Patent Application
20070245810
The present invention relates detection cartridges and methods for detecting one or more target analytes in fluid sample material.
Unlike classical clinical assays such as tube and slide coagulase tests, the detection cartridges of the present invention employ an integrated sensor. As used herein “sensor” refers to a device that detects a change in at least one physical property and produces a signal in response to the detectable change. The manner in which the sensor detects a change may include, e.g., electrochemical changes, optical changes, electro-optical changes, acousto-mechanical changes, etc. For example, electrochemical sensors utilize potentiometric and amperometric measurements, whereas optical sensors may utilize absorbance, fluorescence, luminescence and evanescent waves.
One technical problem that may be associated with many sensors is that the flow rate and/or flow front progression across the detection surface of a sensor may affect accurate detection of target analytes. Control over both volumetric flow rate and fluid flow front progression may, however, be difficult if the detection surface of the sensor is flat because such surfaces may be subject to the formation of voids, bubbles, etc. due to surface tension in liquids moving across a such a surface. Although some sensors may be adapted to address these concerns by including detection surfaces that are not flat and/or featureless, others, such as, e.g., acousto-mechanical sensors, may preferably include a relatively flat, featureless detection surface to function well.
Many biological analytes are introduced to the sensors in combination with a liquid carrier. The liquid carrier may undesirably reduce the sensitivity of the acousto-mechanical detection systems. Furthermore, the selectivity of such sensors may rely on properties that cannot be quickly detected, e.g., the test sample may need to be incubated or otherwise developed over time. Selectivity can, however, be obtained by binding a target biological analyte to, e.g., a detector surface.
Selective binding of known target biological analytes to detector surfaces can, however, raise issues when the sensor used relies on acousto-mechanical energy to detect the target biological analyte due to the size and relative low level of mechanical rigidity of many or most biological analytes. This issue may be especially problematic in connection with shear-horizontal surface acoustic wave detection systems.
Shear horizontal surface acoustic wave sensors are designed to propagate a wave of acousto-mechanical energy along the plane of the sensor detection surface. In some systems, a waveguide may be provided at the detection surface to localize the acousto-mechanical wave at the surface and increase the sensitivity of the sensor (as compared to a non-wave-guided sensor). This modified shear horizontal surface acoustic wave is often referred to as a Love-wave shear horizontal surface acoustic wave biosensor (“LSH-SAW”).
Such sensors have been used in connection with the detection of chemicals and other materials where the size of the target analytes is relatively small. As a result, the mass of the target analytes is largely located within the effective wave field of the sensors (e.g., about 60 nanometers (nm) for a sensor operating at a frequency of 103 Megahertz (MHz) in water).
What has not heretofore been appreciated is that the effective wave field of the sensors is significantly limited relative to the size of biological analytes to be detected. For example, biological analytes that are found, e.g., in the form of single cell microorganisms, may have a typical diameter of, e.g., about 1 micrometer (1000 nm). As noted above, however, the effective wave field of the sensors is only about 60 nm. As a result, significant portions of the mass of the target analyte may be located outside of the effective wave field of the sensors.
In addition to the size differential, the target biological analytes are often membranes filled with various components including water. As a result, the effect of acousto-mechanical energy traveling within the effective wave field above a sensor on the total mass of the biological analytes can be significantly limited. In many instances, target biological analytes attached to the surfaces of such sensors cannot be accurately distinguished from the liquid medium used to deliver the agents to the detector.
Although not wishing to be bound by theory, it is theorized that the relative lack of mechanical rigidity in biological analytes attached to a detection surface, i.e., their fluid nature, may significantly limit the amount of mass of the biological analytes that is effectively coupled to the detection surface. In other words, although the biological analytes may be attached to the detection surface, a significant portion of the mass of the biological analyte is not acoustically or mechanically coupled to the acousto-mechanical wave produced by the sensor. As a result, the ability of an acousto-mechanical biosensor (e.g., a LSH-SAW biosensor) to effectively detect the presence or absence of target biological analytes can be severely limited.
The present invention provides detection cartridges and associated components, as well as methods of using the same that provide sample materials to a sensor for detection. Among the components that may be used in connection with the detection cartridges of the present invention are, e.g., input (or fluid) modules, fluid flow front control features, volumetric flow rate control features, etc.
Potential advantages of the apparatus and methods of the present invention are the presentation of sample materials (which may include, e.g., test specimens, reagents, carrier fluids, buffers, etc.) to the detection surface of a sensor in a controlled manner that may enhance detection and/or reproducibility.
The controlled presentation may include control over the delivery of sample material to the detection surface. The control may preferably be provided using a module-based input system in which sample materials such as, e.g., test specimens, reagents, buffers, wash materials, etc. can be introduced into the detection cartridge at selected times, at selected rates, in selected orders, etc.
Controlled presentation may also include control over the fluid flow front progression across the detection surface. The “flow front”, as that term is used herein, refers to the leading edge of a bolus of fluid moving across a detection surface within a detection chamber. A potential advantage of control over the flow front progression is that preferably all of the detection surface may be wetted out by the sample material, i.e., bubbles or voids in the fluid that could occupy a portion of the detection surface may preferably be reduced or eliminated.
Controlled presentation may also encompass volumetric flow control through a detection chamber that, in some embodiments of the present invention, may be achieved by drawing fluid through the detection chamber using, e.g., capillary forces, porous membranes, absorbent media, etc. Controlling the flow rate of sample material over the detection surface may provide advantages. If, for example, the flow rate is too fast, target analyte in the sample material may not be accurately detected because selective attachment may be reduced or prevented. Conversely, if the flow rate is too slow, excessive non-specific binding of non-targeted analytes or other materials to the detection surface may occur, thereby potentially providing a false positive signal. The present invention also provides sealed modules that may be selectively incorporated into, e.g., a detection cartridge, to facilitate the detection of different target analytes within the detection cartridge. Before use, the modules may preferably be sealed to prevent materials located therein from escaping and/or to prevent contamination of the interior volume of the modules. The modules may preferably include two or more isolated chambers in which different constituents may be stored before they are introduced to each other and to the detection cartridges. The introduction and mixing of the different constituents, along with their introduction into the detection cartridge (and, ultimately, the sensor) may be controlled using the modules and actuators. Isolated storage of many different reagents may greatly enhance the shelf-life of materials that may be used to assist in the detection of target analytes. Some reagents that may benefit from isolated dry storage conditions may include, e.g., lysing reagents, fibrinogen, assay-tagged magnetic particles, etc.
