United States Patent Application: 0070066877

From: Subject: United States Patent Application: 0070066877 Date: Tue, 15 Jan 2008 14:49:46 -0600 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C85785.DF2AF360" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.3198 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C85785.DF2AF360 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1='20070066877'.PGNR.&OS=DN/20070066877&RS=DN/20070066877 United States Patent Application: 0070066877

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United States Patent = Application	*20070066877* =
Kind Code	A1
Arnold; Mark A. ; et = al.	March 22, 2007 =

Reagentless optical analyte detection system =

Abstract

Disclosed is an implantable microspectrometer for the reagentless = optical=20 detection of an analyte in a sample fluid. The microspectrometer = comprises an=20 optical sampling cell having a cell housing defining a fluid inlet port = and a=20 fluid outlet port, the fluid inlet port configured to receive an optical = sampling fluid from a test subject; an electromagnetic radiation source = in=20 communication with a first portion of the optical sampling cell housing = and=20 configured to irradiate at least a portion of the optical sampling fluid = with=20 electromagnetic radiation; and an electromagnetic radiation detector in=20 communication with a second portion of the optical sampling cell housing = and=20 configured to detect electromagnetic radiation emanating from the = optical=20 sampling cell. In use, the implantable microspectrometer can optically = detect at=20 least one parameter of an analyte contained within the optical sampling = fluid in=20 the absence of an added reagent.

Inventors:	Arnold; Mark A.; (Iowa = City, IA)=20 ; Olesberg; Jonathon T.; (Iowa City, IA) ; = Coretsopoulos;=20 Chris; (Iowa City, IA)
Correspondence Name and = Address:	NEEDLE & ROSENBERG, = P.C. SUITE 1000 999 PEACHTREE STREET ATLANTA GA 30309-3915 US
Serial No.:	397927
Series Code:	11
Filed:	April 4, = 2006

U.S. Current = Class: 600/315 =

U.S. Class at = Publication: 600/315 =

Intern'l Class: = A61B 5/00 20060101=20 A61B005/00

Goverment Interests

[0002] The invention described in the foregoing specification = has been=20 developed in part with funds received from the National Institutes of = Health=20 under grant number DK-64569. The United States Government may have = certain=20 rights under this invention.=20

Claims

1. An implantable microspectrometer, comprising: an optical = sampling=20 cell having a cell housing defining a fluid inlet port and a fluid = outlet port,=20 the fluid inlet port configured to receive an optical sampling fluid = from a test=20 subject; an electromagnetic radiation source in communication with a = first=20 portion of the optical sampling cell housing and configured to irradiate = at=20 least a portion of the optical sampling fluid with electromagnetic = radiation;=20 and an electromagnetic radiation detector in communication with a second = portion=20 of the optical sampling cell housing and configured to detect = electromagnetic=20 radiation emanating from the optical sampling cell, whereby the = implantable=20 microspectrometer can optically detect at least one parameter of an = analyte=20 contained within the optical sampling fluid in the absence of a reagent. =

2. The implantable microspectrometer of claim 1, wherein the=20 electromagnetic radiation source comprises a light emitting diode. =

3.=20 The implantable microspectrometer of claim 2, wherein the light emitting = diode=20 comprises GaInAsSb.

4. The implantable microspectrometer of = claim 2,=20 wherein the light emitting diode comprises a cascade of two or more = p-i-n=20 junction emitter regions.

5. The implantable microspectrometer = of claim=20 2, wherein the light emitting diode exhibits a maximum voltage draw less = than=20 about 4.0 volts and a maximum current draw less than about 30 mA. =

6. The=20 implantable microspectrometer of claim 1, wherein the electromagnetic = radiation=20 source is configured to generate infrared electromagnetic radiation. =

7.=20 The implantable microspectrometer of claim 5, wherein the infrared=20 electromagnetic radiation is in the spectral range of from 4000 = cm.sup.-1 to=20 6500 cm.sup.-1.

8. The implantable microspectrometer of claim 5, = wherein=20 the infrared electromagnetic radiation is in the spectral range of from = 300=20 cm.sup.-1 to 4000 cm.sup.-1.

9. The implantable = microspectrometer of=20 claim 1, wherein the electromagnetic radiation source is connected to = the first=20 portion of the optical sampling cell housing.

10. The = implantable=20 microspectrometer of claim 1, wherein the radiation detector comprises a = photodiode array comprising a plurality of photodiode detector elements. =

11. The implantable microspectrometer of claim 9, wherein the = photodiode=20 array comprises an array of from 16 to 64 photodiode detector elements.=20

12. The implantable microspectrometer of claim 9, wherein the = photodiode=20 array has a specific detectivity of from about 10.sup.8 cmHz.sup.1/2 = watt to=20 about 1012 cmHz.sup.1/2 watt.

13. The implantable = microspectrometer of=20 claim 9, wherein the photodiode array comprises a plurality of solid = state p-i-n=20 photo diodes.

14. The implantable microspectrometer of claim 12, = wherein=20 the plurality of solid state p-i-n photodiodes comprise GaInAsSb, = InGaAs, PbS,=20 PbSe, or any combination thereof.

