue is known, acceleration and displacement of the lancet is known and the start position of the lancet is know, the time and position of tissue contact and depth of penetration can be determined by the processor 193.

Any number of configurations for a magnetic bar 219 can be used for the purposes discussed above. In particular, a second permanent bar magnet (not shown) could be added to the proximal end of the driver coil pack 188 with the magnetic fields of the two bar magnets configured to complement each other. In addition, a disc magnet 219′ could be used as illustrated in FIG. 22. Disc magnet 219′ is shown disposed at the proximal end of the driver coiled pack 188 with a polymer non-magnetic disc 219″ disposed between the proximal-most coil 217 and disc magnet 219′ and positions disc magnet 219′ away from the proximal end of the proximal-most coil 217. The polymer non-magnetic disc spacer 219″ is used so that the magnetic member 202 can be centered in a zero or start position slightly proximal of the proximal-most coil 217 of the driver coil pack 188. This allows the magnetic member to be attracted by the proximal-most coil 217 at the initiation of the lancing cycle instead of being passive in the forward drive portion of the lancing cycle.

An inner lumen of the polymer non-magnetic disc 219″ can be configured to allow the magnetic member 202 to pass axially there through while an inner lumen of the disc magnet 219′ can be configured to allow the elongate coupler shaft 184 to pass through but not large enough for the magnetic member 202 to pass through. This results in the magnetic member 202 being attracted to the disc magnet 219′ and coming to rest with the proximal surface of the magnetic member 202 against a distal surface of the disc magnet 219′. This arrangement provides for a positive and repeatable stop for the magnetic member, and hence the lancet. A similar configuration could also be used for the bar magnet 219 discussed above.

Typically, when the electrical current in the coils 214-217 of the driver coil pack 188 is off, a magnetic member 202 made of soft iron is attracted to the bar magnet 219 or disc magnet 219′. The magnetic field of the driver coil pack 188 and the bar magnet 219 or disc magnet 219′, or any other suitable magnet, can be configured such that when the electrical current in the coils 214-217 is turned on, the leakage magnetic field from the coils 214-217 has the same polarity as the bar magnet 219 or disc magnet 219′. This results in a magnetic force that repels the magnetic member 202 from the bar magnet 219 or disc magnet 219′ and attracts the magnetic member 202 to the activated coils 214-217. For this configuration, the bar magnet 219 or disc magnet thus act to facilitate acceleration of the magnetic member 202 as opposed to working against the acceleration.

Electrical conductors 222 couple the driver coil pack 188 with the processor 193 which can be configured or programmed to control the current flow in the coils 214-217 of the driver coil pack 188 based on position feedback from the position sensor 191, which is coupled to the processor 193 by electrical conductors 194. A power source 225 is electrically coupled to the processor 193 and provides electrical power to operate the processor 193 and power the coil driver pack 188. The power source 225 may be one or more batteries that provide direct current power to the 193 processor.

FIG. 23 shows a transverse cross sectional view of drive coupler 185 in more detail. The drive head 198 of the lancet 183 is disposed within the drive coupler 185 with a first retaining rail 226 and second retaining rail 227 capturing the drive head 198 while allowing the drive head 198 to be inserted laterally into the drive coupler 185 and retracted laterally with minimal mechanical resistance. The drive coupler 185 may optionally be configured to include snap ridges 228 which allow the drive head 198 to be laterally inserted and retracted, but keep the drive head 198 from falling out of the drive coupler 185 unless a predetermined amount of externally applied lateral force is applied to the drive head 198 of the lancet 183 towards the lateral opening 231 of the drive coupler 185. FIG. 27 shows an enlarged side view into the coupler opening 231 of the drive coupler 185 showing the snap ridges 228 disposed in the lateral opening 231 and the retaining rails 226 and 227. FIG. 28 shows an enlarged front view of the drive coupler 185. The drive coupler 185 can be made from an alloy such as stainless steel, titanium or aluminum, but may also be made from a suitable polymer such as ABS, PVC, polycarbonate plastic or the like. The drive coupler may be open on both sides allowing the drive head and lancet to pass through.

Referring to FIG. 24, the magnetic member 202 is disposed about and secured to the elongate coupler shaft 184. The magnetic member 202 is disposed within the axial lumen 232 of the fourth coil 217. The driver coil pack 188 is secured to the base 213. In FIG. 25 the position sensor 191 is secured to the base 213 with the first body portion 208 of the position sensor 191 disposed opposite the second body portion 209 of the position sensor 191 with the first and second body portions 208 and 209 of the position sensor 191 separated by the gap or slot 207. The elongate coupler shaft 184 is slidably disposed within the gap 207 between the first and second body portions 208 and 209 of the position sensor 191. The optical encoder flag 206 is secured to the elongate coupler shaft 184 and disposed between the first body portion 208 and second body portion 209 of the position sensor 191. Referring to FIG. 26, the proximal portion 192 of the elongate coupler shaft 184 is disposed within the guide lumen 212 of the coupler shaft guide 211. The guide lumen 212 of the coupler shaft guide 211 may be lined with a low friction material such as Teflon® or the like to reduce friction of the elongate coupler shaft 184 during the power stroke of the lancing device 180.

Referring to FIGS. 29A-29C, a flow diagram is shown that describes the operations performed by the processor 193 in controlling the lancet 183 of the lancing device 180 discussed above during an operating cycle. FIGS. 30-36 illustrate the interaction of the lancet 183 and skin 233 of the patient's finger 234 during an operation cycle of the lancet device 183. The processor 193 operates under control of programming steps that are stored in an associated memory. When the programming steps are executed, the processor 193 performs operations as described herein. Thus, the programming steps implement the functionality of the operations described with respect to the flow diagram of FIG. 29. The processor 193 can receive the programming steps from a program product stored in recordable media, including a direct access program product storage device such as a hard drive or flash ROM, a removable program product storage device such as a floppy disk, or in any other manner known to those of skill in the art. The processor 193 can also download the programming steps through a network connection or serial connection.

In the first operation, represented by the flow diagram box numbered 245 in FIG. 29A, the processor 193 initializes values that it stores in memory relating to control of the lancet, such as variables that it uses to keep track of the controllable driver 179 during movement. For example, the processor may set a clock value to zero and a lancet position value to zero or to some other initial value. The processor 193 may also cause power to be removed from the coil pack 188 for a period of time, such as for about 10 ms, to allow any residual flux to dissipate from the coils.

In the initialization operation, the processor 193 also causes the lancet to assume an initial stationary position. When in the initial stationary position, the lancet 183 is typically fully retracted such that the magnetic member 202 is positioned substantially adjacent the fourth coil 217 of the driver coil pack 188, shown in FIG. 21 above. The processor 193 can move the lancet 183 to the initial stationary position by pulsing an electrical current to the fourth coil 217 to thereby attract the magnetic member 202 on the lancet 183 to the fourth coil 217. Alternatively, the magnetic member can be positioned in the initial stationary position by virtue of a permanent magnet, such as bar magnet 219, disc magnet 219′ or any other suitable magnet as discussed above with regard to the tissue penetration device illustrated in FIGS. 20 and 21.

In the next operation, represented by the flow diagram box numbered 247, the processor 193 energizes one or more of the coils in the coil pack 188. This should cause the lancet 183 to begin to move (i.e., achieve a non-zero speed) toward the skin target 233. The processor 193 then determines whether or not the lancet is indeed moving, as represented by the decision box numbered 249. The processor 193 can determine whether the lancet 183 is moving by monitoring the position of the lancet 183 to determine whether the position changes over time. The processor 193 can monitor the position of the lancet 183 by keeping track of the position of the optical encoder flag 206 secured to the elongate coupler shaft 184 wherein the encoder 191 produces a signal coupled to the processor 193 that indicates the spatial position of the lancet 183.

If the processor 193 determines (via timeout without motion events) that the lancet 183 is not moving (a “No” result from the decision box 249), then the process proceeds to the operation represented by the flow diagram box numbered 253, where the processor deems that an error condition is present. This means that some error in the system is causing the lancet 183 not to move. The error may be mechanical, electrical, or software related. For example, the lancet 183 may be stuck in the stationary position because something is impeding its movement.

If the processor 193 determines that the lancet 183 is indeed moving (a “Yes” result from the decision box numbered 249), then the process proceeds to the operation represented by the flow diagram box numbered 257. In this operation, the processor 193 causes the lancet 183 to continue to accelerate and launch toward the skin target 233, as indicated by the arrow 235 in FIG. 30. The processor 193 can achieve acceleration of the lancet 183 by sending an electrical current to an appropriate coil 214-217 such that the coil 214-217 exerts an attractive magnetic launching force on the magnetic member 202 and causes the magnetic member 202 and the lancet 183 coupled thereto to move in a desired direction. For example, the processor 193 can cause an electrical current to be sent to the third coil 216 so that the third coil 216 attracts the magnetic member 202 and causes the magnetic member 202 to move from a position adjacent the fourth coil 217 toward the third coil 216. The processor preferably determines which coil 214-217 should be used to attract the magnetic member 202 based on the position of the magnetic member 202 relative to the coils 214-217. In this manner, the processor 193 provides a controlled force to the lancet that controls the movement of the lancet.

During this operation, the processor 193 periodically or continually monitors the position and/or velocity of the lancet 183. In keeping track of the velocity and position of the lancet 183 as the lancet 183 moves towards the patient's skin 233 or other tissue, the processor 193 also monitors and adjusts the electrical current to the coils 214-217. In some embodiments, the processor 193 applies current to an appropriate coil 214-217 such that the lancet 183 continues to move according to a desired direction and acceleration. In the instant case, the processor 193 applies current to the appropriate coil 214-217 that will cause the lancet 183 to continue to move in the direction of the patient's skin 233 or other tissue to be penetrated.

The processor 193 may successively transition the current between coils 214-217 so that as the magnetic member 202 moves past a particular coil 214-217, the processor 193 then shuts off current to that coil 214-217 and then applies current to another coil 214-217 that will attract the magnetic member 202 and cause the magnetic member 202 to continue to move in the desired direction. In transitioning current between the coils 214-217, the processor 193 can take into account various factors, including the speed of the lancet 183, the position of the lancet 183 relative to the coils 214-217, the number of coils 214-217, and the level of current to be applied to the coils 214-217 to achieve a desired speed or acceleration.

In the next operation, the processor 193 determines whether the cutting or distal end tip 196 of the lancet 183 has contacted the patient's skin 233, as shown in FIG. 31 and as represented by the decision box numbered 265 in FIG. 29B. The processor 193 may determine whether the lancet 183 has made contact with the target tissue 233 by a variety of methods, including some that rely on parameters which are measured prior to initiation of a lancing cycle and other methods that are adaptable to use during a lancing cycle without any predetermined parameters.

In one embodiment, the processor 193 determines that the skin has been contacted when the end tip 196 of the lancet 183 has moved a predetermined distance with respect to its initial position. If the distance from the tip 961 of the lancet 183 to the target tissue 233 is known prior to initiation of lancet 183 movement, the initial position of the lancet 183 is fixed and known, and the movement and position of the lancet 183 can be accurately measured during a lancing cycle, then the position and time of lancet contact can be determined.

This method requires an accurate measurement of the distance between the lancet tip 196 and the patient's skin 233 when the lancet 183 is in the zero time or initial position. This can be accomplished in a number of ways. One way is to control all of the mechanical parameters that influence the distance from the lancet tip 196 to the patient's tissue or a surface of the lancing device 180 that will contact the patient's skin 233. This could include the start position of the magnetic member 202, magnetic path tolerance, magnetic member 202 dimensions, driver coil pack 188 location within the lancing device 180 as a whole, length of the elongate coupling shaft 184, placement of the magnetic member 202 on the elongate coupling shaft 184, length of the lancet 183 etc.

If all these parameters, as well as others can be suitably controlled in manufacturing with a tolerance stack-up that is acceptable, then the distance from the lancet tip 196 to the target tissue 233 can be determined at the time of manufacture of the lancing device 180. The distance could then be programmed into the memory of the processor 193. If an adjustable feature is added to the lancing device 180, such as an adjustable length elongate coupling shaft 184, this can accommodate variations in all of the parameters noted above, except length of the lancet 183. An electronic alternative to this mechanical approach would be to calibrate a stored memory contact point into the memory of the processor 193 during manufacture based on the mechanical parameters described above.

In another embodiment, moving the lancet tip 196 to the target tissue 233 very slowly and gently touching the skin 233 prior to actuation can accomplish the distance from the lancet tip 196 to the tissue 233. The position sensor can accurately measure the distance from the initialization point to the point of contact, where the resistance to advancement of the lancet 183 stops the lancet movement. The lancet 183 is then retracted to the initialization point having measured the distance to the target tissue 233 without creating any discomfort to the user.

In another embodiment, the processor 193 may use software to determine whether the lancet 183 has made contact with the patient's skin 233 by measuring for a sudden reduction in velocity of the lancet 183 due to friction or resistance imposed on the lancet 183 by the patient's skin 233. The optical encoder 191 measures displacement of the lancet 183. The position output data provides input to the interrupt input of the processor 193. The processor 193 also has a timer capable of measuring the time between interrupts. The distance between interrupts is known for the optical encoder 191, so the velocity of the lancet 183 can be calculated by dividing the distance between interrupts by the time between the interrupts.

This method requires that velocity losses to the lancet 183 and elongate coupler 184 assembly due to friction are known to an acceptable level so that these velocity losses and resulting deceleration can be accounted for when establishing a deceleration threshold above which contact between lancet tip 196 and target tissue 233 will be presumed. This same concept can be implemented in many ways. For example, rather than monitoring the velocity of the lancet 183, if the processor 193 is controlling the lancet driver in order to maintain a fixed velocity, the power to the driver 188 could be monitored. If an amount of power above a predetermined threshold is required in order to maintain a constant velocity, then contact between the tip of the lancet 196 and the skin 233 could be presumed.

In yet another embodiment, the processor 193 determines skin 233 contact by the lancet 183 by detection of an acoustic signal produced by the tip 196 of the lancet 183 as it strikes the patient's skin 233. Detection of the acoustic signal can be measured by an acoustic detector 236 placed in contact with the patient's skin 233 adjacent a lancet penetration site 237, as shown in FIG. 31. Suitable acoustic detectors 236 include piezo electric transducers, microphones and the like. The acoustic detector 236 transmits an electrical signal generated by the acoustic signal to the processor 193 via electrical conductors 238. In another embodiment, contact of the lancet 183 with the patient's skin 233 can be determined by measurement of electrical continuity in a circuit that includes the lancet 183, the patient's finger 234 and an electrical contact pad 240 that is disposed on the patient's skin 233 adjacent the contact site 237 of the lancet 183, as shown in FIG. 31. In this embodiment, as soon as the lancet 183 contacts the patient's skin 233, the circuit 239 is completed and current flows through the circuit 239. Completion of the circuit 239 can then be detected by the processor 193 to confirm skin 233 contact by the lancet 183.

If the lancet 183 has not contacted the target skin 233, then the process proceeds to a timeout operation, as represented by the decision box numbered 267 in FIG. 29B. In the timeout operation, the processor 193 waits a predetermined time period. If the timeout period has not yet elapsed (a “No” outcome from the decision box 267), then the processor continues to monitor whether the lancet has contacted the target skin 233. The processor 193 preferably continues to monitor the position and speed of the lancet 183, as well as the electrical current to the appropriate coil 214-217 to maintain the desired lancet 183 movement.

If the timeout period elapses without the lancet 183 contacting the skin (a “Yes” output from the decision box 267), then it is deemed that the lancet 183 will not contact the skin and the process proceeds to a withdraw phase, where the lancet is withdrawn away from the skin 233, as discussed more fully below. The lancet 183 may not have contacted the target skin 233 for a variety of reasons, such as if the patient removed the skin 233 from the lancing device or if something obstructed the lancet 183 prior to it contacting the skin.

The processor 193 may also proceed to the withdraw phase prior to skin contact for other reasons. For example, at some point after initiation of movement of the lancet 183, the processor 193 may determine that the forward acceleration of the lancet 183 towards the patient's skin 233 should be stopped or that current to all coils 214-217 should be shut down. This can occur, for example, if it is determined that the lancet 183 has achieved sufficient forward velocity, but has not yet contacted the skin 233. In one embodiment, the average penetration velocity of the lancet 183 from the point of contact with the skin to the point of maximum penetration may be about 2.0 to about 10.0 m/s, specifically, about 3.8 to about 4.2 m/s. In another embodiment, the average penetration velocity of the lancet may be from about 2 to about 8 meters per second, specifically, about 2 to about 4 m/s.

The processor 193 can also proceed to the withdraw phase if it is determined that the lancet 183 has fully extended to the end of the power stroke of the operation cycle of lancing procedure. In other words, the process may proceed to withdraw phase when an axial center 241 of the magnetic member 202 has moved distal of an axial center 242 of the first coil 214 as show in FIG. 21. In this situation, any continued power to any of the coils 214-217 of the driver coil pack 188 serves to decelerate the magnetic member 202 and thus the lancet 183. In this regard, the processor 193 considers the length of the lancet 183 (which can be stored in memory) the position of the lancet 183 relative to the magnetic member 202, as well as the distance that the lancet 183 has traveled.

With reference again to the decision box 265 in FIG. 29B, if the processor 193 determines that the lancet 183 has contacted the skin 233 (a “Yes” outcome from the decision box 265), then the processor 193 can adjust the speed of the lancet 183 or the power delivered to the lancet 183 for skin penetration to overcome any frictional forces on the lancet 183 in order to maintain a desired penetration velocity of the lancet. The flow diagram box numbered 267 represents this.

As the velocity of the lancet 183 is maintained after contact with the skin 233, the distal tip 196 of the lancet 183 will first begin to depress or tent the contacted skin 237 and the skin 233 adjacent the lancet 183 to form a tented portion 243 as shown in FIG. 32 and further shown in FIG. 33. As the lancet 183 continues to move in a distal direction or be driven in a distal direction against the patient's skin 233, the lancet 183 will eventually begin to penetrate the skin 233, as shown in FIG. 34. Once penetration of the skin 233 begins, the static force at the distal tip 196 of the lancet 183 from the skin 233 will become a dynamic cutting force, which is generally less than the static tip force. As a result in the reduction of force on the distal tip 196 of the lancet 183 upon initiation of cutting, the tented portion 243 of the skin 233 adjacent the distal tip 196 of the lancet 183 which had been depressed as shown in FIGS. 32 and 24 will spring back as shown in FIG. 34.

In the next operation, represented by the decision box numbered 271 in FIG. 29B, the processor 193 determines whether the distal end 196 of the lancet 183 has reached a brake depth. The brake depth is the skin penetration depth for which the processor 193 determines that deceleration of the lancet 183 is to be initiated in order to achieve a desired final penetration depth 244 of the lancet 183 as show in FIG. 35. The brake depth may be pre-determined and programmed into the processor's memory, or the processor 193 may dynamically determine the brake depth during the actuation. The amount of penetration of the lancet 183 in the skin 233 of the patient may be measured during the operation cycle of the lancet device 180. In addition, as discussed above, the penetration depth necessary for successfully obtaining a useable sample can depend on the amount of tenting of the skin 233 during the lancing cycle. The amount of tenting of the patient's skin 233 can in turn depend on the tissue characteristics of the patient such as elasticity, hydration etc. A method for determining these characteristics is discussed below with regard to skin 233 tenting measurements during the lancing cycle and illustrated in FIGS. 37-41.

Penetration measurement can be carried out by a variety of methods that are not dependent on measurement of tenting of the patient's skin. In one embodiment, the penetration depth of the lancet 183 in the patient's skin 233 is measured by monitoring the amount of capacitance between the lancet 183 and the patient's skin 233. In this embodiment, a circuit includes the lancet 183, the patient's finger 234, the processor 193 and electrical conductors connecting these elements. As the lancet 183 penetrates the patient's skin 233, the greater the amount of penetration, the greater the surface contact area between the lancet 183 and the patient's skin 233. As the contact area increases, so does the capacitance between the skin 233 and the lancet 183. The increased capacitance can be easily measured by the processor 193 using methods known in the art and penetration depth can then be correlated to the amount of capacitance. The same method can be used by measuring the electrical resistance between the lancet 183 and the patient's skin.

If the brake depth has not yet been reached, then a “No” results from the decision box 271 and the process proceeds to the timeout operation represented by the flow diagram box numbered 273. In the timeout operation, the processor 193 waits a predetermined time period. If the timeout period has not yet elapsed (a “No” outcome from the decision box 273), then the processor continues to monitor whether the brake depth has been reached. If the timeout period elapses without the lancet 183 achieving the brake depth (a “Yes” output from the decision box 273), then the processor 193 deems that the lancet 183 will not reach the brake depth and the process proceeds to the withdraw phase, which is discussed more fully below. This may occur, for example, if the lancet 183 is stuck at a certain depth.

With reference again to the decision box numbered 271 in FIG. 29B, if the lancet does reach the brake depth (a “Yes” result), then the process proceeds to the operation represented by the flow diagram box numbered 275. In this operation, the processor 193 causes a braking force to be applied to the lancet to thereby reduce the speed of the lancet 183 to achieve a desired amount of final skin penetration depth 244, as shown in FIG. 26. Note that FIGS. 32 and 33 illustrate the lancet making contact with the patient's skin and deforming or depressing the skin prior to any substantial penetration of the skin. The speed of the lancet 183 is preferably reduced to a value below a desired threshold and is ultimately reduced to zero. The processor 193 can reduce the speed of the lancet 183 by causing a current to be sent to a 214-217 coil that will exert an attractive braking force on the magnetic member 202 in a proximal direction away from the patient's tissue or skin 233, as indicated by the arrow 290 in FIG. 36. Such a negative force reduces the forward or distally oriented speed of the lancet 183. The processor 193 can determine which coil 214-217 to energize based upon the position of the magnetic member 202 with respect to the coils 214-217 of the driver coil pack 188, as indicated by the position sensor 191.

In the next operation, the process proceeds to the withdraw phase, as represented by the flow diagram box numbered 277. The withdraw phase begins with the operation represented by the flow diagram box numbered 279 in FIG. 29C. Here, the processor 193 allows the lancet 183 to settle at a position of maximum skin penetration 244, as shown in FIG. 35. In this regard, the processor 193 waits until any motion in the lancet 183 (due to vibration from impact and spring energy stored in the skin, etc.) has stopped by monitoring changes in position of the lancet 183. The processor 193 preferably waits until several milliseconds (ms), such as on the order of about 8 ms, have passed with no changes in position of the lancet 183. This is an indication that movement of the lancet 183 has ceased entirely. In some embodiments, the lancet may be allowed to settle for about 1 to about 2000 milliseconds, specifically, about 50 to about 200 milliseconds. For other embodiments, the settling time may be about 1 to about 200 milliseconds.

It is at this stage of the lancing cycle that a software method can be used to measure the amount of tenting of the patient's skin 233 and thus determine the skin 233 characteristics such as elasticity, hydration and others. Referring to FIGS. 37-41, a lancet 183 is illustrated in various phases of a lancing cycle with target tissue 233. FIG. 37 shows tip 196 of lancet 183 making initial contact with the skin 233 at the point of initial impact.

FIG. 38 illustrates an enlarged view of the lancet 183 making initial contact with the tissue 233 shown in FIG. 37. In FIG. 39, the lancet tip 196 has depressed or tented the skin 233 prior to penetration over a distance of X, as indicated by the arrow labeled X in FIG. 39. In FIG. 40, the lancet 183 has reached the full length of the cutting power stroke and is at maximum displacement. In this position, the lancet tip 196 has penetrated the tissue 233 a distance of Y, as indicated by the arrow labeled Y in FIG. 39. As can be seen from comparing FIG. 38 with FIG. 40, the lancet tip 196 was displaced a total distance of X plus Y from the time initial contact with the skin 233 was made to the time the lancet tip 196 reached its maximum extension as shown in FIG. 40. However, the lancet tip 196 has only penetrated the skin 233 a distance Y because of the tenting phenomenon.

At the end of the power stroke of the lancet 183, as discussed above with regard to FIG. 26 and box 279 of FIG. 29C, the processor 193 allows the lancet to settle for about 8 msec. It is during this settling time that the skin 233 rebounds or relaxes back to approximately its original configuration prior to contact by the lancet 183 as shown in FIG. 41. The lancet tip 196 is still buried in the skin to a depth of Y, as shown in FIG. 41, however the elastic recoil of the tissue has displaced the lancet rearward or retrograde to the point of inelastic tenting that is indicated by the arrows Z in FIG. 41. During the rearward displacement of the lancet 183 due to the elastic tenting of the tissue 233, the processor reads and stores the position data generated by the position sensor 191 and thus measures the amount of elastic tenting, which is the difference between X and Z.

The tenting process and retrograde motion of the lancet 183 during the lancing cycle is illustrated graphically in FIG. 42 which shows both a velocity versus time graph and a position versus time graph of a lancet tip 196 during a lancing cycle that includes elastic and inelastic tenting. In FIG. 42, from point 0 to point A, the lancet 183 is being accelerated from the initialization position or zero position. From point A to point B, the lancet is in ballistic or coasting mode, with no additional power being delivered. At point B, the lancet tip 196 contacts the tissue 233 and begins to tent the skin 233 until it reaches a displacement C. As the lancet tip 196 approaches maximum displacement, braking force is applied to the lancet 183 until the lancet comes to a stop at point D. The lancet 183 then recoils in a retrograde direction during the settling phase of the lancing cycle indicated between D and E. Note that the magnitude of inelastic tenting indicated in FIG. 42 is exaggerated for purposes of illustration.

The amount of inelastic tenting indicated by Z tends to be fairly consistent and small compared to the magnitude of the elastic tenting. Generally, the amount of inelastic tenting Z can be about 120 to about 140 microns. As the magnitude of the inelastic tenting has a fairly constant value and is small compared to the magnitude of the elastic tenting for most patients and skin types, the value for the total amount of tenting for the penetration stroke of the lancet 183 is effectively equal to the rearward displacement of the lancet during the settling phase as measured by the processor 193 plus a predetermined value for the inelastic recoil, such as 130 microns. Inelastic recoil for some embodiments can be about 100 to about 200 microns. The ability to measure the magnitude of skin 233 tenting for a patient is important to controlling the depth of penetration of the lancet tip 196 as the skin is generally known to vary in elasticity and other parameters due to age, time of day, level of hydration, gender and pathological state.

This value for total tenting for the lancing cycle can then be used to determine the various characteristics of the patient's skin 233. Once a body of tenting data is obtained for a given patient, this data can be analyzed in order to predict the total lancet displacement, from the point of skin contact, necessary for a successful lancing procedure. This enables the tissue penetration device to achieve a high success rate and minimize pain for the user. A rolling average table can be used to collect and store the tenting data for a patient with a pointer to the last entry in the table. When a new entry is input, it can replace the entry at the pointer and the pointer advances to the next value. When an average is desired, all the values are added and the sum divided by the total number of entries by the processor 193. Similar techniques involving exponential decay (multiply by 0.95, add 0.05 times current value, etc.) are also possible.

With regard to tenting of skin 233 generally, some typical values relating to penetration depth are now discussed. FIG. 43 shows a cross sectional view of the layers of the skin 233. In order to reliably obtain a useable sample of blood from the skin 233, it is desirable to have the lancet tip 196 reach the venuolar plexus of the skin. The stratum corneum is typically about 0.1 to about 0.6 mm thick and the distance from the top of the dermis to the venuole plexus can be from about 0.3 to about 1.4 mm. Elastic tenting can have a magnitude of up to about 2 mm or so, specifially, about 0.2 to about 2.0 mm, with an average magnitude of about 1 mm. This means that the amount of lancet displacement necessary to overcome the tenting can have a magnitude greater than the thickness of skin necessary to penetrate in order to reach the venuolar plexus. The total lancet displacement from point of initial skin contact may have an average value of about 1.7 to about 2.1 mm. In some embodiments, penetration depth and maximum penetration depth may be about 0.5 mm to about 5 mm, specifically, about 1 mm to about 3 mm. In some embodiments, a maximum penetration depth of about 0.5 to about 3 mm is useful.

Referring back to FIG. 29C, in the next operation, represented by the flow diagram box numbered 280 in FIG. 29C, the processor 193 causes a withdraw force to be exerted on the lancet 183 to retract the lancet 183 from the skin 233, as shown by arrow 290 in FIG. 36 The processor 193 sends a current to an appropriate coil 214-217 so that the coil 214-217 exerts an attractive distally oriented force on the magnetic member 202, which should cause the lancet 183 to move backward in the desired direction. In some embodiments, the lancet 183 is withdrawn with less force and a lower speed than the force and speed during the penetration portion of the operation cycle. Withdrawal speed of the lancet in some embodiments can be about 0.004 to about 0.5 m/s, specifically, about 0.006 to about 0.01 m/s. In other embodiments, useful withdrawal velocities can be about 0.001 to about 0.02 meters per second, specifically, about 0.001 to about 0.01 meters per second. For embodiments that use a relatively slow withdrawal velocity compared to the penetration velocity, the withdrawal velocity may up to about 0.02 meters per second. For such embodiments, a ratio of the average penetration velocity relative to the average withdrawal velocity can be about 100 to about 1000. In embodiments where a relatively slow withdrawal velocity is not important, a withdrawal velocity of about 2 to about 10 meters per second may be used.

In the next operation, the processor 193 determines whether the lancet 183 is moving in the desired backward direction as a result of the force applied, as represented by the decision box numbered 281. If the processor 193 determines that the lancet 183 is not moving (a “No” result from the decision box 281), then the processor 193 continues to cause a force to be exerted on the lancet 183, as represented by the flow diagram box numbered 282. The processor 193 may cause a stronger force to be exerted on the lancet 183 or may just continue to apply the same amount of force. The processor then again determines whether the lancet is moving, as represented by the decision box numbered 283. If movement is still not detected (a “No” result from the decision box numbered 283), the processor 193 determines that an error condition is present, as represented by the flow diagram box numbered 284. In such a situation, the processor preferably de-energizes the coils to remove force from the lancet, as the lack of movement may be an indication that the lancet is stuck in the skin of the patient and, therefore, that it may be undesirable to continue to attempt pull the lancet out of the skin.

With reference again to the decision boxes numbered 281 and 283 in FIG. 29C, if the processor 193 determines that the lancet is indeed moving in the desired backward direction away from the skin 233, then the process proceeds to the operation represented by the flow diagram box numbered 285. In this operation, the backward movement of the lancet 183 continues until the lancet distal end has been completely withdrawn from the patient's skin 233. As discussed above, in some embodiments the lancet 183 is withdrawn with less force and a lower speed than the force and speed during the penetration portion of the operation cycle. The relatively slow withdrawal of the lancet 183 may allow the blood from the capillaries of the patient accessed by the lancet 183 to follow the lancet 183 during withdrawal and reach the skin surface to reliably produce a usable blood sample. The process then ends.

Controlling the lancet motion over the operating cycle of the lancet 183 as discussed above allows a wide variety of lancet velocity profiles to be generated by the lancing device 180. In particular, any of the lancet velocity profiles discussed above with regard to other embodiments can be achieved with the processor 193, position sensor 191 and driver coil pack 188 of the lancing device 180.

Another example of an embodiment of a velocity profile for a lancet can be seen in FIGS. 44 and 45, which illustrates a lancet profile with a fast entry velocity and a slow withdrawal velocity. FIG. 44 illustrates an embodiment of a lancing profile showing velocity of the lancet versus position. The lancing profile starts at zero time and position and shows acceleration of the lancet towards the tissue from the electromagnetic force generated from the electromagnetic driver. At point A, the power is shut off and the lancet 183 begins to coast until it reaches the skin 233 indicated by B at which point, the velocity begins to decrease. At point C, the lancet 183 has reached maximum displacement and settles momentarily, typically for a time of about 8 milliseconds.

A retrograde withdrawal force is then imposed on the lancet by the controllable driver, which is controlled by the processor to maintain a withdrawal velocity of no more than about 0.006 to about 0.01 meters/second. The same cycle is illustrated in the velocity versus time plot of FIG. 45 where the lancet is accelerated from the start point to point A. The lancet 183 coasts from A to B where the lancet tip 196 contacts tissue 233. The lancet tip 196 then penetrates the tissue and slows with braking force eventually applied as the maximum penetration depth is approached. The lancet is stopped and settling between C and D. At D, the withdrawal phase begins and the lancet 183 is slowly withdrawn until it returns to the initialization point shown by E in FIG. 45. Note that retrograde recoil from elastic and inelastic tenting was not shown in the lancing profiles of FIGS. 44 and 45 for purpose of illustration and clarity.

In another embodiment, the withdrawal phase may use a dual speed profile, with the slow 0.006 to 0.01 meter per second speed used until the lancet is withdrawn past the contact point with the tissue, then a faster speed of 0.01 to 1 meters per second may be used to shorten the complete cycle.

Referring to FIG. 46, another embodiment of a lancing device including a controllable driver 294 with a driver coil pack 295, position sensor and lancet 183 are shown. The lancet 297 has a proximal end 298 and a distal end 299 with a sharpened point at the distal end 299 of the lancet 297. A magnetic member 301 disposed about and secured to a proximal end portion 302 of the lancet 297 with a lancet shaft 303 being disposed between the magnetic member 301 and the sharpened point 299. The lancet shaft 303 may be comprised of stainless steel, or any other suitable material or alloy. The lancet shaft 303 may have a length of about 3 mm to about 50 mm specifically, about 5 mm to about 15 mm.