The modules may be selected and attached to the detection cartridge by the manufacturer or, in some instances, by an end user. The flexibility offered to an end user to, essentially, customize a detection cartridge at the point-of-use may offer additional advantages in terms of economy and efficiency. For example, different modules containing different reagents, buffers, etc. may be supplied to the end-user for their selective combination of modules in a detection cartridge to perform a specific assay for a specific target analyte.
The detection cartridges of the present invention may incorporate a wide variety of sensors to detect one or more target analytes. The sensors may preferably be in the form of biosensors, where “biosensors” are sensors adapted to detect one or more target biological analytes in sample material.
Although the exemplary embodiments described herein may include a single sensor, the detection cartridges of the present invention may include two or more sensors, with the two or more sensors being substantially similar to each other or different. Furthermore, each sensor in a detection cartridge according to the present invention may include two or more channels (e.g., a detection channel and a reference channel). Alternatively, different sensors may be used to provide a detection channel and a reference channel within a detection cartridge. If multiple sensors are provided, they may be located in the same detection chamber or in different detection chambers within a detection cartridge.
The sensors used in connection with the detection cartridges of the present invention may rely on a wide variety of different sensor technologies. Examples of some potentially useful sensor technologies may include, but are not limited to, sensing electrochemical changes, optical changes, electro-optical changes, acousto-mechanical changes, etc.
It may be preferred that the detection cartridges detect the presence of target analytes in the sample material using acousto-mechanical energy generated by a sensor-located within the cartridge. The acousto-mechanical energy may preferably be provided using an acousto-mechanical sensor, e.g., a surface acoustic wave sensor such as, e.g., a shear horizontal surface acoustic wave sensor (e.g., a LSH-SAW biosensor), although other acousto-mechanical sensor technologies may be used in connection with the systems and methods of the present invention in some instances.
It may be preferred that the detection cartridges and modules of the present invention be designed to detect target analytes that are biological in nature, e.g., target biological analytes. As used herein, “target biological analyte” may include, e.g., microorganisms (e.g., bacteria, viruses, endospores, fungi, protozoans, etc.), proteins, peptides, amino acids, fatty acids, nucleic acids, carbohydrates, hormones, steroids, lipids, vitamins, etc.
The target biological analyte may be obtained from a test specimen that is obtained by any suitable method and may largely be dependent on the type of target biological agent to be detected. For example, the test specimen may be obtained from a subject (human, animal, etc.) or other source by e.g., collecting a biological tissue and/or fluid sample (e.g., blood, urine, feces, saliva, semen, bile, ocular lens fluid, synovial fluid, cerebral spinal fluid, pus, sweat, exudate, mucous, lactation milk, skin, hair, nails, etc.). In other instances, the test specimen may be obtained as an environmental sample, product sample, food sample, etc. The test specimen as obtained may be a liquid, gas, solid or combination thereof.
Before delivery to the detection cartridge and/or modules of the present invention, the test specimen may be subjected to prior treatment, e.g., dilution of viscous fluids, concentration, filtration, distillation, dialysis, addition of reagents, chemical treatment, etc.
The present invention may be utilized in combination with various materials, methods, systems, apparatus, etc. as described in various U.S. and PCT patent applications identified below, all of which are incorporated by reference in their respective entireties. They include U.S. patent application Ser. No. 60/533,162, filed on Dec. 30, 2003; U.S. patent application Ser. No. 60/533,178, filed on Dec. 30, 2003; U.S. patent application Ser. No. 10/896,392, filed Jul. 22, 2004; U.S. patent application Ser. No. 10/713,174, filed Nov. 14, 2003; U.S. patent application Ser. No. 10/987,522, filed Nov. 12, 2004; U.S. patent application Ser. No. 10/714,053, filed Nov. 14, 2003; U.S. patent application Ser. No. 10/987,075, filed Nov. 12, 2004; U.S. patent application Ser. No. 60/533,171, filed Dec. 30, 2003; U.S. patent application Ser. No. 10/960,491, filed Oct. 7, 2004; U.S. patent application Ser. No. 60/533,177, filed Dec. 30, 2003; U.S. patent application Ser. No. 60/533,176, filed Dec. 30, 2003; U.S. patent application Ser. No. 60/533,169, filed Dec. 30, 2003; U.S. patent application Ser. No. ______, titled “Method of Enhancing Signal Detection of Cell-Wall Components of Cells”, filed on even date herewith (Attorney Docket No. 59467US002); U.S. patent application Ser. No. ______, titled “Soluble Polymers as Amine Capture Agents and Methods”, filed on even date herewith (Attorney Docket No. 59995US002); U.S. patent application Ser. No. ______, titled “Multifunctional Amine Capture Agents”, filed on even date herewith (Attorney Docket No. 59996US002); PCT Application No. ______, titled “Estimating Propagation Velocity Through A Surface Acoustic Wave Sensor”, filed on even date herewith (Attorney Docket No. 58927WO003); PCT Application No. ______, titled “Surface Acoustic Wave Sensor Assemblies”, filed on even date herewith (Attorney Docket No. 58928WO003); PCT Application No. ______, titled “Acousto-Mechanical Detection Systems and Methods of Use”, filed on even date herewith (Attorney Docket No. 59468WO003); and PCT Application No. ______, titled “Acoustic Sensors and Methods”, filed on even date herewith (Attorney Docket No. 60209WO003).
