|Publication number||US20080058624 A1|
|Application number||US 11/980,853|
|Publication date||Mar 6, 2008|
|Filing date||Oct 30, 2007|
|Priority date||Mar 26, 2001|
|Also published as||EP1379165A2, US7310543, US20020137998, US20080097171, WO2002077638A2, WO2002077638A3|
|Publication number||11980853, 980853, US 2008/0058624 A1, US 2008/058624 A1, US 20080058624 A1, US 20080058624A1, US 2008058624 A1, US 2008058624A1, US-A1-20080058624, US-A1-2008058624, US2008/0058624A1, US2008/058624A1, US20080058624 A1, US20080058624A1, US2008058624 A1, US2008058624A1|
|Inventors||Wilson Smart, Kumar Subramanian, Eugene Orloff|
|Original Assignee||Wilson Smart, Kumar Subramanian, Eugene Orloff|
|Export Citation||BiBTeX, EndNote, RefMan|
|Referenced by (15), Classifications (13)|
|External Links: USPTO, USPTO Assignment, Espacenet|
The present application is a division of U.S. patent application Ser. No. 09/816,472 filed on Mar. 26, 2001, which is pending.
This invention relates to silicon microprobes, and more particularly to microprobes with biosensor capability incorporated therein for measuring analyte concentrations in a subject's blood, tissue, or other bodily fluids.
Diabetes mellitus is an insidious disease which affects more than 15 million Americans. About 1.5 million of these are Type I diabetics (insulin-dependent) and 12 to 14 million are Type II diabetics (noninsulin-dependent). The characteristics of diabetes include chronic and persistently high levels of glucose in blood and in urine. Although urine glucose has been used to monitor glucose levels, the measurement of blood glucose is more reliable and logistically feasible. Blood glucose has therefore become the most commonly followed clinical marker for monitoring the progress of diabetes (and other diseases) to determine treatment and control protocols. Glucose levels are routinely measured in doctors' offices, clinical laboratories, and hospitals. However, the most convenient and important measuring is in-home self-monitoring of blood glucose levels by the patients themselves to permit adjustment of the quantities of insulin and hypoglycemics administered. Such self-monitoring is known as self-monitored blood glucose. Normal blood glucose levels in humans are in the 70-100 mg/dl range and in the 160-200 mg/dl range after a heavy meal.
There are many products for diabetes related testing of glucose for diagnostic and monitoring purposes. These products range from skin swabs, reagent test strips, portable electronic meters, sensors and other instruments, lancets and needles of various shapes and sizes, syringes and other paraphernalia. Most of the currently available technologies, especially for self-monitored blood glucose measurements, are not satisfactory because they require some kind of deep lancing or finger stick with associated pain and sometimes excessive bleeding.
The smallest lancet or needle currently marketed for blood sampling has a diameter between 300 micrometers and 500 micrometers, and is constructed of stainless steel with beveled edges. Due to the large cross-section of these lancets, fingertip lancing is painful and frequent lancing causes calluses, impairment of the use of hands, psychological trauma and other unpleasant consequences. Further, blood samples recovered from the patient must be transferred to a test strip or cartridge for assaying analyte concentrations. Obtaining blood samples by lancing and performing the analysis can be messy as well as painful for the patient.
It is therefore an object of this invention to provide a miniature microprobe device with integrated analyte sensing capability. The analyte concentration is determined by a biosensor built into the microprobe, which is in data communication with an external meter via an analyte signal. A blood sample is not transferred from the subject to an external test mechanism as in the prior art. The present self-contained process minimizes messy blood smears, which is convenient for the subjects. Further, the closed nature of the present process also minimizes ambient exposure of the subject's blood. Blood may harbor undesirable biological forms (such as HIV) which could contaminate the local environment constituting a biohazard. By eliminating the blood transfer step, the present microprobe avoids such hazard.
It is another object of this invention to provide such a miniature microprobe device which accesses the blood and determines the analyte concentration in one simple step. The subject simply places the microprobe in a holder against the skin and waits for a signal to be sent to an external meter. The microprobe penetrates the stratum corneum (the tough outer layer of the skin) and contacts the tissue within. A separate ex vivo testing step with testing strips and the like is not required. The present one-step process eliminates the following prior art steps:
It is a further object of this invention to provide such a miniature microprobe device which is fabricated from a silicon wafer. A biosensor may be integrated into the surface of the microprobe. Alternately, the biosensor may be placed in a cavity in the surface of the silicon.
Silicon is compatible with integrated circuit (IC) fabrication and MEMS (microelectromechanical systems) technologies employing well established masking, deposition, etching, and high resolution photolithographic techniques. The present microprobe devices may be fabricated in mass quantities from silicon wafers through automatic IC and MEMS processing steps at minimal cost per device.