15. The implantable = microspectrometer=20 of claim 1, wherein the electromagnetic radiation source is configured = to detect=20 infrared electromagnetic radiation.

16. The implantable=20 microspectrometer of claim 14, wherein the infrared electromagnetic = radiation is=20 in the spectral range of from 4000 cm.sup.-1 to 6500 cm.sup.-1. =

17. The=20 implantable microspectrometer of claim 14, wherein the infrared = electromagnetic=20 radiation is in the spectral range of from 300 cm.sup.-1 to 4000 = cm.sup.-1.=20

18. The implantable microspectrometer of claim 1, wherein the=20 electromagnetic radiation detector is capable of substantially = continuous=20 operation while maintaining a detector temperature less than about = 100.degree.=20 F.

19. The implantable microspectrometer of claim 1, wherein the = electromagnetic radiation detector comprises a bandpass filter. =

20. The=20 implantable microspectrometer of claim 18, wherein the bandpass filter = comprises=20 a passband width of from approximately 12 cm.sup.-1 to approximately 20=20 cm.sup.-1.

21. The implantable microspectrometer of claim 1, = wherein the=20 electromagnetic radiation detector is connected to the second portion of = the=20 optical sampling cell housing.

22. The implantable = microspectrometer of=20 claim 1, wherein the optical sampling cell housing is comprised of an=20 electromagnetic radiation transparent material.

23. The = implantable=20 microspectrometer of claim 22, wherein the electromagnetic radiation = transparent=20 material comprises a fluoropolymer.

24. The implantable=20 microspectrometer of claim 1, wherein the optical fluid sampling cell is = substantially cylindrical in shape.

25. The implantable=20 microspectrometer of claim 24, wherein the fluid sampling cell has a = diameter in=20 the range of from approximately 150 .mu.m to approximately 250 .mu.m, an = optical=20 path length in the range of from approximately 0.5 mm to approximately = 1.5 mm,=20 and an interior volume in the range of from approximately 25 nL to = approximately=20 35 nL.

26. The implantable microspectrometer of claim 1, wherein = the=20 fluid sampling chamber is substantially rectangular in shape. =

27. The=20 implantable microspectrometer of claim 1, further comprising a vacuum = source in=20 communication with the fluid outlet port of the sampling cell and = configured to=20 generate a flow of fluid sample from the test subject, through the fluid = inlet=20 port, through the optical sampling cell, and through the fluid outlet = port.=20

28. The implantable microspectrometer of claim 27, wherein the = vacuum=20 source is configured to generate a flow of fluid sample having a flow = rate in=20 the range of from about 30 nL/min to about 150 nL/min.

29. The=20 implantable microspectrometer of claim 1, further comprising a fluid = sampling=20 assembly in communication with the sample fluid inlet port and = configured to=20 obtain a fluid sample containing an analyte from a test subject. =

30. The=20 implantable microspectrometer of claim 29, wherein the fluid sampling = assembly=20 comprises an implantable ultrafiltration probe.

31. The = implantable=20 microspectrometer of claim 29, wherein the fluid sampling assembly = comprises an=20 implantable microdialysis probe.

32. The implantable = microspectrometer=20 of claim 1, wherein the fluid outlet port is in fluid communication with = the=20 test subject.

33. The implantable microspectrometer of claim 1, = wherein=20 the implantable microspectrometer occupies a total volume less in the = range of=20 from about 0.01 cm.sup.3 to about 1.0 cm.sup.3.

34. The = implantable=20 microspectrometer of claim 1, wherein the optical detection of at least = one=20 parameter of an analyte contained within the optical sampling fluid = comprises=20 the detection of electromagnetic radiation absorption, reflection, = scattering,=20 or a combination thereof.

35. The implantable microspectrometer = of claim=20 1, wherein at least one component of the microspectrometer is in = electronic=20 communication with an electronic support unit.

36. An = implantable=20 microspectrometer for the reagentless optical detection of an analyte in = fluid=20 sample, comprising an optical sampling cell having a cell housing = defining a=20 fluid inlet port and a fluid outlet port, the fluid inlet port = configured to=20 receive an optical sampling fluid from a test subject; a means for = generating=20 electromagnetic radiation, whereby the means for generating radiation is = in=20 communication with a first portion of the optical sampling cell housing = and=20 configured to irradiate at least a portion of the optical sampling fluid = with=20 electromagnetic radiation; a means for detecting electromagnetic = radiation,=20 whereby the means for detecting electromagnetic radiation is in = communication=20 with a second portion of the optical sampling cell housing and = configured to=20 detect electromagnetic radiation emanating from the optical sampling = cell,=20 whereby the implantable microspectrometer can optically detect at least = one=20 parameter of an analyte contained within the optical sampling fluid in = the=20 absence of a reagent.