In one aspect, the present invention provides a detection cartridge that includes a housing with an interior volume; a sensor operably attached to the housing, the sensor including a detection surface; a detection chamber located within the interior volume of the housing, wherein the detection chamber has a volume defined by the detection surface and an opposing surface spaced apart from and facing the detection surface, wherein the opposing surface includes a flow front control feature; and a waste chamber located within the interior volume of the housing, the waste chamber in fluid communication with the detection chamber.
In another aspect, the present invention provides a detection cartridge that includes a housing with an interior volume; a sensor operably attached to the housing, the sensor including surface acoustic wave acousto-mechanical sensor; a detection chamber located within the interior volume of the housing, wherein the detection chamber has a volume defined by the detection surface and an opposing surface spaced apart from and facing the detection surface, wherein the opposing surface includes one or more channels formed therein; a waste chamber located within the interior volume of the housing, the waste chamber in fluid communication with the detection chamber; absorbent material located within the waste chamber; and capillary structure located between the detection chamber and the waste chamber.
In another aspect, the present invention provides a detection cartridge that includes a cartridge housing with an interior volume; a sensor operably attached to the cartridge housing, the sensor including a detection surface; a detection chamber located within the interior volume of the cartridge housing, wherein the detection chamber has a volume defined by the detection surface and an opposing surface spaced apart from and facing the detection surface, wherein the opposing surface includes a flow front control feature; a waste chamber located within the interior volume of the cartridge housing, the waste chamber in fluid communication with the detection chamber; one or more sealed modules, wherein each module of the one or more sealed modules includes an exit port attached to the cartridge housing through one or more module ports that open into the interior volume of the cartridge housing. Each module further includes a module housing with an exit port and a sealed interior volume; an exit seal located over the exit port of the module; and a plunger located within the interior volume of the module housing. The plunger is movable from a loaded position in which the plunger is distal from the exit port to an unloaded position in which the plunger is proximate the exit port, and movement of the plunger towards the exit port opens the exit seal such that material from the interior volume of the module housing exits through the exit port into the interior volume of the cartridge housing.
In another aspect, the present invention provides a method of moving sample material through a detection cartridge that includes delivering sample material into the interior volume of the housing of the detection cartridge, wherein the sample material flows into the detection chamber, and wherein flow front progression of the sample material through the detection chamber and towards the waste chamber is controlled at least in part by the flow front control feature on the opposing surface within the detection chamber.
In another aspect, the present invention provides a sealed module including a housing with an exit port and a sealed interior volume; an exit seal located over the exit port; a first chamber located within the interior volume of the housing, the first chamber having a liquid located therein; a second chamber located within the interior volume of the housing, the second chamber including a reagent located therein; an inter-chamber seal isolating the second chamber from the first chamber within the housing; and a plunger, wherein the first chamber, the inter-chamber seal, the second chamber, and the exit seal are located between the plunger and the exit port, and wherein the plunger is movable from a loaded position in which the plunger is distal from the exit port to an unloaded position in which the plunger is proximate the exit port. Movement of the plunger towards the exit port opens the inter-chamber seal such that the liquid in the first chamber contacts the reagent in the second chamber, and wherein further movement of the plunger into the unloaded position opens the exit seal such that the liquid and the reagent from the interior volume of the housing exit through the exit port.
In another aspect, the present invention provides a method of delivering materials using a sealed module of the invention. The method includes moving a plunger towards the exit port of the sealed module to open the inter-chamber seal and force the liquid from the first chamber into contact with the reagent in the second chamber; and moving the plunger towards the exit port to open the exit seal and expel the liquid and the reagent from the interior volume of the housing through the exit port.
In another aspect, the present invention provides a module that includes a housing with an exit port and a sealed interior volume; an exit seal located over the exit port; a chamber located within the interior volume of the housing, the chamber having one or more reagents located therein; a plunger movable from a loaded position in which the plunger is distal from the exit port to an unloaded position in which the plunger is proximate the exit port; and an input port in fluid communication with the chamber, wherein the input port enters the chamber between the plunger and the exit port when the plunger is in the loaded position. Movement of the plunger towards the exit port opens the exit seal such that material from the interior volume of the housing exits through the exit port.
In another aspect, the present invention provides a method of delivering materials using a module of the invention. The method includes delivering sample material comprising a liquid into the chamber of the module through an input port, wherein the sample material contacts the reagent located within the chamber; and moving the plunger towards the exit port to open the exit seal such that the liquid exits from the chamber through the exit port.
These and other features and advantages of the detection systems and methods of the present invention may be described in connection with various illustrative embodiments of the invention below.
In the following detailed description of exemplary embodiments of the invention, reference is made to the accompanying figures of the drawings which form a part hereof, and in which are shown, by way of illustration, specific embodiments in which the invention may be practiced. It is to be understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present invention.
In one aspect, the present invention provides detection cartridges that include an integrated sensor and fluid control features that assist in selective delivery of a sample analyte to the sensor. The exemplary detection cartridge 10 depicted schematically in
The detection chamber 30 of the detection cartridge 10 preferably defines an interior volume between the detection surface of the sensor 50 and an opposing surface 60 located opposite from the detection surface of the sensor. The detection chamber 30 may preferably provide sidewalls or other structures that define the remainder of the interior volume of the detection chamber 30 (i.e., that portion of the detection chamber 30 that is not defined by the detection surface of the sensor 50 and the opposing surface 60).
Also depicted in
In addition to the detection chamber 30, the detection cartridge 10 depicted in
The volumetric flow control feature 70 may preferably draw fluid through the detection chamber 30 so that it can move into the waste chamber 40. In various exemplary embodiments as described herein, the volumetric flow control feature 70 may include one or more of the following components: one or more capillary channels, a porous membrane, absorbent material, a vacuum source, etc. These different components may, in various embodiments, limit or increase the flow rate depending on how and where they are deployed within the cartridge 10. For example, a capillary structure may be provided between the detection chamber 30 and the waste chamber 40 to limit flow from the detection chamber 30 into the waste chamber 40 if, e.g., the waste chamber 40 includes absorbent material that might cause excessively high flow rates in the absence of a capillary structure.