The magnetic member 301 is configured to slide within an axial lumen 304 of the driver coil pack 295. The driver coil pack 295 includes a most distal first coil 305, a second coil 306, which is axially disposed between the first coil 305 and a third coil 307, and a proximal-most fourth coil 308. Each of the first coil 305, second coil 306, third coil 307 and fourth coil 308 has an axial lumen. The axial lumens of the first through fourth coils 305-308 are configured to be coaxial with the axial lumens of the other coils and together form the axial lumen 309 of the driver coil pack 295 as a whole. Axially adjacent each of the coils 305-308 is a magnetic disk or washer 310 that augments completion of the magnetic circuit of the coils 305-308 during a lancing cycle of the driven coil pack 295. The magnetic washers 310 of the embodiment of FIG. 46 are made of ferrous steel but could be made of any other suitable magnetic material, such as iron or ferrite. The magnetic washers 310 have an outer diameter commensurate with an outer diameter of the driver coil pack 295 of about 4.0 to about 8.0 mm. The magnetic washers 310 have an axial thickness of about 0.05, to about 0.4 mm, specifically, about 0.15 to about 0.25 mm. The outer shell 294 of the coil pack is also made of iron or steel to complete the magnetic path around the coils and between the washers 310.

Wrapping or winding an elongate electrical conductor 311 about the axial lumen 309 until a sufficient number of windings have been achieved forms the coils 305-308. The elongate electrical conductor 311 is generally an insulated solid copper wire. The particular materials, dimensions number of coil windings etc. of the coils 305-308, washers 310 and other components of the driver coil pack 295 can be the same or similar to the materials, dimensions number of coil windings etc. of the driver coil pack 188 discussed above.

Electrical conductors 312 couple the driver coil pack 295 with a processor 313 which can be configured or programmed to control the current flow in the coils 305-308 of the driver coil pack 295 based on position feedback from the position sensor 296, which is coupled to the processor 313 by electrical conductors 315. A power source 316 is electrically coupled to the processor 313 and provides electrical power to operate the processor 313 and power the driver coil pack 295. The power source 316 may be one or more batteries (not shown) that provide direct current power to the processor 313 as discussed above.

The position sensor 296 is an analog reflecting light sensor that has a light source and light receiver in the form of a photo transducer 317 disposed within a housing 318 with the housing 318 secured in fixed spatial relation to the driver coil pack 295. A reflective member 319 is disposed on or secured to a proximal end 320 of the magnetic member 301. The processor 313 determines the position of the lancet 299 by first emitting light from the light source of the photo transducer 317 towards the reflective member 319 with a predetermined solid angle of emission. Then, the light receiver of the photo transducer 317 measures the intensity of light reflected from the reflective member 319 and electrical conductors 315 transmit the signal generated therefrom to the processor 313.

By calibrating the intensity of reflected light from the reflective member 319 for various positions of the lancet 297 during the operating cycle of the driver coil pack 295, the position of the lancet 297 can thereafter be determined by measuring the intensity of reflected light at any given moment. In one embodiment, the sensor 296 uses a commercially available LED/photo transducer module such as the OPB703 manufactured by Optek Technology, Inc., 1215 W. Crosby Road, Carrollton, Tex., 75006. This method of analog reflective measurement for position sensing can be used for any of the embodiments of lancet actuators discussed herein. In addition, any of the lancet actuators or drivers that include coils may use one or more of the coils to determine the position of the lancet 297 by using a magnetically permeable region on the lancet shaft 303 or magnetic member 301 itself as the core of a Linear Variable Differential Transformer (LVDT).

Referring to FIGS. 47 and 48, a flat coil lancet driver 325 is illustrated which has a main body housing 326 and a rotating frame 327. The rotating frame 327 pivots about an axle 328 disposed between a base 329, a top body portion 330 of the main body housing 326 and disposed in a pivot guide 331 of the rotating frame 327. An actuator arm 332 of the rotating frame 327 extends radially from the pivot guide 331 and has a linkage receiving opening 333 disposed at an outward end 334 of the actuator arm 332. A first end 335 of a coupler linkage 336 is coupled to the linkage receiving opening 333 of the actuator arm 332 and can rotate within the linkage receiving opening 333. A second end 337 of the coupler linkage 336 is disposed within an opening at a proximal end 338 of a coupler translation member 341. This configuration allows circumferential forces imposed upon the actuator arm 332 to be transferred into linear forces on a drive coupler 342 secured to a distal end 343 of the coupler translation member 341. The materials and dimensions of the drive coupler 342 can be the same or similar to the materials and dimensions of the drive coupler 342 discussed above.

Opposite the actuator arm 332 of the rotating frame 327, a translation substrate in the form of a coil arm 344 extends radially from the pivot guide 331 of the rotating frame 327. The coil arm 344 is substantially triangular in shape. A flat coil 345 is disposed on and secured to the coil arm 344. The flat coil 345 has leading segment 346 and a trailing segment 347, both of which extend substantially orthogonal to the direction of motion of the segments 346 and 347 when the rotating frame 327 is rotating about the pivot guide 331. The leading segment 346 is disposed within a first magnetically active region 348 generated by a first upper permanent magnet 349 secured to an upper magnet base 351 and a first lower permanent magnet 352 secured to a lower magnet base 353. The trailing segment 347 is disposed within a second magnetically active region 354 generated by a second upper permanent magnet 355 secured to the upper magnet base 351 and a second lower permanent magnet secured to the lower magnet base 353.

The magnetic field lines or circuit of the first upper and lower permanent magnets 349, 352, 355 and 356 can be directed upward from the first lower permanent magnet 352 to the first upper permanent magnet 349 or downward in an opposite direction. The magnetic field lines from the second permanent magnets 355 and 356 are also directed up or down, and will have a direction opposite to that of the first upper and lower permanent magnets 349 and 352. This configuration produces rotational force on the coil arm 344 about the pivot guide 331 with the direction of the force determined by the direction of current flow in the flat coil 345.

A position sensor 357 includes an optical encoder disk section 358 is secured to the rotating frame 327 which rotates with the rotating frame 327 and is read by an optical encoder 359 which is secured to the base 329. The position sensor 357 determines the rotational position of the rotating frame 327 and sends the position information to a processor 360 which can have features which are the same or similar to the features of the processor 193 discussed above via electrical leads 361. Electrical conductor leads 363 of the flat coil 345 are also electrically coupled to the processor 360.

As electrical current is passed through the leading segment 346 and trailing segment 347 of the flat coil 345, the rotational forces imposed on the segments 346 and 347 are transferred to the rotating frame 327 to the actuator arm 332, through the coupler linkage 336 and coupler translation member 341 and eventually to the drive coupler 342. In use, a lancet (not shown) is secured into the drive coupler 342, and the flat coil lancet actuator 325 activated. The electrical current in the flat coil 345 determines the forces generated on the drive coupler 342, and hence, a lancet secured to the coupler 342. The processor 360 controls the electrical current in the flat coil 345 based on the position and velocity of the lancet as measured by the position sensor 357 information sent to the processor 360. The processor 360 is able to control the velocity of a lancet in a manner similar to the processor 193 discussed above and can generate any of the desired lancet velocity profiles discussed above, in addition to others.

FIGS. 49 and 50 depict yet another embodiment of a controlled driver 369 having a driver coil pack 370 for a tissue penetration device. The driver coil pack 370 has a proximal end 371, a distal end 372 and an axial lumen 373 extending from the proximal end 371 to the distal end 372. An inner coil 374 is disposed about the axial lumen 373 and has a tapered configuration with increasing wraps per inch of an elongate conductor 375 in a distal direction. The inner coil 374 extends from the proximal end 371 of the coil driver pack 370 to the distal end 372 of the driver coil pack 370 with a major outer diameter or transverse dimension of about 1 to about 25 mm, specifically about 1 to about 12 mm.

The outer diameter or transverse dimension of the inner coil 374 at the proximal end 371 of the driver coil pack 370 is approximately equal to the diameter of the axial lumen 373 at the proximal end 371 of the coil pack 370. That is, the inner coil 374 tapers to a reduce outer diameter proximally until there are few or no wraps of elongate electrical conductor 375 at the proximal end 371 of the driver coil pack 370. The tapered configuration of the inner coil 374 produces an axial magnetic field gradient within the axial lumen 373 of the driver coil pack 370 when the inner coil 374 is activated with electrical current flowing through the elongate electrical conductor 375 of the inner coil 374.

The axial magnetic field gradient produces a driving force for a magnetic member 376 disposed within the axial lumen 373 that drives the magnetic member 376 towards the distal end 372 of the driver coil pack 370 when the inner coil 374 is activated. The driving force on the magnetic member produced by the inner coil 374 is a smooth continuous force, which can produce a smooth and continuous acceleration of the magnetic member 376 and lancet 377 secured thereto. In some embodiments, the ratio of the increase in outer diameter versus axial displacement along the inner coil 374 in a distal direction can be from about 1 to about 0.08, specifically, about 1 to about 0.08.

An outer coil 378 is disposed on and longitudinally coextensive with the inner coil 374. The outer coil 378 can have the same or similar dimensions and construction as the inner coil 374, except that the outer coil 378 tapers proximally to an increased diameter or transverse dimension. The greater wraps per inch of elongate electrical conductor 379 in a proximal direction for the outer coil 378 produces a magnetic field gradient that drives the magnetic member 376 in a proximal direction when the outer coil 378 is activated with electrical current. This produces a braking or reversing effect on the magnetic member 376 during an operational cycle of the lancet 377 and driver coil pack 370. The elongate electrical conductors 375 and 379 of the inner coil 374 and outer coil 378 are coupled to a processor 381, which is coupled to an electrical power source 382. The processor 381 can have properties similar to the other processors discussed above and can control the velocity profile of the magnetic member 376 and lancet 377 to produce any of the velocity profiles above as well as others. The driver coil pack 370 can be used as a substitute for the coil driver pack discussed above, with other components of the lancing device 180 being the same or similar.

Embodiments of driver or actuator mechanisms having been described, we now discuss embodiments of devices which can house lancets, collect samples of fluids, analyze the samples or any combination of these functions. These front-end devices may be integrated with actuators, such as those discussed above, or any other suitable driver or controllable driver.

Generally, most known methods of blood sampling require several steps. First, a measurement session is set up by gathering various articles such as lancets, lancet drivers, test strips, analyzing instrument, etc. Second, the patient must assemble the paraphernalia by loading a sterile lancet, loading a test strip, and arming the lancet driver. Third, the patient must place a finger against the lancet driver and using the other hand to activate the driver. Fourth, the patient must put down the lancet driver and place the bleeding finger against a test strip, (which may or may not have been loaded into an analyzing instrument). The patient must insure blood has been loaded onto the test strip and the analyzing instrument has been calibrated prior to such loading. Finally, the patient must dispose of all the blood-contaminated paraphernalia including the lancet. As such, integrating the lancing and sample collection features of a tissue penetration sampling device can achieve advantages with regard to patient convenience.

FIG. 51 shows a disposable sampling module 410, which houses the lancet 412. The lancet 412 has a head on a proximal end 416 which connects to the driver 438 and a distal end 414, which lances the skin. The distal end 414 is disposed within the conduit 418. The proximal end 416 extends into the cavity 420. The sample reservoir 422 has a narrow input port 424 on the ergonomically contoured surface 426, which is adjacent to the distal end 414 of the lancet 412. The term ergonomically contoured, as used herein, generally means shaped to snugly fit a finger or other body portion to be lanced or otherwise tested placed on the surface. The sampling module 410 is capable of transporting the blood sample from the sample reservoir 422 through small passages (not shown), to an analytical region 428. The analytical region 428 can include chemical, physical, optical, electrical or other means of analyzing the blood sample. The lancet, sample flow channel, sample reservoir and analytical region are integrated into the sampling module 410 in a single packaged unit.

FIG. 52 shows the chamber 430 in the housing 410′ where the sampling module 410 is loaded. The sampling module 410 is loaded on a socket 432 suspended with springs 434 and sits in slot 436. A driver 438 is attached to the socket 432. The driver 438 has a proximal end 440 and a distal end 442. The driver 438 can be either a controllable driver or non-controllable driver any mechanical, such as spring or cam driven, or electrical, such as electromagnetically or electronically driven, means for advancing, stopping, and retracting the lancet. There is a clearance 444 between the distal end 442 of the driver 438 and the sensor 446, which is attached to the chamber 430. The socket 432 also contains an analyzer 448, which is a system for analyzing blood. The analyzer 448 corresponds to the analytical region 428 on the module 410 when it is loaded into the socket 432.

FIG. 53 shows a tissue penetration sampling device 411 with the sampling module 410 loaded into the socket 432 of housing 410′. The analytical region 428 and analyzer 448 overlap. The driver 438 fits into the cavity 420. The proximal end 440 of the driver 438 abuts the distal end 416 of the lancet 412. The patient's finger 450 sits on the ergonomically contoured surface 426.

FIG. 54 shows a drawing of an alternate lancet configuration where the lancet 412 and driver 438 are oriented to lance the side of the finger 450 as it sits on the ergonomically contoured surface 426.

FIG. 55 illustrates the orifice 452 and ergonomically contoured surface 426. The conduit 418 has an orifice 452, which opens on a blood well 454. The sample input port 424 of the reservoir 422 also opens on the blood well 454. The diameter of the sample input port 424 is significantly greater than the diameter of the orifice 452, which is substantially the same diameter as the diameter of the lancet 412. After the lancet is retracted, the blood flowing from the finger 450 will collect in the blood well 454. The lancet 412 will have been retracted into the orifice 452 effectively blocking the passage of blood down the orifice 452. The blood will flow from the blood well 454 through the sample input port 424 into the reservoir 422.

FIG. 56 shows a drawing of the lancing event. The patient applies pressure by pushing down with the finger 450 on the ergonomically contoured surface 426. This applies downward pressure on the sampling module 410, which is loaded into the socket 432. As the socket 432 is pushed downward it compresses the springs 434. The sensor 446 makes contact with the distal end 442 of the driver 438 and thereby electrically detects the presence of the finger on the ergonomically contoured surface. The sensor can be a piezoelectric device, which detects this pressure and sends a signal to circuit 456, which actuates the driver 438 and advances and then retracts the lancet 412 lancing the finger 450. In another embodiment, the sensor 446 is an electric contact, which closes a circuit when it contacts the driver 438 activating the driver 438 to advance and retract the lancet 412 lancing the finger 450.

An embodiment of a method of sampling includes a reduced number of steps that must be taken by a patient to obtain a sample and analysis of the sample. First, the patient loads a sampling module 410 with an embedded sterile lancet into the housing device 410′. Second, the patient initiates a lancing cycle by turning on the power to the device or by placing the finger to be lanced on the ergonomically contoured surface 426 and pressing down. Initiation of the sensor makes the sensor operational and gives control to activate the launcher.

The sensor is unprompted when the lancet is retracted after its lancing cycle to avoid unintended multiple lancing events. The lancing cycle consists of arming, advancing, stopping and retracting the lancet, and collecting the blood sample in the reservoir. The cycle is complete once the blood sample has been collected in the reservoir. Third, the patient presses down on the sampling module, which forces the driver 38 to make contact with the sensor, and activates the driver 438. The lancet then pierces the skin and the reservoir collects the blood sample.

The patient is then optionally informed to remove the finger by an audible signal such as a buzzer or a beeper, and/or a visual signal such as an LED or a display screen. The patient can then dispose of all the contaminated parts by removing the sampling module 410 and disposing of it. In another embodiment, multiple sampling modules 410 may be loaded into the housing 410′ in the form of a cartridge (not shown). The patient can be informed by the tissue penetration sampling device 411 as to when to dispose of the entire cartridge after the analysis is complete.

In order to properly analyze a sample in the analytical region 428 of the sampling module 410, it may be desirable or necessary to determine whether a fluid sample is present in a given portion of the sample flow channel, sample reservoir or analytical area. A variety of devices and methods for determining the presence of a fluid in a region are discussed below.

In FIG. 57, a thermal sensor 500 embedded in a substrate 502 adjacent to a surface 504 over which a fluid may flow. The surface may be, for example, a wall of a channel through which fluid may flow or a surface of a planar device over which fluid may flow. The thermal sensor 500 is in electrical communication with a signal-conditioning element 506, which may be embedded in the substrate 502 or may be remotely located. The signal-conditioning element 506 receives the signal from the thermal sensor 500 and modifies it by means such as amplifying it and filtering it to reduce noise. FIG. 57 also depicts a thermal sensor 508 located at an alternate location on the surface where it is directly exposed to the fluid flow.

FIG. 58 shows a configuration of a thermal sensor 500 adjacent to a separate heating element 510. The thermal sensor 500 and the heating element 510 are embedded in a substrate 502 adjacent to a surface 504 over which a fluid may flow. In an alternate embodiment, one or more additional thermal sensors may be adjacent the heating element and may provide for increased signal sensitivity. The thermal sensor 500 is in electrical communication with a signal-conditioning element 506, which may be embedded in the substrate 502 or may be remotely located.

The signal-conditioning element 506 receives the signal from the thermal sensor 500 and modifies it by means such as amplifying it and filtering it to reduce noise. The heating element 510 is in electrical communication with a power supply and control element 512, which may be embedded in the substrate 502 or may be remotely located. The power supply and control element 512 provides a controlled source of voltage and current to the heating element 510.

FIG. 59 depicts a configuration of thermal sensors 500 having three thermal sensor/heating element pairs (500/510), or detector elements, (with associated signal conditioning elements 506 and power supply and control elements 512 as described in FIG. 58) embedded in a substrate 502 near each other alongside a surface 504. The figure depicts the thermal sensors 500 arranged in a linear fashion parallel to the surface 504, but any operable configuration may be used. In alternate embodiments, fewer than three or more than three thermal sensor/heating element pairs (500/510) may be used to indicate the arrival of fluid flowing across a surface 504. In other embodiments, self-heating thermal sensors are used, eliminating the separate heating elements.

Embodiments of the present invention provide a simple and accurate methodology for detecting the arrival of a fluid at a defined location. Such detection can be particularly useful to define the zero- or start-time of a timing cycle for measuring rate-based reactions. This can be used in biochemical assays to detect a variety of analytes present in a variety of types of biological specimens or fluids and for rate-based reactions such as enzymatic reactions. Examples of relevant fluids include, blood, serum, plasma, urine, cerebral spinal fluid, saliva, enzymatic substances and other related substances and fluids that are well known in the analytical and biomedical art. The reaction chemistry for particular assays to analyze biomolecular fluids is generally well known, and selection of the particular assay used will depend on the biological fluid of interest.

Assays that are relevant to embodiments of the present invention include those that result in the measurement of individual analytes or enzymes, e.g., glucose, lactate, creatinine kinase, etc, as well as those that measure a characteristic of the total sample, for example, clotting time (coagulation) or complement-dependent lysis. Other embodiments for this invention provide for sensing of sample addition to a test article or arrival of the sample at a particular location within that article.

Referring now to FIG. 60, a substrate 502 defines a channel 520 having an interior surface 522 over which fluid may flow. An analysis site 524 is located within the channel 520 where fluid flowing in the channel 520 may contact the analysis site 524. In various embodiments, the analysis site 524 may alternatively be upon the interior surface 522, recessed into the substrate 502, or essentially flush with the interior surface 522. FIG. 60, depicts several possible locations for thermal sensors relative the substrate, the channel, and the analysis site; also, other locations may be useful and will depend upon the design of the device, as will be apparent to those of skill in art.

In use, thermal sensors may be omitted from one or more of the locations depicted in FIG. 60, depending on the intended design. A recess in the analysis site 524 may provide the location for a thermal sensor 526, as may the perimeter of the analysis site provide the location for a thermal sensor 528. One or more thermal sensors 530, 532, 534 may be located on the upstream side of the analysis site 524 (as fluid flows from right to left in FIG. 60), or one or more thermal sensors 536, 538, 540 may be located on the downstream side of the analysis site 524.

The thermal sensor may be embedded in the substrate near the surface, as thermal sensor 542 is depicted. In various other embodiments, the thermal sensor(s) may be located upon the interior surface, recessed into the interior surface, or essentially flush with the interior surface. Each thermal sensor may also be associated with a signal conditioning element, heating element, and power supply and control elements, as described above, and a single signal conditioning element, heating element, or power supply and control element may be associated with more than one thermal sensor.

FIG. 61 shows possible positions for thermal sensors relative to analysis sites 524 arranged in an array on a surface 556. A recess in the analysis site 524 may provide the location for a thermal sensor 544, as may the perimeter of the analysis site provide the location for a thermal sensor 546. The edge of the surface surrounding the array of analysis sites may provide the position for one or more thermal sensors 548. Thermal sensors may be positioned between analysis sites in a particular row 550 or column 552 of the array, or may be arranged on the diagonal 554.

In various embodiments, the thermal sensor(s) may be may be embedded in the substrate near the surface or may be located upon the surface, recessed into the surface, or essentially flush with the surface. Each thermal sensor may also be associated with a signal conditioning elements, heating elements, and power supply and control elements, as described above, and a single signal conditioning element, heating element, or power supply and control element may be associated with more than one thermal sensor.

The use of small thermal sensors can be useful in miniaturized systems, such as microfluidic devices, which perform biomolecular analyses on very small fluid samples. Such analyses generally include passing a biomolecular fluid through, over, or adjacent to an analysis site and result in information about the biomolecular fluid being obtained through the use of reagents and/or test circuits and/or components associated with the analysis site.

FIG. 62 depicts several possible configurations of thermal sensors relative to channels and analysis sites. The device schematically depicted in FIG. 62 may be, e.g., a microfluidic device for analyzing a small volume of a sample fluid, e.g. a biomolecular fluid. The device has a sample reservoir 560 for holding a quantity of a sample fluid. The sample fluid is introduced to the sample reservoir 560 via a sample inlet port 562 in fluid communication with the sample reservoir 560. A thermal sensor 564 is located in or near the sample inlet port 562. A primary channel 566 originates at the sample reservoir 560 and terminates at an outflow reservoir 568.

One or more supplemental reservoirs 570 are optionally present and are in fluid communication with the primary channel 566 via one or more supplemental channels 572, which lead from the supplemental reservoir 570 to the primary channel 566. The supplemental reservoir 570 functions to hold fluids necessary for the operation of the assay, such as reagent solutions, wash solutions, developer solutions, fixative solutions, et cetera. In the primary channel 566 at a predetermined distance from the sample reservoir 560, an array of analysis sites 574 is present.

Thermal sensors are located directly upstream (as fluid flows from right to left in the figure) from the array 576 and directly downstream from the array 578. Thermal sensors are also located in the primary channel adjacent to where the primary channel originates at the sample reservoir 580 and adjacent to where the primary channel terminates at the outflow reservoir 582. The supplemental channel provides the location for another thermal sensor 584.

When the device is in operation, the thermal sensor 564 located in or near the sample inlet port 562 is used to indicate the arrival of the sample fluid, e.g. the biomolecular fluid, in the local environment of the thermal sensor, as described herein, and thus provides confirmation that the sample fluid has successfully been introduced into the device. The thermal sensor 580 located in the primary channel 566 adjacent to where the primary channel 566 originates at the sample reservoir 560 produces a signal indicating that sample fluid has started to flow from the sample reservoir 560 into the primary channel 566. The thermal sensors 576 in the primary channel 566 just upstream from the array of analysis sites 574 may be used to indicate that the fluid sample is approaching the array 574. Similarly, the thermal sensors 578 in the primary channel 566 just downstream from the array of analysis sites 574 may be used to indicate that the fluid sample has advanced beyond the array 574 and has thus contacted each analysis site.

The thermal sensor 584 in the supplemental channel 572 provides confirmation that the fluid contained within the supplemental reservoir 570 has commenced to flow therefrom. The thermal sensor 582 in the primary channel 566 adjacent to where the primary channel 566 terminates at the outflow reservoir 568 indicates when sample fluid arrives near the outflow reservoir 568, which may then indicate that sufficient sample fluid has passed over the array of analysis sites 574 and that the analysis at the analysis sites is completed.

Embodiments of the invention provide for the use of a thermal sensor to detect the arrival of the fluid sample at a determined region, such as an analysis site, in the local environment of the thermal sensor near the thermal sensor. A variety of thermal sensors may be used. Thermistors are thermally-sensitive resistors whose prime function is to detect a predictable and precise change in electrical resistance when subjected to a corresponding change in temperature Negative Temperature Coefficient (NTC) thermistors exhibit a decrease in electrical resistance when subjected to an increase in temperature and Positive Temperature Coefficient (PTC) thermistors exhibit an increase in electrical resistance when subjected to an increase in temperature.

A variety of thermistors have been manufactured for over the counter use and application. Thermistors are capable of operating over the temperature range of −100 degrees to over 600 degrees Fahrenheit. Because of their flexibility, thermistors are useful for application to micro-fluidics and temperature measurement and control.

A change in temperature results in a corresponding change in the electrical resistance of the thermistor. This temperature change results from either an external transfer of heat via conduction or radiation from the sample or surrounding environment to the thermistor, or as an internal application of heat due to electrical power dissipation within the device. When a thermistor is operated in “self-heating” mode, the power dissipated in the device is sufficient to raise its temperature above the temperature of the local environment, which in turn more easily detects thermal changes in the conductivity of the local environment.

Thermistors are frequently used in “self heating” mode in applications such as fluid level detection, airflow detection and thermal conductivity materials characterization. This mode is particularly useful in fluid sensing, since a self-heating conductivity sensor dissipates significantly more heat in a fluid or in a moving air stream than it does in still air.

Embodiments of the invention may be designed such that the thermal sensor is exposed directly to the sample. However, it may also be embedded in the material of the device, e.g., in the wall of a channel meant to transport the sample. The thermal sensor may be covered with a thin coating of polymer or other protective material.

Embodiments of the device need to establish a baseline or threshold value of a monitored parameter such as temperature. Ideally this is established during the setup process. Once fluid movement has been initiated, the device continuously monitors for a significant change thereafter. The change level designated as “significant” is designed as a compromise between noise rejection and adequate sensitivity. The actual definition of the “zero- or start-time” may also include an algorithm determined from the time history of the data, i.e., it can be defined ranging from the exact instant that a simple threshold is crossed, to a complex mathematical function based upon a time sequence of data.

In use, a signal is read from a thermal sensor in the absence of the sample or fluid. The fluid sample is then introduced. The sample flows to or past the site of interest in the local environment of the thermal sensor, and the thermal sensor registers the arrival of the sample. The site of interest may include an analysis site for conducting, e.g., an enzymatic assay. Measuring the arrival of fluid at the site of interest thus indicates the zero- or start-time of the reaction to be performed. For detection of fluid presence, these sites may be any of a variety of desired locations along the fluidic pathway. Embodiments of the invention are particularly well suited to a microfluidic cartridge or platform, which provide the user with an assurance that a fluid sample has been introduced and has flowed to the appropriate locations in the platform.

A rate-based assay must measure both an initiation time, and some number of later time points, one of which is the end-point of the assay. Therefore, baseline or threshold value can be established, and then continuously monitored for a significant change thereafter; one such change is the arrival of the fluid sample that initiates the enzyme reaction. Baseline values are frequently established during the device setup process. The threshold is designed as a compromise between noise rejection and adequate sensitivity. The defined zero- or “start-time” can be defined ranging from the exact instant that a simple threshold is crossed, to the value algorithmically determined using a filter based on a time sequence of data.

Embodiments of the invention accomplish this in a variety of ways. In one embodiment, an initial temperature measurement is made at a thermal sensor without the sample present. The arrival of a sample changes causes the thermal sensor to register a new value. These values are then compared.

Another embodiment measures the change in thermal properties (such as thermal conductivity or thermal capacity) in the local environment of a thermal sensor caused by the arrival of a fluid sample. In general this is the operating principle of a class of devices known as “thermal conductivity sensors” or “heat flux sensors”. At least two hardware implementations have been used and are described above. One implementation utilizes a thermal sensor in a “self-heating mode.” In “self-heating mode,” a self-heating thermal sensor may utilize a positive temperature coefficient thermistor placed in or near the flow channel, e.g. located in the wall of the flow channel.

An electrical current is run through the thermistor, causing the average temperature of the thermistor to rise above that of the surrounding environment. The temperature can be determined from the electrical resistance, since it is temperature dependent. When fluid flows through the channel, it changes the local thermal conductivity near the thermistor (usually to become higher) and this causes a change in the average temperature of the thermistor. It also changes the thermal capacity, which modifies the thermal dynamic response. These changes give rise to a signal, which can be detected electronically by well-known means, and the arrival of the fluid can thereby be inferred.

A second hardware implementation requires a separate heating element in or near the flow channel, plus a thermal sensor arrangement in close proximity. Passing a current through the element provides heat to the local environment and establishes a local temperature detected by the thermocouple device. This temperature or its dynamic response is altered by the arrival of the fluid or blood in or near the local environment, similar to the previously described implementation, and the event is detected electronically.

The heating element can be operated in a controlled input mode, which may include controlling one or more of the following parameters—applied current, voltage or power—in a prescribed manner. When operating in controlled input mode, fluctuations of the temperature of the thermal sensor are monitored in order to detect the arrival of the fluid.

Alternatively, the heating element can be operated in such a fashion as to control the temperature of the thermal sensor in a prescribed manner. In this mode of operation, the resulting fluctuations in one or more of the input parameters to the heating element (applied current, voltage, and power) can be monitored in order to detect the arrival of the fluid.

In either of the above-described operating modes, the prescribed parameter can be held to a constant value or sequence of values that are held constant during specific phases of operation of the device. The prescribed parameter can also varied as a known function or waveform in time.

The change in the monitored parameters caused by the arrival of the fluid can be calculated in any of a number of ways, using methods well known in the art of signal processing. The signal processing methods allow the relation of the signal received prior to arrival of the fluid with the signal received upon arrival of the fluid to indicate that the fluid has arrived. For example, and after suitable signal filtering is applied, changes in the monitored value or the rate of change of the value of the signal can be monitored to detect the arrival of the fluid. Additionally, the arrival of fluid will cause a dynamic change in the thermodynamic properties of the local environment, such as thermal conductivity or thermal capacity. When the input parameter is a time varying function this change of thermodynamic properties will cause a phase shift of the measured parameter relative to the controlled parameter. This phase shift can be monitored to detect the arrival of the fluid.

It should also be noted that sensitivity to thermal noise and operating power levels could be reduced in these either of these modes of operation by a suitable choice of time-varying waveforms for the prescribed parameter, together with appropriate and well-known signal processing methods applied to the monitored parameters. However, these potential benefits may come at the cost of slower response time.

Referring to FIG. 63, an alternative embodiment of a tissue penetration sampling device is shown which incorporates disposable sampling module 590, a lancet driver 591, and an optional module cartridge 592 are shown. The optional module cartridge comprises a case body 593 having a storage cavity 594 for storing sampling modules 590. A cover to this cavity has been left out for clarity. The cartridge further comprises a chamber 595 for holding the lancet driver 591. The lancet driver has a preload adjustment knob 596, by which the trigger point of the lancet driver may be adjusted. This insures a reproducible tension on the surface of the skin for better control of the depth of penetration and blood yield. In one embodiment, the sampling module 590 is removably attached to the lancet driver 591, as shown, so that the sampling module 590 is disposable and the lancet driver 591 is reusable. In an alternative embodiment, the sampling module and lancet driver are contained within a single combined housing, and the combination sample acquisition module/lancet driver is disposable. The sampling module 590 includes a sampling site 597, preferably having a concave depression 598, or cradle, that can be ergonomically designed to conform to the shape of a user's finger or other anatomical feature (not shown).

The sampling site further includes an opening 599 located in the concave depression. The lancet driver 591 is used to fire a lancet contained within and guided by the sampling module 590 to create an incision on the user's finger when the finger is placed on the sampling site 597. In one embodiment, the sampling site forms a substantially airtight seal at the opening when the skin is firmly pressed against the sampling site; the sampling site may additionally have a soft, compressible material surrounding the opening to further limit contamination of the blood sample by ambient air. “Substantially airtight” in this context means that only a negligible amount of ambient air may leak past the seal under ordinary operating conditions, the substantially airtight seal allowing the blood to be collected seamlessly.

Referring to FIGS. 64 and 65, the lancet 600 is protected in the integrated housing 601 that provides a cradle 602 for positioning the user's finger or other body part, a sampling port 603 within the cradle 602, and a sample reservoir 603′ for collecting the resulting blood sample. The lancet 600 is a shaft with a distal end 604 sharpened to produce the incision with minimal pain. The lancet 600 further has an enlarged proximal end 605 opposite the distal end. Similar lancets are commonly known in the art.

Rather than being limited to a shaft having a sharp end, the lancet may have a variety of configurations known in the art, with suitable modifications being made to the system to accommodate such other lancet configurations, such configurations having a sharp instrument that exits the sampling port to create a wound from which a blood sample may be obtained.

In the figures, the lancet 600 is slidably disposed within a lancet guide 606 in the housing 601, and movement of the lancet 600 within the lancet guide 606 is closely controlled to reduce lateral motion of the lancet, thereby reducing the pain of the lance stick. The sample acquisition module also includes a return stop 613, which retains the lancet within the sample acquisition module. The sampling module has an attachment site 615 for attachment to the lancet driver.

The sampling module further includes a depth selector allowing the user to select one of several penetration depth settings. The depth selector is shown as a multi-position thumbwheel 607 having a graduated surface. By rotating the thumbwheel 607, the user selects which part of the graduated surface contacts the enlarged proximal end 605 of the lancet to limit the movement of the lancet 600 within the lancet guide 606.