37. A method for the reagentless optical = detection=20 of an analyte in a fluid sample, comprising the steps of: providing a=20 microspectrometer, comprising: (i) an optical sampling cell having a = cell=20 housing defining a fluid inlet port and a fluid outlet port, the fluid = inlet=20 port; (ii) an electromagnetic radiation source in communication with a = first=20 portion of the optical sampling cell housing; and (iii) an = electromagnetic=20 radiation detector in communication with a second portion of the optical = sampling cell housing; obtaining a fluid sample containing an analyte = from a=20 test subject; conveying the obtained fluid sample through the inlet port = in to=20 the optical sampling cell; generating electromagnetic radiation from the = electromagnetic radiation source and irradiating at least a portion of = the fluid=20 sample within the optical sampling cell; optically detecting = electromagnetic=20 radiation emanating from the optical sampling cell with the = electromagnetic=20 radiation detector; and returning at least a portion of the obtained = fluid=20 sample contained within the optical sampling cell to the test subject.=20

38. The method of claim 37, wherein the fluid sample is a = biological=20 fluid.

39. The method of claim 37, wherein the analyte comprises = glucose, urea, creatinine, phosphate, sulfate, or a mixture thereof. =

40.=20 The method of claim 37, wherein the analyte comprises glucose. =

41. The=20 method of claim 37, wherein the fluid sample comprises blood. =

42. The=20 method of claim 37, wherein the fluid sample comprises interstitial = fluid.=20

43. The method of claim 37, further comprising implanting the = optical=20 sampling cell subcutaneously in the test subject

44. The method = of=20 claims 37 or 43, wherein the fluid sample is obtained from the = subcutaneous=20 tissue bed surrounding the peritoneal cavity of a mammalian test = subject.=20

45. The method of claim 37, wherein the electromagnetic = radiation=20 detector comprises a photodiode array connected to the optical sampling = cell.=20

46. The method of claim 37, further comprising applying a = negative=20 pressure gradient to the optical sampling cell to convey the obtained = sample=20 fluid to the optical sampling cell.

47. The method of claims 37 = or 46,=20 wherein the portion of the fluid sample conveyed to the optical sampling = cell is=20 irradiated with infrared electromagnetic radiation.

48. The = method of=20 claim 47, wherein the infrared electromagnetic radiation is in the = spectral=20 range of from 4000 cm.sup.-1 to 6500 cm.sup.-1.

49. The method = of claim=20 47, wherein the infrared electromagnetic radiation is in the spectral = range of=20 from 300 cm.sup.-1 to 4000 cm.sup.-1.=20

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This = application=20 claims priority to and the benefit of U.S. Provisional Patent = Application Ser.=20 No. 60/667,973 filed in the United States Patent and Trademark Office on = Apr. 4,=20 2005, the disclosure of which is hereby incorporated by reference in its = entirety for all purposes. This application also claims priority to and = the=20 benefit of U.S. patent application Ser. No. 11/348,615, filed in the = United=20 States Patent and Trademark Office on Feb. 7, 2006, which application = claims=20 priority to and the benefit of U.S. Provisional Patent Application Ser. = No.=20 60/650,678 filed in the United States Patent and Trademark Office on = Feb. 7,=20 2005, and to U.S. Provisional Patent Application Ser. No. 60/667,973 = filed in=20 the United States Patent and Trademark Office on Apr. 4, 2005. The = entire=20 disclosures of these applications are also hereby incorporated by = reference in=20 their entirety for all purposes.

FIELD OF THE INVENTION =

[0003]=20 The present invention relates generally to the field of analyte = detection=20 systems and more particularly to a reagentless optical analyte detection = system.=20

BACKGROUND OF THE INVENTION

[0004] Diabetes is a = chronic,=20 incurable disease that causes an array of serious medical complications = and even=20 premature death. Complications include heart disease, stroke, kidney = failure,=20 and nervous system disorders. Although diabetes is a potentially = devastating=20 disease, early diagnosis and tight glycemic control can greatly diminish = the=20 medical complications and cost of this disease.

[0005] The goal = of tight=20 control is to maintain one's blood glucose levels within a = physiologically=20 acceptable range. Tight control therefore typically requires frequent = blood=20 glucose measurements, which provides the information needed to = administer=20 insulin or glucose properly. The pain, cost and inconvenience of=20 state-of-the-art glucose monitoring technology impede frequent = monitoring and=20 are primarily responsible for the failure of patients to maintain tight = control.=20 Thus, it has been recognized for several decades that an ideal treatment = of=20 diabetes would involve a closed-loop insulin delivery system that is = implanted=20 within the patient's body.

[0006] This so-called artificial = pancreas=20 could comprise an insulin delivery pump coupled with some type of=20 glucose-sensing technology. Using this system, insulin could be = delivered=20 continuously in response to detected changes in the blood glucose=20 concentrations. However, for this system to be operable, the glucose = sensing=20 component must be able to provide accurate and rapid blood glucose = values to a=20 micro-processing unit, which would compute the amount of insulin = required and=20 then control the required insulin delivery. Accordingly, the successful=20 development of an artificial pancreas or other artificial biological = delivery=20 system as described above depends on the development of implantable = analyte=20 (i.e., glucose) sensing technology and corresponding electronic support = that can=20 reliably control the instrumentation. Thus, there is a need in the art = for=20 implantable analyte sensing technology and electronic support that can = enable=20 the continuous operation of an analyte detection system for extended = durations=20 with minimal or even no user intervention required.