Another feature depicted in
The vent 78 may include a closure element 79 in the form of a seal, cap, valve, or other structure(s) to open, close or adjust the size of the vent opening. In some embodiments, the closure element 79 may be used to either open or close the vent. In other embodiments, the closure element 79 may be adjustable such that the size of the vent opening may be adjusted to at least one size between fully closed and fully open to adjust fluid flow rate through the detection cartridge 10. For example, increasing the size of the vent opening (using, e.g., the closure element 79) may increase fluid flow rate while restricting the size of the vent opening may cause a controllable reduction the fluid flow rate through the interior volume of the detection cartridge 10, e.g., through the staging chamber 20, detection chamber 30, etc. If the vent 78 includes multiple orifices, one or more of the orifices can be opened or closed using the closure element(s), etc.
Although volumetric flow rate of fluid moving through the detection chamber 30 may be controlled by the volumetric flow control feature 70, it may be preferred to provide for control over the flow front progression through the detection chamber 30. Flow front progression control may assist in ensuring that all portions of a detection surface of the sensor 50 exposed within the detection chamber 30 are covered or wetted out by the fluid of the sample analyte such that bubbles or voids are not formed. It may be preferred for example that the flow front progress through the detection chamber 30 in the form of a generally straight line that is oriented perpendicular to the direction of flow through the detection chamber 30.
In the exemplary embodiment depicted in
In view of the concerns described above, it may be preferred to provide flow front control features in or on the opposing surface 60 of the detection chamber 30 to assist in the control of fluid flow progression over the detection surface of sensor 50. Flow front control may preferably provide control over the progression of sample material over the detection surface while also reducing or preventing bubble formation (or retention) on the detection surface.
The flow front control features provided on the opposing surface 60 may preferably be passive, i.e., they do not require any external input or energy to operate while the fluid is moving through the detection chamber 30. The flow front control features may also preferably operate over a wide range of sample volumes that may pass through the detection chamber 30 (e.g., small sample volumes in the range of 10 microliters or less up to larger sample volumes of 5 milliliters or more).
It may be preferred that the opposing surface 60 and the detection surface of the sensor 50 be spaced apart from each other such that the opposing surface 60 (and any features located thereon) does not contact the detection surface of the sensor 50. With respect to acoustic sensors, even close proximity may adversely affect the properties of the sensor operation. It may be preferred, for example, that spacing between the detection surface of the sensor 50 and the lowermost feature of the opposing surface 60 be 20 micrometers or more, or even more preferably 50 micrometers or more. For effective flow front control, it may be preferred that the distance between the lowermost feature of the opposing surface 60 and the detection surface of the sensor 50 be 10 millimeters, alternatively 1 millimeter or less, in some instances 500 micrometers or less, and in other instances 250 micrometers or less.
In one class of flow front control features, the opposing surface 60 may include physical structure such as channels, posts, etc. that may be used to control the flow of fluid through the detection chamber 30. Regardless of the particular physical structure, it is preferably of a large enough scale such that flow front progression through the detection chamber is meaningfully affected.
In other embodiments, the channels may be separated by land areas between peaks or include valleys that have a land area (i.e., that does not reach a bottom and then immediately turn upward to the adjacent peak). The land areas may be flat or take other shapes as desired. One such variation is depicted in
Even though the channels 62d are more rectangular in shape, it may be preferred that the wall 63d at the leading edge of each channel 62d forms an angle θ (theta) with the surface 64d leading up to the channel 62d that is less than 270 degrees. As used herein, the “leading edge” of a channel is that edge that is encountered first by liquids moving in the downstream direction over the detection surface. Limiting the angle θ (theta) may promote fluid flow into the channels 62d because higher angles between the walls 63d at the leading edges and the surfaces 64d may impede fluid flow front progression. By virtue of their triangular shape, the channels in the opposing surfaces in
In addition to the variations described above with respect to
Referring again to
Generally, the susceptibility of a solid surface to be wet out by a liquid is characterized by the contact angle that the liquid makes with the solid surface after being deposited on the horizontally disposed surface and allowed to stabilize thereon. It is sometimes referred to as the “static equilibrium contact angle,” sometimes referred to herein merely as “contact angle”. As discussed in U.S. Pat. No. 6,372,954 B1 (Johnston et al.) and International Publication No. WO 99/09923 (Johnston et al.), the contact angle is the angle between a line tangent to the surface of a bead of liquid on a surface at its point of contact to the surface and the plane of the surface. A bead of liquid whose tangent was perpendicular to the plane of the surface would have a contact angle of 90 degrees. Typically, if the contact angle is 90 degrees or less, the solid surface is considered to be wet by the liquid. Liquid sample materials that yield a contact angle of near zero on a surface are considered to completely wet out the surface.
Frequently, horizontal surfaces on which drops of water at 20 degrees Celsius exhibit a contact angle of 90 degrees or less are considered to be hydrophilic while horizontal surfaces on which drops of water at 20 degrees Celsius exhibit a contact angle of more than 90 degrees are considered to be hydrophobic.
For the purposes of the present invention, it may be preferred that the hydrophilicity/hydrophobicity of surfaces be determined on a relative scale. For example, it may be preferred that the difference in contact angle between what would be considered hydrophilic and hydrophobic horizontal surfaces be about 10 degrees or more (or, in some instances, 20 degrees or more) for drops of water at 20 degrees Celsius. In other words, the hydrophobic surfaces of the present invention may exhibit a contact angle that is 10 degrees or more (or 20 degrees or more) higher than the contact angle of a hydrophilic surface (for water on a horizontal surface at 20 degrees Celsius).
As used herein, “hydrophilic” is used only to refer to the surface characteristics of a material, i.e., that it is wet by aqueous solutions, and does not express whether or not the material absorbs or adsorbs aqueous solutions. Accordingly, a material may be referred to as hydrophilic whether or not a layer of the material is impermeable or permeable to water or aqueous solutions.