The thumbwheel is maintained in the selected position by a retainer 608 having a protruding, rounded surface which engages at least one of several depressions 609 (e.g. dimples, grooves, or slots) in the thumbwheel 607. The depressions 609 are spatially aligned to correspond with the graduated slope of the thumbwheel 607, so that, when the thumbwheel 607 is turned, the depth setting is selected and maintained by the retainer 608 engaging the depression 609 corresponding to the particular depth setting selected.

In alternate embodiments, the retainer may be located on the depth selector and the depressions corresponding to the depth setting located on the housing such that retainer may functionally engage the depressions. Other similar arrangements for maintaining components in alignment are known in the art and may be used. In further alternate embodiments, the depth selector may take the form of a wedge having a graduated slope, which contacts the enlarged proximal end of the lancet, with the wedge being retained by a groove in the housing.

The sample reservoir 603′ includes an elongate, rounded chamber 610 within the housing 601 of the sample acquisition module. The chamber 610 has a flat or slightly spherical shape, with at least one side of the chamber 610 being formed by a smooth polymer, preferably absent of sharp corners. The sample reservoir 603′ also includes a sample input port 611 to the chamber 610, which is in fluid communication with the sampling port 603, and a vent 612 exiting the chamber.

A cover (not shown), preferably of clear material such as plastic, positions the lancet 600 and closes the chamber 603′, forming an opposing side of the chamber 603′. In embodiments where the cover is clear, the cover may serve as a testing means whereby the sample may be analyzed in the reservoir via optical sensing techniques operating through the cover. A clear cover will also aid in determining by inspection when the sample reservoir is full of the blood sample.

FIG. 66 shows a portion of the sampling module illustrating an alternate embodiment of the sample reservoir. The sample reservoir has a chamber 616 having a sample input port 617 joining the chamber 616 to a blood transport capillary channel 618; the chamber 616 also has a vent 619. The chamber has a first side 620 that has a flat or slightly spherical shape absent of sharp corners and is formed by a smooth polymer. An elastomeric diaphragm 621 is attached to the perimeter of the chamber 616 and preferably is capable of closely fitting to the first side of the chamber 620.

To control direction of blood flow, the sample reservoir is provided with a first check valve 622 located at the entrance 617 of the sample reservoir and a second check valve 623 leading to an exit channel 624 located at the vent 619. Alternately, a single check valve (at the location 622) may be present controlling both flow into the chamber 616 via the blood transport capillary channel 618 and flow out of the chamber 616 into an optional alternate exit channel 625. The sample reservoir has a duct 626 connecting to a source of variable pressure facilitating movement of the diaphragm 621.

When the diaphragm 621 is flexed away from the first side of the chamber 620 (low pressure supplied from the source via duct 626), the first check valve 622 is open and the second check valve 623 is closed, aspiration of the blood sample into the sample reservoir follows. When the diaphragm 621 is flexed in the direction of the first side of the chamber 620 (high pressure supplied from the source via duct 626) with the first check valve 622 closed and the second check valve 623 open, the blood is forced out of the chamber 616. The direction of movement and actuation speed of the diaphragm 621 can be controlled by the pressure source, and therefore the flow of the sample can be accelerated or decelerated. This feature allows not only reduced damage to the blood cells but also for the control of the speed by which the chamber 616 is filled.

While control of the diaphragm 621 via pneumatic means is described in this embodiment, mechanical means may alternately be used. Essentially, this micro diaphragm pump fulfills the aspiration, storage, and delivery functions. The diaphragm 621 may be used essentially as a pump to facilitate transfer of the blood to reach all areas required. Such required areas might be simple sample storage areas further downstream for assaying or for exposing the blood to a chemical sensor or other testing means. Delivery of the blood may be to sites within the sampling module or to sites outside the sampling module, i.e. a separate analysis device.

In an alternate embodiment, a chemical sensor or other testing means is located within the sampling module, and the blood is delivered to the chemical sensor or other testing means via a blood transfer channel in fluid communication with the sample reservoir. The components of the sampling module may be injection molded and the diaphragm may be fused or insertion molded as an integral component.

FIG. 67 depicts a portion of the disposable sampling module surrounding the sampling port 627, including a portion of the sampling site cradle surface 628. The housing of the sampling module includes a primary sample flow channel 629 that is a capillary channel connecting the sample input port to the sample reservoir. The primary sample flow channel 629 includes a primary channel lumenal surface 630 and a primary channel entrance 631, the primary channel entrance 631 opening into the sample input port 627. The sampling module may optionally include a supplemental sample flow channel 632 that is also a capillary channel having a supplemental channel lumenal surface 633 and a supplemental channel entrance 634, the supplemental channel entrance 634 opening into the sample input port 627.

The primary sample flow channel 629 has a greater cross-sectional area than the supplemental sample flow channel 632, preferably by at least a factor of two. Thus, the supplemental sample flow channel 632 draws fluid faster than the primary sample flow channel 629. When the first droplet of blood is received into the sample input port 627, the majority of this droplet is drawn through the supplemental sample flow channel 632. However, as the blood continues to flow from the incision into the sample input port 627, most of this blood is drawn through the primary sample flow channel 629, since the supplemental sample flow channel 632 is of limited capacity and is filled or mostly filled with the first blood droplet. This dual capillary channel configuration is particularly useful in testing where there is a concern with contamination of the sample, e.g. with debris from the lancet strike or (particularly in the case of blood gas testing) with air.

In order to improve blood droplet flow, some priming or wicking of the surface with blood is at times necessary to begin the capillary flow process. Portions of the surfaces of the sample input port 627 and the primary and supplemental (if present) sample flow channels 629, 632 are treated to render those surfaces hydrophilic. The surface modification may be achieved using mechanical, chemical, corona, or plasma treatment. Examples of such coatings and methods are marketed by AST Products (Billerica, Mass.) and Spire Corporation (Bedford, Mass.).

However, a complete blanket treatment of the surface could prove detrimental by causing blood to indiscriminately flow all over the surface and not preferentially through the capillary channel(s). This ultimately will result in losses of blood fluid. The particular surfaces which receive the treatment are selected to improve flow of blood from an incised finger on the sampling site cradle surface 628 through the sample input port 627 and at least one of the sample flow channels 629, 632 to the sample reservoir. Thus, the treatment process should be masked off and limited only to the selected surfaces. The masking process of selectively modifying the sampling surface from hydrophobic to hydrophilic may be done with mechanical masking techniques such as with metal shielding, deposited dielectric or conductive films, or electrical shielding means.

In some embodiments, the treated surfaces are limited to one or more of the following: the surface of the sampling port which lies between the sampling site cradle surface and the primary and supplemental sample flow channel, the surface immediately adjacent to the entrances to the primary and/or supplemental sample flow channels 631, 634 (both within the sample input port and within the sample flow channel), and the lumenal surface of the primary and/or supplemental sample flow channels 630, 633.

Upon exiting the incision blood preferentially moves through the sample input port 627 into the supplementary sample flow channel 632 (if present) and into the primary sample flow channel 629 to the sample reservoir, resulting in efficient capture of the blood. Alternatively, the substrate material may be selected to be hydrophilic or hydrophobic, and a portion of the surface of the substrate material may be treated for the opposite characteristic.

In an embodiment, FIG. 67 a membrane 635 at the base of the sample input port 627 is positioned between the retracted sharpened distal end of the lancet 636 and the entrance to the sample flow channels 631, 634. The membrane 635 facilitates the blood sample flow through the sample flow channels 629, 632 by restricting the blood from flowing into the area 636 surrounding the distal end of the lancet 637. The blood thus flows preferentially into the sample reservoir. In an embodiment, the membrane 635 is treated to have a hydrophobic characteristic. In another embodiment, the membrane 635 is made of polymer-based film 638 that has been coated with a silicone-based gel 639.

For example, the membrane structure may comprise a polymer-based film 638 composed of polyethylene terephthalate, such as the film sold under the trademark MYLAR. The membrane structure may further comprise a thin coating of a silicone-based gel 639 such as the gel sold under the trademark SYLGARD on at least one surface of the film. The usefulness of such a film is its ability to reseal after the lancet has penetrated it without physically affecting the lancet's cutting tip and edges. The MYLAR film provides structural stability while the thin SYLGARD silicone laminate is flexible enough to retain its form and close over the hole made in the MYLAR film. Other similar materials fulfilling the structural stability and flexibility roles may be used in the manufacture of the membrane in this embodiment.

The membrane 635 operates to allow the sharpened distal end of the lancet 637 to pierce the membrane as the sharpened distal end of the lancet 637 travels into and through the sample input port 627. In an embodiment, the silicone-based gel 639 of the membrane 635 automatically seals the cut caused by the piercing lancet. Therefore, after an incision is made on a finger of a user, the blood from the incision is prevented from flowing through the membrane 635, which aids the blood to travel through the primary sample flow channel 629 to accumulate within the sample reservoir. Thus the film prevents any blood from flowing into the lancet device assembly, and blood contamination and loss into the lancet device mechanism cavity are prevented. Even without the resealing layer 639, the hydrophobic membrane 635 deters the flow of blood across the membrane 635, resulting in improved flow through the primary sample flow channel 629 and reduced or eliminated flow through the pierced membrane 635.

FIGS. 68-70 illustrate one implementation of a lancet driver 640 at three different points during the use of the lancet driver. In this description of the lancet driver, proximal indicates a position relatively close to the site of attachment of the sampling module; conversely, distal indicates a position relatively far from the site of attachment of the sampling module. The lancet driver has a driver handle body 641 defining a cylindrical well 642 within which is a preload spring 643. Proximal to the preload spring 643 is a driver sleeve 644, which closely fits within and is slidably disposed within the well 642. The driver sleeve 644 defines a cylindrical driver chamber 645 within which is an actuator spring 646. Proximal to the actuator spring 646 is a plunger sleeve 647, which closely fits within and is slidably disposed within the driver sleeve 644.

The driver handle body 641 has a distal end 648 defining a threaded passage 649 into which a preload screw 650 fits. The preload screw defines a counterbore 651. The preload screw 650 has a distal end 652 attached to a preload adjustment knob 653 and a proximal end 654 defining an aperture 655. The driver sleeve 644 has a distal end 656 attached to a catch fitting 657. The catch fitting 657 defines a catch hole 658. The driver sleeve 644 has a proximal end 659 with a sloped ring feature 660 circling the interior surface of the driver sleeve's proximal end 659.

The lancet driver includes a plunger stem 660 having a proximal end 661 and a distal end 662. At its distal end 662, an enlarged plunger head 663 terminates the plunger stem 660. At its proximal end 661, the plunger stem 660 is fixed to the plunger tip 667 by adhesively bonding, welding, crimping, or threading into a hole 665 in the plunger tip 667. A plunger hook 665 is located on the plunger stem 660 between the plunger head 663 and the plunger tip 667. The plunger head 663 is slidably disposed within the counterbore 651 defined by the preload screw 650. The plunger stem 660 extends from the plunger head 663, through the aperture 655 defined by the proximal end 654 of the preload screw, thence through the hole 658 in the catch fitting 657, to the joint 664 in the plunger tip 667. For assembly purposes, the plunger base joint 664 may be incorporated into the plunger sleeve 647, and the plunger stem 660 attached to the plunger base 664 by crimping, swaging, gluing, welding, or some other means. Note that the lancet driver 640 could be replaced with any of the controlled electromagnetic drivers discussed above.

The operation of the tissue penetration sampling device may be described as follows, with reference to FIGS. 63-70. In operation, a fresh sampling module 590 is removed from the storage cavity 594 and adjusted for the desired depth setting using the multi-position thumbwheel 607. The sampling module 590 is then placed onto the end of the lancet driver 591. The preload setting may be checked, but will not change from cycle to cycle once the preferred setting is found; if necessary, the preload setting may be adjusted using the preload adjustment knob 596.

The combined sampling module and lancet driver assembly is then pressed against the user's finger (or other selected anatomical feature) in a smooth motion until the preset trigger point is reached. The trigger point corresponds to the amount of preload force that needs to be overcome to actuate the driver to drive the lancet towards the skin. The preload screw allows the preload setting to be adjusted by the user such that a consistent, preset (by the user) amount of preload force is applied to the sampling site 597 each time a lancing is performed.

When the motion to press the assembly against the user's finger is begun (see FIG. 68), the plunger hook 665 engages catch fitting 657, holding the actuator spring 646 in a cocked position while the force against the finger builds as the driver sleeve 644 continues to compress the preload spring 643. Eventually (see FIG. 69) the sloped back of the plunger hook 665 slides into the hole 655 in the proximal end of the preload screw 654 and disengages from the catch fitting 657. The plunger sleeve 647 is free to move in a proximal direction once the plunger hook 665 releases, and the plunger sleeve 647 is accelerated by the actuator spring 646 until the plunger tip 667 strikes the enlarged proximal end of the lancet 212.

Upon striking the enlarged proximal end of the lancet 605, the plunger tip 667 of the actuated lancet driver reversibly engages the enlarged proximal end of the lancet 605. This may be accomplished by mechanical means, e.g. a fitting attached to the plunger tip 667 that detachably engages a complementary fitting on the enlarged proximal end of the lancet 605, or the enlarged proximal end of the lancet 605 may be coated with an adhesive that adheres to the plunger tip 667 of the actuated lancet driver. Upon being engaged by the plunger tip 667, the lancet 600 slides within the lancet guide 606 with the sharpened distal end of the lancet 604 emerging from the housing 601 through the sampling port 603 to create the incision in the user's finger.

At approximately the point where the plunger tip 667 contacts the enlarged proximal end of the lancet 605, the actuator spring 646 is at its relaxed position, and the plunger tip 667 is traveling at its maximum velocity. During the extension stroke, the actuator spring 646 is being extended and is slowing the plunger tip 667 and lancet 600. The end of stroke occurs (see FIG. 70) when the enlarged proximal end of the lancet 605 strikes the multi-position thumbwheel 607.

The direction of movement of the lancet 600 is then reversed and the extended actuator spring then quickly retracts the sharpened distal end of the lancet 604 back through the sampling port 603. At the end of the return stroke, the lancet 600 is stripped from the plunger tip 667 by the return stop 613. The adhesive adheres to the return stop 613 retaining the lancet in a safe position.

As blood seeps from the wound, it fills the sample input port 603 and is drawn by capillary action into the sample reservoir 603′. In this embodiment, there is no reduced pressure or vacuum at the wound, i.e. the wound is at ambient air pressure, although embodiments which draw the blood sample by suction, e.g. supplied by a syringe or pump, may be used. The vent 612 allows the capillary action to proceed until the entire chamber is filled, and provides a transfer port for analysis of the blood by other instrumentation. The finger is held against the sample acquisition module until a complete sample is observed in the sample reservoir.

As the sampling module 600 is removed from the lancet driver 591, a latch 614 that is part of the return stop 613 structure engages a sloped ring feature 660 inside the lancet driver 591. As the lancet driver 591 is removed from the sampling module 600, the latch forces the return stop 613 to rotate toward the lancet 600, bending it to lock it in a safe position, and preventing reuse.

As the sampling module 600 is removed from the lancet driver 591, the driver sleeve 644 is forced to slide in the driver handle body 641 by energy stored in the preload spring 643. The driver sleeve 644, plunger sleeve 647, and actuator spring 646 move outward together until the plunger head 663 on the plunger stem 660 contacts the bottom of the counterbore 651 at the proximal end of the preload screw 654. The preload spring 643 continues to move the driver sleeve 644 outward compressing the actuator spring 646 until the plunger hook 665 passes through the hole 658 in the catch fitting 657. Eventually the two springs reach equilibrium and the plunger sleeve 647 comes to rest in a cocked position.

After the sampling module 600 is removed from the lancet driver 591, it may be placed in a separate analysis device to obtain blood chemistry readings. In a preferred embodiment, the integrated housing 601 or sample reservoir 603′ of the sampling module 600 contains at least one biosensor, which is powered by and/or read by the separate analysis device. In another embodiment, the analysis device performs an optical analysis of the blood sample directly through the clear plastic cover of the sampling module. Alternatively, the blood sample may be transferred from the sampling module into an analysis device for distribution to various analysis processes.

Alternate embodiments of the invention offer improved success rates for sampling, which reduces the needless sacrifice of a sample storage reservoir or an analysis module due to inadequate volume fill. Alternate embodiments allow automatic verification that sufficient blood has been collected before signaling the user (e.g. by a signal light or an audible beep) that it is okay to remove the skin from the sampling site. In such alternate embodiments, one or more additional lancet(s) (denoted backup lancets) and/or lancet driver(s) (denoted backup lancet drivers) and/or sample reservoir(s) (denoted backup sample reservoirs) are present with the “primary” sampling module.

In one such preferred embodiment, following detection of inadequate blood sample volume (e.g., by light or electronic methods), a backup sampling cycle is initiated automatically. The “backup sampling cycle” includes disconnecting the primary sample reservoir via a simple valving system, bringing the backup components online, lancing of the skin, collection of the blood, and movement of the blood to the backup sample reservoir.

Blood flows into the backup sample reservoir until the required volume is obtained. The cycle repeats itself, if necessary, until the correct volume is obtained. Only then is the sample reservoir made available as a source of sampled blood for use in measurements or for other applications. The series of reservoirs and/or lancets and/or lancet drivers may easily be manufactured in the same housing and be transparent to the user.

In one embodiment, up to three sample reservoirs (the primary plus two backup) are present in a single sample acquisition module, each connected via a capillary channel/valving system to one or more sampling ports. Another embodiment has four sample reservoirs (the primary plus three backup) present in a single sample acquisition module, each connected via a capillary channel/valving system to one or more sampling ports. With three or four sample reservoirs, at least an 80% sampling success rate can be achieved for some embodiments.

Another embodiment includes a miniaturized version of the tissue penetration sampling device. Several of the miniature lancets may be located in a single sampling site, with corresponding sample flow channels to transfer blood to one or more reservoirs. The sample flow channels may optionally have valves for controlling flow of blood. The device may also include one or more sensors, such as the thermal sensors discussed above, for detecting the presence of blood, e.g. to determine if a sufficient quantity of blood has been obtained. In such an embodiment, the disposable sampling module, the lancet driver, and the optional module cartridge will have dimensions no larger than about 150 mm long, 60 mm wide, and 25 mm thick.

In other embodiments, the size of the tissue penetration sampling device including the disposable sampling module, the lancet driver, and the optional cartridge will have dimensions no larger than about 100 mm long, about 50 mm wide, and about 20 mm thick, and in still other embodiments no larger than about 70 mm long, about 30 mm wide, and about 10 mm thick. The size of the tissue penetration sampling device including the disposable sampling module, the lancet driver, and the optional cartridge will generally be at least about 10 mm long, about 5 mm wide, and about 2 mm thick.

In another miniature embodiment, the dimensions of the lancet driver without the cartridge or sampling module are no larger than about 80 mm long, 10 mm wide, and 10 mm thick, or specifically no larger than about 50 mm long, 7 mm wide, and 7 mm thick, or even more specifically no larger than about 15 mm long, 5 mm wide, and 3 mm thick; dimensions of the lancet driver without the cartridge or sampling module are generally at least about 1 mm long, 0.1 mm wide, and 0.1 mm thick, or specifically at least about 2 mm long, 0.2 mm wide, and 0.2 mm thick, or more specifically at least about 4 mm long, 0.4 mm wide, and 0.4 mm thick.

In yet another miniature embodiment, dimensions of the miniature sampling module without the lancet driver or cartridge are no larger than about 15 mm long, about 10 mm wide, and about 10 mm thick, or no larger than about 10 mm long, about 7 mm wide, and about 7 mm thick, or no larger than about 5 mm long, about 3 mm wide, and about 2 mm thick; dimensions of the miniature sampling module without the lancet driver or cartridge are generally at least about 1 mm long, 0.1 mm wide, and 0.1 mm thick, specifically at least about 2 mm long, 0.2 mm wide, and 0.2 mm thick, or more specifically at least about 4 mm long, 0.4 mm wide, and 0.4 mm thick.

In another embodiment, the miniaturized sampling module and the lancet driver form a single unit having a shared housing, and the combined sample acquisition module/lancet driver unit is disposable. Such a combined unit is no larger than about 80 mm long, about 30 mm wide, and about 10 mm thick, specifically no larger than about 50 mm long, about 20 mm wide, and about 5 mm thick, more specifically, no larger than about 20 mm long, about 5 mm wide, and about 3 mm thick; the combined unit is generally at least about 2 mm long, about 0.3 mm wide, and about 0.2 mm thick, specifically at least about 4 mm long, 0.6 mm wide, and 0.4 mm thick, more specifically, at least about 8 mm long, 1 mm wide, and 0.8 mm thick.

Referring to FIG. 71, another embodiment of a tissue penetration sampling device is shown, incorporating a disposable sampling module 608 cartridge and analyzer device 669 is shown. The analyzer device 669 includes a deck 670 having a lid 671 attached to the deck by hinges along the rear edge of the system 672. A readout display 673 on the lid 671 functions to give the user information about the status of the analyzer device 669 and/or the sampling module cartridge 668, or to give readout of a blood test. The analyzer device 669 has several function buttons 674 for controlling function of the analyzer device 669 or for inputting information into the reader device 669. Alternatively, the reader device may have a touch-sensitive screen, an optical scanner, or other input means known in the art.

An analyzer device with an optical scanner may be particularly useful in a clinical setting, where patient information may be recorded using scan codes on patients' wristbands or files. The analyzer reader device may have a memory, enabling the analyzer device to store results of many recent tests. The analyzer device may also have a clock and calendar function, enabling the results of tests stored in the memory to be time and date-stamped. A computer interface 675 enables records in memory to be exported to a computer. The analyzer device 669 has a chamber located between the deck 670 and the lid 671, which closely accommodates a sampling module cartridge 668. Raising the lid 671, allowing a sampling module cartridge 668 to be inserted or removed, accesses the chamber.

FIG. 72 is an illustration showing some of the features of an embodiment of a sampling module cartridge. The sampling module cartridge 668 has a housing having an orientation sensitive contact interface for mating with a complementary surface on the analyzer device. The contact interface functions to align the sampling module cartridge with the analyzer device, and also allows the analyzer device to rotate the sampling module cartridge in preparation for a new sampling event. The contact interface may take the form of cogs or grooves formed in the housing, which mate with complementary cogs, or grooves in the chamber of the analyzer device.

The sampling module cartridge has a plurality of sampling sites 678 on the housing, which are shown as slightly concave depressions near the perimeter of the sampling module cartridge 668. Each sampling site defines an opening 679 contiguous with a sample input port entering the sampling module. In an alternate embodiment, the sampling sites and sample input ports are located on the edge of the sampling module cartridge. Optical windows 680 allow transmission of light into the sampling module cartridge for the purpose of optically reading test results. Alternatively, sensor connection points allow transmission of test results to the analyzer device via electrical contact. Access ports 681, if present, allow transmission of force or pressure into the sampling module cartridge from the analyzer device. The access ports may be useful in conjunction with running a calibration test or combining reagents with sampled blood or other bodily fluids.

The described features are arranged around the sampling module cartridge, and the sampling module cartridge is radially partitioned into many sampling modules, each sampling module having the components necessary to perform a single blood sampling and testing event. A plurality of sampling modules are present on a sampling module cartridge, generally at least ten sampling modules are present on a single disposable sampling module cartridge; at least about 20, or more on some embodiments, and at least about 34 sampling modules are present on one embodiment, allowing the sampling module cartridge to be maintained in the analyzer device for about a week before replacing with a new sampling module cartridge (assuming five sampling and testing events per day for seven days). With increasing miniaturization, up to about 100, or more preferably up to about 150, sampling modules may be included on a single sampling module cartridge, allowing up to a month between replacements with new sampling module cartridges. It may be necessary for sampling sites to be located in several concentric rings around the sampling module cartridge or otherwise packed onto the housing surface to allow the higher number of sampling modules on a single sampling module cartridge.

In other embodiments, the sampling module cartridge may be any other shape which may conveniently be inserted into a analyzer device and which are designed to contain multiple sampling modules, e.g. a square, rectangular, oval, or polygonal shape. Each sampling module is miniaturized, being generally less than about 6.0 cm long by about 1.0 cm wide by about 1.0 cm thick, so that thirty five more or less wedge-shaped sampling modules can fit around a disk having a radius of about 6.0 cm. In some embodiments, the sampling modules can be much smaller, e.g. less than about 3.0 cm long by about 0.5 cm wide by about 0.5 cm thick.

FIG. 73 depicts, in a highly schematic way, a single sampling module, positioned within the analyzer device. Of course, it will occur to the person of ordinary skill in the art that the various recited components may be physically arranged in various configurations to yield a functional system. FIG. 73 depicts some components, which might only be present in alternate embodiments and are not necessarily all present in any single embodiment. The sampling module has a sample input port 682, which is contiguous with an opening 683 defined by a sampling site 684 on the cartridge housing 685. A lancet 686 having a lancet tip 687 adjacent to the sample input port 682 is operably maintained within the housing such that the lancet 686 can move to extend the lancet tip 687 through the sample input port 682 to outside of the sampling module cartridge.

The lancet 686 also has a lancet head 688 opposite the lancet tip. The lancet 686 driven to move by a lancet driver 689, which is schematically depicted as a coil around the lancet 686. The lancet driver 689 optionally is included in the sampling module cartridge as pictured or alternatively is external to the sampling module cartridge. The sampling module may further include a driver port 690 defined by the housing adjacent to the lancet head 688—the driver port 690 allows an external lancet driver 691 access to the lancet 686.

In embodiments where the lancet driver 689 is in the sampling module cartridge, it may be necessary to have a driver connection point 694 upon the housing accessible to the analyzer device. The driver connection point 694 may be a means of triggering the lancet driver 689 or of supplying motive force to the lancet driver 689, e.g. an electrical current to an electromechanical lancet driver. Note that any of the drivers discussed above, including controllable drivers, electromechanical drivers, etc., can be substituted for the lancet driver 689 shown.

In one embodiment a pierceable membrane 692 is present between the lancet tip 687 and the sample input port 682, sealing the lancet 686 from any outside contact prior to use. A second membrane 693 may be present adjacent to the lancet head 688 sealing the driver port 690. The pierceable membrane 692 and the second membrane 693 function to isolate the lancet 686 within the lancet chamber to maintain sterility of the lancet 686 prior to use. During use the lancet tip 687 and the external lancet driver 691 pierce the pierceable membrane 692 and the second membrane 693, if present respectively.

A sample flow channel 695 leads from the sample input port 682 to an analytical region 696. The analytical region 696 is associated with a sample sensor capable of being read by the analyzer device. If the sample sensor is optical in nature, the sample sensor may include optically transparent windows 697 in the housing above and below the analytical region 696, allowing a light source in the analyzer device to pass light 698 through the analytical region. An optical sensor 698′, e.g. a CMOS array, is present in the analyzer device for sensing the light 699 that has passed through the analytical region 696 and generating a signal to be analyzed by the analyzer device.

In a separate embodiment, only one optically transparent window is present, and the opposing side of the analytical region is silvered or otherwise reflectively coated to reflect light back through the analytical region and out the window to be analyzed by the analyzer device. In an alternate embodiment, the sensor is electrochemical 700, e.g. an enzyme electrode, and includes a means of transmitting an electric current from the sampling module cartridge to the analyzer device, e.g. an electrical contact 701, or plurality of electrical contacts 701, on the housing accessible to the analyzer device.

In one embodiment, the pierceable membrane 692 may be made of polymer-based film that has been coated with a silicone-based gel. For example, the membrane structure may comprise a polymer-based film composed of polyethylene terephthalate, such as the film sold under the trademark MYLAR®. The membrane structure may further comprise a thin coating of a silicone-based gel such as the gel sold under the trademark SYLGARD® on at least one surface of the film.

The usefulness of such a film is its ability to reseal after the lancet tip has penetrated it without physically affecting the lancet's cutting tip and edges. The MYLAR® film provides structural stability while the thin SYLGARD® silicone laminate is flexible enough to retain its form and close over the hole made in the MYLAR® film. Other similar materials fulfilling the structural stability and flexibility roles may be used in the manufacture of the pierceable membrane in this embodiment.

The pierceable membrane 692 operates to allow the lancet tip 687 to pierce the pierceable membrane 692 as the lancet tip 687 travels into and through the sampling port 682. In the described embodiment, the silicone-based gel of the membrane 692 automatically seals the cut caused by the lancet tip 687. Therefore, after an incision is made on a finger of a user and the lancet tip 687 is retracted back through the pierceable membrane 692, the blood from the incision is prevented from flowing through the pierceable membrane 692, which aids the blood to travel through the sample flow channel 695 to accumulate within the analytical region 696.

Thus the pierceable membrane 692 prevents blood from flowing into the lancet device assembly, and blood contamination and loss into the lancet device mechanism cavity are prevented. In yet another embodiment, used sample input ports are automatically sealed off before going to the next sample acquisition cycle by a simple button mechanism. A similar mechanism seals off a sample input port should sampling be unsuccessful.

In an alternate embodiment, a calibrant supply reservoir 702 is also present in each sampling module. The calibrant supply reservoir 702 is filled with a calibrant solution and is in fluid communication with a calibration chamber 703. The calibration chamber 703 provides a source of a known signal from the sampling module cartridge to be used to validate and quantify the test conducted in the analytical region 696. As such, the configuration of the calibration chamber 703 closely resembles the analytical region 696.

During use, the calibrant solution is forced from the calibrant supply reservoir 702 into the calibration chamber 703. The figure depicts a stylized plunger 704 above the calibrant supply reservoir 702 ready to squeeze the calibrant supply reservoir 702. In practice, a variety of methods of transporting small quantities of fluid are known in the art and can be implemented on the sampling module cartridge. The calibration chamber 703 is associated with a calibrant testing means.

FIG. 73 shows two alternate calibrant testing means—optical windows 697 and an electrochemical sensor 676. In cases where the sampling module is designed to perform several different tests on the blood, both optical and electrochemical testing means may be present. The optical windows 697 allow passage of light 677 from the analyzer device through the calibration chamber 703, whereupon the light 703′ leaving the calibration chamber 703 passes onto an optical sensor 698′ to result in a signal in the analyzer device.

The electrochemical sensor 676 is capable of generating a signal that is communicated to the analyzer device via, e.g. an electrical contact 704′, which is accessible to a contact probe 702′ on the analyzer device that can be extended to contact the electrical contact 704′. The calibrant solution may be any solution, which, in combination with the calibrant testing means, will provide a suitable signal, which will serve as calibration measurement to the analyzer device. Suitable calibrant solutions are known in the art, e.g. glucose solutions of known concentration. The calibration measurement is used to adjust the results obtained from sample sensor from the analytical region 696.

To maintain small size in some sampling module cartridge embodiments, allowing small quantities of sampled blood to be sufficient, each component of the sampling module must be small, particularly the sample flow channel and the analytical region. The sample flow channel can be less than about 0.5 mm in diameter, specifically less than about 0.3 mm in diameter, more specifically less than about 0.2 mm in diameter, and even more specifically less than about 0.1 mm in diameter.

The sample flow channel may generally be at least about 50 micrometers in diameter. The dimensions of the analytical region may be less than about 1 mm by about 1 mm by about 1 mm, specifically less than about 0.6 mm by about 0.6 mm by about 0.4 mm, more specifically less than about 0.4 mm by 0.4 mm by 0.2 mm, and even more specifically less than about 0.2 mm by about 0.2 mm by about 0.1 mm. The analytical region can generally be at least about 100 micrometers by 100 micrometers by 50 micrometers.

The sampling module cartridge is able to return a valid testing result with less than about 5 microliters of blood taken from the skin of a patient, specifically less than about 1 microliter, more specifically less than about 0.4 microliters, and even more specifically less than about 0.2 microliters. Generally, at least 0.05 microliters of blood is drawn for a sample.

The cartridge housing may be made in a plurality of distinct pieces, which are then assembled to provide the completed housing. The distinct pieces may be manufactured from a wide range of substrate materials. Suitable materials for forming the described apparatus include, but are not limited to, polymeric materials, ceramics (including aluminum oxide and the like), glass, metals, composites, and laminates thereof. Polymeric materials are particularly preferred herein and will typically be organic polymers that are homopolymers or copolymers, naturally occurring or synthetic, crosslinked or uncrosslinked.

It is contemplated that the various components and devices described herein, such as sampling module cartridges, sampling modules, housings, etc., may be made from a variety of materials, including materials such as the following: polycarbonates; polyesters, including poly (ethylene terephthalate) and poly(butylene terephthalate); polyamides, (such as nylons); polyethers, including polyformaldehyde and poly (phenylene sulfide); polyimides, such as that manufactured under the trademarks KAPTON (DuPont, Wilmington, Del.) and UPILEX (Ube Industries, Ltd., Japan); polyolefin compounds, including ABS polymers, Kel-F copolymers, poly(methyl methacrylate), poly(styrene-butadiene) copolymers, poly(tetrafluoroethylene), poly(ethylenevinyl acetate) copolymers, poly(N-vinylcarbazole) and polystyrene.

The various components and devices described herein may also be fabricated from a “composite,” i.e., a composition comprised of unlike materials. The composite may be a block composite, e.g., an A-B-A block composite, an A-B-C block composite, or the like. Alternatively, the composite may be a heterogeneous combination of materials, i.e., in which the materials are distinct from separate phases, or a homogeneous combination of unlike materials. A laminate composite with several different bonded layers of identical or different materials can also be used.