SUMMARY OF = THE=20 INVENTION

[0007] The present invention is based, in part, upon = the=20 invention of a reagentless optical analyte detection system. In one = aspect, the=20 reagentless optical analyte detection system can enable continuous and=20 reagentless operation for extended periods of time with minimal or even = no user=20 intervention required.

[0008] In one aspect, the present = invention=20 provides an implantable microspectrometer, comprising an optical = sampling cell=20 having a cell housing defining a fluid inlet port and a fluid outlet = port,=20 wherein the fluid inlet port can be configured to receive an optical = sampling=20 fluid from a test subject. An electromagnetic radiation source is = positioned in=20 communication with a first portion of the optical sampling cell housing = and=20 configured to irradiate at least a portion of the optical sampling fluid = with=20 electromagnetic radiation. An electromagnetic radiation detector is also = positioned in communication with a second portion of the optical = sampling cell=20 housing and configured to detect electromagnetic radiation emanating = from the=20 optical sampling cell.

[0009] In another aspect, the present = invention=20 provides an implantable microspectrometer, comprising an optical = sampling cell=20 having a cell housing defining a fluid inlet port and a fluid outlet = port,=20 wherein the fluid inlet port can be configured to receive an optical = sampling=20 fluid from a test subject. A means for generating electromagnetic = radiation is=20 provided whereby the means for generating radiation is in communication = with a=20 first portion of the optical sampling cell housing and configured to = irradiate=20 at least a portion of the optical sampling fluid with electromagnetic = radiation.=20 A means for detecting electromagnetic radiation is also provided, = whereby the=20 means for detecting electromagnetic radiation is in communication with a = second=20 portion of the optical sampling cell housing and configured to detect=20 electromagnetic radiation emanating from the optical sampling cell.=20

[0010] According to various aspect, a microspectrometer of the = present=20 invention and as summarized herein is capable of irradiating a fluid = sample with=20 electromagnetic radiation and subsequently detecting variations in the=20 electromagnetic radiation resulting at least from the interaction of the = electromagnetic radiation with the fluid sample and, in particular, with = a=20 target analyte contained in the fluid sample. In another aspect, the = analyte=20 detection system can enable the continuous and reagent-free optical = analysis of=20 a sample fluid obtained from a test subject for extended periods of time = without=20 the need for user intervention.

[0011] In still another aspect, = the=20 present invention provides a method for the reagentless optical = detection of an=20 analyte in a fluid sample, comprising the steps of: providing a=20 microspectrometer, comprising: (i) an optical sampling cell having a = cell=20 housing defining a fluid inlet port and a fluid outlet port, the fluid = inlet=20 port; (ii) an electromagnetic radiation source in communication with a = first=20 portion of the optical sampling cell housing; and (iii) an = electromagnetic=20 radiation detector in communication with a second portion of the optical = sampling cell housing; obtaining a fluid sample containing an analyte = from a=20 test subject; conveying the obtained fluid sample through the inlet port = in to=20 the optical sampling cell; generating electromagnetic radiation from the = electromagnetic radiation source and irradiating at least a portion of = the fluid=20 sample within the optical sampling cell; optically detecting = electromagnetic=20 radiation emanating from the optical sampling cell with the = electromagnetic=20 radiation detector; and optionally returning at least a portion of the = obtained=20 fluid sample contained within the optical sampling cell to the test = subject.=20

[0012] Additional aspects of the invention will be set forth, in = part,=20 in the detailed description, figures and any claims which follow, and in = part=20 will be derived from the detailed description, or may be learned by = practice of=20 the invention. It is to be understood that both the foregoing general=20 description and the following detailed description are exemplary and = explanatory=20 only and are not restrictive of the invention as disclosed. =

BRIEF=20 DESCRIPTION OF THE FIGURES

[0013] The accompanying drawings, = which are=20 incorporated in and constitute a part of this specification, illustrate = several=20 embodiments of the instant invention and together with the description, = serve to=20 explain, without limitation, the principles of the invention. =

[0014]=20 FIG. 1 illustrates a schematic view of a reagentless optical analyte = detection=20 system according to one aspect of the instant invention.

[0015] = FIG. 2=20 illustrates a perspective view of microspectrometer according to one = aspect of=20 the present invention.

[0016] FIG. 3 illustrates an optical = sensing=20 element according to one aspect of the invention. As depicted, the = optical=20 sensing element comprises an array of 32 photodiodes.

[0017] = FIG. 4=20 illustrates a side view of a microspectrometer according to one aspect = of the=20 present invention.

[0018] FIG. 5 illustrates a functional block = diagram=20 of an exemplary electronic support unit according to one aspect of the = present=20 invention.

[0019] FIG. 6 is a schematic of an exemplary main = controller=20 unit according to one aspect of the present invention.

[0020] = FIG. 7=20 illustrates an exemplary data acquisition from one photodiode of the = photodiode=20 array depicted in FIG. 3.

[0021] FIG. 8 is an exemplary = schematic of a=20 data acquisition unit according to one aspects of the present invention. =

[0022] FIG. 9 is an exemplary schematic of a data acquisition = unit=20 according to one aspect of the present invention.