In use, the flow directors 264 at the inlet end 265 may preferably assist in expanding the flow front across the width of the opposing surface 260 (and, thus, the detection chamber in which the opposing surface 260 is located) as fluid enters the detection chamber. As the fluid reaches the first cross-chamber channel 262, the flow front may preferably stop moving in the direction of outlet end 267 until the flow front extends across the width the opposing surface 260. Once the flow front reaches across the opposing surface 260, it may preferably advance to the next cross-chamber channel 262 where it again halts until the flow front extends across the width of the opposing surface 260.
The flow front proceeds in the manner described in the preceding paragraph until reaching the optional flow directors 266 near the outlet end of the opposing surface 260. There the flow is directed to the outlet end 267 of the detection chamber where it can be directed to the waste chamber as described herein.
The flow control features depicted in
The variety of flow front control approaches described herein may be used in combinations that are not explicitly depicted. For example, it may be preferred to use selected areas of hydrophobic and/or hydrophilic materials on the opposing surface in combination with physical structures (e.g., channels, discrete protruding structures, etc.) to provide control over the flow front progression through a detection chamber in the present invention. Further, although the interior volume of the detection chamber 30 may preferably have a generally rectilinear shape, it will be understood that detection chambers used in connection with the present invention may take other shapes, e.g., cylindrical, arcuate, etc.
Returning to
An optional port 22 may be provided in the staging chamber 20 (or in another location that leads to the interior of the cartridge 10) such that material may be introduced into the interior volume of the cartridge 10 by, e.g., by syringe, pipette, etc. If provided, the port 22 may be sealed by, e.g., a septum, a valve, and/or other structure before and/or after materials are inserted into the cartridge 10. In some embodiments, the port 22 may preferably include, e.g., an external structure designed to mate with a test sample delivery device, e.g., a Luer lock fitting, threaded fitting, etc. Although only one port 22 is depicted, it should be understood that two or more separate ports may be provided.
In some embodiments, the staging chamber 20 may be isolated from direct fluid communication with the detection chamber 30 by a flow control structure/mechanism 24 (e.g., a valve). If a flow control structure/mechanism 24 is provided to isolate the detection chamber 30 from the staging chamber 20, then the staging chamber 20 may potentially be more effectively used to store materials before releasing them into the detection chamber 30. In the absence of a flow control structure/mechanism 24, some control over the flow of materials into the detection chamber 30 may potentially be obtained by other techniques, e.g., holding the cartridge 10 in an orientation in which the force of gravity, centripetal forces, etc. may help to retain materials in the staging chamber 20 until their delivery to the detection chamber 30 is desired.
Another optional feature depicted in
Although depicted as monitoring the detection chamber 30, it should be understood that the fluid monitor may be located at any suitable location within the interior volume of the detection cartridge 10. For example, the fluid monitor could be located in the staging chamber 20, the waste chamber 40, etc. In addition, multiple fluid monitors may be employed at different locations within the cartridge 10.
Potential advantages of the fluid monitor 27 may include, e.g., the ability to automatically activate the introduction of sample materials, reagents, wash buffers, etc. in response to conditions sensed by the fluid monitor 27 that are employed in a feedback loop to, e.g., operate actuators 90 associated with modules 80, etc. Alternatively, the conditions sensed by the fluid monitor 27 can provide signals or feedback to a human operator for evaluation and/or action. For some applications, e.g., diagnostic healthcare applications, the fluid monitor 27 may be used to ensure that the detection cartridge is operating properly, i.e., receiving fluid within acceptable parameters.
Also depicted in
It may be preferred that the modules 80 be independent of each other such that the materials contained within each module 80 can be introduced into the detection cartridge at selected times, at selected rates, in selected orders, etc. In some instances an actuator 90 may be associated with each module 80 to move the materials within the module 80 into the cartridge 10. The actuators 90 may be selected based on the design of the module 80. The actuators 90 may be manually operated or they may be automated using, e.g., hydraulics, pneumatics, solenoids, stepper motors, etc.
A potential advantage of using modules 80 to deliver materials such as reagents, buffers, etc. may be the opportunity to tailor the cartridge 10 for use with a wide variety of sample materials, tests, etc.
Various aspects of the detection cartridge 10 schematically depicted in
It may be preferred that the sensor 450 be an acousto-mechanical sensor such as, e.g., a Love wave shear horizontal surface acoustic wave sensor. As depicted, the sensor 450 may preferably be attached such that, with the possible exception of its perimeter, the backside 454 of the sensor 450 (i.e., the surface facing away from the detection chamber 430) does not contact any other structures within the cartridge 410. Examples of some potentially suitable methods of attaching acousto-mechanical sensors within a cartridge that may be used in connection with the present invention may be found in, e.g., U.S. patent application Ser. No. 60/533,176, filed on Dec. 30, 2003 as well as PCT Application No. ______, titled “Surface Acoustic Wave Sensor Assemblies”, filed on even date herewith, (Attorney Docket No. 58928WO003).
It should, however, be understood that acousto-mechanical sensors represent only one class of sensors that may be used in connection with the present invention. Many other sensor technologies may be used in connection with the cartridges of the present invention, e.g., surface plasmon resonance, electrochemical detection, conductivity sensors, fluorescent microarrays, chemiluminescence, etc.
Regardless of the specific detection technology used in sensor 450, it may be preferred that the portion of the detection surface 452 exposed within the detection chamber 430 be positioned to contact sample material flowing through the detection chamber 430. It may be preferred, for example, that the detection surface 452 be located at the bottom (relative to gravitational forces) of the detection chamber 430 such that materials flowing through the detection chamber 430 are urged in the direction of the detection surface 452 through at least the force of gravity (if not through other forces).
The detection chamber 430 may also preferably include an opposing surface 460 spaced apart from and facing the detection surface 452. One or more different flow front control features may preferably be provided on the opposing surface 460 to assist in controlling the progression of a flow front through the detection chamber 430. Various examples of potentially suitable flow front control features are discussed herein.