It is a further object of this invention to provide such a miniature microprobe device which minimizes subject discomfort during probe penetration and analyte measurement. The dimensions of the probe (length, width, and thickness) are very small and cause minimal tissue displacement and related lateral tissue pressure and nerve ending contact. In some cases the displacement may be so minimal that the subject feels no sensation at all during the process. For example in a clinical trial of 62 patients using a microprobe with a thickness of 100 micrometers, the majority found the insertion and retraction of the microprobe device in the arm to be painless. Of the total patients tested, 15% could not even feel the probe penetration and an additional 58% found the penetration to be barely noticeable.
It is a further object of this invention to provide such a miniature microprobe device which minimizes mechanical probe failure (breakage) during penetration and removal. Only minimal penetration effort is required due to the small probe cross-section defined by the width and thickness dimensions. These dimensions are much smaller than those of conventional metal lancets. The microprobe device retains the single-crystal structure of the silicon starting wafer and can reliably penetrate skin without breakage because of the strength provided by this single-crystal structure. The strength of the miniature probe may be further increased by optimal shaping. Data from skin puncturing tests show that the average force required to puncture the skin (0.038 Newton) is minimal compared to the buckling force required to break the probe (0.134 Newton).
It is a further object of this invention to provide such a miniature microprobe device which functions in vivo. The biosensor may be located near the probe tip for maximum penetration. The biosensors may be placed in a cavity in the surface of the silicon. The probe accesses the blood, and the analyte signal is carried along the length of the probe to the ex vivo environment by conductive leads.
It is a further object of this invention to provide such a miniature microprobe device which functions ex vivo. The biosensor may be distant from the probe on an ex vivo portion of the device, and not in direct contact with the analyte tissue. The blood is transported from the in vivo probe tip to the ex vivo portion by one or more channels.
It is a further object of this invention to provide such a miniature microprobe device which may be emplaced into the skin of the subject for a single measurement of analytes.
It is a further object of this invention to provide such a miniature microprobe device which may be installed on the subject for continuous monitoring of analytes.
It is a further object of this invention to provide such a miniature microprobe device which has multiple biosensors. The biosensor(s) may be formed by IC fabrication and are significantly smaller than the microprobe. Several biosensors may be spaced along a single microprobe for sensing several analytes per penetration, or for sensing the same analyte at different depths.
Briefly, these and other objects of the present invention are accomplished by providing a biosensor microprobe device for providing a signal to an external analyte meter. The signal indicates analyte presence in an analyte-containing fluid of a subject. The device is fabricated from a silicon wafer and has a body portion and a microprobe portion. The microprobe has a body end connected to the body portion, and having a penetration end extending away from the body portion for penetrating into the subject to access the bodily fluid. A biosensor integrated into the silicon substrate senses analyte presence and provides a signal in response to the analyte presence.
Further objects and advantages of the present microprobe and the operation of the biosensor become apparent from the following detailed description and drawings (not drawn to scale) in which:
The first digit of each reference numeral in the above figures indicates the figure in which an element or feature is most prominently shown. The second digit indicates related elements or features, and a final letter (when used) indicates a sub-portion of an element or feature.
The table below lists the reference numerals employed in the figures, and identifies the element designated by each numeral.
Microprobe device 10 provides an analyte signal from biosensor 12 to an external analyte meter (not shown) indicating analyte presence in an analyte-containing fluid of a subject (not shown). Silicon substrate 10S extends in the X length dimension, and the Y width dimension, and the Z thickness dimension, forming large body portion 14 and pointed microprobe portion 16 (as shown in
In the in vivo embodiment the biosensor is positioned on the microprobe sufficiently distant from the body end to pass into the subject during penetration. Positioning the biosensor ex vivo affords greater flexibility in reagent selection. As shown in
Diabetes monitoring is the primary focus of this disclosure for illustrative purposes. However, the microprobe device has uses in the diagnostic procedures and treatment of other diseases, emergency room status monitoring, sports medicine, veterinary medicine, research and development, with human subjects or experimental animals.