[0023] FIG. 10 = is a=20 graphical illustration of exemplary digitized data obtained from a data=20 acquisition unit according to one aspect of the present invention. Error = bars on=20 the diagram indicate the standard deviation of the noise on the data.=20

[0024] FIG. 11 is a graphical illustration of the exemplary = digitized=20 data obtained from a data acquisition unit according to one aspect of = the=20 present invention, wherein the signal to noise ratio of the data has = been=20 increased by the use of a digital filtering algorithm. No error bars are = shown=20 because their width is insignificant on the scale of the drawing. =

[0025]=20 FIG. 12 is an exemplary schematic of a remote charger unit according to = one=20 aspect of the present invention.

[0026] FIG. 13 is an exemplary=20 schematic diagram of an internal power unit according to one aspect of = the=20 present invention.

[0027] FIG. 14 illustrates a flow chart = diagram of a=20 battery charging cycle according to one aspect of the present invention. =

[0028] FIG. 15 illustrates an exemplary schematic diagram of an = internal=20 telemetry unit according to one aspect of the present invention. =

[0029]=20 FIG. 16 illustrates an exemplary schematic diagram of an external = telemetry unit=20 according to one aspect of the present invention.

[0030] FIG. 17 = illustrates an exemplary physical implantation and use of an electronic = support=20 unit and analyte sensor according to the present invention. =

[0031] FIG.=20 18 illustrates the near infrared absorption spectrum for glucose in the = spectral=20 range of from approximately 2.05 .mu.m to approximately 2.4 .mu.m.=20

[0032] FIG. 19 illustrates an exemplary schematic diagram of an = internal=20 module according to an alternative aspect of the present invention.=20

[0033] FIG. 20 illustrates an exemplary schematic diagram of an = external=20 module according to an alternative aspect of the present invention.=20

DETAILED DESCRIPTION OF THE INVENTION

[0034] The present = invention may be understood more readily by reference to the following = detailed=20 description, and figures, and their previous and following description.=20

[0035] Before the present compositions, devices, and/or methods = are=20 disclosed and described, it is to be understood that this invention is = not=20 limited to the specific articles, devices, and/or methods disclosed = unless=20 otherwise specified, as such may, of course, vary. It is also to be = understood=20 that the terminology used herein is for the purpose of describing = particular=20 aspects only and is not intended to be limiting.

[0036] As used = herein,=20 the singular forms "a," "an" and "the" include plural referents unless = the=20 context clearly dictates otherwise. Thus, for example, reference to an = "analyte"=20 includes aspects having two or more such analytes unless the context = clearly=20 indicates otherwise.

[0037] Ranges may be expressed herein as = from=20 "about" one particular value, and/or to "about" another particular = value. When=20 such a range is expressed, another aspect includes from the one = particular value=20 and/or to the other particular value. Similarly, when values are = expressed as=20 approximations, by use of the antecedent "about," it will be understood = that the=20 particular value forms another aspect. It will be further understood = that the=20 endpoints of each of the ranges are significant both in relation to the = other=20 endpoint, and independently of the other endpoint.

[0038] As = used=20 herein, the terms "optional" or "optionally" mean that the subsequently=20 described event or circumstance may or may not occur, and that the = description=20 includes instances where said event or circumstance occurs and instances = where=20 it does not.

[0039] As used herein, the term "tissue" includes = an=20 aggregate of cells of a particular kind, together with their = intercellular=20 substance, that forms a structural material.

[0040] As used = herein, the=20 term "interstitial" means relating to or situated in the small, narrow = spaces=20 between tissues or parts of an organ. Interstitial fluid is an = extracellular=20 fluid that is prevalent throughout the body and the skin. Because = interstitial=20 fluid is found in the outermost layers of the skin where there are fewer = nerve=20 endings, relatively painless samples can be obtained.

[0041] As = used=20 herein, "analyte" includes any physiological chemical having a = functional group=20 and/or chemical bond capable of providing an identifiable spectral = signature or=20 feature when irradiated with electromagnetic radiation, such as = radiation in the=20 near infrared (NIR) and/or middle infrared (MIR) wavebands. In one = aspect, the=20 functional group and/or chemical bond can be C-H, N-H, O-H, or any = combination=20 thereof. Specific and non-limiting examples of suitable analytes = according to=20 the instant invention include glucose, urea, lactate, creatinine, = triglyceride,=20 protein, cholesterol, and ethanol. In one aspect, the analyte is = glucose. In=20 still another aspect, the analyte is urea. In another aspect, an analyte = is any=20 target molecule capable of freely passing from blood into the = interstitial fluid=20 of a test subject. To this end, it should be appreciated that the = present=20 invention is not limited to use in connection with any one particular = analyte or=20 group of analytes.