Other preferred composite substrates include polymer laminates, polymer-metal laminates, e.g., polymer coated with copper, a ceramic-in-metal or a polymer-in-metal composite. One composite material is a polyimide laminate formed from a first layer of polyimide such as KAPTON polyimide, available from DuPont (Wilmington, Del.), that has been co-extruded with a second, thin layer of a thermal adhesive form of polyimide known as KJ®, also available from DuPont (Wilmington, Del.).

Any suitable fabrication method for the various components and devices described herein can be used, including, but not limited to, molding and casting techniques, embossing methods, surface machining techniques, bulk machining techniques, and stamping methods. Further, injection-molding techniques well known in the art may be useful in shaping the materials used to produce sample modules and other components.

For some embodiments, the first time a new sampling module cartridge 668 is used, the user removes any outer packaging material from the sampling module cartridge 668 and opens the lid 671 of the analyzer device 669, exposing the chamber. The sampling module cartridge 668 is slipped into the chamber and the lid 671 closed. The patient's skin is positioned upon the sampling site 678 and the integrated process of lancing the skin, collecting the blood sample, and testing the blood sample is initiated, e.g. by pressing a function button 674 to cause the lancet driver to be triggered. The patient's skin is maintained in position upon the sampling site 678, adjacent the sample input port 682, until an adequate volume of blood has been collected, whereupon the system may emit a signal (e.g. an audible beep) that the patient's skin may be lifted from the sampling site 678.

When the testing of the sample is complete, the analyzer device 669 automatically reads the results from the sampling module cartridge 668 and reports the results on the readout display 673. The analyzer device 669 may also store the result in memory for later downloading to a computer system. The sampling module cartridge 668 may then automatically be advanced to bring the next sampling module inline for the next use. Each successive time the system is used (optionally until the sampling module cartridge 668 is used up), the patient's skin may be placed upon the sampling site 678 of the (already installed) sampling module cartridge 668, thus simplifying the process of blood sampling and testing.

A method of providing more convenient blood sampling, wherein a series of blood samples may be collected and tested using a single disposable sampling module cartridge which is designed to couple to an analyzer device is described. Embodiments of the sampling module cartridge include a plurality of sampling modules. Each sampling module can be adapted to perform a single blood sampling cycle and is functionally arranged within the sampling module cartridge to allow a new sampling module to be brought online after a blood sampling cycle is completed.

Each blood sampling cycle may include lancing of a patient's skin, collection of a blood sample, and testing of the blood sample. The blood sampling cycle may also include reading of information about the blood sample by the analyzer device, display and/or storage of test results by the analyzer device, and/or automatically advancing the sampling module cartridge to bring a new sampling module online and ready for the next blood sampling cycle to begin.

A method embodiment starts with coupling of the sampling module cartridge and analyzer device and then initiating a blood sampling cycle. Upon completion of the blood sampling cycle, the sampling module cartridge is advanced to bring a fresh, unused sampling module online, ready to perform another blood sampling cycle. Generally, at least ten sampling modules are present, allowing the sampling module cartridge to be advanced nine times after the initial blood sampling cycle.

In some embodiments, more sampling modules are present and the sampling module cartridge may be advanced about 19 times, and about 34 times in some embodiments, allowing about 19 or about 34 blood sampling cycles, respectively, after the initial blood sampling cycle. After a series of blood sampling cycles has been performed and substantially all (i.e. more than about 80%) of the sampling modules have been used, the sampling module cartridge is decoupled from the analyzer device and discarded, leaving the analyzer device ready to be coupled with a new sampling module cartridge.

Referring to FIGS. 74-76, a tissue penetration sampling device 180 is shown with the controllable driver 179 of FIG. 20 coupled to a sampling module cartridge 705 and disposed within a driver housing 706. A ratchet drive mechanism 707 is secured to the driver housing 706, coupled to the sampling module cartridge 705 and configured to advance a sampling module belt 708 within the sampling module cartridge 705 so as to allow sequential use of each sampling module 709 in the sampling module belt 708. The ratchet drive mechanism 707 has a drive wheel 711 configured to engage the sampling modules 709 of the sampling module belt 708. The drive wheel 711 is coupled to an actuation lever 712 that advances the drive wheel 711 in increments of the width of a single sampling module 709. A T-slot drive coupler 713 is secured to the elongated coupler shaft 184.

A sampling module 709 is loaded and ready for use with the drive head 198 of the lancet 183 of the sampling module 709 loaded in the T-slot 714 of the drive coupler 713. A sampling site 715 is disposed at the distal end 716 of the sampling module 709 disposed about a lancet exit port 717. The distal end 716 of the sampling module 709 is exposed in a module window 718, which is an opening in a cartridge cover 721 of the sampling module cartridge 705. This allows the distal end 716 of the sampling module 709 loaded for use to be exposed to avoid contamination of the cartridge cover 721 with blood from the lancing process.

A reader module 722 is disposed over a distal portion of the sampling module 709 that is loaded in the drive coupler 713 for use and has two contact brushes 724 that are configured to align and make electrical contact with sensor contacts 725 of the sampling module 709 as shown in FIG. 77. With electrical contact between the sensor contacts 725 and contact brushes 724, the processor 193 of the controllable driver 179 can read a signal from an analytical region 726 of the sampling module 709 after a lancing cycle is complete and a blood sample enters the analytical region 726 of the sampling module 709. The contact brushes 724 can have any suitable configuration that will allow the sampling module belt 708 to pass laterally beneath the contact brushes 724 and reliably make electrical contact with the sampling module 709 loaded in the drive coupler 713 and ready for use. A spring loaded conductive ball bearing is one example of a contact brush 724 that could be used. A resilient conductive strip shaped to press against the inside surface of the flexible polymer sheet 727 along the sensor contact region 728 of the sampling module 709 is another embodiment of a contact brush 724.

The sampling module cartridge 705 has a supply canister 729 and a receptacle canister 730. The unused sampling modules of the sampling module belt 708 are disposed within the supply canister 729 and the sampling modules of the sampling module belt 708 that have been used are advanced serially after use into the receptacle canister 730.

FIG. 77 is a perspective view of a section of the sampling module belt 708 shown in the sampling module cartridge 705 in FIG. 74. The sampling module belt 708 has a plurality of sampling modules 709 connected in series by a sheet of flexible polymer 727. The sampling module belt 708 shown in FIG. 77 is formed from a plurality of sampling module body portions 731 that are disposed laterally adjacent each other and connected and sealed by a single sheet of flexible polymer 727. The flexible polymer sheet 727 can optionally have sensor contacts 725, flexible electrical conductors 732, sample sensors 733 or any combination of these elements formed on the inside surface 734 of the flexible polymer sheet 727. These electrical, optical or chemical elements can be formed by a variety of methods including vapor deposition and the like.

The proximal portion 735 of the flexible polymer sheet 727 has been folded over on itself in order to expose the sensor contacts 725 to the outside surface of the sampling module 709. This makes electrical contact between the contact brushes 724 of the reader module 722 and the sensor contacts 725 easier to establish as the sampling modules 709 are advanced and loaded into position with the drive coupler 713 of the controllable driver 179 ready for use. The flexible polymer sheet 727 can be secured to the sampling module body portion 731 by adhesive bonding, solvent bonding, ultrasonic thermal bonding or any other suitable method.

FIG. 78 shows a perspective view of a single sampling module 709 of the sampling module belt 708 of FIG. 77 during the assembly phase of the sampling module 709. The proximal portion 735 of the flexible polymer sheet 727 is being folded over on itself as shown in order to expose the sensor contacts 725 on the inside surface of the flexible polymer sheet 727. FIG. 79 is a bottom view of a section of the flexible polymer sheet 727 of the sampling module 709 of FIG. 78 illustrating the sensor contacts 725, flexible conductors 732 and sample sensors 733 deposited on the bottom surface of the flexible polymer sheet 727.

A lancet 183 is shown disposed within the lancet channel 736 of the sampling module 709 of FIG. 78 as well as within the lancet channels 736 of the sampling modules 709 of the sampling module belt 708 of FIG. 77. The lancet 183 has a tip 196 and a shaft portion 201 and a drive head 198. The shaft portion 201 of the lancet slides within the lancet channel 736 of the sampling module 709 and the drive head 198 of the lancet 183 has clearance to move in a proximal and distal direction within the drive head slot 737 of the sampling module 709. Disposed adjacent the drive head slot 737 and at least partially forming the drive head slot are a first protective strut 737′ and a second protective strut 737″ that are elongated and extend substantially parallel to the lancet 183.

In one lancet 183 embodiment, the drive head 198 of the lancet 183 can have a width of about 0.9 to about 1.1 mm. The thickness of the drive head 198 of the lancet 183 can be about 0.4 to about 0.6 mm. The drive head slot 714 of the sampling module 709 should have a width that allows the drive head 198 to move freely within the drive head slot 714. The shaft portion 201 of the lancet 183 can have a transverse dimension of about 50 μm to about 1000 μm. Typically, the shaft portion 201 of the lancet 183 has a round transverse cross section, however, other configurations are contemplated.

The sampling module body portions 731 and the sheet of flexible polymer 727 can both be made of polymethylmethacrylate (PMMA), or any other suitable polymer, such as those discussed above. The dimensions of a typical sampling module body portion 731 can be about 14 to about 18 mm in length, about 4 to about 5 mm in width, and about 1.5 to about 2.5 mm in thickness. In other embodiments, the length of the sample module body portion can be about 0.5 to about 2.0 inch and the transverse dimension can be about 0.1 to about 0.5 inch. The thickness of the flexible polymer sheet 727 can be about 100 to about 150 microns. The distance between adjacent sampling modules 709 in the sampling module belt 708 can vary from about 0.1 mm to about 0.3 mm, and in some embodiments, from about 0.2 to about 0.6.

FIGS. 80 and 81 show a perspective view of the body portion 731 of the sampling module 709 of FIG. 77 without the flexible polymer cover sheet 727 or lancet 183 shown for purposes of illustration. FIG. 81 is an enlarged view of a portion of the body portion 731 of the sampling module 709 of FIG. 80 illustrating the sampling site 715, sample input cavity 715′, sample input port 741, sample flow channel 742, analytical region 743, control chamber 744, vent 762, lancet channel 736, lancet channel stopping structures 747 and 748 and lancet guides 749-751 of the sampling module 709.

The lancet channel 736 has a proximal end 752 and a distal end 753 and includes a series of lancet bearing guide portions 749-751 and sample flow stopping structures 747-748. The lancet guides 749-751 may be configured to fit closely with the shaft of the lancet 183 and confine the lancet 183 to substantially axial movement. At the distal end 753 of the lancet channel 736 the distal-most lancet guide portion 749 is disposed adjacent the sample input port 741 and includes at its distal-most extremity, the lancet exit port 754 which is disposed adjacent the sample input cavity 715′. The sample input cavity can have a transverse dimension, depth or both, of about 2 to 5 times the transverse dimension of the lancet 183, or about 0.2 to about 2 mm, specially, about 0.4 to about 1.5 mm, and more specifially, about 0.5 to about 1.0 mm. The distal-most lancet guide 749 can have inner transverse dimensions of about 300 to about 350 microns in width and about 300 to about 350 microns in depth. Proximal of the distal-most lancet guide portion 749 is a distal sample flow stop 747 that includes a chamber adjacent the distal-most lancet 749. The chamber has a transverse dimension that is significantly larger than the transverse dimension of the distal-most lancet guide 749. The chamber can have a width of about 600 to about 800 microns, and a depth of about 400 to about 600 microns and a length of about 2000 to about 2200 microns. The rapid transition of transverse dimension and cross sectional area between the distal-most lancet bearing guide 749 and the distal sample flow stop 747 interrupts the capillary action that draws a fluid sample through the sample input cavity 715′ and into the lancet channel 736.

A center lancet bearing guide 750 is disposed proximal of the distal lancet channel stop 747 and can have dimensions similar to those of the distal-most lancet bearing guide 749. Proximal of the center lancet guide 750 is a proximal lancet channel stop 748 with a chamber. The dimensions of the proximal lancet channel stop can be the same or similar to those of the distal lancet channel stop 747. The proximal lancet channel stop 748 can have a width of about 600 to about 800 microns, and a depth of about 400 to about 600 microns and a length of about 2800 to about 3000 microns. Proximal of the proximal lancet channel stop 748 is a proximal lancet guide 751. The proximal lancet guide 751 can dimensions similar to those of the other lancet guide 749 and 750 portions with inner transverse dimensions of about 300 to about 350 microns in width and about 300 to about 350 microns in depth. Typically, the transverse dimension of the lancet guides 749-751 are about 10 percent larger than the transverse dimension of the shaft portion 201 of the lancet 183 that the lancet guides 749-751 are configured to guide.

A proximal fracturable seal (not shown) can be positioned between the proximal lancet guide 751 and the shaft portion 201 of the lancet 183 that seals the chamber of the proximal lancet channel stop 748 from the outside environment. The fracturable seal seals the chamber of the proximal lancet channel stop 748 and other interior portions of the sample chamber from the outside environment when the sampling module 709 is stored for use. The fracturable seal remains intact until the lancet 183 is driven distally during a lancet cycle at which point the seal is broken and the sterile interior portion of the sample chamber is exposed and ready to accept input of a liquid sample, such as a sample of blood. A distal fracturable seal (not shown) can be disposed between the lancet 183 and the distal-most lancet guide 749 of the sampling module 709 to seal the distal end 753 of the lancet channel 736 and sample input port 741 to maintain sterility of the interior portion of the sampling module 709 until the lancet 183 is driven forward during a lancing cycle.

Adjacent the lancet exit port 754 within the sample input cavity 715′ is the sample input port 741 that is configured to accept a fluid sample that emanates into the sample input cavity 715′ from target tissue 233 at a lancing site after a lancing cycle. The dimensions of the sample input port 741 can a depth of about 60 to about 70 microns, a width of about 400 to about 600 microns. The sample input cavity can have a transverse dimension of about 2 to about 5 times the transverse dimension of the lancet 183, or about 400 to about 1000 microns. The sample input cavity serves to accept a fluid sample as it emanates from lanced tissue and direct the fluid sample to the sample input port 741 and thereafter the sample flow channel 742. The sample flow channel 742 is disposed between and in fluid communication with the sample input port 741 and the analytical region 743. The transverse dimensions of the sample flow channel 742 can be the same as the transverse dimensions of the sample input port 741 with a depth of about 60 to about 70 microns, a width of about 400 to about 600 microns. The length of the sample flow channel 742 can be about 900 to about 1100 microns. Thus, in use, target tissue is disposed on the sampling site 715 and a lancing cycle initiated. Once the target tissue 233 has been lanced and the sample begins to flow therefrom, the sample enters the sample input cavity 715′ and then the sample input port 741. The sample input cavity 715′ may be sized and configured to facilitate sampling success by applying pressure to a perimeter of target tissue 233 before, during and after the lancing cycle and hold the wound track open after the lancing cycle to allow blood or other fluid to flow from the wound track and into the sample input cavity 715′. From the sample input port 741, the sample in then drawn by capillary or other forces through the sample flow channel 742 and into the analytical region 743 and ultimately into the control chamber 744. The control chamber 744 may be used to provide indirect confirmation of a complete fill of the analytical region 743 by a sample fluid. If a fluid sample has been detected in the control chamber 744, this confirms that the sample has completely filled the analytical region 743. Thus, sample detectors may be positioned within the control chamber 744 to confirm filling of the analytical region 743.

The analytical region 743 is disposed between and in fluid communication with the sample flow channel 742 and the control chamber 744. The analytical region 743 can have a depth of about 60 to about 70 microns, a width of about 900 to about 1100 microns and a length of about 5 to about 6 mm. A typical volume for the analytical region 743 can be about 380 to about 400 nanoliters. The control chamber 744 is disposed adjacent to and proximal of the analytical region 743 and can have a transverse dimension or diameter of about 900 to about 1100 microns and a depth of about 60 to about 70 microns.

The control chamber 744 is vented to the chamber of the proximal lancet channel stop 748 by a vent that is disposed between and in fluid communication with the control chamber 744 and the chamber of the proximal lancet channel stop 748. Vent 762 can have transverse dimensions that are the same or similar to those of the sample flow channel 742 disposed between the analytical region 743 and the sample input port 741. Any of the interior surfaces of the sample input port 741, sample flow channels 742 and 762, analytical region 743, vents 745 or control chamber 744 can be coated with a coating that promotes capillary action. A hydrophilic coating such as a detergent is an example of such a coating.

The analytical region 743 accommodates a blood sample that travels by capillary action from the sampling site 715 through the sample input cavity 715′ and into the sample input port 741, through the sample flow channel 742 and into the analytical region 743. The blood can then travel into the control chamber 744. The control chamber 744 and analytical region 743 are both vented by the vent 762 that allows gases to escape and prevents bubble formation and entrapment of a sample in the analytical region 743 and control chamber 744. Note that, in addition to capillary action, flow of a blood sample into the analytical region 743 can be facilitated or accomplished by application of vacuum, mechanical pumping or any other suitable method.

Once a blood sample is disposed within the analytical region 743, analytical testing can be performed on the sample with the results transmitted to the processor 193 by electrical conductors 732, optically or by any other suitable method or means. In some embodiments, it may be desirable to confirm that the blood sample has filled the analytical region 743 and that an appropriate amount of sample is present in the chamber in order to carry out the analysis on the sample.

Confirmation of sample arrival in either the analytical region 743 or the control chamber 744 can be achieved visually, through the flexible polymer sheet 727 which can be transparent. However, it may be desirable in some embodiments to use a very small amount of blood sample in order to reduce the pain and discomfort to the patient during the lancing cycle. For sampling module 709 embodiments such as described here, having the sample input cavity 715′ and sample input port 741 adjacent the lancet exit port 754 allows the blood sample to be collected from the patient's skin 233 without the need for moving the sampling module 709 between the lancing cycle and the sample collection process. As such, the user does not need to be able to see the sample in order to have it transferred into the sampling module 709. Because of this, the position of the sample input cavity 715′ and the sample input port 741 adjacent the lancet exit port 754 allows a very small amount of sample to be reliably obtained and tested.

Samples on the order of tens of nanoliters, such as about 10 to about 50 nanoliters can be reliably collected and tested with a sampling module 709. This size of blood sample is too small to see and reliably verify visually. Therefore, it is necessary to have another method to confirm the presence of the blood sample in the analytical region 743. Sample sensors 733, such as the thermal sample sensors discussed above can positioned in the analytical region 743 or control chamber 744 to confirm the arrival of an appropriate amount of blood sample.

In addition, optical methods, such as spectroscopic analysis of the contents of the analytical region 743 or control chamber 744 could be used to confirm arrival of the blood sample. Other methods such as electrical detection could also be used and these same detection methods can also be disposed anywhere along the sample flow path through the sampling module 709 to confirm the position or progress of the sample (or samples) as it moves along the flow path as indicated by the arrows 763 in FIG. 81. The detection methods described above can also be useful for analytical methods requiring an accurate start time.

The requirement for having an accurate start time for an analytical method can in turn require rapid filling of an analytical region 743 because many analytical processes begin once the blood sample enters the analytical region 743. If the analytical region 743 takes too long to fill, the portion of the blood sample that first enters the analytical region 743 will have been tested for a longer time that the last portion of the sample to enter the analytical region 743 which can result in inaccurate results. Therefore, it may be desirable in these circumstances to have the blood sample flow first to a reservoir, filling the reservoir, and then have the sample rapidly flow all at once from the reservoir into the analytical region 743.

In one embodiment of the sampling module 709, the analytical region 743 can have a transverse cross section that is substantially greater than a transverse cross section of the control chamber 744. The change in transverse cross section can be accomplished by restrictions in the lateral transverse dimension of the control chamber 744 versus the analytical region 743, by step decreases in the depth of the control chamber 744, or any other suitable method. Such a step between the analytical region 743 and the control chamber 744 is shown in FIG. 81. In such an embodiment, the analytical region 743 can behave as a sample reservoir and the control chamber 744 as an analytical region that requires rapid or nearly instantaneous filling in order to have a consistent analysis start time. The analytical region 743 fills by a flow of sample from the sample flow channel 742 until the analytical region is full and the sample reaches the step decrease in chamber depth at the boundary with the control chamber 744. Once the sample reaches the step decrease in cross sectional area of the control chamber 744, the sample then rapidly fills the control chamber 744 by virtue of the enhanced capillary action of the reduced cross sectional area of the control chamber 744. The rapid filling of the control chamber allows any analytical process initiated by the presence of sample to be carried out in the control chamber 744 with a reliable start time for the analytical process for the entire sample of the control chamber 744.

Filling by capillary force is passive. It can also be useful for some types of analytical testing to discard the first portion of a sample that enters the sampling module 709, such as the case where there may be interstitial fluid contamination of the first portion of the sample. Such a contaminated portion of a sample can be discarded by having a blind channel or reservoir that draws the sample by capillary action into a side sample flow channel (not shown) until the side sample flow channel or reservoir in fluid communication therewith, is full. The remainder of the sample can then proceed to a sample flow channel adjacent the blind sample flow channel to the analytical region 743.

For some types of analytical testing, it may be advantageous to have multiple analytical regions 743 in a single sampling module 709. In this way multiple iterations of the same type of analysis could be performed in order to derive some statistical information, e.g. averages, variation or confirmation of a given test or multiple tests measuring various different parameters could be performed in different analytical regions 743 in the same sampling module 709 filled with a blood sample from a single lancing cycle.

FIG. 82 is an enlarged elevational view of a portion of an alternative embodiment of a sampling module 766 having a plurality of small volume analytical regions 767. The small volume analytical regions 767 can have dimensions of about 40 to about 60 microns in width in both directions and a depth that yields a volume for each analytical region 767 of about 1 nanoliter to about 100 nanoliters, specifically about 10 nanoliters to about 50 nanoliters. The array of small volume analytical regions 767 can be filled by capillary action through a sample flow channel 768 that branches at a first branch point 769, a second branch point 770 and a third branch point 771. Each small volume analytical region 767 can be used to perform a like analytical test or a variety of different tests can be performed in the various analytical regions 767.

For some analytical tests, the analytical regions 767 must have maintain a very accurate volume, as some of the analytical tests that can be performed on a blood sample are volume dependent. Some analytical testing methods detect glucose levels by measuring the rate or kinetic of glucose consumption. Blood volume required for these tests is on the order of about 1 to about 3 microliters. The kinetic analysis is not sensitive to variations in the volume of the blood sample as it depends on the concentration of glucose in the relatively large volume sample with the concentration of glucose remaining essentially constant throughout the analysis. Because this type of analysis dynamically consumes glucose during the testing, it is not suitable for use with small samples, e.g. samples on the order of tens of nanoliters where the consumption of glucose would alter the concentration of glucose.

Another analytical method uses coulomb metric measurement of glucose concentration. This method is accurate if the sample volume is less than about 1 microliter and the volume of the analytical region is precisely controlled. The accuracy and the speed of the method is dependent on the small and precisely known volume of the analytical region 767 because the rate of the analysis is volume dependent and large volumes slow the reaction time and negatively impact the accuracy of the measurement.

Another analytical method uses an optical fluorescence decay measurement that allows very small sample volumes to be analyzed. This method also requires that the volume of the analytical region 767 be precisely controlled. The small volume analytical regions 767 discussed above can meet the criteria of maintaining small accurately controlled volumes when the small volume analytical regions 767 are formed using precision manufacturing techniques. Accurately formed small volume analytical regions 767 can be formed in materials such as PMMA by methods such as molding and stamping. Machining and etching, either by chemical or laser processes can also be used. Vapor deposition and lithography can also be used to achieve the desired results.

The sampling modules 709 and 766 discussed above all are directed to embodiments that both house the lancet 183 and have the ability to collect and analyze a sample. In some embodiments of a sampling module, the lancet 183 may be housed and a sample collected in a sample reservoir without any analytical function. In such an embodiment, the analysis of the sample in the sample reservoir may be carried out by transferring the sample from the reservoir to a separate analyzer. In addition, some modules only serve to house a lancet 183 without any sample acquisition capability at all. The body portion 774 of such a lancet module 775 is shown in FIG. 83. The lancet module 775 has an outer structure similar to that of the sampling modules 709 and 766 discussed above, and can be made from the same or similar materials.

A flexible polymer sheet 727 (not shown) can be used to cover the face of the lancet module 775 and contain the lancet 183 in a lancet channel 776 that extends longitudinally in the lancet module body portion 774. The flexible sheet of polymer 727 can be from the same material and have the same dimensions as the flexible polymer sheet 727 discussed above. Note that the proximal portion of the flexible polymer sheet 727 need not be folded over on itself because there are no sensor contacts 725 to expose. The flexible polymer sheet 727 in such a lancet module 775 serves only to confine the lancet 183 in the lancet channel 776. The lancet module 775 can be configured in a lancet module belt, similar to the sampling module belt 708 discussed above with the flexible polymer sheet 727 acting as the belt. A drive head slot 777 is dispose proximal of the lancet channel 776.

With regard to the tissue penetration sampling device 180 of FIG. 74, use of the device 180 begins with the loading of a sampling module cartridge 705 into the controllable driver housing 706 so as to couple the cartridge 705 to the controllable driver housing 706 and engage the sampling module belt 708 with the ratchet drive 707 and drive coupler 713 of the controllable driver 179. The drive coupler 713 can have a T-slot configuration such as shown in FIGS. 84 and 85. The distal end of the elongate coupler shaft 184 is secured to the drive coupler 713 which has a main body portion 779, a first and second guide ramp 780 and 781 and a T-slot 714 disposed within the main body portion 779. The T-slot 714 is configured to accept the drive head 198 of the lancet 183. After the sampling module cartridge 705 is loaded into the controllable driver housing 706, the sampling module belt 708 is advanced laterally until the drive head 198 of a lancet 183 of one of the sampling modules 709 is fed into the drive coupler 713 as shown in FIGS. 86-88. FIGS. 86-88 also illustrate a lancet crimp device 783 that bends the shaft portion 201 of a used lancet 183 that is adjacent to the drive coupler 713. This prevents the used lancet 183 from moving out through the module body 731 and being reused.

As the sampling modules 709 of the sampling module belt 708 are used sequentially, they are advanced laterally one at a time into the receptacle canister 730 where they are stored until the entire sampling module belt 708 is consumed. The receptacle canister 730 can then be properly disposed of in accordance with proper techniques for disposal of blood-contaminated waste. The sampling module cartridge 705 allows the user to perform multiple testing operations conveniently without being unnecessarily exposed to blood waste products and need only dispose of one cartridge after many uses instead of having to dispose of a contaminated lancet 183 or module 709 after each use.

FIGS. 89 and 90 illustrate alternative embodiments of sampling module cartridges. FIG. 89 shows a sampling module cartridge 784 in a carousel configuration with adjacent sampling modules 785 connected rigidly and with sensor contacts 786 from the analytical regions of the various sampling modules 785 disposed near an inner radius 787 of the carousel. The sampling modules 785 of the sampling module cartridge 784 are advanced through a drive coupler 713 but in a circular as opposed to a linear fashion.

FIG. 90 illustrates a block of sampling modules 788 in a four by eight matrix. The drive head 198 of the lancets 183 of the sampling modules 789 shown in FIG. 90 are engaged and driven using a different method from that of the drive coupler 713 discussed above. The drive heads 198 of the lancets 183 have an adhesive coating 790 that mates with and secures to the drive coupler 791 of the lancet driver 179, which can be any of the drivers, including controllable drivers, discussed above.

The distal end 792 of the drive coupler 791 contacts and sticks to the adhesive 790 of proximal surface of the drive head 198 of the lancet 183 during the beginning of the lancet cycle. The driver coupler 791 pushes the lancet 183 into the target tissue 237 to a desired depth of penetration and stops. The drive coupler 791 then retracts the lancet 183 from the tissue 233 using the adhesive contact between the proximal surface of the drive head 198 of the lancet 183 and distal end surface of the drive coupler 791, which is shaped to mate with the proximal surface.

At the top of the retraction stroke, a pair of hooked members 793 which are secured to the sampling module 789 engage the proximal surface of the drive head 198 and prevent any further retrograde motion by the drive head 198 and lancet 183. As a result, the drive coupler 791 breaks the adhesive bond with the drive head 198 and can then be advanced by an indexing operation to the next sampling module 789 to be used.

FIG. 91 is a side view of an alternative embodiment of a drive coupler 796 having a lateral slot 797 configured to accept the L-shaped drive head 798 of the lancet 799 that is disposed within a lancet module 800 and shown with the L-shaped drive head 798 loaded in the lateral slot 797. FIG. 92 is an exploded view of the drive coupler 796, lancet 799 with L-shaped drive head 798 and lancet module 800 of FIG. 91. This type of drive coupler 796 and drive head 798 arrangements could be substituted for the configuration discussed above with regard to FIGS. 84-88. The L-shaped embodiment of the drive head 798 may be a less expensive option for producing a coupling arrangement that allows serial advancement of a sampling module belt or lancet module belt through the drive coupler 796 of a lancet driver, such as a controllable lancet driver 179.

For some embodiments of multiple lancing devices 180, it may be desirable to have a high capacity-lancing device that does not require a lancet module 775 in order to house the lancets 183 stored in a cartridge. Eliminating the lancet modules 775 from a multiple lancet device 180 allows for a higher capacity cartridge because the volume of the cartridge is not taken up with the bulk of multiple modules 775. FIGS. 93-96 illustrate a high capacity lancet cartridge coupled to a belt advance mechanism 804. The belt advance mechanism 804 is secured to a controlled driver 179 housing which contains a controlled electromagnetic driver.

The lancet cartridge 803 has a supply canister 805 and a receptacle canister 806. A lancet belt 807 is disposed within the supply canister 805. The lancet belt 807 contains multiple sterile lancets 183 with the shaft portion 201 of the lancets 183 disposed between the adhesive surface 808 of a first carrier tape 809 and the adhesive surface 810 of a second carrier tape 811 with the adhesive surfaces 808 and 810 pressed together around the shaft portion 201 of the lancets 183 to hold them securely in the lancet belt 807. The lancets 183 have drive heads 198 which are configured to be laterally engaged with a drive coupler 713, which is secured to an elongate coupler shaft 184 of the controllable driver 179.

The belt advance mechanism 804 includes a first cog roller 814 and a second cog roller 815 that have synchronized rotational motion and are advanced in unison in an incremental indexed motion. The indexed motion of the first and second cog rollers 814 and 815 advances the lancet belt 807 in units of distance equal to the distance between the lancets 183 disposed in the lancet belt 807. The belt advance mechanism 804 also includes a first take-up roller 816 and a second take-up roller 817 that are configured to take up slack in the first and second carrier tapes 809 and 811 respectively.

When a lancet belt cartridge 803 is loaded in the belt advance mechanism 804, a lead portion 818 of the first carrier tape 809 is disposed between a first cog roller 814 and a second cog roller 815 of the belt advance mechanism 804. The lead portion 818 of the first carrier tape 809 wraps around the outer surface 819 of the first turning roller 827, and again engages roller 814 with the cogs 820 of the first cog roller 814 engaged with mating holes 821 in the first carrier tape 809. The lead portion 818 of the first carrier tape 809 is then secured to a first take-up roller 816. A lead portion 822 of the second carrier tape 811 is also disposed between the first cog roller 814 and second cog roller 815 and is wrapped around an outer surface 823 of the second turning roller 828, and again engages roller 815 with the cogs 826′ of the second cog roller 815 engaged in with mating holes 825 of the second carrier tape 811. The lead portion 822 of the second carrier tape 811 is thereafter secured to a second take-up roller 817.

As the first and second cog rollers 814 and 815 are advanced, the turning rollers 827 and 828 peel the first and second carrier tapes 809 and 811 apart and expose a lancet 183. The added length or slack of the portions of the first and second carrier tapes 809 and 811 produced from the advancement of the first and second cog rollers 814 and 815 is taken up by the first and second take-up rollers 816 and 817. As a lancet 183 is peeled out of the first and second carrier tapes 809 and 811, the exposed lancet 183 is captured by a lancet guide wheel 826′ of the belt advance mechanism 804, shown in FIG. 96, which is synchronized with the first and second cog rollers 814 and 815. The lancet guide wheel 826′ then advances the lancet 183 laterally until the drive head 198 of the lancet 183 is loaded into the drive coupler 713 of the controllable driver 179. The controllable driver 179 can then be activated driving the lancet 183 into the target tissue 233 and retracted to complete the lancing cycle.

Once the lancing cycle is complete, the belt advance mechanism 804 can once again be activated which rotates the lancet guide wheel 826 and advances the used lancet 183 laterally and into the receptacle canister 806. At the same time, a new unused lancet 183 is loaded into the drive coupler 713 and readied for the next lancing cycle. This repeating sequential use of the multiple lancing device 180 continues until all lancets 183 in the lancet belt 807 have been used and disposed of in the receptacle canister 806. After the last lancet 183 has been consumed, the lancet belt cartridge 803 can then be removed and disposed of without exposing the user to any blood contaminated materials. The belt advance mechanism 804 can be activated by a variety of methods, including a motorized drive or a manually operated thumbwheel which is coupled to the first and second cog rollers 814 and 815 and lancet guide wheel 826.