It may be preferred that the opposing surface 460 and the detection surface 452 be spaced apart from each other such that the opposing surface 460 (and any features located thereon) does not contact the detection surface 452. With respect to acoustic sensors, even close proximity may adversely affect the properties of the sensor operation if the opposing surface 460 disrupts the propagation of acoustic energy by the detection surface 452. It may be preferred, for example, that spacing between the detection surface 452 and the lowermost feature of the opposing surface 460 facing the active part of the detection surface 452 be 20 micrometers or more, or even more preferably 50 micrometers or more. For effective flow front control, it may be preferred that the distance between the lowermost feature of the opposing surface 460 and the detection surface 452 be 10 millimeters, alternatively 1 millimeter or less, in some instances 500 micrometers or less, and in other instances 250 micrometers or less.
The cartridge 410 of
Although the volumetric flow control feature may take many different forms, in the embodiment depicted in
The porous membrane 474 may preferably provide a fluid pressure drop from the side facing the detection chamber 430 to the side facing the waste chamber 440. The porous membrane 474 preferably assists in controlling the flow rate from the detection chamber 430 into the waste chamber 440. The pressure drop may preferably be provided by capillary action of the passageways within the porous membrane 474. The pressure drop across a porous membrane is typically a function of the pore size and the thickness of the membrane. It may be preferred that the porous membrane have a pore size in the range of, e.g., 0.2 microns to 50 microns. Some suitable examples of materials that may be useful as a porous membrane include, e.g., acrylic copolymers, nitrocellulose, polyvinylidene fluoride (PVDF), polysulfone, polyethersulfone, nylon, polycarbonate, polyester, etc.
Referring to
The porous membrane 1474 is held in place by a cover plate 1475 that, in the preferred embodiment may be ultrasonically welded over the orifices 1471 with the porous membrane 1474 located therebetween. The cover plate 1475 may preferably include orifices 1479 through which fluids may pass into a waste chamber. The ultrasonic welding of the cover plate 1475 may be assisted by the use of an energy director 1477 surrounding the opening 1472 and the height of the energy director 1477 may be sufficient to allow some clearance for the thickness of the porous membrane 1474. In such a system, the cover plate 1475 and energy director 1477 may assist in the formation of a fluid-tight attachment without destruction of the porous membrane 1474. Other techniques for retaining the membrane 1474 over opening 1472 may also be used, e.g., adhesives, thermal welding, solvent welding, mechanical clamping, etc. These techniques may be used with or without a cover plate 1475, i.e., the porous membrane 1474 itself may be directly attached to the structures surrounding the opening 1472.
Referring again to the embodiment of
It may be preferred that negative fluid pressure within the waste chamber 440 be provided passively, e.g., through the use of absorbent material or other techniques that do not require the input of energy (as would, for example, maintaining a vacuum within the waste chamber). Examples of some potentially suitable absorbent materials that may provided within the waste chamber 440 may include, but are not limited to, foams (e.g., polyurethane, etc.), particulate materials (e.g., alumina-silicate, polyacrylic acid, etc.), granular materials (e.g., cellulose, wood pulp, etc.).
If the waste chamber 440 is provided with absorbent material 476 located therein as depicted in
If absorbent material 476 is provided within the waste chamber 440, it may be beneficial to provide a variety of layers of absorbent materials to control the volumetric flow rate into the waste chamber 440. For example, a first layer of absorbent material may be provided proximate the membrane 474, with the first layer material having a characteristic wicking rate and a defined fluid volume. After the first layer of absorbent material has been loaded to its capacity, the fluid entering the waste chamber 440 may be drawn into a second layer of absorbent material with a different wicking rate, thereby potentially providing a different negative pressure in the waste chamber 440.
Changing the negative pressure within the waste chamber 440 using, e.g., different layers of absorbent materials, may be used to compensate for other changes within the cartridge 410 such as, e.g., changes in fluid head pressure as sample material is drawn through the cartridge 410. Other techniques may also be used to compensate for changes in the fluid head pressure such as, e.g., changing a vacuum level held in the waste chamber, opening one or more vents in the cartridge, etc.
The embodiment of
Although depicted as being in direct fluid communication with the waste chamber 440, one or more vents may be provided and they may be directly connected to any suitable location that leads to the interior volume of the detection cartridge 410, e.g., staging chamber 420, detection chamber 430, etc. The vent 478 may take any suitable form, e.g., one or more voids, tubes, fitting, etc.
The vent 478 may preferably include a closure element 479 in the form of a seal, cap, valve, or other structure(s) to open, close or adjust the size of the vent opening. If provided as a seal, the seal may be adhesively or otherwise attached over or located within the vent 478. In some embodiments, the closure element 479 may be used to either open or close the vent. In other embodiments, the closure element 479 may be adjustable such that the size of the vent opening may be adjusted to at least one size between fully closed and fully open to adjust fluid flow rate through the detection cartridge 410. For example, increasing the size of the vent opening may increase fluid flow rate while restricting the size of the vent opening may cause a controllable reduction the fluid flow rate through the interior volume of the detection cartridge 410, e.g., through the staging chamber 420, detection chamber 430, etc. If the vent 478 includes multiple orifices, one or more of the orifices can be opened or closed to control fluid flow, etc.
In the embodiment of
In some instances, it may be preferred to provide both a porous membrane and one or more capillary channels to provide a capillary structure between the detection chamber and the waste chamber in detection cartridges of the present invention. Other capillary structures such as tubes, etc. could be substituted for the exemplary embodiments described herein.
Although the capillary channels 572 may draw fluid from the detection chamber 530, surface tension in the fluid may prevent the fluid from flowing out of the flow passage 570 and into the waste chamber. 540. As a result, it may be preferred to draw fluid from the flow passage 570 into the waste chamber 540 using, e.g., negative fluid pressure within the waste chamber 540. The negative fluid pressure within the waste chamber 540 may be provided using a variety of techniques. One technique for providing a negative fluid pressure within the waste chamber 540 may include, e.g., absorbent material 576 located within the waste chamber 540 as depicted in
It may be preferred that negative fluid pressure within the waste chamber 540 be provided passively, e.g., through the use of absorbent material or other techniques that do not require the input of energy (as would, for example, maintaining a vacuum within the waste chamber). The use of absorbent materials within a waste chamber is described above in connection with the embodiment depicted in
If absorbent materials are used within the waste chamber 540, it may be preferred that the absorbent material be in contact with the end or ends of any capillary channel(s) 572 to overcome any surface tension that might otherwise prevent fluid from exiting the capillary channel(s).