[0042] As used herein, the term physiological = "lag=20 time" in one aspect refers to the delay or time differential in the=20 equilibration between the concentration of a target analyte in = interstitial=20 fluid and the concentration of the same target analyte in blood. One of = skill in=20 the art will appreciate that the "lag time" of, for example, glucose in=20 interstitial fluid, will vary depending on physiologic conditions. In = another=20 aspect, a so called instrumental "lag time" refers to the delay or time=20 differential between the actual concentration of a target analyte in the = interstitial fluid of a test subject and the concentration of the same = analyte=20 in a sample of interstitial fluid that is analyzed in the optical cell = of a=20 microspectrometer described herein. One of skill in the art will = appreciate that=20 instrumental lag time can be dependent, in part, on fluid dynamics and = the flow=20 rate of a sample stream within a microspectrometer as described herein. = In still=20 another aspect, it will be appreciated that a net "lag time" can refer = to the=20 combination of physiological and instrumental lag times as described = herein. To=20 this end, in one aspect, a net lag time can be used to calibrate, for = example,=20 an artificial pancreas.

[0043] As used herein, the term "test = subject"=20 includes any living organism from which a sample of interstitial fluid = or any=20 other sample fluid containing a target analyte can be obtained. In one = aspect, a=20 test subject can be any living organism in which an analyte detection = system or=20 any component thereof can be implanted in the subcutaneous tissue = thereof. For=20 example, in one aspect a test subject can be a plant. Alternatively, in = another=20 aspect, the test subject can be an animal. In one aspect the animal can = be=20 mammalian. In an alternative aspect the animal can be non-mammalian. The = animal=20 can also be a cold-blooded animal, such as a fish, a reptile, or an = amphibian.=20 Alternatively, the animal can be a warm-blooded animal, such as a human, = a farm=20 animal, a domestic animal, or even a laboratory animal. Accordingly, it = should=20 be understood that the present invention is not limited to its use in = connection=20 with any one particular test subject or group of test subjects. =

[0044]=20 As briefly stated above, the present invention is based, in part, upon = the=20 invention of a reagentless optical analyte detection system. To this = end, in one=20 aspect, the detection system can enable the continuous and reagent-free = optical=20 analysis of a sample fluid, such as interstitial fluid (ISF), sampled = from a=20 test subject for extended periods of time without requiring user = intervention.=20 Thus, it will be appreciated upon practicing the present invention that = the=20 reagentless analyte detection system can provide continuous analyte = detection=20 and analysis without resulting in the formation of reaction byproducts = that have=20 until now prevented the return of the analytical sample to the body or = tissue of=20 the test subject and which have needed to be stored, recycled or = otherwise=20 disposed of.

[0045] Referring specifically to FIG. 1, a = schematic=20 diagram of an exemplary and non-limiting analyte detection system 110 = according=20 to one aspect of the present invention is shown. The exemplified system = is=20 comprised of an integrated solid-state microspectrometer 120 that is = capable of=20 irradiating a sample of interstitial fluid delivered to an optical cell = with=20 electromagnetic radiation. The microspectrometer 120 can subsequently = detect=20 variations in the electromagnetic radiation resulting at least from the=20 interaction of the electromagnetic radiation with the interstitial = fluid.=20 Interstitial fluid can be obtained by a sampling assembly 130 and = subsequently=20 conveyed to the optical cell of the microspectrometer 120 through a = microfluidic=20 channel 140. In one aspect, the interstitial fluid is drawn into the = sampling=20 assembly and propagated through the microfluidic pathway using a = negative=20 pressure gradient produced by a vacuum source 150. Once the sample has = been=20 analyzed by the microspectrometer 120, the sample can then be returned = to the=20 test subject or disposed of externally through an exit port 160. As = further=20 illustrated, the detection system can be coupled to one or more = components of an=20 electronic support unit (ESU) 170, which can provide electronic support = for the=20 detection system. In one aspect, the ESU can provide a power supply for = the=20 optical components of the microspectrometer and/or the vacuum source. In = another=20 aspect, the ESU can provide a means for transmitting spectroscopic data=20 generated by the microspectrometer downstream for further processing.=20

[0046] In one aspect, and as exemplified in FIG. 2, the analyte=20 detection system of the present invention can comprise an implantable=20 microspectrometer 120, comprising an optical sampling cell 122 having a = cell=20 housing 124 defining a fluid inlet port 126 and a fluid outlet port 128, = wherein=20 the fluid inlet port can be configured to receive an optical sampling = fluid from=20 a test subject. An electromagnetic radiation source 121 can be = positioned in=20 communication with at least a first portion of the optical sampling cell = housing=20 and configured to irradiate at least a portion of an optical sampling = fluid with=20 electromagnetic radiation. Still further, an electromagnetic radiation = detector=20 assembly 127 can be positioned in communication with at least a second = portion=20 of the optical sampling cell housing and configured to detect = electromagnetic=20 radiation emanating from the optical sampling cell. In one aspect, the=20 implantable microspectrometer 120 can be configured to optically detect = at least=20 one parameter of an analyte contained within the optical sampling fluid = in the=20 absence of a reagent. In use, a sample of interstitial fluid can be = delivered to=20 the optical cell. The microspectrometer according to this aspect is = capable of=20 irradiating the sample of interstitial fluid with electromagnetic = radiation=20 generated by, for example, an electromagnetic radiation source and = subsequently=20 detecting electromagnetic radiation emanating from the optical sampling = cell.=20

[0047] The microspectrometer of the instant invention can, in = one=20 aspect, be configured to measure the absorption spectra resulting from = the=20 interaction of the electromagnetic radiation with a sample. In an = alternative=20 aspect, the microspectrometer of the instant invention can be configured = to=20 measure the scattering spectra using conventional Raman spectroscopy = techniques.=20 As such, there are several conventional methods that can be used for = performing=20 spectrally resolved measurements on electromagnetic radiation that = passes=20 through the optical sampling chamber of a spectrometer including, = without=20 limitation, Fourier transform and dispersive techniques (utilizing = diffraction=20 gratings or dispersive prisms).