Although discussion of the devices described herein has been directed primarily to substantially painless methods and devices for access to capillary blood of a patient, there are many other uses for the devices and methods. For example, the tissue penetration devices discussed herein could be used for substantially painless delivery of small amounts of drugs, or other bioactive agents such as gene therapy agents, vectors, radioactive sources etc. As such, it is contemplated that the tissue penetration devices and lancet devices discussed herein could be used to delivery agents to positions within a patient's body as well as taking materials from a patient's body such as blood, lymph fluid, spinal fluid and the like. Drugs delivered may include analgesics that would further reduce the pain perceived by the patient upon penetration of the patient's body tissue, as well as anticoagulants that may facilitate the successful acquisition of a blood sample upon penetration of the patient's tissue.

Referring to FIGS. 97-101, a device for injecting a drug or other useful material into the tissue of a patient is illustrated. The ability to localize an injection or vaccine to a specific site within a tissue, layers of tissue or organ within the body can be important. For example, epithelial tumors can be treated by injection of antigens, cytokine, or colony stimulating factor by hypodermic needle or high-pressure injection sufficient for the antigen to enter at least the epidermis or the dermis of a patient. Often, the efficacy of a drug or combination drug therapy depends on targeted delivery to localized areas thus affecting treatment outcome.

The ability to accurately deliver drugs or vaccinations to a specific depth within the skin or tissue layer may avoid wastage of expensive drug therapies therefore impacting cost effectiveness of a particular treatment. In addition, the ability to deliver a drug or other agent to a precise depth can be a clear advantage where the outcome of treatment depends on precise localized drug delivery (such as with the treatment of intralesional immunotherapy). Also, rapid insertion velocity of a hypodermic needle to a precise predetermined depth in a patient's skin is expected to reduce pain of insertion of the needle into the skin. Rapid insertion and penetration depth of a hypodermic needle, or any other suitable elongated delivery device suitable for penetrating tissue, can be accurately controlled by virtue of a position feedback loop of a controllable driver coupled to the hypodermic needle.

FIG. 97 illustrates 901 distal end 901 of a hypodermic needle 902 being driven into layers of skin tissue 903 by an electromagnetic controllable driver 904. The electromagnetic controllable driver 904 of FIG. 79 can have any suitable configuration, such as the configuration of electromagnetic controllable drivers discussed above. The layers of skin 903 being penetrated include the stratum corneum 905, the stratum lucidum 906, the stratum granulosum 907, the stratum spinosum 908, the stratum basale 909 and the dermis 911. The thickness of the stratum corneum 905 is typically about 300 micrometers in thickness. The portion of the epidermis excluding the stratum corneum 905 includes the stratum lucidum 906, stratum granulosum 907, and stratum basale can be about 200 micrometers in thickness. The dermis can be about 1000 micrometers in thickness. In FIG. 97, an outlet port 912 of the hypodermic needle 902 is shown disposed approximately in the stratum spinosum 908 layer of the skin 903 injecting an agent 913 into the stratum spinosum 908.

FIGS. 98-101 illustrate an agent injection module 915 including an injection member 916, that includes a collapsible canister 917 and the hypodermic needle 902, that may be driven or actuated by a controllable driver, such as any of the controllable drivers discussed above, to drive the hypodermic needle into the skin 903 for injection of drugs, vaccines or the like. The agent injection module 915 has a reservoir, which can be in the form of the collapsible canister 917 having a main chamber 918, such as shown in FIG. 98, for the drug or vaccine 913 to be injected. A cassette of a plurality of agent injection modules 915 (not shown) may provide a series of metered doses for long-term medication needs. Such a cassette may be configured similarly to the module cassettes discussed above. Agent injection modules 915 and needles 902 may be disposable, avoiding biohazard concerns from unspent drug or used hypodermic needles 902. The geometry of the cutting facets 921 of the hypodermic needle shown in FIG. 79, may be the same or similar to the geometry of the cutting facets of the lancet 183 discussed above.

Inherent in the position and velocity control system of some embodiments of a controllable driver is the ability to precisely determine the position or penetration depth of the hypodermic needle 902 relative to the controllable driver or layers of target tissue or skin 903 being penetrated. For embodiments of controllable drivers that use optical encoders for position sensors, such as an Agilent HEDS 9200 series, and using a four edge detection algorithm, it is possible to achieve an in plane spatial resolution of +/−17 μm in depth. If a total tissue penetration stroke is about 3 mm in length, such as might be used for intradermal or subcutaneous injection, a total of 88 position points can be resolved along the penetration stroke. A spatial resolution this fine allows precise placement of a distal tip 901 or outlet port 912 of the hypodermic needle 902 with respect to the layers of the skin 903 during delivery of the agent or drug 913. In some embodiments, a displacement accuracy of better than about 200 microns can be achieved, in others a displacement accuracy of better than about 40 microns can be achieved.

The agent injection module 915 includes the injection member 916 which includes the hypodermic needle 902 and drug reservoir or collapsible canister 917, which may couple to an elongated coupler shaft 184 via a drive coupler 185 as shown. The hypodermic needle 902 can be driven to a desired penetration depth, and then the drug or other agent 913, such as a vaccine, is passed into an inlet port 922 of the needle 902 through a central lumen 923 of the hypodermic needle 902 as shown by arrow 924, shown in FIG. 98, and out of the outlet port 912 at the distal end 901 of the hypodermic needle 902, shown in FIG. 97.

Drug or agent delivery can occur at the point of maximum penetration, or following retraction of the hypodermic needle 902. In some embodiments, it may be desirable to deliver the drug or agent 913 during insertion of the hypodermic needle 902. Drug or agent delivery can continue as the hypodermic needle 902 is being withdrawn (this is commonly the practice during anesthesia in dental work). Alternatively drug delivery can occur while the needle 902 is stationary during any part of the retraction phase.

The hollow hypodermic needle 902 is fitted with the collapsible canister 917 containing a drug or other agent 913 to be dispensed. The walls 928 of this collapsible canister 917 can be made of a soft resilient material such as plastic, rubber, or any other suitable material. A distal plate 925 is disposed at the distal end 926 of the collapsible canister is fixed securely to the shaft 927 of the hypodermic needle proximal of the distal tip 901 of the hypodermic needle 902. The distal plate 925 is sealed and secured to the shaft 927 of the hypodermic needle 902 to prevent leakage of the medication 913 from the collapsible canister 917.

A proximal plate 931 disposed at a proximal end 932 of the collapsible canister 917 is slidingly fitted to a proximal portion 933 of the shaft 927 of the hypodermic needle 902 with a sliding seal 934. The sliding seal 934 prevents leakage of the agent or medication 913 between the seal 934 and an outside surface of the shaft 927 of the hypodermic needle 902. The sliding seal allows the proximal plate 931 of the collapsible canister 917 to slide axially along the needle 902 relative to the distal plate 925 of the collapsible canister 917. A drug dose may be loaded into the main chamber 918 of the collapsible canister 917 during manufacture, and the entire assembly protected during shipping and storage by packaging and guide fins 935 surrounding the drive head slot 936 of the agent injection module 915.

An injection cycle may begin when the agent injection module 915 is loaded into a ratchet advance mechanism (not shown), and registered at a drive position with a drive head 937 of the hypodermic needle 902 engaged in the drive coupler 185. The position of the hypodermic needle 902 and collapsible canister 917 in this ready position is shown in FIG. 99.

Once the drive head 937 of the agent injection module 915 is loaded into the driver coupler 185, the controllable driver can then be used to launch the injection member 916 including the hypodermic needle 902 and collapsible canister 917 towards and into the patient's tissue 903 at a high velocity to a pre-determined depth into the patient's skin or other organ. The velocity of the injection member 916 at the point of contact with the patient's skin 903 or other tissue can be up to about 10 meters per second for some embodiments, specifically, about 2 to about 5 m/s. In some embodiments, the velocity of the injection member 916 may be about 2 to about 10 m/s at the point of contact with the patient's skin 903. As the collapsible canister 917 moves with the hypodermic needle 902, the proximal plate 931 of the collapsible canister 917 passes between two latch springs 938 of module body 939 that snap in behind the proximal plate 931 when the collapsible canister 917 reaches the end of the penetration stroke, as shown in FIG. 100.

The controllable driver then reverses, applies force in the opposite retrograde direction and begins to slowly (relative to the velocity of the penetration stroke) retract the hypodermic needle 902. The hypodermic needle 902 slides through the sliding seal 934 of the collapsible canister 917 while carrying the distal plate 925 of the collapsible canister with it in a proximal direction relative to the proximal plate 931 of the collapsible canister 917. This relative motion between the distal plate 925 of the collapsible canister 917 and the proximal plate 931 of the collapsible canister 917 causes the volume of the main chamber 918 to decrease. The decreasing volume of the main chamber 918 forces the drug or other agent 913 disposed within the main chamber 918 of the collapsible canister 917 out of the main chamber 918 into the inlet port 922 in the shaft 927 of the hypodermic needle 902. The inlet port 922 of the hypodermic needle 902 is disposed within an in fluid communication with the main chamber 918 of the collapsible canister 917 as shown in FIG. 80. The drug or agent then passes through the central lumen 923 of the hollow shaft 927 of the hypodermic needle 902 and is then dispensed from the output port 912 at the distal end 901 of the hypodermic needle 902 into the target tissue 903. The rate of perfusion of the drug or other agent 913 may be determined by an inside diameter or transverse dimension of the collapsible canister 917. The rate of perfusion may also be determined by the viscosity of the drug or agent 913 being delivered, the transverse dimension or diameter of the central lumen 923, the input port 922, or the output port 912 of the hypodermic needle 902, as well as other parameters.

During the proximal retrograde retraction stroke of the hypodermic needle 902, drug delivery continues until the main chamber 918 of the collapsible canister 917 is fully collapsed as shown in FIG. 101. At this point, the drive coupler 185 may continue to be retracted until the drive head 937 of the hypodermic needle 902 breaks free or the distal seal 941 between the distal plate 925 of the chamber and the hypodermic needle 902 fails, allowing the drive coupler 185 to return to a starting position. The distal tip 901 of the hypodermic needle 902 can be driven to a precise penetration depth within the tissue 903 of the patient using any of the methods or devices discussed above with regard to achieving a desired penetration depth using a controllable driver or any other suitable driver.

In another embodiment, the agent injection module 915 is loaded into a ratchet advance mechanism that includes an adjustable or movable distal stage or surface (not shown) that positions the agent injection 915 module relative to a skin contact point or surface 942. In this way, an agent delivery module 915 having a penetration stroke of predetermined fixed length, such as shown in FIGS. 99-101, reaches a pre-settable penetration depth. The movable stage remains stationary during a drug delivery cycle. In a variation of this embodiment, the moveable stage motion may be coordinated with a withdrawal of the hypodermic needle 902 to further control the depth of drug delivery.

In another embodiment, the latch springs 938 shown in the agent injection module 915 of FIGS. 99-101 may be molded with a number of ratchet teeth (not shown) that engage the proximal end 932 of the collapsible canister 917 as it passes by on the penetration stroke. If the predetermined depth of penetration is less than the full stroke, the intermediate teeth retain the proximal end 932 of the collapsible canister 917 during the withdrawal stroke in order to collapse the main chamber 918 of the collapsible canister 917 and dispense the drug or agent 913 as discussed above.

In yet another embodiment, drive fingers (not shown) are secured to an actuation mechanism (not shown) and replace the latch springs 938. The actuation mechanism is driven electronically in conjunction with the controllable driver by a processor or controller, such as the processor 60 discussed above, to control the rate and amount of drug delivered anywhere in the actuation cycle. This embodiment allows the delivery of medication during the actuation cycle as well as the retraction cycle.

Inherent in the position and velocity control system of a controllable driver is the ability to precisely define the position in space of the hypodermic needle 902, allowing finite placement of the hypodermic needle in the skin 903 for injection of drugs, vaccines or the like. Drug delivery can be discrete or continuous depending on the need.

FIGS. 102-106 illustrate an embodiment of a cartridge 945 that may be used for sampling that has both a lancet cartridge body 946 and an sampling cartridge body 947. The sampling cartridge body 947 includes a plurality of sampling module portions 948 that are disposed radially from a longitudinal axis 949 of the sampling cartridge body 947. The lancet cartridge body 946 includes a plurality of lancet module portions 950 that have a lancet channel 951 with a lancet 183 slidably disposed therein. The lancet module portions 950 are disposed radially from a longitudinal axis 952 of the lancet cartridge body 946.

The sampling cartridge body 947 and lancet cartridge body 946 are disposed adjacent each other in an operative configuration such that each lancet module portion 950 can be readily aligned in a functional arrangement with each sampling module portion 948. In the embodiment shown in FIGS. 102-106, the sampling cartridge body 947 is rotatable with respect to the lancet cartridge body 946 in order to align any lancet channel 951 and corresponding lancet 183 of the lancet cartridge body 946 with any of the lancet channels 953 of the sampling module portions 948 of the sampling cartridge body 947. The operative configuration of the relative location and rotatable coupling of the sampling cartridge body 947 and lancet cartridge body 946 allow ready alignment of lancet channels 951 and 953 in order to achieve a functional arrangement of a particular lancet module portion 950 and sampling module portion 948. For the embodiment shown, the relative motion used to align the particular lancet module portions 950 and sampling module portions 948 is confined to a single degree of freedom via relative rotation.

The ability of the cartridge 945 to align the various sampling module 948 portions and lancet module portions 950 allows the user to use a single lancet 183 of a particular lancet module portion 950 with multiple sampling module portions 948 of the sampling cartridge body 947. In addition, multiple different lancets 183 of lancet module portions 950 could be used to obtain a sample in a single sampling module portion 948 of the sampling cartridge body 947 if a fresh unused lancet 183 is required or desired for each lancing action and previous lancing cycles have been unsuccessful in obtaining a usable sample.

FIG. 102 shows an exploded view in perspective of the cartridge 945, which has a proximal end portion 954 and a distal end portion 955. The lancet cartridge body 946 is disposed at the proximal end portion 954 of the cartridge 945 and has a plurality of lancet module portions 950, such as the lancet module portion 950 shown in FIG. 103. Each lancet module portion 950 has a lancet channel 951 with a lancet 183 slidably disposed within the lancet channel 951. The lancet channels 951 are substantially parallel to the longitudinal axis 952 of the lancet cartridge body 946. The lancets 183 shown have a drive head 198, shaft portion 201 and sharpened tip 196. The drive head 198 of the lancets are configured to couple to a drive coupler (not shown), such as the drive coupler 185 discussed above.

The lancets 183 are free to slide in the respective lancet channels 951 and are nominally disposed with the sharpened tip 196 withdrawn into the lancet channel 951 to protect the tip 196 and allow relative rotational motion between the lancet cartridge body 946 and the sampling cartridge body 947 as shown by arrow 956 and arrow 957 in FIG. 102. The radial center of each lancet channel 951 is disposed a fixed, known radial distance from the longitudinal axis 952 of the lancet cartridge body 946 and a longitudinal axis 958 of the cartridge 945. By disposing each lancet channel 951 a fixed known radial distance from the longitudinal axes 952 and 958 of the lancet cartridge body 946 and cartridge 945, the lancet channels 951 can then be readily and repeatably aligned in a functional arrangement with lancet channels 953 of the sampling cartridge body 947. The lancet cartridge body 946 rotates about a removable pivot shaft 959 which has a longitudinal axis 960 that is coaxial with the longitudinal axes 952 and 950 of the lancet cartridge body 946 and cartridge 945.

The sampling cartridge body 947 is disposed at the distal end portion 955 of the cartridge and has a plurality of sampling module portions 948 disposed radially about the longitudinal axis 949 of the sampling cartridge body 947. The longitudinal axis 949 of the sampling cartridge body 947 is coaxial with the longitudinal axes 952, 958 and 960 of the lancet cartridge body 946, cartridge 945 and pivot shaft 959. The sampling cartridge body 947 may also rotate about the pivot shaft 959. In order to achieve precise relative motion between the lancet cartridge body 946 and the sampling cartridge body 947, one or both of the cartridge bodies 946 and 947 must be rotatable about the pivot shaft 959, however, it is not necessary for both to be rotatable about the pivot shaft 959, that is, one of the cartridge bodies 946 and 947 may be secured, permanently or removably, to the pivot shaft 959.

The sampling cartridge body 947 includes a base 961 and a cover sheet 962 that covers a proximal surface 963 of the base forming a fluid tight seal. Each sampling module portion 948 of the sampling cartridge body 947, such as the sampling module portion 948 shown in FIG. 104 (without the cover sheet for clarity of illustration), has a sample reservoir 964 and a lancet channel 953. The sample reservoir 964 has a vent 965 at an outward radial end that allows the sample reservoir 964 to readily fill with a fluid sample. The sample reservoir 964 is in fluid communication with the respective lancet channel 953 which extends substantially parallel to the longitudinal axis 949 of the sampling cartridge body 947. The lancet channel 953 is disposed at the inward radial end of the sample reservoir 964.

The lancet channels 953 of the sample cartridge body 947 allow passage of the lancet 183 and also function as a sample flow channel 966 extending from an inlet port 967 of the lancet channel 953, shown in FIG. 106, to the sample reservoir 964. Note that a proximal surface 968 of the cover sheet 962 is spatially separated from a distal surface 969 of the lancet cartridge body 946 at the lancet channel site in order to prevent any fluid sample from being drawn by capillary action into the lancet channels 951 of the lancet cartridge body 946. The spatial separation of the proximal surface 968 of the cover sheet 962 from the distal surface 969 of the lancet cartridge body 946 is achieved with a boss 970 between the two surfaces 968 and 969 that is formed into the distal surface 969 of the lancet cartridge body as shown in FIG. 105.

The sample reservoirs 964 of the sampling cartridge body 947 may include any of the sample detection sensors, testing sensors, sensor contacts or the like discussed above with regard to other sampling module embodiments. The cover sheet 962 may be formed of PMMA and have conductors, sensors or sensor contacts formed on a surface thereof. It may also be desirable to have the cover sheet 962 made from a transparent or translucent material in order to use optical sensing or testing methods for samples obtained in the sample reservoirs. In the embodiment shown, the outer radial location of at least a portion of the sample reservoirs 964 of the sampling cartridge body 967 is beyond an outer radial dimension of the lancet cartridge body 946. Thus, an optical detector or sensor 971, such as shown in FIG. 105, can detect or test a sample disposed within a sample reservoir 964 by transmitting an optical signal through the cover sheet 962 and receiving an optical signal from the sample.

The cartridge bodies 946 and 947 may have features, dimensions or materials that are the same as, or similar to, features, dimensions or materials of the sampling cartridges and lancet cartridges, or any components thereof, discussed above. The module portions 948 and 950 may also have features, dimensions or materials that are the same as, or similar to, features, dimensions or materials of the lancet or sampling modules, or any components thereof, discussed above. In addition, the cartridge 945 can be coupled to, or positioned adjacent any of the drivers discussed above, or any other suitable driver, in an operative configuration whereby the lancets of the lancet cartridge body can be selectively driven in a lancing cycle. Although the embodiment shown in FIGS. 102-106 allows for alignment of various sampling module portions 948 and lancet module portions 950 with relative rotational movement, other embodiments that function similarly are also contemplated. For example, lancet module portions, sampling module portions or both, could be arranged in a two dimensional array with relative x-y motion being used to align the module portions in a functional arrangement. Such relative x-y motion could be accomplished with position sensors and servo motors in such an alternative embodiment order to achieve the alignment.

Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the appended claims.

Claims

1. A body fluid collection system, comprising: a housing with a body fluid sample chamber and a sample transport channel;a plurality of penetrating members each with a sharpened tip;a cartridge positionable in the housing;a penetrating member body positionable in the cartridge;an advancement device coupled to the penetrating member body and configured to move the penetrating member body in the cartridge to position an un-used penetrating member in a launch position;a penetrating member driver configured to be coupled to the penetrating member, drive the penetrating member along a movement path to penetrate a skin surface in a first direction during a penetration phase, and withdraw the penetrating member in an opposing second direction during a retraction phase; andan audible signal generator configured to provide an audible signal of results.
2. The system of claim 1, wherein the penetrating member driver is controllable.
3. The system of claim 1, further comprising: a processor that determines when a penetrating member has contacted a skin surface.
4. The system of claim 1, wherein a position of the skin is detected prior to launch of the penetrating member.
5. The system of claim 1, wherein the penetrating member driver includes an actuator spring.
6. The system of claim 5, further comprising: a penetrating member driver sleeve and a penetrating member plunger sleeve.
7. The system of claim 6, wherein the penetrating member driver sleeve, penetrating member plunger sleeve, and actuator spring move outward together until a plunger head contacts a bottom of a counterbore at an end of a preload screw.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 11/244,822 filed Oct. 5, 2005, U.S. Ser. No. 11/318,276, Dec. 23, 2005; and U.S. Ser. No. 11/317,913 filed Dec. 23, 2005, all of which applications are divisionals of U.S. Ser. No. 10/127,395, now U.S. Pat. No. 7,025,744, and all of which applications are fully incorporated herein by reference.

US Referenced Citations (2164)