The microprobe may be width tapered along the X length dimension, converging from a larger Y width dimension (of about 200 micrometers) at the body end to a smaller Y width dimension (of about 30 micrometers) at the penetration end. The X length of the microprobe may be from about 0.5 mm to about 2.5 mm with a penetration depth of from about 0.5 mm to about 2 mm. The discomfort or sensation experienced by the subject normally decreases with decreasing probe cross-section and length. However, a sensation floor exists where sensation is so minimal that probes smaller then this floor threshold do not offer any advantage. The taper permits easier penetration due to the gradually increasing cross-section of the probe. In addition, the taper reduces the volume of the probe causing less tissue displacement and less discomfort to the subject. The volume of the probe may be further reduced by thinning the Z dimension (see
The convergence of the microprobe taper may be uniform (as shown in
In the ex vivo embodiment biosensor 22 is positioned on body 24 of device 20, and does not to pass into the subject during penetration. Alternatively, the biosensor may be positioned on the microprobe sufficiently close to the body end so as not to penetrate. The analyte fluid may be guided along microprobe 26 to biosensor 22 through a suitable conduit such as open fluid channel or groove 26G formed along the probe. The channel extends between the penetration end of the probe and the biosensor, and conveys the fluid by capillary action. The absence of a prior art type internal bore along the length of the probe reduces the probe diameter and simplifies probe fabrication. The open fluid channel may be a V-groove etched in the silicon of microprobe 26. The minute dimensions along apex 26A of triangular groove 26G (shown in
In general the biosensor may be an electrotype biosensor (see
The biosensor may be integrated into the surface of the substrate, or housed in a cavity formed in the substrate or in a hole extending through the substrate. The surface of side 10A of silicon substrate 10S is planar (see
The electrotype biosensor may have a suitable electrically insulative layer such as silicon oxide film 10F (see
Multiple biosensors may be employed on a single probe. Each of these multiple biosensors may sense the presence of a different analyte. Further, each of the multiple biosensors may be positioned at a different location along the X dimension of microprobe 36 to sense analyte presence at a different penetration depth (deep, medium, and shallow). In other embodiments, multiple biosensors may sense the same analyte at different depths, or sense different analytes at the same depth. For example (see
Further, the multiple biosensors may be located on either or both sides of the microprobe. Biosensor 32S is located on back side 30B on insulating layer 31F, with conductive lead 33S extending though layer 31F and substrate 30S and layer 30F to front side 30A.
Microprobe device 50M may be sealed within a housing or cover 58C with signal transmitter 54T forming monitoring assembly 50A as shown in
Base 58B extends in the Y dimension and Z dimension generally normal to the X dimension of microprobe portion 56, and forms the bottom of the assembly. Cover 58C is installed over body portion 54 of the substrate and engages base 58B for sealing the assembly. Stabilizing surface 58S forms an in vivo face of base member 58B and disposed toward the subject when emplaced. The stabilizing surface engages the subject to maintain the penetration orientation of the microprobe portion into the subject. The stabilizing surface may have adhesive film 58A thereon for retaining the assembly at the emplacement site for the duration of the monitoring period. The adhesive holds the assembly onto the skin preventing displacement along the X dimension. The adhesive prevents the probe from working loose during the monitoring period as the subject moves around. In addition, the adhesive prevents lateral displacement of the assembly along the Y and Z dimensions. This lateral retention minimizes shear forces along the length of probe 56 preventing the probe from snapping off during subject activity. As the assembly is emplaced, the stabilizing surface engages the subject's skin and limits the penetration of the microprobe portion.
Signal transmitter 54T provides a transmitted analyte signal to a meter (not shown). Analog to digital converter 54A converts the sensed signal from the biosensor into a digital transmitted signal. A suitable power source such as battery 54B may be provided to activate the signal transmitter and the converter. The transmitter, converter and battery may be deposited into the silicon of body portion 54.
Pain Perception Testing
It will be apparent to those skilled in the art that the objects of this invention have been achieved as described hereinbefore by providing a microprobe device with integrated analyte sensing capability, which accesses the blood and determines the analyte concentration in one simple step. The device is fabricated from a silicon wafer for compatibility with IC fabrication and MEMS technologies. Because the strength of the single-crystal structure of the starting silicon wafer is retained in the finished device, the microprobe can penetrate skin reliably without breaking. The small length, width, and thickness dimensions of the probe introduce minimal tissue displacement, rendering probe insertion and retraction essentially painless. Minimal penetration effort is required which also minimizes mechanical probe failure. The device may function in vivo or ex vivo with one or multiple biosensors, and has both single measurement and continuous monitoring applications.
Various changes may be made in the structure and embodiments shown herein without departing from the concept of the invention. For example, the various types of biosensors may be employed in either the ex vivo embodiment (
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|International Classification||A61B5/00, A61B5/05|
|Cooperative Classification||A61B5/14532, A61B5/0002, A61B5/685, A61B5/14546, A61B5/6849, A61B2560/0412|
|European Classification||A61B5/145G, A61B5/68D1B2, A61B5/68D1D, A61B5/145P|