[0048] While any of these = methods can be=20 used in connection with the present invention, in one aspect, the=20 microspectrometer according to the present invention is configured to = measure=20 infrared absorption spectra. According to this exemplary aspect, and as = further=20 depicted in FIG. 2, an exemplary microspectrometer can provide a = spectrally=20 resolved measurement using a spectroscopy system comprised of a high = efficiency=20 solid state broadband light source and a solid state photodetector = assembly 127=20 comprised of a spatially variable bandpass filter 125 mounted on a = photodiode=20 array 123. As one of skill in the art will appreciate, the use of a = photodiode=20 array can allow for the real-time collection of a signal simultaneously = at all=20 wavelengths within the band of interest. The photodetector array can = further=20 convert the detected light signal to electrical signals or photo = currents, which=20 can then be passed downstream and analyzed by a processing system.=20

[0049] According to this exemplary spectroscopy system, light = exiting=20 the optical sampling chamber will be incident on the bandpass filter. = The filter=20 can be configured such that the central wavelength of the passband = varies along=20 one of the dimensions of the filter. Thus, each photodetector element, = or=20 photodiode, can be adapted to be sensitive to a different wavelength of = light.=20 Spectral resolution can then be determined from a combination of the = width of=20 the filter passband at each point and the width and packing separation = distance=20 of detector elements. The spectral point spacing can be determined from = the=20 number of detector array elements. It will be appreciated that a = detector=20 assembly can comprise any number of individual photodetector elements, = depending=20 on the spectral resolution necessary for obtaining sound analytical=20 measurements. For example, an array of 16, 24, 32, or even 64 = photodetector=20 elements can be used. In one aspect, the electromagnetic radiation = detector=20 assembly 127 can comprise an array 123 of 32 photodiodes, as exemplified = in FIG.=20 3.

[0050] Unlike conventional diffraction-based instruments, = this=20 exemplary and non-limiting spectroscopy system does not require the use = of=20 imaging optics. Thus, the bandpass filter and detector assembly can be = mounted=20 directly on the output region of an optical sampling cell, eliminating = the need=20 for free space coupling and enhancing the brightness and efficiency of = the light=20 source. Accordingly, in one aspect, the present invention provides a = rugged,=20 compact and durable spectrometer that can, for example, better suited = for=20 implantation into a test subject than conventional spectroscopy = techniques.=20

[0051] It should also be understood that a microspectrometer = according=20 to the present invention is not limited to use in connection with a = particular=20 waveband in the infrared spectrum. Thus, in one aspect, the = microspectrometer=20 can be configured to operate in the near infrared electromagnetic = region,=20 including radiation in the wave number range of from approximately 4000=20 cm.sup.-1 to approximately 14500 cm.sup.-1. To this end, the = microspectrometer=20 can be configured to operate in additional wave numbers of 4000, 4500, = 5000,=20 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10000, 10500, = 11000,=20 11500, 12000, 12500, 13000, 13500 and 14000 cm.sup.-1 and any range = derived from=20 these values.

[0052] For example, and without limitation, when = used in=20 connection with an aqueous environment or aqueous sample such as the=20 interstitial fluid obtained from the human body, the microspectrometer = can be=20 configured to operate in the so-called combination spectral range of the = near=20 infrared spectrum over a wavenumber range from approximately 4000 = cm.sup.-1 to=20 approximately 5000 cm.sup.-1. As one of ordinary skill in the art will=20 appreciate, spectral features in the combination spectral range = originate from=20 the combination of stretching and bending vibrational modes associated = with C-H,=20 O-H, and N-H chemical bonds within the molecules in a sample matrix. In = still=20 another aspect, and again for exemplary aqueous samples, the = microspectrometer=20 can operate in the so-called first overtone spectral region of the near = infrared=20 spectrum over the wavenumber range from approximately 5500 cm.sup.-1 to=20 approximately 6500 cm.sup.-1. Spectral features in this first overtone = spectral=20 range can correspond to the first overtone of C-H chemical bonds within = these=20 sample molecules.

[0053] In an alternative aspect, the = microspectrometer=20 can also be configured to operate in the mid infrared electromagnetic = region,=20 including radiation in the wavenumber range from approximately 300 = cm.sup.-1 to=20 approximately 4000 cm.sup.-1. To this end, the analyte detection system = can be=20 configured to operate in additional sub-ranges within the wave number = bands of=20 500, 1000, 1500, 2000, 2500, 3000, and 3500 cm.sup.-1 and any range = derived from=20 these values. It should also be understood that for both near infrared = and mid=20 infrared analyte measurements, it is not required by the invention that = the=20 wavelength range used be a single contiguous range of wavenumbers. For = example,=20 in still another aspect, a plurality of different segments of shorted = wavenumber=20 ranges can be used, including the combination of wavenumber segments = from both=20 the near infrared and mid infrared spectral regions.