Number	Name	Date	Kind
2061	Osdel	Apr 1841	A
55620	Capewell	Jun 1866	A
1135465	Pollock	Apr 1915	A
1733847	Wilmot	Oct 1929	A
2258857	McCann	Oct 1941	A
2628319	Vang	Feb 1953	A
2714890	Alfred	Aug 1955	A
2763935	Whaley	Sep 1956	A
2801633	Ehrlich	Aug 1957	A
2880876	Dujardin	Apr 1959	A
3046987	Ehrlich	Jul 1962	A
3030959	Grunert	Sep 1962	A
3063451	Kowalk	Nov 1962	A
3086288	Balamuth	Apr 1963	A
3090384	Baldwin et al.	May 1963	A
3208452	Stern	Sep 1965	A
3358689	Higgins	Dec 1967	A
3412729	Smith, Jr.	Nov 1968	A
3424154	Kinsley	Jan 1969	A
3448307	Rudolph	Jun 1969	A
3494358	Grossenbacher	Feb 1970	A
3607097	Auphan et al.	Sep 1971	A
3620209	Kravitz	Nov 1971	A
3626929	Sanz	Dec 1971	A
3628026	Cronin	Dec 1971	A
3665672	Speelman	May 1972	A
3673475	Britton, Jr.	Jun 1972	A
3712293	Mielke, Jr.	Jan 1973	A
3734812	Yazawa	May 1973	A
3742954	Strickland	Jul 1973	A
3780960	Tokuno	Dec 1973	A
3832776	Sawyer	Sep 1974	A
3836148	Manning	Sep 1974	A
3851543	Krom	Dec 1974	A
3853010	Christen	Dec 1974	A
3924818	Pfeifle	Dec 1975	A
3938526	Anderson	Feb 1976	A
3953172	Shapiro	Apr 1976	A
3971365	Smith	Jul 1976	A
4057394	Genshaw	Nov 1977	A
4077406	Sandhage	Mar 1978	A
4109655	Chacornac	Aug 1978	A
4139011	Benoit	Feb 1979	A
4154228	Feldstein	May 1979	A
4168130	Barth	Sep 1979	A
4184486	Papa	Jan 1980	A
4190420	Covington	Feb 1980	A
4191193	Seo	Mar 1980	A
4193690	Levenson	Mar 1980	A
4203446	Hofert	May 1980	A
4207870	Eldridge	Jun 1980	A
4223674	Fluent	Sep 1980	A
4224125	Nakamura	Sep 1980	A
4224949	Scott	Sep 1980	A
4230118	Holman et al.	Oct 1980	A
4240439	Abe	Dec 1980	A
4254083	Columbus	Mar 1981	A
4258001	Pierce	Mar 1981	A
4259653	McGonigal	Mar 1981	A
4299230	Kubota	Nov 1981	A
4301412	Hill	Nov 1981	A
4321397	Nix	Mar 1982	A
4340669	Bauer	Jul 1982	A
4350762	De Luca	Sep 1982	A
4353984	Yamada	Oct 1982	A
4356826	Kubota	Nov 1982	A
4360016	Sarrine	Nov 1982	A
4388922	Telang	Jun 1983	A
4391905	Bauer	Jul 1983	A
4391906	Bauer	Jul 1983	A
4392933	Nakamura	Jul 1983	A
4394512	Batz	Jul 1983	A
4397556	Muller	Aug 1983	A
4407008	Schmidt	Sep 1983	A
4411266	Cosman	Oct 1983	A
4414975	Ryder	Nov 1983	A
4418037	Katsuyama	Nov 1983	A
4425039	Grant	Jan 1984	A
4426451	Columbus	Jan 1984	A
4426884	Polchaninoff	Jan 1984	A
4440301	Intengan	Apr 1984	A
4442836	Meinecke	Apr 1984	A
4442972	Sahay	Apr 1984	A
4449529	Burns	May 1984	A
4462405	Ehrlich	Jul 1984	A
4469110	Slama	Sep 1984	A
4490139	Huizenga et al.	Dec 1984	A
4517978	Levin	May 1985	A
4518384	Tarello	May 1985	A
4523994	Shono	Jun 1985	A
4535769	Burns	Aug 1985	A
4535773	Yoon	Aug 1985	A
4537197	Hulka	Aug 1985	A
4539988	Shirley	Sep 1985	A
4545382	Higgins	Oct 1985	A
4553541	Burns	Nov 1985	A
4561445	Berke	Dec 1985	A
4577630	Nitzsche	Mar 1986	A
4580564	Anderson	Apr 1986	A
4580565	Cornell	Apr 1986	A
4586819	Tochigi	May 1986	A
4586926	Osborne	May 1986	A
4595479	Kimura	Jun 1986	A
4600014	Beraha	Jul 1986	A
4603209	Tsien	Jul 1986	A
4608997	Conway	Sep 1986	A
4615340	Cronenberg	Oct 1986	A
4616649	Burns	Oct 1986	A
4619754	Niki	Oct 1986	A
4622974	Coleman	Nov 1986	A
4624253	Burns	Nov 1986	A
4627445	Garcia	Dec 1986	A
4637403	Garcia	Jan 1987	A
4643189	Mintz	Feb 1987	A
4648408	Hutcheson	Mar 1987	A
4648714	Benner	Mar 1987	A
4653511	Goch	Mar 1987	A
4653513	Dombrowski	Mar 1987	A
4655225	Dahne	Apr 1987	A
4661768	Carusillo	Apr 1987	A
4666438	Raulerson	May 1987	A
4676244	Enstrom	Jun 1987	A
4677979	Burns	Jul 1987	A
4678277	Delhaye	Jul 1987	A
4682892	Chawla	Jul 1987	A
4702594	Grant	Oct 1987	A
4711245	Higgins	Dec 1987	A
4712460	Allen	Dec 1987	A
4712548	Enstrom	Dec 1987	A
4714462	DiDomenico	Dec 1987	A
4715374	Maggio	Dec 1987	A
4731330	Hill et al.	Mar 1988	A
4731726	Allen, III	Mar 1988	A
4734360	Phillips	Mar 1988	A
4735203	Ryder	Apr 1988	A
4737458	Batz	Apr 1988	A
4750489	Berkman	Jun 1988	A
4753776	Hillman	Jun 1988	A
4756884	Hillman	Jul 1988	A
4757022	Shults et al.	Jul 1988	A
4774192	Teriniello	Sep 1988	A
4784486	Van Wagenen	Nov 1988	A
4787398	Garcia	Nov 1988	A
4790979	Teriniello	Dec 1988	A
4794926	Munsch et al.	Jan 1989	A
4797283	Allen	Jan 1989	A
4814142	Gleisner	Mar 1989	A
4814661	Ratzlaff	Mar 1989	A
4817603	Turner	Apr 1989	A
4818493	Coville	Apr 1989	A
4820010	Sciefres	Apr 1989	A
4820399	Senda	Apr 1989	A
4823806	Bajada	Apr 1989	A
4824639	Hildenbrand	Apr 1989	A
RE32922	Levin	May 1989	E
4825711	Jensen	May 1989	A
4827763	Bourland	May 1989	A
4829011	Gibbons	May 1989	A
4830959	McNeill	May 1989	A
4836904	Armstron	Jun 1989	A
4840893	Hill et al.	Jun 1989	A
4844095	Chiodo	Jul 1989	A
4845392	Mumbower	Jul 1989	A
4850973	Jordan	Jul 1989	A
4857274	Simon	Aug 1989	A
4868129	Gibbons	Sep 1989	A
4869249	Crossman	Sep 1989	A
4869265	McEwen	Sep 1989	A
4873993	Meserol	Oct 1989	A
4877026	de Laforcade	Oct 1989	A
4882013	Turner	Nov 1989	A
4883055	Merrick	Nov 1989	A
4883068	Dechow	Nov 1989	A
4889529	Haindl	Dec 1989	A
4892097	Ranalletta	Jan 1990	A
4895147	Bodicky	Jan 1990	A
4895156	Schulze	Jan 1990	A
4897173	Nankai	Jan 1990	A
4900424	Birch	Feb 1990	A
4900666	Phillips	Feb 1990	A
4911794	Parce	Mar 1990	A
4920977	Haynes	May 1990	A
4924879	O'brien	May 1990	A
4935346	Phillips	Jun 1990	A
4938218	Goodman	Jul 1990	A
4940468	Petillo	Jul 1990	A
4944304	Nishina	Jul 1990	A
4945045	Forrest	Jul 1990	A
4946795	Gibbons	Aug 1990	A
4948727	Cass	Aug 1990	A
4948961	Hillman	Aug 1990	A
4952373	Sugarman	Aug 1990	A
4952515	Gleisner	Aug 1990	A
4953552	DeMarzo	Sep 1990	A
4953976	Adler-Golden	Sep 1990	A
4963498	Hillman	Oct 1990	A
4966581	Landau	Oct 1990	A
4966646	Zdeblick	Oct 1990	A
4966671	Nylander	Oct 1990	A
4975581	Robinson	Dec 1990	A
4976724	Nieto	Dec 1990	A
4977910	Miyahara	Dec 1990	A
4983178	Schnell	Jan 1991	A
4984085	Landowski	Jan 1991	A
4990154	Brown	Feb 1991	A
4995402	Smith	Feb 1991	A
5001054	Wagner	Mar 1991	A
5001873	Rufin	Mar 1991	A
5004923	Hillman	Apr 1991	A
5010772	Bourland	Apr 1991	A
5010774	Kikuo	Apr 1991	A
5014718	Mitchen	May 1991	A
5026388	Ingalz	Jun 1991	A
D318331	Phillips	Jul 1991	S
5028142	Ostoich et al.	Jul 1991	A
5029583	Meserol	Jul 1991	A
5035704	Lambert	Jul 1991	A
5039617	McDonald	Aug 1991	A
5043143	Shaw	Aug 1991	A
5046496	Betts	Sep 1991	A
5047044	Smith	Sep 1991	A
5049373	Ballou	Sep 1991	A
5049487	Phillips	Sep 1991	A
5054487	Clarke	Oct 1991	A
5054499	Swierczek	Oct 1991	A
5057082	Burchette, Jr.	Oct 1991	A
5057277	Mauze	Oct 1991	A
5059394	Phillips	Oct 1991	A
5059789	Salcudean	Oct 1991	A
5060174	Gross	Oct 1991	A
5062898	McDermott	Nov 1991	A
5064411	Gordon, III	Nov 1991	A
5070874	Barnes	Dec 1991	A
5070886	Mitchen	Dec 1991	A
5073500	Saito et al.	Dec 1991	A
5074872	Brown	Dec 1991	A
5077017	Gorin	Dec 1991	A
5077199	Basagni	Dec 1991	A
5080865	Leiner	Jan 1992	A
5086229	Rosenthal	Feb 1992	A
5089112	Skotheim	Feb 1992	A
5092842	Bechtold	Mar 1992	A
5094943	Siedel	Mar 1992	A
5096669	Lauks	Mar 1992	A
5097810	Fishman	Mar 1992	A
5100427	Crossman	Mar 1992	A
5100428	Mumford	Mar 1992	A
5104380	Holman	Apr 1992	A
5104382	Brinkerhoff et al.	Apr 1992	A
5104619	de Castro et al.	Apr 1992	A
5104813	Besemer	Apr 1992	A
5107764	Gasparrini	Apr 1992	A
5108564	Szuminsky	Apr 1992	A
5108889	Smith	Apr 1992	A
5116759	Klainer	May 1992	A
5120420	Nankai	Jun 1992	A
5122244	Hoenes	Jun 1992	A
5126034	Carter	Jun 1992	A
5128015	Szuminsky	Jul 1992	A
5128171	Gleisner	Jul 1992	A
5132801	Yamano	Jul 1992	A
5133730	Biro	Jul 1992	A
5135719	Hillman	Aug 1992	A
5139685	de Castro et al.	Aug 1992	A
5140161	Hillman	Aug 1992	A
5141868	Shanks	Aug 1992	A
5144139	Hillman	Sep 1992	A
5145565	Kater	Sep 1992	A
5146091	Knudson	Sep 1992	A
5152296	Simons	Oct 1992	A
5152775	Ruppert	Oct 1992	A
5153671	Miles	Oct 1992	A
5156611	Haynes	Oct 1992	A
5162525	Masilamani	Nov 1992	A
5163442	Ono	Nov 1992	A
5164598	Hillman	Nov 1992	A
5167619	Wuchinich	Dec 1992	A
5170364	Gross	Dec 1992	A
5174726	Findlay	Dec 1992	A
D332490	Brown	Jan 1993	S
5179005	Phillips	Jan 1993	A
5185256	Nankai	Feb 1993	A
5187100	Matzinger	Feb 1993	A
5188118	Terwilliger	Feb 1993	A
5189751	Giuliani	Mar 1993	A
5192415	Yoshioka	Mar 1993	A
5194391	Mauze	Mar 1993	A
5196025	Ranalletta	Mar 1993	A
5201324	Swierczek	Apr 1993	A
5205920	Oyama	Apr 1993	A
5208163	Charlton et al.	May 1993	A
5209028	McDermott	May 1993	A
5211652	Derbyshire	May 1993	A
5212879	Biro	May 1993	A
5215587	McConnellogue	Jun 1993	A
5217476	Wishinsky	Jun 1993	A
5217480	Haber	Jun 1993	A
5218966	Yamasawa	Jun 1993	A
5222504	Solomon	Jun 1993	A
5229282	Yoshioka	Jul 1993	A
5230866	Shartle	Jul 1993	A
5231993	Haber et al.	Aug 1993	A
5241969	Carson	Sep 1993	A
5247932	Chung	Sep 1993	A
5249583	Mallaby	Oct 1993	A
5250066	Lambert	Oct 1993	A
5253656	Rincoe	Oct 1993	A
5256998	Becker	Oct 1993	A
5264103	Yoshioka	Nov 1993	A
5264105	Gregg	Nov 1993	A
5264106	McAleer	Nov 1993	A
5266179	Nankai	Nov 1993	A
5266359	Spielvogel	Nov 1993	A
D342573	Cerola	Dec 1993	S
5267974	Lambert	Dec 1993	A
5272087	El Murr	Dec 1993	A
5279294	Anderson	Jan 1994	A
5279791	Aldrich	Jan 1994	A
5282822	Macors	Feb 1994	A
5286362	Hoenes	Feb 1994	A
5286364	Yacynych	Feb 1994	A
5288636	Pollman	Feb 1994	A
5294261	McDermott	Mar 1994	A
5296378	Sakata	Mar 1994	A
5300779	Hillman	Apr 1994	A
5304192	Crouse	Apr 1994	A
5304193	Zhadanov	Apr 1994	A
5304347	Mann	Apr 1994	A
5304468	Phillips	Apr 1994	A
5306623	Kiser	Apr 1994	A
5307263	Brown	Apr 1994	A
5312590	Gunasingham	May 1994	A
5314441	Cusack	May 1994	A
5314442	Morita	May 1994	A
5315793	Peterson	May 1994	A
5316012	Siegal	May 1994	A
5318583	Rabenau	Jun 1994	A
5318584	Lange	Jun 1994	A
5320607	Ishibashi	Jun 1994	A
5320808	Holen	Jun 1994	A
5324302	Crouse	Jun 1994	A
5324303	Strong	Jun 1994	A
5330634	Wong	Jul 1994	A
5332479	Uenoyama	Jul 1994	A
5341206	Pittaro	Aug 1994	A
5342382	Brinkerhoff	Aug 1994	A
5344703	Kovar	Sep 1994	A
5350392	Purcell	Sep 1994	A
5354287	Wacks	Oct 1994	A
5354447	Uenoyama	Oct 1994	A
5356420	Czernecki	Oct 1994	A
5360410	Wacks	Nov 1994	A
5365699	Armstrong	Nov 1994	A
5366469	Steg	Nov 1994	A
5366470	Ramel	Nov 1994	A
5366609	White	Nov 1994	A
5368047	Suzuki	Nov 1994	A
5370509	Golding	Dec 1994	A
5372135	Mendelson	Dec 1994	A
5375397	Ferrand	Dec 1994	A
5378628	Graetzel	Jan 1995	A
5382346	Uenoyama	Jan 1995	A
5383885	Bland	Jan 1995	A
5389534	von Gentzkow et al.	Feb 1995	A
5390450	Goenka	Feb 1995	A
5393903	Graetzel	Feb 1995	A
5395339	Talonn	Mar 1995	A
5395387	Burns	Mar 1995	A
5397334	Schenk	Mar 1995	A
5401376	Foos	Mar 1995	A
5402798	Swierczek	Apr 1995	A
5405283	Goenka	Apr 1995	A
5405510	Betts	Apr 1995	A
5407545	Hirose	Apr 1995	A
5407554	Saurer	Apr 1995	A
5407818	von Gentzkow et al.	Apr 1995	A
5409583	Yoshioka	Apr 1995	A
5409664	Allen	Apr 1995	A
5410059	Fraser	Apr 1995	A
5410474	Fox	Apr 1995	A
5415169	Siczek	May 1995	A
5418142	Kiser	May 1995	A
5423847	Strong	Jun 1995	A
5424545	Block	Jun 1995	A
5426032	Phillips	Jun 1995	A
5436161	Bergstrom	Jul 1995	A
5437999	Diebold	Aug 1995	A
5443701	Willner	Aug 1995	A
5445920	Saito	Aug 1995	A
D362719	Kaplan	Sep 1995	S
5453360	Yu	Sep 1995	A
5454828	Schraga	Oct 1995	A
5456875	Lambert	Oct 1995	A
5459325	Hueton et al.	Oct 1995	A
5460182	Goodman	Oct 1995	A
5462533	Daugherty	Oct 1995	A
5464418	Schraga	Nov 1995	A
5465722	Fort	Nov 1995	A
5471102	Becker	Nov 1995	A
5472427	Rammler	Dec 1995	A
5474084	Cunniff	Dec 1995	A
5476474	Davis	Dec 1995	A
5480387	Gabriel	Jan 1996	A
5487748	Marshall	Jan 1996	A
D367109	Ryner	Feb 1996	S
5490505	Diab	Feb 1996	A
5496274	Graves	Mar 1996	A
5496453	Uenoyama	Mar 1996	A
5498542	Corey	Mar 1996	A
5501836	Myerson	Mar 1996	A
5501893	Laermer et al.	Mar 1996	A
5507629	Jarvik	Apr 1996	A
5509410	Hill	Apr 1996	A
5510266	Bonner et al.	Apr 1996	A
5512159	Yoshioka	Apr 1996	A
5514152	Smith	May 1996	A
5515170	Matzinger	May 1996	A
5518006	Mawhirt	May 1996	A
D371198	Savage	Jun 1996	S
5524636	Sarvazyan	Jun 1996	A
5525511	D'Costa	Jun 1996	A
5525518	Lundsgaard	Jun 1996	A
5526120	Jina	Jun 1996	A
5527333	Nikkels	Jun 1996	A
5527334	Kanner	Jun 1996	A
5529074	Greenfield	Jun 1996	A
5540676	Freiberg	Jul 1996	A
5540709	Ramel	Jul 1996	A
5543326	Heller	Aug 1996	A
5545174	Schenk	Aug 1996	A
5545291	Smith	Aug 1996	A
5547702	Gleisner	Aug 1996	A
D373419	Muramatsu	Sep 1996	S
5554153	Costello	Sep 1996	A
5554166	Lange	Sep 1996	A
5558834	Chu	Sep 1996	A
5562384	Alvite	Oct 1996	A
5562696	Nobles	Oct 1996	A
5563031	Yu	Oct 1996	A
5563042	Phillips	Oct 1996	A
5569286	Peckham	Oct 1996	A
5569287	Tezuka	Oct 1996	A
5571132	Mawhirt	Nov 1996	A
5575284	Athan	Nov 1996	A
5575403	Charlton	Nov 1996	A
5575895	Ikeda	Nov 1996	A
5582697	Ikeda	Dec 1996	A
5584846	Mawhirt	Dec 1996	A
5591139	Lin	Jan 1997	A
5593852	Heller	Jan 1997	A
5599501	Carey	Feb 1997	A
5605837	Karimi	Feb 1997	A
D378612	Clark	Mar 1997	S
5608006	Myerson	Mar 1997	A
5609749	Yamauchi	Mar 1997	A
5611809	Marshall	Mar 1997	A
5611810	Arnold	Mar 1997	A
5613978	Harding	Mar 1997	A
5616135	Thorne	Apr 1997	A
5617851	Lipkovker	Apr 1997	A
5618297	Hart	Apr 1997	A
5620579	Genshaw	Apr 1997	A
5620863	Tomasco	Apr 1997	A
5624458	Lipscher	Apr 1997	A
5624459	Kortenbach et al.	Apr 1997	A
5624537	Turner	Apr 1997	A
D379516	Rutter	May 1997	S
5628764	Schraga	May 1997	A
5628765	Morita	May 1997	A
5628890	Carter	May 1997	A
5628961	Davis	May 1997	A
5630828	Mawhirt	May 1997	A
5630986	Charlton	May 1997	A
5632410	Moulton	May 1997	A
D381591	Rice	Jul 1997	S
5643306	Schraga	Jul 1997	A
5643308	Markman	Jul 1997	A
5645555	Davis	Jul 1997	A
5647851	Pokras	Jul 1997	A
5650062	Ikeda	Jul 1997	A
5653863	Genshaw	Aug 1997	A
5657760	Ying et al.	Aug 1997	A
5658444	Black	Aug 1997	A
5660791	Brenneman	Aug 1997	A
D383550	Larson	Sep 1997	S
5662127	De Vaughn	Sep 1997	A
5662672	Pambianchi	Sep 1997	A
5666966	Horie	Sep 1997	A
5678306	Bozeman	Oct 1997	A
5680872	Sesekura	Oct 1997	A
5682233	Brinda	Oct 1997	A
5682884	Hill	Nov 1997	A
5683562	Schaffar	Nov 1997	A
5691898	Rosenberg	Nov 1997	A
5692514	Bowman	Dec 1997	A
5695947	Guo	Dec 1997	A
5700695	Yassinzadeh et al.	Dec 1997	A
5705045	Park	Jan 1998	A
5707384	Kim	Jan 1998	A
5708247	McAleer	Jan 1998	A
5709668	Wacks	Jan 1998	A
5710011	Forrow	Jan 1998	A
5714123	Sohrab	Feb 1998	A
5714390	Hallowitz	Feb 1998	A
5719034	Kiser	Feb 1998	A
5720862	Hamamoto	Feb 1998	A
5720924	Eikmeier	Feb 1998	A
D392391	Douglas	Mar 1998	S
D392740	Yung	Mar 1998	S
5723284	Ye	Mar 1998	A
5727548	Hill	Mar 1998	A
5729905	Mathiasmeier	Mar 1998	A
5730753	Morita	Mar 1998	A
5733085	Shida	Mar 1998	A
5733300	Pambianchi	Mar 1998	A
D393716	Brenneman	Apr 1998	S
D393717	Brenneman	Apr 1998	S
5735868	Lee	Apr 1998	A
5736103	Pugh	Apr 1998	A
5738244	Charlton	Apr 1998	A
5741634	Nozoe	Apr 1998	A
RE35803	Lange	May 1998	E
5746217	Erickson	May 1998	A
5746761	Turchin	May 1998	A
5753429	Pugh	May 1998	A
5753452	Smith	May 1998	A
5755228	Wilson	May 1998	A
5755733	Morita	May 1998	A
5758643	Wong	Jun 1998	A
5759364	Charlton	Jun 1998	A
5762770	Pritchard	Jun 1998	A
5770086	Indriksons	Jun 1998	A
5770369	Meade	Jun 1998	A
5772586	Heinonen	Jun 1998	A
5772677	Mawhirt	Jun 1998	A
5773270	D'Orazio	Jun 1998	A
5776157	Thorne	Jul 1998	A
5776719	Douglas	Jul 1998	A
5779365	Takaki	Jul 1998	A
5780304	Matzinger	Jul 1998	A
5782770	Mooradian	Jul 1998	A
5782852	Foggia	Jul 1998	A
5788651	Weilandt	Aug 1998	A
5788652	Rahn	Aug 1998	A
5789255	Yu	Aug 1998	A
5795725	Buechler	Aug 1998	A
5795774	Matsumoto	Aug 1998	A
5797940	Mawhirt	Aug 1998	A
5797942	Schraga	Aug 1998	A
5798030	Raguse	Aug 1998	A
5798031	Charlton	Aug 1998	A
5800781	Gavin	Sep 1998	A
5801057	Smart	Sep 1998	A
5810199	Charlton	Sep 1998	A
D399566	Sohrab	Oct 1998	S
5820551	Hill	Oct 1998	A
5823973	Racchini	Oct 1998	A
5824491	Priest	Oct 1998	A
5827181	Dias	Oct 1998	A
5829589	Nguyen	Nov 1998	A
5830219	Bird	Nov 1998	A
5840020	Heinonen	Nov 1998	A
5840171	Birch	Nov 1998	A
5843691	Douglas	Dec 1998	A
5843692	Phillips	Dec 1998	A
5846216	Gonzales	Dec 1998	A
5846486	Pugh	Dec 1998	A
5846490	Yokota	Dec 1998	A
5849174	Sanghera	Dec 1998	A
5854074	Charlton	Dec 1998	A
D403975	Douglas	Jan 1999	S
5855377	Murphy	Jan 1999	A
5855801	Lin	Jan 1999	A
5856174	Lipshutz	Jan 1999	A
5856195	Charlton	Jan 1999	A
5857967	Frid	Jan 1999	A
5857983	Douglas	Jan 1999	A
5858804	Zanzucchi	Jan 1999	A
5860922	Gordon et al.	Jan 1999	A
5863800	Eikmeier	Jan 1999	A
5866353	Berneth	Feb 1999	A
5868772	LeVaughn	Feb 1999	A
5869972	Birch	Feb 1999	A
5871494	Simons	Feb 1999	A
5872713	Douglas	Feb 1999	A
5873887	King	Feb 1999	A
5876351	Rohde	Mar 1999	A
5876957	Douglas	Mar 1999	A
5879311	Duchon	Mar 1999	A
5879373	Roeper	Mar 1999	A
5880829	Kauhaniemi	Mar 1999	A
5882494	van Antwerp	Mar 1999	A
5886056	Hershkowitz	Mar 1999	A
5890128	Diaz	Mar 1999	A
5891053	Sesekura	Apr 1999	A
5892569	Van de Velde	Apr 1999	A
5893848	Negus et al.	Apr 1999	A
5897569	Kellogg	Apr 1999	A
5899915	Saadat	May 1999	A
5900130	Benvegnu	May 1999	A
5902731	Ouyang	May 1999	A
5906921	Ikeda	May 1999	A
D411619	Duchon	Jun 1999	S
5908416	Costello	Jun 1999	A
5911937	Hekal	Jun 1999	A
5912134	Shartle	Jun 1999	A
5916156	Hildenbrand	Jun 1999	A
5916229	Evans	Jun 1999	A
5916230	Brenneman	Jun 1999	A
5919711	Boyd	Jul 1999	A
5921963	Erez	Jul 1999	A
5922188	Ikeda	Jul 1999	A
5922530	Yu	Jul 1999	A
5922591	Anderson	Jul 1999	A
RE36268	Szuminsky	Aug 1999	E
5931794	Pitesky	Aug 1999	A
5935075	Casscells et al.	Aug 1999	A
5938635	Kuhle	Aug 1999	A
5938679	Freeman	Aug 1999	A
5940153	Castaneda	Aug 1999	A
5942189	Wolfbeis	Aug 1999	A
5947957	Morris	Sep 1999	A
5951492	Douglas	Sep 1999	A
5951493	Douglas	Sep 1999	A
5951582	Thorne	Sep 1999	A
5951836	McAleer	Sep 1999	A
5954738	LeVaughn	Sep 1999	A
5957846	Chiang	Sep 1999	A
5958199	Miyamoto	Sep 1999	A
5959098	Goldberg	Sep 1999	A
5961451	Reber et al.	Oct 1999	A
5965380	Heller	Oct 1999	A
5968063	Chu	Oct 1999	A
5968760	Phillips	Oct 1999	A
5968836	Matzinger	Oct 1999	A
5971941	Simons	Oct 1999	A
5972199	Heller	Oct 1999	A
5972294	Smith	Oct 1999	A
5976085	Kimball	Nov 1999	A
5983193	Heinonen	Nov 1999	A
5985116	Ikeda	Nov 1999	A
5986754	Harding	Nov 1999	A
5993400	Rincoe	Nov 1999	A
5993434	Dev	Nov 1999	A
D417504	Love	Dec 1999	S
5997561	Boecker	Dec 1999	A
5997817	Crismore	Dec 1999	A
5997818	Hackner	Dec 1999	A
6001067	Shults	Dec 1999	A
6007497	Huitema	Dec 1999	A
D418602	Prokop	Jan 2000	S
6014577	Henning	Jan 2000	A
6018289	Sekura	Jan 2000	A
6020110	Williams	Feb 2000	A
6022324	Skinner	Feb 2000	A
6022366	Schraga	Feb 2000	A
6022748	Charych	Feb 2000	A
6023629	Tamada	Feb 2000	A
6027459	Shain	Feb 2000	A
6030399	Ignotz	Feb 2000	A
6030827	Davis	Feb 2000	A
6030967	Marui	Feb 2000	A
6032059	Henning	Feb 2000	A
6033421	Theiss	Mar 2000	A
6033866	Guo	Mar 2000	A
6036924	Simons	Mar 2000	A
6037178	Leiner	Mar 2000	A
6045567	Taylor	Apr 2000	A
6046055	Wolfbeis	Apr 2000	A
D424696	Ray	May 2000	S
6059815	Lee et al.	May 2000	A
6060327	Keen	May 2000	A
6063039	Cunningham	May 2000	A
6066243	Anderson	May 2000	A
6066296	Brady	May 2000	A
6067463	Jeng	May 2000	A
D426638	Ray	Jun 2000	S
6070761	Bloom	Jun 2000	A
6071249	Cunningham	Jun 2000	A
6071250	Douglas	Jun 2000	A
6071251	Cunningham	Jun 2000	A
6071294	Simons	Jun 2000	A
6071391	Gotoh	Jun 2000	A
6074360	Haar et al.	Jun 2000	A
6077408	Miyamoto	Jun 2000	A
6080106	Lloyd	Jun 2000	A
6080172	Fujiwara	Jun 2000	A
D428150	Ruf	Jul 2000	S
6083196	Trautman	Jul 2000	A
6083710	Heller	Jul 2000	A
6084660	Shartle	Jul 2000	A
6085576	Sunshine	Jul 2000	A
6086544	Hibner	Jul 2000	A
6086562	Jacobsen	Jul 2000	A
6090078	Erskine	Jul 2000	A
6091975	Daddona	Jul 2000	A
6093156	Cunningham et al.	Jul 2000	A
D428993	Lubs	Aug 2000	S
6099484	Douglas	Aug 2000	A
6099802	Pugh	Aug 2000	A
6100107	Lei	Aug 2000	A
6102933	Lee	Aug 2000	A
6103033	Say	Aug 2000	A
6103509	Sode	Aug 2000	A
6104940	Watanabe	Aug 2000	A
6106751	Talbot	Aug 2000	A
6107083	Collins	Aug 2000	A
6117155	Lee	Sep 2000	A
6117630	Reber	Sep 2000	A
6118126	Zanzucchi	Sep 2000	A
6119033	Spigelman	Sep 2000	A
6120462	Hibner	Sep 2000	A
6120676	Heller	Sep 2000	A
6121009	Heller	Sep 2000	A
6126804	Andresen	Oct 2000	A
6126899	Woudenberg	Oct 2000	A
6129823	Hughes	Oct 2000	A
6132449	Lum	Oct 2000	A
6133837	Riley	Oct 2000	A
6134461	Say	Oct 2000	A
6136013	Marshall	Oct 2000	A
6139562	Mauze	Oct 2000	A
6143164	Heller et al.	Nov 2000	A
6144976	Silva et al.	Nov 2000	A
6149203	Hanlon	Nov 2000	A
6152875	Hakamata	Nov 2000	A
6152942	Brenneman	Nov 2000	A
6153069	Pottgen	Nov 2000	A
RE36991	Yamamoto	Dec 2000	E
6155992	Henning et al.	Dec 2000	A
6156051	Schraga	Dec 2000	A
6157442	Raskas	Dec 2000	A
6159147	Lichter	Dec 2000	A
6159424	Kauhaniemi	Dec 2000	A
6162397	Jurik	Dec 2000	A
6162611	Heller	Dec 2000	A
6168957	Matzinger	Jan 2001	B1
6171325	Mauze	Jan 2001	B1
6172743	Kley et al.	Jan 2001	B1
6175752	Say	Jan 2001	B1
6176847	Humphreys	Jan 2001	B1
6176865	Mauze	Jan 2001	B1
6177000	Peterson	Jan 2001	B1
6177931	Alexander	Jan 2001	B1
6183489	Douglas	Feb 2001	B1
6190612	Berger	Feb 2001	B1
6191852	Paffhausen	Feb 2001	B1
6192891	Gravel	Feb 2001	B1
6193673	Viola	Feb 2001	B1
6193873	Ohara	Feb 2001	B1
6194900	Freeman	Feb 2001	B1
6197040	LeVaughn	Mar 2001	B1
6197257	Raskas	Mar 2001	B1
6200773	Ouyang	Mar 2001	B1
6203504	Latterell	Mar 2001	B1
6206841	Cunningham et al.	Mar 2001	B1
6210133	Aboul-Hosn	Apr 2001	B1
6210369	Wilmot	Apr 2001	B1
6210420	Mauze et al.	Apr 2001	B1
6210421	Bocker et al.	Apr 2001	B1
6212417	Ikeda	Apr 2001	B1
6214626	Meller	Apr 2001	B1
6214804	Felgner	Apr 2001	B1
6218571	Zheng	Apr 2001	B1
6219574	Cormier	Apr 2001	B1
6221023	Matsuba	Apr 2001	B1
6221238	Grundig	Apr 2001	B1
6224617	Saadat et al.	May 2001	B1
6225078	Ikeda	May 2001	B1
6228100	Schraga	May 2001	B1
6230051	Cormier	May 2001	B1
6230501	Bailey	May 2001	B1
6231531	Lum	May 2001	B1
6234772	Wampler	May 2001	B1
D444235	Roberts	Jun 2001	S
6241862	McAleer	Jun 2001	B1
6242207	Douglas	Jun 2001	B1
6245060	Loomis	Jun 2001	B1
6245215	Douglas	Jun 2001	B1
6251083	Yum	Jun 2001	B1
6251121	Saadat	Jun 2001	B1
6251260	Heller	Jun 2001	B1
6251344	Goldstein	Jun 2001	B1
D444557	Levaughn	Jul 2001	S
6254831	Barnard	Jul 2001	B1
6256533	Vuzhakov	Jul 2001	B1
6258111	Ross	Jul 2001	B1
6258229	Winarta	Jul 2001	B1
6258254	Miyamoto	Jul 2001	B1
6261241	Burbank	Jul 2001	B1
6261245	Kawai	Jul 2001	B1
6261519	Harding	Jul 2001	B1
6264635	Wampler	Jul 2001	B1
6268161	Han	Jul 2001	B1
6268162	Phillips	Jul 2001	B1
6269314	Iitawaki	Jul 2001	B1
6270637	Crismore	Aug 2001	B1
6272359	Kivela	Aug 2001	B1
6272364	Kurnik	Aug 2001	B1
6275717	Gross	Aug 2001	B1
6280254	Wu	Aug 2001	B1
6281006	Heller et al.	Aug 2001	B1
6283926	Cunningham et al.	Sep 2001	B1
6283982	Levaughn	Sep 2001	B1
6284478	Heller	Sep 2001	B1
6285448	Kuenstner	Sep 2001	B1
6285454	Douglas	Sep 2001	B1
6289254	Shimizu	Sep 2001	B1
6290683	Erez	Sep 2001	B1
6295506	Heinonen	Sep 2001	B1
6299578	Kurnik	Oct 2001	B1
6299596	Ding	Oct 2001	B1
6299757	Feldman	Oct 2001	B1
6302855	Lav	Oct 2001	B1
6306104	Cunningham	Oct 2001	B1
6306152	Verdonk et al.	Oct 2001	B1
6306347	Mason	Oct 2001	B1
6309351	Kurnik	Oct 2001	B1
6309535	Williams	Oct 2001	B1
6312612	Sherman	Nov 2001	B1
6315738	Nishikawa	Nov 2001	B1
6318970	Backhouse	Nov 2001	B1
6319210	Douglas	Nov 2001	B1
6322574	Lloyd	Nov 2001	B1
6322808	Trautman	Nov 2001	B1
6322963	Bauer	Nov 2001	B1
6331163	Kaplan	Dec 2001	B1
6332871	Douglas	Dec 2001	B1
6334363	Testud	Jan 2002	B1
6334856	Allen et al.	Jan 2002	B1
6335203	Patel	Jan 2002	B1
6336900	Alleckson	Jan 2002	B1
6338790	Feldman	Jan 2002	B1
6346120	Yamazaki	Feb 2002	B1
6350273	Minagawa	Feb 2002	B1
6350451	Horn	Feb 2002	B1
6352514	Douglas	Mar 2002	B1
6352523	Brown	Mar 2002	B1
6353753	Flock	Mar 2002	B1
6364889	Kheiri et al.	Apr 2002	B1
6364890	Lum	Apr 2002	B1
6375626	Allen et al.	Apr 2002	B1
6375627	Mauze	Apr 2002	B1
6379301	Worthington et al.	Apr 2002	B1
6379317	Kintzig	Apr 2002	B1
6379324	Gartstein	Apr 2002	B1
6379969	Mauze	Apr 2002	B1
D456910	Clark	May 2002	S
6387709	Mason	May 2002	B1
6391005	Lum	May 2002	B1
6395227	Kiser	May 2002	B1
6398522	Skill	Jun 2002	B2
6398562	Butler	Jun 2002	B1
6399394	Dahm	Jun 2002	B1
6402701	Kaplan	Jun 2002	B1
6402704	Mcmorrow	Jun 2002	B1
6409740	Kuhr	Jun 2002	B1
6413410	Hodges	Jul 2002	B1
6413411	Pottgen	Jul 2002	B1
6415821	Kamholz	Jul 2002	B2
6420128	Ouyang	Jul 2002	B1
6421633	Heinonen	Jul 2002	B1
6423014	Churchill	Jul 2002	B1
6428664	Bhullar	Aug 2002	B1
6436055	Roe	Aug 2002	B1
6436256	Williams	Aug 2002	B1
6436721	Kuo	Aug 2002	B1
6440645	Yon-Hin	Aug 2002	B1
6444115	Hodges	Sep 2002	B1
6447119	Stewart et al.	Sep 2002	B1
6447265	Antaki	Sep 2002	B1
6451040	Purcell	Sep 2002	B1
6453810	Rossmeisl	Sep 2002	B1
6458258	Taniike	Oct 2002	B2
6461496	Feldman	Oct 2002	B1
6462162	van Antwerp	Oct 2002	B2
6471903	Sherman	Oct 2002	B2
6472220	Simons	Oct 2002	B1
6475360	Hodges	Nov 2002	B1
6475372	Ohara	Nov 2002	B1
6475436	Schabbach	Nov 2002	B1
6475750	Han	Nov 2002	B1
6484046	Say	Nov 2002	B1
6485439	Roe	Nov 2002	B1
6485461	Mason	Nov 2002	B1
6485923	Yani	Nov 2002	B1
6488827	Shartle	Dec 2002	B1
6488872	Beebe et al.	Dec 2002	B1
6488891	Mason	Dec 2002	B2
6489133	Phillips	Dec 2002	B2
6491709	Sharma	Dec 2002	B2
6491870	Patel	Dec 2002	B2
6497845	Sacherer	Dec 2002	B1
6501404	Walker	Dec 2002	B2
6501976	Sohrab	Dec 2002	B1
6503209	Hakky et al.	Jan 2003	B2
6503210	Hirao	Jan 2003	B1
6503231	Praunsnitz	Jan 2003	B1
6503290	Jarosinski	Jan 2003	B1
6506165	Sweeney	Jan 2003	B1
6506168	Fathallah	Jan 2003	B1
6506575	Knappe	Jan 2003	B1
6508785	Eppstein	Jan 2003	B1
6512986	Harmon	Jan 2003	B1
6514270	Schraga	Feb 2003	B1
6514460	Fendrock	Feb 2003	B1
6519241	Theimer	Feb 2003	B1
6520326	McIvor	Feb 2003	B2
6521110	Hodges	Feb 2003	B1
6521182	Shartle	Feb 2003	B1
6527521	Noda	Mar 2003	B2
6527716	Eppstein	Mar 2003	B1
6527778	Athanasiou	Mar 2003	B2
6529377	Nelson et al.	Mar 2003	B1
6530892	Kelly	Mar 2003	B1
6530937	Schraga	Mar 2003	B1
6531322	Jurik	Mar 2003	B1
6533949	Yeshurun	Mar 2003	B1
6537242	Palmer	Mar 2003	B1
6537264	Cormier et al.	Mar 2003	B1
6537292	Lee	Mar 2003	B1
6540672	Simonsen	Apr 2003	B1
6540675	Aceti	Apr 2003	B2
6540762	Bertling	Apr 2003	B1
6540891	Stewart	Apr 2003	B1
6547954	Ikeda	Apr 2003	B2
6549796	Sohrab	Apr 2003	B2
6551494	Heller	Apr 2003	B1
6555061	Leong	Apr 2003	B1
D475136	Taniguchi	May 2003	S
6558361	Yeshurun	May 2003	B1
6558402	Chelak	May 2003	B1
6558528	Matzinger	May 2003	B1
6561989	Whitson	May 2003	B2
6565808	Hudak	May 2003	B2
6569157	Shain	May 2003	B1
6571651	Hodges	Jun 2003	B1
6572566	Effenhauser	Jun 2003	B2
6572822	Jurik	Jun 2003	B2
6574490	Abbink	Jun 2003	B2
6576101	Heller	Jun 2003	B1
6576416	Haviland	Jun 2003	B2
6579690	Bonnecaze et al.	Jun 2003	B1
6584338	Van Muiswinkel	Jun 2003	B1
D477670	Jurik	Jul 2003	S
6586199	Ouyang	Jul 2003	B2
6587705	Kim	Jul 2003	B1
6589260	Schmelzeisen-Redeker	Jul 2003	B1
6589261	Abulhaj	Jul 2003	B1
6591124	Sherman et al.	Jul 2003	B2
6591125	Buse	Jul 2003	B1
6592744	Hodges	Jul 2003	B1
6592745	Feldman	Jul 2003	B1
6599407	Taniike	Jul 2003	B2
6599693	Webb	Jul 2003	B1
6599769	Kondo	Jul 2003	B2
6601534	Hebrank	Aug 2003	B2
6602205	Erickson	Aug 2003	B1
6602268	Kuhr	Aug 2003	B2
6602678	Kwon	Aug 2003	B2
6607362	Lum	Aug 2003	B2
6607658	Heller	Aug 2003	B1
6612111	Hodges	Sep 2003	B1
6616616	Fritz	Sep 2003	B2
6616819	Liamos	Sep 2003	B1
6618934	Feldman	Sep 2003	B1
6620112	Klitmose	Sep 2003	B2
6620310	Ohara	Sep 2003	B1
6623501	Heller	Sep 2003	B2
6626851	Hirao	Sep 2003	B2
6632349	Hodges	Oct 2003	B1
6635222	Kent	Oct 2003	B2
6638415	Hodges	Oct 2003	B1
6641533	Causey	Nov 2003	B2
6645368	Beatty	Nov 2003	B1
6649416	Kauer	Nov 2003	B1
6652720	Mansouri	Nov 2003	B1
6652734	Hodges	Nov 2003	B1
6652814	House	Nov 2003	B1
D484600	Kaar	Dec 2003	S
6656428	Clark et al.	Dec 2003	B1
6656697	Ouyang	Dec 2003	B1
6656702	Yugawa	Dec 2003	B1
6659966	Essenpreis	Dec 2003	B2
6660018	Lum	Dec 2003	B2
6662439	Bhullar	Dec 2003	B1
6669669	Flaherty	Dec 2003	B2
6671527	Peterson	Dec 2003	B2
D484980	Hartwein	Jan 2004	S
6673617	Patel	Jan 2004	B2
6676995	Dick	Jan 2004	B2
6679841	Bojan	Jan 2004	B2
6679852	Schmelzeisen-Redeker	Jan 2004	B1
6682933	Patel et al.	Jan 2004	B2
6689411	Dick	Feb 2004	B2
6706000	Perez	Mar 2004	B2
6706159	Moerman	Mar 2004	B2
6706232	Hasegawa	Mar 2004	B2
6709692	Sudor	Mar 2004	B2
6713660	Roe	Mar 2004	B1
6716577	Yu	Apr 2004	B1
6719887	Hasegawa	Apr 2004	B2
6719923	Stiene	Apr 2004	B2
6723111	Abulhaj	Apr 2004	B2
6723371	Chih-hui	Apr 2004	B2
6723500	Yu	Apr 2004	B2
6726818	Cui et al.	Apr 2004	B2
6729546	Roustaei	May 2004	B2
6730494	Toranto	May 2004	B1
6731966	Spigelman	May 2004	B1
6733493	Gruzdev	May 2004	B2
6736777	Kim	May 2004	B2
6738654	Sohrab	May 2004	B2
6740215	Nakaminami et al.	May 2004	B1
6743211	Prausnitz et al.	Jun 2004	B1
6743597	Guo	Jun 2004	B1
6746872	Zheng	Jun 2004	B2
6749740	Liamos et al.	Jun 2004	B2
6749792	Olsen	Jun 2004	B2
6749887	Dick	Jun 2004	B1
6751491	Lew	Jun 2004	B2
6752817	Flora	Jun 2004	B2
6753187	Cizdziel	Jun 2004	B2
6759190	Lin	Jul 2004	B2
6764496	Schraga	Jul 2004	B2
6764581	Forrow	Jul 2004	B1
6767441	Cai	Jul 2004	B1
6773671	Lewis	Aug 2004	B1
6776888	Yamamoto	Aug 2004	B2
6780645	Hayter	Aug 2004	B2
6780647	Fujiwara	Aug 2004	B2
6783502	Orloff	Aug 2004	B2
6783537	Kuhr	Aug 2004	B1
6784274	van Antwerp	Aug 2004	B2
6786874	Grace	Sep 2004	B2
6787013	Chang	Sep 2004	B2
6787109	Haar	Sep 2004	B2
6790327	Ikeda	Sep 2004	B2
6790599	Madou	Sep 2004	B1
6792791	Sato	Sep 2004	B2
6793632	Sohrab	Sep 2004	B2
6793633	Douglas	Sep 2004	B2
6793802	Lee	Sep 2004	B2
6797150	Kermani	Sep 2004	B2
6800488	Khan	Oct 2004	B2
6801041	Karinka	Oct 2004	B2
6801804	Miller	Oct 2004	B2
6802199	Hilgers	Oct 2004	B2
6802811	Slepian	Oct 2004	B1
6802957	Jung	Oct 2004	B2
6805780	Ryu	Oct 2004	B1
6808908	Yao	Oct 2004	B2
6808937	Ligler	Oct 2004	B2
6809807	Erickson	Oct 2004	B1
6811406	Grube	Nov 2004	B2
6811557	Schraga	Nov 2004	B2
6811659	Vachon	Nov 2004	B2
6811753	Hirao	Nov 2004	B2
6811792	Roser	Nov 2004	B2
6812031	Carlsson	Nov 2004	B1
6814843	Bhullar	Nov 2004	B1
6814844	Bhullar	Nov 2004	B2
6814845	Wilson	Nov 2004	B2
6815186	Clark	Nov 2004	B2
6816742	Kim	Nov 2004	B2
6818180	Douglas	Nov 2004	B2
6821483	Phillips	Nov 2004	B2
6823750	Hodges	Nov 2004	B2
6825047	Woudenberg	Nov 2004	B1
6827250	Uhland	Dec 2004	B2
6827829	Kawanaka	Dec 2004	B2
6829507	Lidman	Dec 2004	B1
6830551	Uchigaki	Dec 2004	B1
6830668	Musho	Dec 2004	B2
6830669	Miyazaki	Dec 2004	B2
6830934	Harding	Dec 2004	B1
6833540	MacKenzie	Dec 2004	B2
6835184	Sage	Dec 2004	B1
6835553	Han	Dec 2004	B2
6835570	Patel	Dec 2004	B2
6837858	Cunningham	Jan 2005	B2
6837976	Cai	Jan 2005	B2
6837988	Leong	Jan 2005	B2
6840912	Kloepfer	Jan 2005	B2
6841052	Musho	Jan 2005	B2
6843254	Tapper	Jan 2005	B2
6843902	Penner	Jan 2005	B1
6847451	Pugh	Jan 2005	B2
6849052	Uchigaki	Feb 2005	B2
6849168	Crumly	Feb 2005	B2
6849216	Rappin	Feb 2005	B2
6849456	Patel	Feb 2005	B2
6850790	Berner	Feb 2005	B2
6852119	Abulhaj	Feb 2005	B1
6852212	Maxwell	Feb 2005	B2
6852500	Hoss	Feb 2005	B1
6853854	Proniewiez	Feb 2005	B1
6855243	Khan	Feb 2005	B2
6856125	Kermani	Feb 2005	B2
6856928	Harmon	Feb 2005	B2
6858015	List	Feb 2005	B2
6858401	Phillips	Feb 2005	B2
6859738	Bush	Feb 2005	B2
6862466	Ackerman	Mar 2005	B2
6862534	Sterling	Mar 2005	B2
6863800	Karinka	Mar 2005	B2
6863801	Hodges	Mar 2005	B2
6865408	Abbink	Mar 2005	B1
6866641	Marshall	Mar 2005	B2
6866675	Perez	Mar 2005	B2
6866758	Bhullar	Mar 2005	B2
6866822	House	Mar 2005	B1
6872297	Mansouri	Mar 2005	B2
6872298	Kermani	Mar 2005	B2
6872299	Kermani	Mar 2005	B2
6872358	Hagen et al.	Mar 2005	B2
6875327	Miyazaki	Apr 2005	B1
6881541	Petersen	Apr 2005	B2
6887202	Currie	May 2005	B2
6911937	Sparrow	Jun 2005	B1
6913210	Baasch	Jul 2005	B2
6913668	Matzinger	Jul 2005	B2
6918901	Theeuwes	Jul 2005	B1
6929631	Brugger	Aug 2005	B1
6939685	Ouyang	Sep 2005	B2
6960323	Guo	Nov 2005	B2
6977722	Wohlstadter et al.	Dec 2005	B2
6982431	Modlin	Jan 2006	B2
7041068	Freeman et al.	May 2006	B2
7041210	Hodges	May 2006	B2
7043821	Hodges	May 2006	B2
7045046	Chambers	May 2006	B2
7049087	Jenny	May 2006	B2
D522656	Orr	Jun 2006	S
7059352	Bohm	Jun 2006	B2
7060168	Taniike	Jun 2006	B2
7079252	Debreezeny	Jul 2006	B1
7113172	Hohl	Sep 2006	B2
7134550	Groth	Nov 2006	B2
7141034	Eppstein	Nov 2006	B2
7144709	Ouyang	Dec 2006	B2
7156117	Bohm	Jan 2007	B2
7156810	Cho	Jan 2007	B2
7157723	Colvin	Jan 2007	B2
7160678	Kayyem	Jan 2007	B1
7162289	Shah	Jan 2007	B2
7166208	Zweig	Jan 2007	B2