Referring again to the cartridge depicted in
Also, the fluid path between the staging chamber 420 and the detection chamber 430 may be open as depicted in
Another optional feature depicted in
Potential advantages of the fluid monitor 427 may include, e.g., the ability to automatically activate the introduction of sample materials, reagents, wash buffers, etc. in response to conditions sensed by the fluid monitor 427. Alternatively, the conditions sensed by the fluid monitor 427 can provide signals or feedback to a human operator for evaluation and/or action. For some applications, e.g., diagnostic healthcare applications, the fluid monitor 427 may be used to ensure that the detection cartridge is operating properly, i.e., receiving fluid within acceptable parameters.
The exemplary cartridge 410 depicted in
Although other exemplary embodiments of modules that may be used to introduce materials into the cartridge 410 are described elsewhere, each of the modules 480 depicted in
In the depicted embodiment, the plunger 481 may preferably be designed to pierce, tear or otherwise open the seal 489 to allow the materials with the modules 480 to enter the staging chamber 420. The depicted plungers 481 include piercing tips for that purpose. It should be understood that the modules 480 could be isolated from the staging chamber 420 by valves or any other suitable fluid structure used to control movement of materials between chambers.
One variation depicted in PIG. 6 is that the upper module 480 includes a port 490 opening into the chamber 486 of the module 480. The port 490 may be used to deliver materials into the chamber 486 for subsequent delivery to the staging chamber using the module 480. For example, the port 490 may be used to introduce a collected specimen, etc. into the module 480 where it can then be introduced into the staging chamber 420 at selected times and/or rates. In addition, the chamber 486 of the module 480 receiving the sample material may include one or more reagents or other materials that may contact the sample material upon its introduction to the module 480. Although not depicted, it may be preferred that the port 490 be sealed before and/or after sample material is introduced into the module 480 using a valve or other structures/materials. The port 490 may be sealed by, e.g., a septum, a valve, induction welded seal, cap, and/or other structure before and/or after materials are inserted into the module 480.
One exemplary embodiment of a module 680 that may be used to deliver reagents and/or other materials in accordance with the present invention is depicted in the cross-sectional views of
By storing the different materials within separate chambers, it may be possible to provide materials in the module 680 that are preferably not mixed until needed. For example, some substances may preferably be stored in a dry state to, e.g., prolong their shelf life, usable life, etc., but the same substances may need to be mixed in liquids that may include water, etc. to provide a usable product. By providing the ability to mix and/or dispense these materials on demand, the modules of the present invention can provide a convenient storage and introduction device for many different materials.
The depicted module 680 includes three chambers 684, 686 and 688 within housing 695. The chambers may preferably be separated by a seal 685 (located between chambers 684 and 686) and seal 687 (located between chambers 686 and 688). The depicted module 680 also includes plunger 681 with a tip 683 that, in the depicted embodiment, is designed to pierce seals 685 and 687 as the plunger 681 is moved from the loaded position depicted in
As the plunger 681 is advanced towards the exit port 682, the tip 683 also preferably pierces seal 687 such that the materials 694 in the chamber 688 can preferably contact the materials 690 and 692 from chambers 684 and 686.
When fully advanced towards the exit port 682, the tip 683 may preferably pierce exit seal 689 provided over exit port 682, thereby releasing the materials 690, 692 and 694 from fluid module 680 and into, e.g., a staging chamber or other space. It may be preferred that the shape of the plunger 681 and tip 683 mate with the shape of the final chamber 688 and exit port 682 such that substantially all of the materials in the various chambers are forced out of the fluid module 680 when the plunger 681 is advanced completely through the fluid module 680 (i.e., all of the way to the right of
Furthermore, it may be preferred that the tip 1683 be provided in a shape or with features that facilitate the transfer of materials past the seals pierced by the tip 1683. The feature may be as simple as a channel 1697 formed in an otherwise conical tip 1683 as depicted in
The plunger 681 in module 680 may be moved by any suitable actuator or technique. For example, the plunger 681 may be driven by a mechanical device (e.g., piston) inserted into module 680 through driver opening 698 or fluid pressure may be introduced into module 680 through driver opening 698 to move the plunger 681 in the desired direction. It may be preferred to drive the plunger 681 using, e.g., a stepper motor or other controlled mechanical structure to allow for enhanced control over the movement of plunger 681 (and any associated structure such as, e.g., tip 683). Other means for moving plunger 681 will be known to those skilled in the art, e.g., solenoid assemblies, hydraulic assemblies, pneumatic assemblies, etc.
The module 680, plunger 681 and tip 683 may be constructed of any suitable material or materials, e.g., polymers, metals, glasses, silicon, ceramics, etc. that provide the desired qualities or mechanical properties and that are compatible with the materials to be stored in the fluid modules. Similarly, the seals 685, 687 and 689 may be manufactured of any suitable material or materials, e.g., polymers, metals, glasses, etc. For example, the seals may preferably be manufactured from polymer film/metallic foil composites to provide desired barrier properties and compatibility with the various materials to be stored in the module 680.
It may be preferred that the materials used for both the seals and the module housing be compatible with the attachment technique or techniques used to attach the seals in a manner that prevents leakage between the different chambers. Examples of some attachment techniques that may be used in connection with modules 680 include, e.g., heat sealing, adhesives, chemical welding, heat welding, ultrasonic welding, combinations thereof, etc. It should also be understood that the modules may be constructed such that the seals are held in place by friction, compression, etc. Furthermore, it should be understood that in some embodiments, it may be possible to open the seals in a fluid module without the use of tip or other structure that pierces the seals. For example, the seals may be opened through fluid pressure alone (i.e., the seals may be designed to burst under pressure as the plunger is moved from the loaded position towards the exit port using, e.g., a line of weakness formed in the seal, etc.).
