Patent Application
20050208648
This application claims priority to and subject matter disclosed in provisional application No. 60/553,564, filed on Mar. 17, 2004; the content of this application being incorporated by reference herein in its entirety. This application also claims subject matter disclosed in issued U.S. Pat. No. 6,582,393, issued Jun. 24, 2003, the contents of which are also incorporated by reference herein in their entirety.
This invention relates to minimally invasive devices and methods for determining the concentration of compounds in body fluids of animals by means of microdialysis. Specifically, it relates to measurement of therapeutically useful analytes such as lactate and glucose in interstitial fluid.
Microdialysis as a method of determining the concentration of compounds such as lactate and glucose in body fluids such as blood and interstitial fluid is well known. In 1987 Lonnroth, et al published “A microdialysis method allowing characterization of intercellular water space in humans” in the American Journal of Physiology 253:E228-E231. Further, in 1995, Stemberg, et al published “Subcutaneous glucose in humans: real time estimation and continuous monitoring” in Diabetes Care 18:1266-1269. The purpose of the efforts of Stemberg, et al, and the efforts and devices of many others working in the field of microdialysis, was to improve the measurement of glucose in blood and other body fluids, and thereby improve the quality of therapy for diabetes. In spite of these efforts, while significant progress has been made, there is yet no basis for a suitable product based on microdialysis.
Many products are currently marketed to measure blood glucose. One class of these products, known as glucose strips and meters, require a blood sample, usually from a fingertip. Strips and meters provide a satisfactory result when they are used, but they only provide a single result for each use. In diabetes, the glucose concentration in the body can change so quickly and so much that a single measurement, while being meaningful at the time it is taken, has little value even a short time later. In general, the more frequently the glucose concentration is measured, the better diabetes can be managed. From a practical point of view, though, a new and accurate glucose measurement with minimal time lag (delay caused by the time it takes to remove the specimen and make the measurement) every three to five minutes is adequate to effectively manage even the most brittle cases of diabetes.
This need for more frequent glucose measurements led to a second class of glucose measuring systems (known as “needle” sensors) that monitor glucose continuously. For over two decades, devices of this class, that measure glucose in a blood vessel or in interstitial fluid just below the surface of the skin, have been under development. Recently, such a device for use in interstitial fluid, developed by the MiniMed Corporation, was approved for sale. It can be used for up to three days.
This product, and other “needle sensors” currently under development, must be calibrated by a blood glucose measurement, usually obtained from fingerstick blood using a “strip and meter” device. The need for calibration is caused by a decrease in the sensitivity of the sensor to glucose over time during use. The sensor must be calibrated once when the product is first placed in the skin and, in the case of the approved product, as frequently as every eight hours until it is removed. While this system does provide superior glucose information, it is inconvenient for the user, who must both insert the needle and provide calibration as needed from fingerstick glucose measurements.
To avoid the decrease in sensitivity with time exhibited by the “needle sensors”, microdialysis systems for glucose were developed. These systems moved the actual glucose assay from the tip of the needle sensor, which is inside the body, to a place outside the body. This change of location resulted in a much more stable glucose sensitivity. However, a microdialysis system is more complicated than a needle sensor, and frequently requires perfusion of large volumes of fluid through the microdialysis needle, making the device too big for routine personal use. The volumes of fluids required for a day of use, for example, in the microdialysis system described by Pfeiffer in U.S. Pat. No. 5,640,954, were measured in hundreds of milliliters to liters per day.
Korf, in U.S. Pat. No. 6,013,029 describes an improved microdialysis system that uses much less fluid. In the preferred flow rate range specified by Korf, less than 20 microliters per hour, the amount of fluid required for a days use is less than 480 microliters, a volume that can be very comfortably worn. However, while Korf describes in detail the operation of his system, he does not provide details of construction of an interface which would be preferred for use in a microdialysis system.
Knoll, in U.S. Pat. No. 6,287,438 describes in broad detail many devices for use in sampling fluids for subsequent analysis, including devices that may be used in microdialysis systems. The systems of Knoll are comprised of laminates of multiple layers of materials each layer included to perform a specific function. The appeal of these devices is that each layer may comprise replicates of the pattern required for that layer, and that during manufacture, the several layers may be laminated in bulk, and the individual devices thus assembled cut out as finished devices.
Effenhauser, in U.S. Pat. No. 6,572,566 also describes a device comprised of several layers. Effenhauser, however, takes a broader approach than Knoll in that he includes in his device reservoirs for the reagents. Effenhauser, Korf, and Knoll all understand the need for smaller and more compact systems and each provides devices which consume minimal amounts of fluids thereby permitting an overall device size which may be conveniently worn by a user. Knoll, on the one hand, in U.S. Pat. No. 6,287,438, goes to great lengths to specify the materials that may be used in the construction of his device. Korf in U.S. Pat. No. 6,287,438 and Effenhauser in U.S. Pat. No. 6,572,566 on the other hand, while they discuss in great detail the many modes of operation of their devices, are quite vague on materials preferred for the construction of their devices.