7167735	Uchida	Jan 2007	B2
7169116	Day	Jan 2007	B2
7169117	Allen	Jan 2007	B2
7169289	Schulein	Jan 2007	B2
7169600	Hoss	Jan 2007	B2
7172728	Otake	Feb 2007	B2
7174199	Berner et al.	Feb 2007	B2
7175641	Schraga	Feb 2007	B1
7175642	Briggs	Feb 2007	B2
7179233	Chang	Feb 2007	B2
7182910	Allen	Feb 2007	B2
7183068	Burson	Feb 2007	B2
7183102	Monfre et al.	Feb 2007	B2
7188034	Staib	Mar 2007	B2
7189576	Fukuoka	Mar 2007	B2
7190988	Say	Mar 2007	B2
7192405	DeNuzzio	Mar 2007	B2
7192450	Brauker	Mar 2007	B2
7195704	Kermani	Mar 2007	B2
7198606	Boecker	Apr 2007	B2
7199594	Kermani	Apr 2007	B2
7202854	Hohl	Apr 2007	B2
7206620	Erickson	Apr 2007	B2
7206623	Blank	Apr 2007	B2
D542681	Young	May 2007	S
7211052	Roe	May 2007	B2
7211096	Kuhr	May 2007	B2
7212925	Genshaw	May 2007	B2
7213720	Giraud	May 2007	B2
7215982	Oshima	May 2007	B2
7215983	Cho	May 2007	B2
7223248	Erikson	May 2007	B2
7225008	Ward	May 2007	B1
D543878	Castillo	Jun 2007	S
D545438	Huang	Jun 2007	S
7225535	Feldman	Jun 2007	B2
7226414	Ballerstadt	Jun 2007	B2
7226461	Boecker	Jun 2007	B2
7226978	Tapsak	Jun 2007	B2
7227156	Colvin	Jun 2007	B2
7228159	Petersson	Jun 2007	B2
7228162	Ward	Jun 2007	B2
7228163	Ackerman	Jun 2007	B2
7229458	Freeman et al.	Jun 2007	B2
7232451	Boecker	Jun 2007	B2
7232510	Miyazaki	Jun 2007	B2
7233816	Blank	Jun 2007	B2
7235056	Duchon	Jun 2007	B2
7235170	Watanabe	Jun 2007	B2
7235378	Yonehara	Jun 2007	B2
7236812	Ballerstadt	Jun 2007	B1
7236814	Shioi	Jun 2007	B2
D545705	Voege	Jul 2007	S
D546216	Bolognesi et al.	Jul 2007	S
D546218	Grasso	Jul 2007	S
7238192	List	Jul 2007	B2
7238534	Zimmer	Jul 2007	B1
7241265	Cummings	Jul 2007	B2
7244264	Roe	Jul 2007	B2
7244265	Freeman	Jul 2007	B2
7244266	Garthe	Jul 2007	B2
7247138	Reghabi et al.	Jul 2007	B2
7247144	Douglas	Jul 2007	B2
7250037	Shermer	Jul 2007	B2
7250056	Hamamoto	Jul 2007	B2
7250095	Black	Jul 2007	B2
7250105	Davies et al.	Jul 2007	B1
7251513	Kondoh et al.	Jul 2007	B2
7251514	Cho	Jul 2007	B2
7251515	Cho	Jul 2007	B2
7251516	Walker	Jul 2007	B2
7251517	Cho	Jul 2007	B2
7251518	Herrmann	Jul 2007	B2
7252804	Miyashita	Aug 2007	B2
7254426	Cho	Aug 2007	B2
7254427	Cho	Aug 2007	B2
7254428	Cho	Aug 2007	B2
7254429	Schurman	Aug 2007	B2
7254430	Cho	Aug 2007	B2
7254432	Fine	Aug 2007	B2
7258673	Racchini	Aug 2007	B2
7258693	Freeman	Aug 2007	B2
7262061	Petrich	Aug 2007	B2
7264139	Brickwood	Sep 2007	B2
7264627	Perez	Sep 2007	B2
7266400	Fine	Sep 2007	B2
7267665	Steil	Sep 2007	B2
7267750	Watanabe	Sep 2007	B2
7270247	Charlton	Sep 2007	B2
7271912	Sterling	Sep 2007	B2
7273484	Thoes	Sep 2007	B2
7276027	Haar	Oct 2007	B2
7276029	Goode	Oct 2007	B2
7276146	Wilsey	Oct 2007	B2
7276147	Wilsey	Oct 2007	B2
7276380	Fukuyama	Oct 2007	B2
7277740	Rohleder	Oct 2007	B2
7278983	Ireland	Oct 2007	B2
7279130	Brown	Oct 2007	B2
7282058	Levin	Oct 2007	B2
7287318	Bhullar	Oct 2007	B2
7288073	Effenhauser	Oct 2007	B2
7288102	Griffin	Oct 2007	B2
7288174	Cui	Oct 2007	B2
7289836	Colvin	Oct 2007	B2
7291117	Boecker	Nov 2007	B2
7291159	Schmelzeisen-Redeker et al.	Nov 2007	B2
7291256	Teodorezyk	Nov 2007	B2
7291497	Holmes	Nov 2007	B2
7294246	Gundel	Nov 2007	B2
7295867	Berner	Nov 2007	B2
7297122	Boecker	Nov 2007	B2
7297151	Boecker	Nov 2007	B2
7297152	Fukuzawa	Nov 2007	B2
7297241	Kontschieder	Nov 2007	B2
7297248	Bae	Nov 2007	B2
7297627	Shah	Nov 2007	B2
7299079	Rebec	Nov 2007	B2
7299080	Acosta	Nov 2007	B2
7299081	Mace	Nov 2007	B2
7299082	Feldman	Nov 2007	B2
7300402	Iliff	Nov 2007	B2
7301629	Bambot	Nov 2007	B2
7303573	D'Agostino	Dec 2007	B2
7303726	McAllister	Dec 2007	B2
7303922	Jeng	Dec 2007	B2
7305896	Howell	Dec 2007	B2
7306560	Iliff	Dec 2007	B2
7308164	Banks	Dec 2007	B1
7308292	Colvin	Dec 2007	B2
7310542	Jeon	Dec 2007	B2
7310543	Smart	Dec 2007	B2
7310544	Brister	Dec 2007	B2
7311718	Schraga	Dec 2007	B2
7311812	Forrow	Dec 2007	B2
7312042	Petyt	Dec 2007	B1
7313425	Finarov	Dec 2007	B2
7314453	Kuo	Jan 2008	B2
7315752	Kraemer	Jan 2008	B2
7316700	Alden	Jan 2008	B2
7316766	Chen	Jan 2008	B2
7316929	Purcell	Jan 2008	B2
7317938	Lorenz	Jan 2008	B2
7317939	Fine	Jan 2008	B2
7322942	Roe	Jan 2008	B2
7322996	Taylor	Jan 2008	B2
7322997	Shi	Jan 2008	B2
7322998	Kuhr	Jan 2008	B2
7323098	Miyashita	Jan 2008	B2
7323141	Kirchhevel et al.	Jan 2008	B2
7323315	Marfurt	Jan 2008	B2
7324012	Mann et al.	Jan 2008	B2
7328052	Samsoondar	Feb 2008	B2
7331931	Freeman	Feb 2008	B2
7335292	Hodges	Feb 2008	B2
7335294	Heller	Feb 2008	B2
7337918	Fowler	Mar 2008	B2
7338639	Burke	Mar 2008	B2
7343188	Sohrab	Mar 2008	B2
7344499	Prausnitz	Mar 2008	B1
7344500	Talbot	Mar 2008	B2
7344507	Briggs	Mar 2008	B2
7344626	Harding	Mar 2008	B2
7347925	Hsieh	Mar 2008	B2
7347926	Morita	Mar 2008	B2
7347973	Douglas	Mar 2008	B2
RE40198	Buck, Jr. et al.	Apr 2008	E
7351213	Wong	Apr 2008	B2
7351323	Iketaki	Apr 2008	B2
7351375	Noda	Apr 2008	B2
7351770	Liu	Apr 2008	B2
7357808	Kennedy	Apr 2008	B2
7357851	Reid	Apr 2008	B2
7361182	Fukuda	Apr 2008	B2
7361307	Schartle	Apr 2008	B2
7371247	Boecker	May 2008	B2
7372277	Diamond	May 2008	B2
7374544	Freeman	May 2008	B2
7374546	Roe	May 2008	B2
7378007	Moerman	May 2008	B2
7378270	Azarnia et al.	May 2008	B2
7402616	Rodgers	Jul 2008	B2
7404815	Kollias	Jul 2008	B2
7410468	Freeman et al.	Aug 2008	B2
7429630	Liu	Sep 2008	B2
7431814	Hodges	Oct 2008	B2
7431820	Hodges	Oct 2008	B2
7438694	Boozer	Oct 2008	B2
D579652	Lim	Nov 2008	S
D579653	Lim	Nov 2008	S
7462265	Leach	Dec 2008	B2
7465380	Rodgers	Dec 2008	B2
7468125	Kraft	Dec 2008	B2
D585314	Schvetz	Jan 2009	S
7473264	Allen	Jan 2009	B2
7474390	Robinson	Jan 2009	B2
7474391	Baskeyfield	Jan 2009	B2
7481776	Boecker	Jan 2009	B2
7481818	Allen	Jan 2009	B2
D586465	Faulkner	Feb 2009	S
D586466	Smith	Feb 2009	S
D586678	Schvetz	Feb 2009	S
D586916	Faulkner	Feb 2009	S
7485128	Boecker	Feb 2009	B2
7491178	Boecker	Feb 2009	B2
7498132	Yu	Mar 2009	B2
7501052	Iyengar	Mar 2009	B2
7501093	Demelo	Mar 2009	B2
7521019	Polak	Apr 2009	B2
7524293	Freeman	Apr 2009	B2
7537571	Freeman	May 2009	B2
7547287	Boecker	Jun 2009	B2
7548772	Shartle et al.	Jun 2009	B2
7553511	Hleong	Jun 2009	B2
7563232	Freeman	Jul 2009	B2
D598126	Alvarez-Icaza	Aug 2009	S
7572356	Rodgers	Aug 2009	B2
7575558	Boecker et al.	Aug 2009	B2
D600349	Bell	Sep 2009	S
D600812	Lei	Sep 2009	S
D600813	Bell	Sep 2009	S
D601255	Schvetz	Sep 2009	S
D601258	Bell	Sep 2009	S
7582063	Wurster	Sep 2009	B2
7582099	Freeman	Sep 2009	B2
7586590	Baskeyfield	Sep 2009	B2
7588670	Rodgers	Sep 2009	B2
7589828	Robinson	Sep 2009	B2
7592151	Liu	Sep 2009	B2
7593097	Robinson	Sep 2009	B2
7604592	Freeman	Oct 2009	B2
7604722	Hodges	Oct 2009	B2
7608175	Hodges	Oct 2009	B2
7618522	Davies	Nov 2009	B2
7648468	Boecker	Jan 2010	B2
7648469	Boecker	Jan 2010	B2
7653492	Davies	Jan 2010	B2
7654127	Krulevitch	Feb 2010	B2
7655119	Davies	Feb 2010	B2
7665303	Bohm	Feb 2010	B2
7666287	Zhao	Feb 2010	B2
D611151	Lei	Mar 2010	S
D611372	Salter	Mar 2010	S
D611489	Bell	Mar 2010	S
D611853	Salter	Mar 2010	S
D612274	Heidemann	Mar 2010	S
D612275	Salter	Mar 2010	S
D612279	Heidemann	Mar 2010	S
7674232	Boecker	Mar 2010	B2
7682318	Alden	Mar 2010	B2
7713214	Freeman et al.	May 2010	B2
7833172	Hein et al.	Nov 2010	B2
7879058	Ikeda	Feb 2011	B2
7901365	Freeman et al.	Mar 2011	B2
8079960	Briggs et al.	Dec 2011	B2
8162968	Boozer et al.	Apr 2012	B2
8206319	Freeman et al.	Jun 2012	B2
8231548	Hoenes	Jul 2012	B2
8251922	List et al.	Aug 2012	B2
20010017269	Heller	Aug 2001	A1
20010018353	Ishigaki	Aug 2001	A1
20010023349	Van Tassel et al.	Sep 2001	A1
20010027328	Lum	Oct 2001	A1
20010031931	Cunningham	Oct 2001	A1
20010037355	Britt	Nov 2001	A1
20010042004	Taub	Nov 2001	A1
20010045355	Gephart	Nov 2001	A1
20010054319	Heller	Dec 2001	A1
20020002326	Causey	Jan 2002	A1
20020002344	Douglas	Jan 2002	A1
20020004196	Whitson	Jan 2002	A1
20020016568	Lebel	Feb 2002	A1
20020016923	Knaus	Feb 2002	A1
20020019606	Lebel	Feb 2002	A1
20020019747	Ware	Feb 2002	A1
20020025469	Heller	Feb 2002	A1
20020029058	Levaughn	Mar 2002	A1
20020040208	Flaherty	Apr 2002	A1
20020040230	Kuhr	Apr 2002	A1
20020042090	Heller	Apr 2002	A1
20020042594	Lum	Apr 2002	A1
20020044890	Black	Apr 2002	A1
20020052618	Haar	May 2002	A1
20020053523	Liamos	May 2002	A1
20020057993	Maisey	May 2002	A1
20020058902	Kollias et al.	May 2002	A1
20020076349	Aitken	Jun 2002	A1
20020078091	Vu	Jun 2002	A1
20020081588	De Lumley-woodyear	Jun 2002	A1
20020082543	Park	Jun 2002	A1
20020084196	Liamos	Jul 2002	A1
20020087056	Aceti	Jul 2002	A1
20020092612	Davies	Jul 2002	A1
20020099308	Bojan	Jul 2002	A1
20020103499	Perez	Aug 2002	A1
20020120216	Fritz	Aug 2002	A1
20020123335	Luna	Sep 2002	A1
20020130042	Moerman	Sep 2002	A1
20020136667	Subramanian	Sep 2002	A1
20020136863	Subramanian	Sep 2002	A1
20020137998	Smart	Sep 2002	A1
20020141032	Guarr et al.	Oct 2002	A1
20020148739	Liamos	Oct 2002	A2
20020156355	Gough	Oct 2002	A1
20020160520	Orloff	Oct 2002	A1
20020161289	Hopkins	Oct 2002	A1
20020168290	Yuzhakov	Nov 2002	A1
20020169393	Cunningham	Nov 2002	A1
20020169394	Eppstein	Nov 2002	A1
20020176984	Smart	Nov 2002	A1
20020177761	Orloff	Nov 2002	A1
20020177763	Burns	Nov 2002	A1
20020188224	Roe	Dec 2002	A1
20030014010	Carpenter	Jan 2003	A1
20030018282	Effenhauser	Jan 2003	A1
20030018300	Duchon	Jan 2003	A1
20030028126	List	Feb 2003	A1
20030032077	Itoh	Feb 2003	A1
20030038047	Sleva	Feb 2003	A1
20030050573	Kuhr	Mar 2003	A1
20030050656	Schraga	Mar 2003	A1
20030057391	Krulevitch	Mar 2003	A1
20030060730	Perez	Mar 2003	A1
20030069509	Matzinger et al.	Apr 2003	A1
20030072647	Lum	Apr 2003	A1
20030073089	Mauze	Apr 2003	A1
20030073229	Greenstein	Apr 2003	A1
20030073931	Boecker	Apr 2003	A1
20030083685	Freeman	May 2003	A1
20030083686	Freeman	May 2003	A1
20030088191	Freeman et al.	May 2003	A1
20030089730	May, Sr.	May 2003	A1
20030093010	Essenpreis	May 2003	A1
20030100040	Bonnecaze	May 2003	A1
20030106810	Douglas	Jun 2003	A1
20030109777	Kloepfer	Jun 2003	A1
20030109860	Black	Jun 2003	A1
20030111357	Black	Jun 2003	A1
20030113827	Burkoth	Jun 2003	A1
20030116447	Sturridge	Jun 2003	A1
20030120297	Beyerlein	Jun 2003	A1
20030135333	Aceti	Jul 2003	A1
20030136189	Lauman	Jul 2003	A1
20030143113	Yuzhakov	Jul 2003	A2
20030144608	Kojima	Jul 2003	A1
20030144609	Kennedy	Jul 2003	A1
20030146110	Karinka	Aug 2003	A1
20030149348	Raskas	Aug 2003	A1
20030149377	Erickson	Aug 2003	A1
20030150745	Teodorczyk et al.	Aug 2003	A1
20030153900	Aceti	Aug 2003	A1
20030191376	Samuels	Oct 2003	A1
20030191415	Moerman	Oct 2003	A1
20030195435	Williams	Oct 2003	A1
20030195540	Moerman	Oct 2003	A1
20030199744	Buse	Oct 2003	A1
20030199789	Boecker	Oct 2003	A1
20030199790	Boecker	Oct 2003	A1
20030199791	Boecker	Oct 2003	A1
20030199891	Argauer	Oct 2003	A1
20030199893	Boecker	Oct 2003	A1
20030199894	Boecker	Oct 2003	A1
20030199896	Boecker	Oct 2003	A1
20030199897	Boecker	Oct 2003	A1
20030199898	Boecker	Oct 2003	A1
20030199899	Boecker	Oct 2003	A1
20030199900	Boecker	Oct 2003	A1
20030199901	Boecker	Oct 2003	A1
20030199902	Boecker	Oct 2003	A1
20030199903	Boecker	Oct 2003	A1
20030199904	Boecker	Oct 2003	A1
20030199905	Boecker	Oct 2003	A1
20030199906	Boecker	Oct 2003	A1
20030199907	Boecker	Oct 2003	A1
20030199908	Boecker	Oct 2003	A1
20030199909	Boecker	Oct 2003	A1
20030199910	Boecker	Oct 2003	A1
20030199911	Boecker	Oct 2003	A1
20030199912	Pugh	Oct 2003	A1
20030201194	Heller	Oct 2003	A1
20030203352	Haviland	Oct 2003	A1
20030206828	Bell	Nov 2003	A1
20030208140	Pugh	Nov 2003	A1
20030210811	Dubowsky	Nov 2003	A1
20030211619	Olson et al.	Nov 2003	A1
20030212344	Yuzhakov	Nov 2003	A1
20030212345	McAllister	Nov 2003	A1
20030212346	McAllister	Nov 2003	A1
20030212347	Sohrab	Nov 2003	A1
20030212379	Bylund	Nov 2003	A1
20030212423	Pugh	Nov 2003	A1
20030212424	Briggs	Nov 2003	A1
20030216767	List	Nov 2003	A1
20030217918	Davies	Nov 2003	A1
20030220552	Reghabi	Nov 2003	A1
20030220663	Fletcher	Nov 2003	A1
20030223906	McAllister	Dec 2003	A1
20030225429	Garthe	Dec 2003	A1
20030225430	Schraga	Dec 2003	A1
20030228637	Wang	Dec 2003	A1
20030232370	Trifiro	Dec 2003	A1
20030233055	Erickson	Dec 2003	A1
20030233112	Alden et al.	Dec 2003	A1
20030233113	Alden et al.	Dec 2003	A1
20040006285	Douglas	Jan 2004	A1
20040007585	Griffith	Jan 2004	A1
20040009100	Simons	Jan 2004	A1
20040010279	Freeman	Jan 2004	A1
20040015064	Parsons	Jan 2004	A1
20040019250	Catelli	Jan 2004	A1
20040026243	Davies	Feb 2004	A1
20040026244	Hodges	Feb 2004	A1
20040030353	Schmelzeisen-Redeker	Feb 2004	A1
20040031682	Wilsey	Feb 2004	A1
20040034318	Fritz	Feb 2004	A1
20040038045	Smart	Feb 2004	A1
20040039303	Wurster	Feb 2004	A1
20040039342	Eppstein	Feb 2004	A1
20040039407	Schraga	Feb 2004	A1
20040039408	Abulhaj	Feb 2004	A1
20040049220	Boecker	Mar 2004	A1
20040054267	Feldman	Mar 2004	A1
20040055898	Heller	Mar 2004	A1
20040059256	Perez	Mar 2004	A1
20040060818	Feldman	Apr 2004	A1
20040061841	Black	Apr 2004	A1
20040064068	DeNuzzio	Apr 2004	A1
20040068283	Fukuzawa et al.	Apr 2004	A1
20040069657	Hodges	Apr 2004	A1
20040092995	Boecker	May 2004	A1
20040096991	Zhang	May 2004	A1
20040098010	Davison	May 2004	A1
20040102803	Boecker	May 2004	A1
20040106858	Say	Jun 2004	A1
20040106859	Say	Jun 2004	A1
20040106860	Say	Jun 2004	A1
20040106904	Gonnelli	Jun 2004	A1
20040106941	Roe	Jun 2004	A1
20040115754	Chang	Jun 2004	A1
20040115831	Meathrel	Jun 2004	A1
20040116829	Raney	Jun 2004	A1
20040122339	Roe	Jun 2004	A1
20040127818	Roe	Jul 2004	A1
20040127819	Roe	Jul 2004	A1
20040127928	Whitson	Jul 2004	A1
20040127929	Roe	Jul 2004	A1
20040132167	Rule	Jul 2004	A1
20040133125	Miyashita	Jul 2004	A1
20040133127	Roe	Jul 2004	A1
20040138541	Ward	Jul 2004	A1
20040138588	Saikley	Jul 2004	A1
20040138688	Giraud	Jul 2004	A1
20040146958	Bae	Jul 2004	A1
20040154932	Deng	Aug 2004	A1
20040157017	Mauze	Aug 2004	A1
20040157149	Hofmann	Aug 2004	A1
20040157319	Keen	Aug 2004	A1
20040157338	Burke	Aug 2004	A1
20040157339	Burke	Aug 2004	A1
20040158137	Eppstein	Aug 2004	A1
20040158271	Hamamoto	Aug 2004	A1
20040161737	Yang	Aug 2004	A1
20040162473	Sohrab	Aug 2004	A1
20040162474	Kiser	Aug 2004	A1
20040162506	Duchon	Aug 2004	A1
20040162573	Keheiri	Aug 2004	A1
20040167383	Kim	Aug 2004	A1
20040171057	Yang	Sep 2004	A1
20040171968	Katsuki	Sep 2004	A1
20040172000	Roe	Sep 2004	A1
20040173472	Jung	Sep 2004	A1
20040173488	Griffin	Sep 2004	A1
20040176705	Stevens	Sep 2004	A1
20040176732	Frazier	Sep 2004	A1
20040178066	Miyazaki	Sep 2004	A1
20040178067	Miyazaki	Sep 2004	A1
20040178216	Brickwood	Sep 2004	A1
20040180379	van Duyne	Sep 2004	A1
20040182703	Bell	Sep 2004	A1
20040185568	Matsumoto	Sep 2004	A1
20040186359	Beaudoin	Sep 2004	A1
20040186394	Roe	Sep 2004	A1
20040186500	Koike	Sep 2004	A1
20040193201	Kim	Sep 2004	A1
20040194302	Bhullar	Oct 2004	A1
20040197231	Katsuki	Oct 2004	A1
20040197821	Bauer	Oct 2004	A1
20040199062	Petersson	Oct 2004	A1
20040200720	Musho	Oct 2004	A1
20040200721	Bhullar	Oct 2004	A1
20040202576	Aceti	Oct 2004	A1
20040204662	Perez	Oct 2004	A1
20040206625	Bhullar	Oct 2004	A1
20040206636	Hodges	Oct 2004	A1
20040206658	Hammerstedt	Oct 2004	A1
20040209307	Valkirs	Oct 2004	A1
20040209350	Sakata	Oct 2004	A1
20040209354	Mathies	Oct 2004	A1
20040210279	Gruzdev	Oct 2004	A1
20040211666	Pamidi	Oct 2004	A1
20040214253	Paek	Oct 2004	A1
20040215224	Sakata	Oct 2004	A1
20040215225	Nakayama	Oct 2004	A1
20040216516	Sato	Nov 2004	A1
20040217019	Cai	Nov 2004	A1
20040219535	Bell	Nov 2004	A1
20040220456	Eppstein	Nov 2004	A1
20040220495	Cahir	Nov 2004	A1
20040220603	Rutynowski	Nov 2004	A1
20040222092	Musho	Nov 2004	A1
20040224369	Cai	Nov 2004	A1
20040225230	Liamos	Nov 2004	A1
20040225311	Levaughn	Nov 2004	A1
20040225312	Orloff	Nov 2004	A1
20040230216	Levaughn	Nov 2004	A1
20040231983	Shen	Nov 2004	A1
20040231984	Lauks	Nov 2004	A1
20040232009	Okuda	Nov 2004	A1
20040236250	Hodges	Nov 2004	A1
20040236251	Roe	Nov 2004	A1
20040236268	Mitragotri	Nov 2004	A1
20040236362	Shraga	Nov 2004	A1
20040238357	Bhullar	Dec 2004	A1
20040238358	Forrow	Dec 2004	A1
20040238359	Ikeda	Dec 2004	A1
20040241746	Adlassnig	Dec 2004	A1
20040242977	Dosmann	Dec 2004	A1
20040243164	D'Agostino	Dec 2004	A1
20040243165	Koike	Dec 2004	A1
20040245101	Willner	Dec 2004	A1
20040248282	Sobha	Dec 2004	A1
20040248312	Vreeke	Dec 2004	A1
20040249310	Shartle	Dec 2004	A1
20040249311	Haar	Dec 2004	A1
20040249405	Watanabe	Dec 2004	A1
20040249406	Griffin	Dec 2004	A1
20040251131	Ueno	Dec 2004	A1
20040253634	Wang	Dec 2004	A1
20040254434	Goodnow	Dec 2004	A1
20040254599	Lipoma	Dec 2004	A1
20040256228	Huang	Dec 2004	A1
20040256248	Burke	Dec 2004	A1
20040256685	Chou	Dec 2004	A1
20040258564	Charlton	Dec 2004	A1
20040260204	Boecker	Dec 2004	A1
20040260324	Fukuzawa	Dec 2004	A1
20040260325	Kuhr	Dec 2004	A1
20040260326	Lipoma	Dec 2004	A1
20040260511	Burke	Dec 2004	A1
20040267105	Monfre	Dec 2004	A1
20040267160	Perez	Dec 2004	A9
20040267229	Moerman	Dec 2004	A1
20040267299	Kuriger	Dec 2004	A1
20040267300	Mace	Dec 2004	A1
20050000806	Hsieh	Jan 2005	A1
20050000807	Wang	Jan 2005	A1
20050000808	Cui	Jan 2005	A1
20050003470	Nelson	Jan 2005	A1
20050004494	Perez	Jan 2005	A1
20050008537	Mosolu	Jan 2005	A1
20050008851	Ezoe	Jan 2005	A1
20050009191	Swenson	Jan 2005	A1
20050010090	Acosta	Jan 2005	A1
20050010093	Ford	Jan 2005	A1
20050010134	Douglas	Jan 2005	A1
20050010137	Hodges	Jan 2005	A1
20050010198	Marchitto	Jan 2005	A1
20050011759	Moerman	Jan 2005	A1
20050013731	Burke	Jan 2005	A1
20050014997	Ruchti	Jan 2005	A1
20050015020	Levaughn	Jan 2005	A1
20050016844	Burke	Jan 2005	A1
20050019212	Bhullar	Jan 2005	A1
20050019219	Oshiman	Jan 2005	A1
20050019805	Groll	Jan 2005	A1
20050019945	Groll	Jan 2005	A1
20050019953	Groll	Jan 2005	A1
20050021066	Kuhr	Jan 2005	A1
20050027181	Goode, Jr.	Feb 2005	A1
20050033340	Lipoma	Feb 2005	A1
20050049472	Manda	Mar 2005	A1
20050054908	Blank	Mar 2005	A1
20050059872	Shartle	Mar 2005	A1
20050061668	Brenneman	Mar 2005	A1
20050064528	Kwon	Mar 2005	A1
20050112712	Ouyang	May 2005	A1
20050118062	Otake	Jun 2005	A1
20050140659	Hohl	Jun 2005	A1
20050149090	Morita et al.	Jul 2005	A1
20050163176	You et al.	Jul 2005	A1
20050164299	Stewart	Jul 2005	A1
20050169810	Hagen	Aug 2005	A1
20050176153	O'hara	Aug 2005	A1
20050205136	Freeman	Sep 2005	A1
20060030050	Milne	Feb 2006	A1
20060030761	Raskas	Feb 2006	A1
20060037859	Hodges	Feb 2006	A1
20060094985	Aceti	May 2006	A1
20060100542	Wong	May 2006	A9
20060160100	Gao	Jul 2006	A1
20060163061	Hodges	Jul 2006	A1
20060184065	Deshmukh	Aug 2006	A1
20060201804	Chambers	Sep 2006	A1
20060222566	Brauker et al.	Oct 2006	A1
20060229652	Lio et al.	Oct 2006	A1
20060231421	Diamond	Oct 2006	A1
20060231423	Harding	Oct 2006	A1
20060231425	Harding	Oct 2006	A1
20060232278	Diamond	Oct 2006	A1
20060232528	Harding	Oct 2006	A1
20060233666	Vu	Oct 2006	A1
20060234263	Light, II	Oct 2006	A1
20060247154	Palmieri	Nov 2006	A1
20060254932	Hodges	Nov 2006	A1
20060266644	Pugh	Nov 2006	A1
20060266765	Pugh	Nov 2006	A1
20060279431	Bakarania	Dec 2006	A1
20060281187	Emery	Dec 2006	A1
20070016239	Sato	Jan 2007	A1
20070017805	Hodges	Jan 2007	A1
20070027370	Brauker	Feb 2007	A1
20070027427	Trautman	Feb 2007	A1
20070032812	Loerwald	Feb 2007	A1
20070032813	Flynn	Feb 2007	A1
20070038149	Calasso	Feb 2007	A1
20070038235	Freeman	Feb 2007	A1
20070043305	Boecker	Feb 2007	A1
20070043386	Freeman	Feb 2007	A1
20070049901	Wu	Mar 2007	A1
20070049959	Feaster	Mar 2007	A1
20070055174	Freeman	Mar 2007	A1
20070055297	Fukuzawa	Mar 2007	A1
20070055298	Uehata	Mar 2007	A1
20070060842	Alvarez-Icaza	Mar 2007	A1
20070060843	Alvarez-Icaza	Mar 2007	A1
20070060844	Alvarez-Icaza	Mar 2007	A1
20070060845	Perez	Mar 2007	A1
20070061393	Moore	Mar 2007	A1
20070062250	Krulevitch	Mar 2007	A1
20070062251	Anex	Mar 2007	A1
20070062315	Hodges	Mar 2007	A1
20070064516	Briggs	Mar 2007	A1
20070066939	Krulevitch	Mar 2007	A1
20070066940	Karunaratne	Mar 2007	A1
20070068807	Feldman	Mar 2007	A1
20070073188	Freeman	Mar 2007	A1
20070073189	Freeman	Mar 2007	A1
20070074977	Guo	Apr 2007	A1
20070078358	Escutia	Apr 2007	A1
20070078360	Matsumoto	Apr 2007	A1
20070078474	Kim	Apr 2007	A1
20070080093	Boozer	Apr 2007	A1
20070083130	Thomson	Apr 2007	A1
20070083131	Escutia	Apr 2007	A1
20070083222	Schraga	Apr 2007	A1
20070083335	Moerman	Apr 2007	A1
20070084749	Demelo	Apr 2007	A1
20070088377	LeVaughn	Apr 2007	A1
20070092923	Chang	Apr 2007	A1
20070093728	Douglas	Apr 2007	A1
20070093752	Zhao	Apr 2007	A1
20070093753	Krulevitch	Apr 2007	A1
20070093863	Pugh	Apr 2007	A1
20070093864	Pugh	Apr 2007	A1
20070095178	Schraga	May 2007	A1
20070100255	Boecker	May 2007	A1
20070100256	Sansom	May 2007	A1
20070100364	Sansom	May 2007	A1
20070102312	Cha	May 2007	A1
20070106178	Roe	May 2007	A1
20070108048	Wang	May 2007	A1
20070112281	Olson	May 2007	A1
20070112367	Olson	May 2007	A1
20070118051	Korner et al.	May 2007	A1
20070119710	Goldberger	May 2007	A1
20070123801	Goldberger	May 2007	A1
20070123802	Freeman	May 2007	A1
20070123803	Fujiwara et al.	May 2007	A1
20070129618	Goldberger	Jun 2007	A1
20070129650	Freeman	Jun 2007	A1
20070131565	Fujiwara	Jun 2007	A1
20070135828	Rutynowski	Jun 2007	A1
20070142747	Boecker	Jun 2007	A1
20070142748	Freeman et al.	Jun 2007	A1
20070142776	Kovelman	Jun 2007	A9
20070142854	Schraga	Jun 2007	A1
20070144235	Werner	Jun 2007	A1
20070149875	Ouyang	Jun 2007	A1
20070149897	Ghesquiere	Jun 2007	A1
20070161960	Chen	Jul 2007	A1
20070162064	Starnes	Jul 2007	A1
20070162065	Li	Jul 2007	A1
20070167869	Roe	Jul 2007	A1
20070167870	Freeman	Jul 2007	A1
20070167871	Freeman	Jul 2007	A1
20070167872	Freeman	Jul 2007	A1
20070167873	Freeman	Jul 2007	A1
20070167874	Freeman	Jul 2007	A1
20070167875	Freeman	Jul 2007	A1
20070173739	Chan	Jul 2007	A1
20070173740	Chan	Jul 2007	A1
20070173741	Boecker et al.	Jul 2007	A1
20070173742	Freeman et al.	Jul 2007	A1
20070173743	Freeman	Jul 2007	A1
20070173874	Uschold	Jul 2007	A1
20070173875	Uschold	Jul 2007	A1
20070173876	Aylett	Jul 2007	A1
20070176120	Schwind et al.	Aug 2007	A1
20070179356	Wessel	Aug 2007	A1
20070179404	Escutia	Aug 2007	A1
20070179405	Emery	Aug 2007	A1
20070179406	DeNuzzio	Aug 2007	A1
20070182051	Harttig	Aug 2007	A1
20070185412	Boecker	Aug 2007	A1
20070185515	Stout	Aug 2007	A1
20070185516	Schosnig	Aug 2007	A1
20070191702	Yodfat	Aug 2007	A1
20070191737	Freeman et al.	Aug 2007	A1
20070191738	Raney	Aug 2007	A1
20070191739	Roe	Aug 2007	A1
20070193019	Feldman	Aug 2007	A1
20070193882	Dai	Aug 2007	A1
20070196240	Boozer	Aug 2007	A1
20070196242	Boozer	Aug 2007	A1
20070203514	Flaherty	Aug 2007	A1
20070203903	Attaran Rezaei	Aug 2007	A1
20070205103	Hodges	Sep 2007	A1
20070207498	Palmieri	Sep 2007	A1
20070213601	Freeman	Sep 2007	A1
20070213637	Boozer	Sep 2007	A1
20070213682	Haar	Sep 2007	A1
20070213756	Freeman	Sep 2007	A1
20070218543	Flaherty	Sep 2007	A1
20070219346	Trifiro	Sep 2007	A1
20070219432	Thompson	Sep 2007	A1
20070219436	Takase	Sep 2007	A1
20070219462	Briggs	Sep 2007	A1
20070219463	Briggs	Sep 2007	A1
20070219572	Deck	Sep 2007	A1
20070219573	Freeman	Sep 2007	A1
20070219574	Freeman	Sep 2007	A1
20070225741	Ikeda	Sep 2007	A1
20070225742	Abe	Sep 2007	A1
20070227907	Shah	Oct 2007	A1
20070227911	Wang	Oct 2007	A1
20070227912	Chatelier	Oct 2007	A1
20070229085	Kawai	Oct 2007	A1
20070232872	Prough	Oct 2007	A1
20070232956	Harman	Oct 2007	A1
20070233013	Schoenberg	Oct 2007	A1
20070233166	Stout	Oct 2007	A1
20070233167	Weiss	Oct 2007	A1
20070233395	Neel	Oct 2007	A1
20070235329	Harding	Oct 2007	A1
20070235347	Chatelier	Oct 2007	A1
20070239068	Rasch-Menges	Oct 2007	A1
20070239188	Boozer	Oct 2007	A1
20070239189	Freeman	Oct 2007	A1
20070239190	Alden	Oct 2007	A1
20070240984	Popovich	Oct 2007	A1
20070240986	Reymond	Oct 2007	A1
20070244380	Say	Oct 2007	A1
20070244412	Lav	Oct 2007	A1
20070244498	Steg	Oct 2007	A1
20070244499	Briggs	Oct 2007	A1
20070249921	Groll	Oct 2007	A1
20070249962	Alden	Oct 2007	A1
20070249963	Alden	Oct 2007	A1
20070250099	Flora	Oct 2007	A1
20070251836	Hsu	Nov 2007	A1
20070254359	Rezania	Nov 2007	A1
20070255141	Esenaliev	Nov 2007	A1
20070255178	Alvarez-Icaza	Nov 2007	A1
20070255179	Alvarez-Icaza	Nov 2007	A1
20070255180	Alvarez-Icaza	Nov 2007	A1
20070255181	Alvarez-Icaza	Nov 2007	A1
20070255300	Vanhiel	Nov 2007	A1
20070255301	Freeman	Nov 2007	A1
20070255302	Koeppel	Nov 2007	A1
20070260271	Freeman	Nov 2007	A1
20070260272	Weiss	Nov 2007	A1
20070264721	Buck	Nov 2007	A1
20070265511	Renouf	Nov 2007	A1
20070265532	Maynard	Nov 2007	A1
20070265654	Iio	Nov 2007	A1
20070273901	Baskeyfield	Nov 2007	A1
20070273903	Baskeyfield	Nov 2007	A1
20070273904	Robinson	Nov 2007	A1
20070273928	Robinson	Nov 2007	A1
20070276197	Harmon	Nov 2007	A1
20070276211	Mir	Nov 2007	A1
20070276290	Boecker	Nov 2007	A1
20070276425	Kim	Nov 2007	A1
20070276621	Davies	Nov 2007	A1
20070278097	Bhullar	Dec 2007	A1
20070282186	Gilmore	Dec 2007	A1
20070282362	Berg	Dec 2007	A1
20070288047	Thoes	Dec 2007	A1
20070293743	Monfre	Dec 2007	A1
20070293744	Monfre	Dec 2007	A1
20070293790	Bainczyk	Dec 2007	A1
20070293882	Harttig	Dec 2007	A1
20070293883	Horie	Dec 2007	A1
20070295616	Harding	Dec 2007	A1
20080004651	Nicholls	Jan 2008	A1
20080007141	Deck	Jan 2008	A1
20080009767	Effenhauser	Jan 2008	A1
20080009768	Sohrab	Jan 2008	A1
20080009892	Freeman	Jan 2008	A1
20080009893	LeVaughn	Jan 2008	A1
20080015425	Douglas	Jan 2008	A1
20080015623	Deck	Jan 2008	A1
20080017522	Heller	Jan 2008	A1
20080019870	Newman	Jan 2008	A1
20080021291	Zocchi	Jan 2008	A1
20080021293	Schurman	Jan 2008	A1
20080021295	Wang	Jan 2008	A1
20080021296	Creaven	Jan 2008	A1
20080021346	Haar	Jan 2008	A1
20080021490	Briggs	Jan 2008	A1
20080021491	Freeman	Jan 2008	A1
20080021492	Freeman	Jan 2008	A1
20080021493	Levaughn	Jan 2008	A1
20080021494	Schmelzeisen-Redeker et al.	Jan 2008	A1
20080027385	Freeman	Jan 2008	A1
20080031778	Kramer	Feb 2008	A1
20080033268	Stafford	Feb 2008	A1
20080033318	Mace	Feb 2008	A1
20080033319	Kloepfer	Feb 2008	A1
20080033468	Lathrop	Feb 2008	A1
20080033469	Winheim	Feb 2008	A1
20080034834	Schell	Feb 2008	A1
20080034835	Schell	Feb 2008	A1
20080039885	Purcell	Feb 2008	A1
20080039886	Shi	Feb 2008	A1
20080039887	Conway	Feb 2008	A1
20080040919	Griss	Feb 2008	A1
20080045825	Melker	Feb 2008	A1
20080045992	Schraga	Feb 2008	A1
20080047764	Lee	Feb 2008	A1
20080053201	Roesicke	Mar 2008	A1
20080057484	Miyata	Mar 2008	A1
20080058624	Smart	Mar 2008	A1
20080058626	Miyata	Mar 2008	A1
20080058631	Draudt	Mar 2008	A1
20080058847	Abe	Mar 2008	A1
20080058848	Griffin	Mar 2008	A1
20080058849	Conway	Mar 2008	A1
20080060424	Babic	Mar 2008	A1
20080064986	Kraemer	Mar 2008	A1
20080064987	Escutia	Mar 2008	A1
20080065130	Patel	Mar 2008	A1
20080065131	List	Mar 2008	A1
20080065132	Trissel	Mar 2008	A1
20080065133	Kennedy	Mar 2008	A1
20080065134	Conway	Mar 2008	A1
20080073224	Diamond	Mar 2008	A1
20080077048	Escutia	Mar 2008	A1
20080077167	Flynn	Mar 2008	A1
20080077168	Nicholls	Mar 2008	A1
20080081969	Feldman	Apr 2008	A1
20080081976	Hodges	Apr 2008	A1
20080082023	Deck	Apr 2008	A1
20080082116	Lathrop	Apr 2008	A1
20080082117	Ruf	Apr 2008	A1
20080086042	Brister	Apr 2008	A1
20080086044	Brister	Apr 2008	A1
20080086273	Shults	Apr 2008	A1
20080093227	Diamond	Apr 2008	A1
20080093228	Diamond	Apr 2008	A1
20080093230	Diamond	Apr 2008	A1
20080094804	Reynolds	Apr 2008	A1
20080097171	Smart	Apr 2008	A1
20080097241	Maltezos	Apr 2008	A1
20080097503	Creaven	Apr 2008	A1
20080098802	Burke	May 2008	A1
20080103396	Johnson	May 2008	A1
20080103415	Roe	May 2008	A1
20080103517	Takemoto	May 2008	A1
20080105024	Creaven	May 2008	A1
20080105568	Wu	May 2008	A1
20080108130	Nakaminami	May 2008	A1
20080108942	Brister	May 2008	A1
20080109024	Berkovitch	May 2008	A1
20080109025	Yang	May 2008	A1
20080109259	Thompson	May 2008	A1
20080114227	Haar	May 2008	A1
20080114228	McCluskey	May 2008	A1
20080118400	Neel	May 2008	A1
20080119703	Brister	May 2008	A1
20080119704	Brister	May 2008	A1
20080119706	Brister	May 2008	A1
20080119761	Boecker	May 2008	A1
20080119883	Conway	May 2008	A1
20080119884	Flora	May 2008	A1
20080121533	Hodges	May 2008	A1
20080125800	List	May 2008	A1
20080125801	List	May 2008	A1
20080134806	Capriccio	Jun 2008	A1
20080134810	Neel	Jun 2008	A1
20080135559	Byrd	Jun 2008	A1
20080140105	Zhong	Jun 2008	A1
20080144022	Schulat	Jun 2008	A1
20080146899	Ruchti	Jun 2008	A1
20080146966	LeVaughn	Jun 2008	A1
20080147108	Kennedy	Jun 2008	A1
20080149268	Zhao	Jun 2008	A1
20080149599	Bohm	Jun 2008	A1
20080152507	Bohm	Jun 2008	A1
20080154187	Krulevitch	Jun 2008	A1
20080154513	Kovatchev	Jun 2008	A1
20080159913	Jung	Jul 2008	A1
20080161664	Mastrototaro	Jul 2008	A1
20080161724	Roe	Jul 2008	A1
20080161725	Wong	Jul 2008	A1
20080166269	Jansen	Jul 2008	A1
20080167578	Bryer	Jul 2008	A1
20080167673	Zhong	Jul 2008	A1
20080188771	Boecker et al.	Aug 2008	A1
20080194987	Boecker	Aug 2008	A1
20080194989	Briggs	Aug 2008	A1
20080208026	Noujaim	Aug 2008	A1
20080208079	Hein	Aug 2008	A1
20080210574	Boecker	Sep 2008	A1
20080214909	Fuerst	Sep 2008	A1
20080214917	Boecker	Sep 2008	A1
20080214919	Harmon	Sep 2008	A1
20080214956	Briggs	Sep 2008	A1
20080228212	List	Sep 2008	A1
20080249435	Haar	Oct 2008	A1
20080249554	Freeman	Oct 2008	A1
20080255598	LeVaughn et al.	Oct 2008	A1
20080262387	List	Oct 2008	A1
20080262388	List	Oct 2008	A1
20080267822	List	Oct 2008	A1
20080269723	Mastrototaro	Oct 2008	A1
20080269791	Hoenes	Oct 2008	A1
20080275365	Guthrie	Nov 2008	A1
20080275384	Mastrototaro	Nov 2008	A1
20080277291	Heller	Nov 2008	A1
20080277292	Heller	Nov 2008	A1
20080277293	Heller	Nov 2008	A1
20080277294	Heller	Nov 2008	A1
20080286149	Roe	Nov 2008	A1
20080294068	Briggs	Nov 2008	A1
20080300614	Freeman et al.	Dec 2008	A1
20080318193	Alvarez-Icaza	Dec 2008	A1
20080319284	Alvarez-Icaza	Dec 2008	A1
20080319291	Freeman	Dec 2008	A1
20090005664	Freeman	Jan 2009	A1
20090020438	Hodges	Jan 2009	A1
20090024009	Freeman	Jan 2009	A1
20090026075	Harding	Jan 2009	A1
20090026091	Harding	Jan 2009	A1
20090027040	Kermani	Jan 2009	A1
20090029479	Docherty	Jan 2009	A1
20090030441	Kudrna et al.	Jan 2009	A1
20090043177	Milledge	Feb 2009	A1
20090043183	Kermani	Feb 2009	A1
20090048536	Freeman	Feb 2009	A1
20090054813	Freeman	Feb 2009	A1
20090057146	Teodorczyk	Mar 2009	A1
20090069716	Freeman	Mar 2009	A1
20090084687	Chatelier	Apr 2009	A1
20090105572	Malecha	Apr 2009	A1
20090105573	Malecha	Apr 2009	A1
20090112123	Freeman	Apr 2009	A1
20090112155	Zhao	Apr 2009	A1
20090112180	Krulevitch	Apr 2009	A1
20090112185	Krulevitch et al.	Apr 2009	A1
20090124932	Freeman	May 2009	A1
20090131829	Freeman	May 2009	A1
20090131830	Freeman	May 2009	A1
20090131964	Freeman	May 2009	A1
20090131965	Freeman	May 2009	A1
20090137930	Freeman	May 2009	A1
20090138032	Freeman	May 2009	A1
20090139300	Pugh	Jun 2009	A1
20090177117	Amano et al.	Jul 2009	A1
20090184004	Chatelier	Jul 2009	A1
20090187351	Orr	Jul 2009	A1
20090192410	Freeman	Jul 2009	A1
20090192411	Freeman	Jul 2009	A1
20090196580	Freeman	Aug 2009	A1
20090204025	Marsot	Aug 2009	A1
20090216100	Ebner	Aug 2009	A1
20090237262	Smith	Sep 2009	A1
20090240127	Ray	Sep 2009	A1
20090247838	Cummings	Oct 2009	A1
20090247982	Kurlevitch	Oct 2009	A1
20090259146	Freeman	Oct 2009	A1
20090270765	Ghesquiere et al.	Oct 2009	A1
20090280551	Cardosi	Nov 2009	A1
20090281457	Faulkner	Nov 2009	A1
20090281458	Faulkner	Nov 2009	A1
20090281459	Faulkner	Nov 2009	A1
20090301899	Hodges	Dec 2009	A1
20090302872	Haggett	Dec 2009	A1
20090302873	Haggett	Dec 2009	A1
20090322630	Friman	Dec 2009	A1
20090325307	Haggett	Dec 2009	A1
20100016700	Sieh	Jan 2010	A1
20100018878	Davies	Jan 2010	A1
20100030110	Choi	Feb 2010	A1
20100041084	Stephens	Feb 2010	A1
20100113981	Oki et al.	May 2010	A1
20100198107	Groll et al.	Aug 2010	A1
20100256525	List et al.	Oct 2010	A1
20100292611	Lum et al.	Nov 2010	A1
20100324452	Freeman et al.	Dec 2010	A1
20110077478	Freeman et al.	Mar 2011	A1
20110077553	Alroy	Mar 2011	A1
20110098541	Freeman et al.	Apr 2011	A1
20120149999	Freeman et al.	Jun 2012	A1
20120232425	Freeman et al.	Sep 2012	A1
20120271197	Castle et al.	Oct 2012	A1
20120296233	Freeman	Nov 2012	A9