Sensor Considerations
The systems and methods of the present invention may preferably detect the presence of target biological analyte in a test sample through the use of acousto-mechanical energy that is measured or otherwise sensed to determine wave attenuation, phase changes, frequency changes, and/or resonant frequency changes.
The acousto-mechanical energy may be generated using, e.g., piezoelectric-based surface acoustic wave (SAW) devices. As described in, e.g., U.S. Pat. No. 5,814,525 (Renschler et al.), the class of piezoelectric-based acoustic mechanical devices can be further subdivided into surface acoustic wave (SAW), acoustic plate mode (APM), or quartz crystal microbalance (QCM) devices depending on their mode of detection.
In some embodiments, the systems and methods of the present invention may be used to detect a target biological analyte attached to a detection surface. In other embodiments, the devices may be used to detect a physical change in a liquid (e.g., an aqueous solution), such as, e.g., a change in viscosity, that is indicative of the presence of the target biological analyte. The propagation velocity of the surface wave is a sensitive probe that may be capable of detecting changes such as mass, elasticity, viscoelasticity, conductivity and dielectric constant in a medium in contact with the detection surface of an acousto-mechanical sensor. Thus, changes in one or more of these (or potentially other) physical properties may result in changes in the attenuation of the surface acoustic wave.
APM devices operate on a similar principle to SAW devices, except that the acoustic wave used can be operated with the device in contact with a liquid. Similarly, an alternating voltage applied to the two opposite electrodes on a QCM (typically AT-cut quartz) device induces a thickness shear wave mode whose resonance frequency changes in proportion to mass changes in a coating material.
The direction of the acoustic wave propagation (e.g., in a plane parallel to the waveguide or perpendicular to the plane of the waveguide) may be determined by the crystal-cut of the piezoelectric material from which the biosensor is constructed. SAW biosensors in which the majority of the acoustic wave propagates in and out of the plane (e.g., Rayleigh wave, most Lamb-waves) are typically not employed in liquid sensing applications because of acoustic damping from the liquid in contact with the surface.
For liquid sample mediums, a shear horizontal surface acoustic wave biosensor (SH-SAW) may preferably be used. SH-SAW sensors are typically constructed from a piezoelectric material with a crystal-cut and orientation that allows the wave propagation to be rotated to a shear horizontal mode, i.e., parallel to the plane defined by the waveguide, resulting in reduced acoustic damping loss to a liquid in contact with the detection surface. Shear horizontal acoustic waves may include, e.g., thickness shear modes (TSM), acoustic plate modes (APM), surface skimming bulk waves (SSBW), Love-waves, leaky acoustic waves (LSAW), and Bleustein-Gulyaev (BG) waves.
In particular, Love wave sensors may include a substrate supporting a SH wave mode such as SSBW of ST quartz or the leaky wave of 36° YXLiTaO3. These modes may preferably be converted into a Love-wave mode by application of thin acoustic guiding layer or waveguide. These waves are frequency dependent and can be generated if the shear wave velocity of the waveguide layer is lower than that of the piezoelectric substrate.
Waveguide materials may preferably be materials that exhibit one or more of the following properties: low acoustic losses, low electrical conductivity, robustness and stability in water and aqueous solutions, relatively low acoustic velocities, hydrophobicity, higher molecular weights, highly cross-linked, etc. In one example, SiO2 has been used as an acoustic waveguide layer on a quartz substrate. Examples of other thermoplastic and crosslinked polymeric waveguide materials include, e.g., epoxy, polymethylmethacrylate, phenolic resin (e.g., NOVALAC), polyimide, polystyrene, etc.
Other potentially suitable materials and constructions for use with acousto-mechanical sensors used in the detection cartridges of the present invention may be described in, e.g., PCT Application No. ______, titled “Acoustic Sensors and Methods”, filed on even date herewith (Attorney Docket No. 60209WO003).
Alternatively, QCM devices can also be used with liquid sample mediums. Biosensors employing acousto-mechanical devices and components may be described in, e.g., U.S. Pat. No. 5,076,094 (Frye et al.); U.S. Pat. No. 5,117,146 (Martin et al.); U.S. Pat. No. 5,235,235 (Martin et al.); U.S. Pat. No. 5,151,110 (Bein et al.); U.S. Pat. No. 5,763,283 (Cernosek et al.); U.S. Pat. No. 5,814,525 (Renschler et al.); U.S. Pat. No. 5,836,203 ((Martin et al.); and U.S. Pat. No. 6,232,139 (Casalnuovo et al.). Shear horizontal SAW devices can be obtained from various manufacturers such as Sandia Corporation, Albuquerque, New Mexico. Some SH-SAW biosensors that may be used in connection with the present invention may also described in Branch et al., “Low-level detection of a Bacillus anthracis simulant using Love-wave biosensors on 36° YX LiTaO3,” Biosensors and Bioelectronics (accepted 22 Aug. 2003).
As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a” or “the” component may include one or more of the components and equivalents thereof known to those skilled in the art.
All references and publications cited herein are expressly incorporated herein by reference in their entirety into this disclosure. Exemplary embodiments of this invention are discussed and reference has been made to some possible variations within the scope of this invention. These and other variations and modifications in the invention will be apparent to those skilled in the art without departing from the scope of the invention, and it should be understood that this invention is not limited to the exemplary embodiments set forth herein. Accordingly, the invention is to be limited only by the claims provided below and equivalents thereof.
The present application claims priority to U.S. Provisional Patent Application Ser. No. 60/533,169, filed on Dec. 30, 2003, which is hereby incorporated by reference in its entirety.
The U.S. Government may have certain rights to this invention under the terms of DAAD 13-03-C-0047 granted by Department of Defense.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US04/42455 | 12/17/2004 | WO | 4/2/2007 |
| Number | Date | Country | |
|---|---|---|---|
| 60533169 | Dec 2003 | US |