Despite the advances described in U.S. Pat. No. 6,013,029, U.S. Pat. Nos. 6,287,438, and 6,572,566, there remain a number of unresolved issues that must be solved before a truly commercializable system is possible. The first such issue relates to body access. The sampling system, usually referred to as a microdialysis needle, must be constructed in such a way to permit easy and relatively painless placement of the needle in contact with the preferred body fluid. For easy and relatively painless body access, the support material must be extremely stiff so that it doesn't bend during insertion into body tissue, it must be able to bend without breaking, and it must be machinable so that a sharp point may be created for tissue penetration. Neither Korf nor Effenhauser describe materials preferred for body access, and none of the materials named by Knoll, that is the plastics, glass, ceramic nor silicon, are described as preferred for this purpose. Indeed—glass, ceramic and silicon are brittle, and subject to breaking upon skin penetration. And none of the plastics mentioned are capable of taking a sharp point for skin penetration.
A second unresolved issue relates to the size of the sampling system. While Korf dwells on overall system size, the dimensions of preferred interfaces are not detailed. And while Effenhauser does describe preferred channel dimensions and sampling fluid flow rates, preferred dimensions of the body access member are not described. Knoll does mention preferred dimensions of the body access member as being from 1 to 10 centimeters in length, 5 to 50 millimeters in width, and 0.1 to 1 millimeter in thickness. Even at the minimums of these dimensions, body access is almost certainly going to be painful.
A third unresolved issue relates to registration and alignment of the various layers during manufacture in the devices of Knoll and Effenhauser. Improper manufacture will result in the devices not functioning as described. Methods of assembly are not provided by Knoll, other than an occasional reference to adhesive bonding, although the methods of creating the various layers are listed exhaustively. When layers such as described are assembled, it is crucial that the various elements of the layers be aligned. Otherwise, for example, through holes may not line up with channels, and flow through the system may not occur or improperly occur.
Thus, there remains a need for improvements to provide a truly commercializable system.
It is an object of at least some of the embodiments of this invention to provide a microdialysis system that may be easily and comfortably worn. The size of the system is such that the user may apply the system to the body using a skin adhesive and use the system for up to three days.
It is a second object of at least some of the embodiments of the invention to provide a microdialysis system which permits the user easy and comfortable body access. The dimensions and materials of the body access components are such that the user may perform the function with ease and a minimum of pain.
It is a further object of at least some of the embodiments of this invention is to provide a system design which permits cost-effective manufacturing and such that precise registration and alignment of the various components and layers is not required.
A microdialysis needle will be described wherein the needle substrate is made of a structural metal, and in one embodiment is made of stainless steel. Stainless steel is rigid enough, even in a small cross-section to permit skin penetration, it almost never breaks during insertion, may be machined to a sharp enough point that skin penetration is nearly painless, and is biocompatible.
The microdialysis needle of an exemplary embodiment of the current invention may be fabricated using photolithographic techniques. Using a structural metal support, a photoresist layer is added to the upper surface of the support. Using an appropriate pattern to create the necessary microfluidic pathways in the photoresist layer, this photoresist layer is exposed using standard photolithographic techniques. The photoresist layer is then partially hardened and etched using methods well known in the art. In one embodiment, the etching is such that channels in the photoresist layer are made completely through the photoresist layer. In one embodiment, the photoresist material is the epoxy SU-8 manufactured by MicroChem Corporation, Newton, Mass. After etching, a semipermeable membrane is placed on the partially hardened photoresist layer. The assembly is now heated further such that the partially hardened photoresist layer hardens further, adhering the semipermeable membrane to the photoresist layer. In a final step of one embodiment of the invention, the assembly is coated with a thin layer of an insulating material which will conformally coat the entire assembly. This coating material may be parylene which when applied by continuous vapor deposition, will conformally coat the assembly, including the microfluidic pathway beneath the semipermeable membrane, thereby creating a non-electrically conducting microfluidic channel.
An exploded view of one embodiment of the invention is shown in
The device shown is
Support 14 of
To create layer 11 on support 14/61 in
The photoresist layer, still in liquid form but of uniform thickness, is then partially hardened. Partial hardening may be done by heating or other methods appropriate for the material.
To create the microfluidic network required for the sensor in layer 11, an example of which is shown in
To complete the basic assembly of the microdialysis sensor, a semi-permeable membrane 12 is placed over the microfluidic network in photoresist layer 11. Alignment of membrane 12 with respect to the microfluidic network is not critical in some embodiments. In the needle portion of the sensor, the microfluidic network comprises a microdialysis channel that combines with membrane 12 to form an analyte exchange region. This is the region of the sensor that will be in contact with body fluid. In this analyte exchange region, the body analyte is able to move across membrane 12 in either direction, that is, into or out of the microdialysis channel. In the analysis section of the sensor, the membrane may be removed as described later, or may be left intact to protect electrodes.