Foreign Referenced Citations (285)

Number	Date	Country
2206674	Aug 1972	DE
3538313	Apr 1986	DE
4212315	Oct 1993	DE
4320347	Dec 1994	DE
4344452	Jun 1995	DE
29800611	Jul 1998	DE
19819407	Nov 1999	DE
20009475	Oct 2000	DE
29824204	Oct 2000	DE
10053974	Dec 2000	DE
10032042	Jan 2002	DE
10057832	Feb 2002	DE
10142232	Mar 2003	DE
0112498	Jul 1984	EP
137975	Apr 1985	EP
0160768	Nov 1985	EP
0199484	Oct 1986	EP
0254246	Jan 1988	EP
0289 269	Nov 1988	EP
0317847	May 1989	EP
0320109	Jun 1989	EP
0364208	Apr 1990	EP
0170375	May 1990	EP
0136362	Dec 1990	EP
0449525	Oct 1991	EP
0453283	Oct 1991	EP
0449147	Aug 1992	EP
0530994	Mar 1993	EP
0374355	Jun 1993	EP
0351891	Sep 1993	EP
0593096	Apr 1994	EP
0630609	Dec 1994	EP
0415388	May 1995	EP
0654659	May 1995	EP
0505494	Jul 1995	EP
0662367	Jul 1995	EP
0359831	Aug 1995	EP
0471986	Oct 1995	EP
0368474	Dec 1995	EP
0461601	Dec 1995	EP
0429076	Jan 1996	EP
0552223	Jul 1996	EP
0735363	Oct 1996	EP
0505504	Mar 1997	EP
0777123	Jun 1997	EP
0406304	Aug 1997	EP
0537761	Aug 1997	EP
0795601	Sep 1997	EP
0562370	Nov 1997	EP
0415393	Dec 1997	EP
0823239	Feb 1998	EP
0560336	May 1998	EP
0878 708	Nov 1998	EP
0505475	Mar 1999	EP
0898936	Mar 1999	EP
0901018	Mar 1999	EP
0470649	Jun 1999	EP
0951939	Oct 1999	EP
0847447	Nov 1999	EP
0964059	Dec 1999	EP
0964060	Dec 1999	EP
0969097	Jan 2000	EP
0985376	Mar 2000	EP
1021950	Jul 2000	EP
0894869	Feb 2001	EP
1074832	Feb 2001	EP
1093854	Apr 2001	EP
1101443	May 2001	EP
1114995	Jul 2001	EP
0736607	Aug 2001	EP
1157660	Nov 2001	EP
0730037	Dec 2001	EP
0636879	Jan 2002	EP
0851224	Mar 2002	EP
0856586	May 2002	EP
0817809	Jul 2002	EP
0872728	Jul 2002	EP
0795748	Aug 2002	EP
0685737	Sep 2002	EP
1337182	Aug 2003	EP
0880692	Jan 2004	EP
1404232	Apr 2004	EP
1404233	Apr 2004	EP
1246688	May 2004	EP
1486766	Dec 2004	EP
1643908	Apr 2006	EP
1790288	May 2007	EP
1790288	May 2007	EP
1881322	Jan 2008	EP
1921992	May 2008	EP
2039294	Mar 2009	EP
2039294	Mar 2009	EP
2130493	Dec 2009	EP
2555432	May 1985	FR
2622457	Nov 1987	FR
1558111	Dec 1979	GB
2168815	Jun 1986	GB
2331936	Jun 1999	GB
2335860	Oct 1999	GB
2335990	Oct 1999	GB
HEI 4 194660	Jul 1992	JP
1996010208	Dec 1992	JP
9-276235	Oct 1997	JP
1014906	Jan 1998	JP
2000-116768	Apr 2000	JP
WO 8001389	Jul 1980	WO
WO 8504089	Sep 1985	WO
WO 8607632	Dec 1985	WO
WO8605966	Oct 1986	WO
WO 8607632	Dec 1986	WO
WO 9109139	Jun 1991	WO
WO9203099	Mar 1992	WO
WO9206971	Apr 1992	WO
WO9207263	Apr 1992	WO
WO9207468	May 1992	WO
WO9300044	Jan 1993	WO
WO 9302720	Feb 1993	WO
WO 9306979	Apr 1993	WO
WO9309723	May 1993	WO
WO 9312726	Jul 1993	WO
WO 9325898	Dec 1993	WO
WO 9427140	Nov 1994	WO
WO 9429703	Dec 1994	WO
WO 9429704	Dec 1994	WO
WO 9429731	Dec 1994	WO
WO 9500662	Jan 1995	WO
WO 9506240	Mar 1995	WO
WO 9510223	Apr 1995	WO
WO9512583	May 1995	WO
WO 9522597	Aug 1995	WO
WO9614799	May 1996	WO
WO 9630431	Oct 1996	WO
WO9637148	Nov 1996	WO
WO 9702359	Jan 1997	WO
WO 9702487	Jan 1997	WO
WO 9711883	Apr 1997	WO
WO 9711883	Apr 1997	WO
WO 9718464	May 1997	WO
WO9728741	Aug 1997	WO
WO 9730344	Aug 1997	WO
WO 9742882	Nov 1997	WO
WO 9742888	Nov 1997	WO
WO 9745720	Dec 1997	WO
WO 9803431	Jan 1998	WO
WO9814436	Apr 1998	WO
WO 9819159	May 1998	WO
WO9819609	May 1998	WO
WO 9820332	May 1998	WO
WO 9820348	May 1998	WO
WO9820867	May 1998	WO
WO 9824366	Jun 1998	WO
WO 98 24373	Jun 1998	WO
WO 9835225	Aug 1998	WO
WO9845276	Oct 1998	WO
WO 9903584	Jan 1999	WO
WO 9905966	Feb 1999	WO
WO9907295	Feb 1999	WO
WO 9907431	Feb 1999	WO
WO 9913100	Mar 1999	WO
WO 9962576	Mar 1999	WO
WO 9919507	Apr 1999	WO
WO 9919717	Apr 1999	WO
WO 9927852	Jun 1999	WO
WO 9913100	Dec 1999	WO
WO 9962576	Dec 1999	WO
WO 9964580	Dec 1999	WO
WO 0009184	Feb 2000	WO
WO 0020626	Apr 2000	WO
WO0029577	May 2000	WO
WO 0030186	May 2000	WO
WO 0039914	Jul 2000	WO
WO 0044084	Jul 2000	WO
WO0046854	Aug 2000	WO
WO 0050771	Aug 2000	WO
WO0055915	Sep 2000	WO
WO 0060340	Oct 2000	WO
WO 0064022	Oct 2000	WO
WO 0067245	Nov 2000	WO
WO 0067268	Nov 2000	WO
WO 0100090	Jan 2001	WO
WO 0107220	Feb 2001	WO
WO 0115807	Mar 2001	WO
WO 0116578	Mar 2001	WO
WO 0175433	Mar 2001	WO
WO 0123885	Apr 2001	WO
WO 0125775	Apr 2001	WO
WO 0126813	Apr 2001	WO
WO0129037	Apr 2001	WO
WO 0133216	May 2001	WO
WO 0134029	May 2001	WO
WO 0136955	May 2001	WO
WO 0145014	Jun 2001	WO
WO 0140788	Jul 2001	WO
WO 0157510	Aug 2001	WO
WO 0163271	Aug 2001	WO
WO 0164105	Sep 2001	WO
WO 0166010	Sep 2001	WO
WO 0172225	Oct 2001	WO
WO 0173124	Oct 2001	WO
WO 0173395	Oct 2001	WO
WO 0189691	Nov 2001	WO
WO 0191634	Dec 2001	WO
WO 0195806	Dec 2001	WO
WO 0200101	Jan 2002	WO
WO 0202796	Jan 2002	WO
WO 0208750	Jan 2002	WO
WO 0208753	Jan 2002	WO
WO 0208950	Jan 2002	WO
WO 0218940	Mar 2002	WO
WO 0232559	Apr 2002	WO
WO 0241779	May 2002	WO
WO 0244948	Jun 2002	WO
WO 0249507	Jun 2002	WO
WO0249507	Jun 2002	WO
WO 02056769	Jul 2002	WO
WO 02059734	Aug 2002	WO
WO 02069791	Sep 2002	WO
WO 02077638	Oct 2002	WO
WO 02100251	Dec 2002	WO
WO 02100252	Dec 2002	WO
WO 02100253	Dec 2002	WO
WO 02100254	Dec 2002	WO
WO 02100460	Dec 2002	WO
WO 02100461	Dec 2002	WO
WO 02101343	Dec 2002	WO
WO 02101359	Dec 2002	WO
WO 03000321	Jan 2003	WO
WO 03023389	Mar 2003	WO
WO 03042691	May 2003	WO
WO 03039369	May 2003	WO
WO 03045557	Jun 2003	WO
WO 03046542	Jun 2003	WO
WO 03049609	Jun 2003	WO
WO 03050534	Jun 2003	WO
WO 03066128	Aug 2003	WO
WO 03070099	Aug 2003	WO
WO 03071940	Sep 2003	WO
WO 03082091	Oct 2003	WO
WO 03082091	Oct 2003	WO
WO 03088824	Oct 2003	WO
WO 03088834	Oct 2003	WO
WO 03088835	Oct 2003	WO
WO03088834	Oct 2003	WO
WO 2004008130	Jan 2004	WO
WO 2004026130	Apr 2004	WO
WO 2004041082	May 2004	WO
WO 2004045375	Jun 2004	WO
WO 2004054455	Jul 2004	WO
WO 2004060174	Jul 2004	WO
WO 2004060446	Jul 2004	WO
WO 2004091693	Oct 2004	WO
WO 2004107964	Dec 2004	WO
WO 2004107975	Dec 2004	WO
WO 2004112602	Dec 2004	WO
WO 2004112612	Dec 2004	WO
WO 2004112612	Dec 2004	WO
WO 2005001418	Jan 2005	WO
WO 2005013824	Feb 2005	WO
WO 2005045414	May 2005	WO
WO2005084546	Sep 2005	WO
WO 2005104948	Nov 2005	WO
WO 2005104948	Nov 2005	WO
WO 2005114185	Dec 2005	WO
WO 2005120197	Dec 2005	WO
WO 2005120199	Dec 2005	WO
WO 2005120365	Dec 2005	WO
WO 2005120365	Dec 2005	WO
WO 2006001797	Jan 2006	WO
WO 2006015615	Feb 2006	WO
WO 2006031920	Mar 2006	WO
WO 2006105146	Oct 2006	WO
WO 2006116441	Nov 2006	WO
WO 2007010087	Jan 2007	WO
WO 2007025635	Mar 2007	WO
WO 2007044834	Apr 2007	WO
WO 2007054335	May 2007	WO
WO 2007070719	Jun 2007	WO
WO 2007084367	Jul 2007	WO
WO 2007088905	Aug 2007	WO
WO 2007106470	Sep 2007	WO
WO 2007119900	Oct 2007	WO
WO 2008085052	Jul 2008	WO
WO 2008112268	Sep 2008	WO
WO 2008112279	Sep 2008	WO
WO 2010109461	Sep 2010	WO

Non-Patent Literature Citations (4)

Entry
G. Jarzabek, Z. Borkowska, On the Real Surface of Smooth Solid Electrodes, 1997, Electrochimica Acta, vol. 42, No. 19, pp. 2915-1918.
A. Bott, W. Heineman, Chronocoulometry, Current Separations, 2004, 20, pp. 121.
Machine translation of DE 10053974 pp. 1-4, provided by epo.org.
Wolfbeis et al. (Sol-gel based glucose biosensors employing optical oxygen transducers, and a method for compensating for variable oxygen background, Biosensors & Bioelectronics 15 (2000) pp. 69-76).

Related Publications (1)

	Number	Date	Country
	20090138032 A1	May 2009	US

Divisions (4)

	Number	Date	Country
Parent	11244822	Oct 2005	US
Child	12325732		US
Parent	11318276	Dec 2005	US
Child	11244822		US
Parent	11317913	Dec 2005	US
Child	11318276		US
Parent	10127395	Apr 2002	US
Child	11317913		US

Tissue penetration device

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Term Extension

Abstract