The membrane 12 is adhered to the partially hardened layer 11 by simply placing the membrane in contact with layer 11 and heating the partially assembled sensor further. In one embodiment where the photoresist layer is SU-8 and the membrane is a polycarbonate film with pores created by the track etch method, this heating further hardens layer 11 and causes strong adherence of the membrane to the photoresist layer. The track-etch method of formation of a semipermeable membrane is well known in the field. The Whatman-Nuclepore website provides a description of this method. The content of this site is incorporated herein by reference. An advantage of track-etch membranes in this use is that these membranes do not permit lateral motion of fluids—the only motion is through the membrane-thereby preventing leakage from one part of the microfluidic network to another.
To seal the assembly, the sensor at this stage of assembly is conformally coated with an insulator (not shown). In one embodiment of the assembly process, this insulator is provided by continuous vapor deposition. In this process, the insulating material is provided in a vapor phase in a chamber that also contains the objects to be coated. When the insulator material is parylene, the coating can be conformal over the entirely of the object, including the metallic bottoms of the channels and chambers of microfluidic network which are exposed if the etching process of layer 11 is a through etch. An advantage of selecting parylene as the insulator is that conformal coatings of parylene formed by the continuous vapor deposition process can be pinhole free at thicknesses of 10 nanometers or more. At this insulator layer thickness, the pores in the track-etch membrane, which may have a diameter as small as 50 nanometers, are not filled during the insulator deposition process but are merely slightly reduced in diameter.
The next step in the fabrication method is to cut out the microfluidic elements from the support. This may be easily done by laser cutting as is known in the industry, but may also be done by die cutting or other such methods. The process of cutting out the microfluidic elements as shown in
The final step in the creation of the microdialysis sensor according to the invention is to add manifold layer 13 to the insulator coated membrane surface of the assembled microfluidic network. Fluid access ports 15 are provided to supply the required fluids to operate the sensor and electrical access leads 17 are provided for the electrochemical aspects of the sensor. Fluid access ports 15 are shown so that they align with similar chambers in photoresist layer 11 in
As may be seen by
The microdialysis sensor of some embodiments of the present invention operates in the following exemplary manner (for a more complete description of the operation of this sensor and operational variants, see copending patent application Ser. No. 10/059,390 entitled Self-Calibrating Body Analyte Monitoring System filed Jan. 31, 2002 which is incorporated herein in its entirely by reference. Perfusate is introduced into the sensor through the lower of fluid access ports 15 in
The body analyte sensor according to some embodiments of the present invention may be used to monitor or measure the concentration of many compounds in many solutions and is not limited to the above example of monitoring the concentration of glucose in a body fluid such as interstitial fluid. Other endogenous compounds such as lactate, or pharmaceutical agents such as theophylline in the treatment of asthma or various anticoagulants in the treatment of thrombosis may be measured. And other body fluids such as blood or cerebral spinal fluid may be sampled using this sensor. Further, at least some of the embodiments of this invention may be used with a self-calibrating system.
In view of the above, some embodiments of the Body Analyte Monitoring System Assembly as described above and/or according to other embodiments of the present invention may be used in combination with one or more of the embodiments of the drug delivery systems described in U.S. application Ser. No. 10/146,588 dated May 15, 2002 and/or U.S. application Ser. No. 10/600,296 dated Jun. 20, 2003, and/or copending application Ser. No. 10/059,390, filed Jan. 31, 2002, and/or U.S. application Ser. No. 09/867,003 filed May 29, 2001, now U.S. Pat. No. 6,582,393, issued Jun. 24, 2003, and/or U.S. application Ser. No. 10/662,871 dated Sep. 16, 2003, and/or copending application number and/or copending application Ser. No. 10/786,562 filed on Feb. 26, 2004, and/or provisional application No. 60/553,564 filed on Mar. 17, 2004. Thus, some embodiments of the present invention include the combination of a body analyte monitoring system/self-calibrating body analyte monitoring system utilizing the Body Analyte Monitoring System Assembly as disclosed herein in combination with a drug delivery system, which may be, by way of example and not by way of limitation, in a single integrated system and/or in two or more quasi-separate systems in communication with each other which may, again by example, be worn or otherwise carried by a user. In such embodiments, a Body Analyte Monitoring System Assembly as described herein may be utilized in or with a body analyte monitoring system/self-calibrating body analyte monitoring system to monitor a body analyte and/or a drug delivery system to control the amount/rate/dosage, etc., of drug delivered to the user based on the results of monitoring by the body analyte monitoring system utilizing the Body Analyte Monitoring System Assembly. Thus, in some embodiments, a device/method may be manufactured/used where the two systems/assemblies work together to ensure/help ensure that a patient receives proper/adequate amounts of a beneficial drug.
While specific embodiments of the invention have been described in detail, it will be appreciated by those skilled in the art that various modifications and alternatives to those details could be developed in light of the teaching of the disclosure. Accordingly, the particular embodiment described in detail is meant to be illustrative and not limiting as to the scope of the invention, which is to be given the full breadth of the appended claims and any and all equivalents thereof.
| Number | Date | Country | |
|---|---|---|---|
| 60553564 | Mar 2004 | US |