[0054] The = desired=20 operational waveband range of the microspectrometer will be dependent, = in part,=20 on the particular analyte under investigation. For example, in one = aspect where=20 the analyte is glucose, interstitial fluid from the subcutaneous space = can be=20 sampled through an embedded filtration probe and subsequently delivered = into a=20 micro-fluidic chamber, which is physically isolated from the biological=20 environment. The sample of interstitial fluid can then be carried to an=20 optimized spectrometer cell, where a 16 cm.sup.-1 resolution near = infrared=20 spectrum can be collected over a spectral range of from approximately = 4000=20 cm.sup.-1 to approximately 5000 cm.sup.-1 which corresponds to the = spectral=20 range containing a spectral signature unique to glucose, as depicted in = FIG. 5.=20 Using conventional mathematical models, the concentration of the glucose = can be=20 obtained from a direct analysis of the detected glucose absorption = spectrum.=20

[0055] As mentioned above, the electromagnetic radiation = detector can,=20 in one aspect, comprise a photodiode array configured to detect a = desired range=20 or plurality of ranges of electromagnetic radiation. An exemplary = photodiode=20 array of the instant invention can comprise an array of solid state = p-i-n=20 diodes. To this end, in one aspect, the p-i-n diode can be a reverse = biased=20 p-i-n diode. In another aspect, the solid state diodes can be comprised = of a=20 semiconductive material suitable for use as a photodetector. For = example, and=20 without limitation, a solid state photodiode adapted for use in = detecting=20 electromagnetic radiation in the near infrared region can comprise = GaInAsSb,=20 InGaAs, PbS, or PbSe. Alternatively, a solid state photodiode adapted = for use in=20 detecting electromagnetic radiation in the mid-infrared region can = comprise, for=20 example, HgCdZnTe, pyroelectrics, thermopiles, and/or an InAs/GaInSb=20 superlattice material.

[0056] In one aspect, a photodetector = diode=20 comprising a semiconductive material as described herein can be = fabricated by=20 conventional molecular beam epitaxy (MBE). As one of skill in the art = will=20 appreciate, MBE is a method of depositing layers of materials with = atomic=20 thicknesses on to substrates. This is done by creating a molecular beam = of a=20 material which impinges on to the substrate. The resulting superlattices = can be=20 suitable for use in semiconducting systems such as the photodetectors = described=20 and exemplified herein.

[0057] In an exemplary aspect comprising = a=20 GaInAsSb p-i-n diode, the light-absorbing "i" layer can, for example, = comprise=20 approximately 3 .mu.m of the alloy GaInAsSb. To this end, the GaInAsSb = can be=20 grown lattice-matched to a GaSb substrate with a cutoff wavelength for = light=20 absorption (depending on alloy composition) ranging from approximately = 1.5-4.1=20 .mu.m at room temperature. In this example, the target band gap for the = detector=20 would be approximately 4000 cm.sup.-1 (2.5 .mu.m), so that the = absorption=20 coefficient in the target wavelength range will be approximately 5000 = cm.sup.-1.=20 The absorption length for the above-band gap of light in GaInAsSb alloy = can then=20 be approximately 2 .mu.m, so that the majority of the light is absorbed = in the=20 "i" layer having the exemplary thickness of approximately 3 .mu.m. As = one of=20 skill in the art will appreciate, electron diffusion lengths in such = materials=20 can also influence the optimal choice of "i" layer thickness. Further, = for these=20 exemplified semiconductive materials, typical mobilities are = approximately 3000=20 cm.sup.-2/s at room temperature, and typical minority electron lifetimes = in=20 highly pure undoped materials are approximately 10 ns. Accordingly, the = carriers=20 can diffuse across an "i" layer that is approximately 10 .mu.m thick. To = this=20 end, by ensuring that as many created electron-hole pairs will be = collected as=20 possible, it will be appreciated that this approach can also maximize = the=20 responsivity of the photodetector.

[0058] The "p" region of the = diode=20 can be comprised of the same semiconductor alloy composition as the "i" = layer in=20 order to facilitate collection of the holes. The "n" region can be = comprised of=20 slightly larger band gap to eliminate the absorption of the desired = wavelength=20 of light. Light absorbed in the "n" region can produce minority holes, = which are=20 not particularly mobile, and hence can contribute more to the dark = current (and=20 hence noise) than to the signal. Thus, in an exemplary aspect, the "n" = region=20 can also be constructed of a relatively thin (0.3 .mu.m) layer of = material to=20 further reduce light absorption in this layer and to reduce the dark = current.=20

[0059] The responsivity of an electromagnetic radiation detector = and/or=20 the presence of dark current can be important considerations when = selecting a=20 suitable photodetector for spectroscopic determinations. For example, = the=20 response time of a photodetector can be a limiting factor in = communication=20 related applications. Additionally, dark current, which is typically the = primary=20 noise source intrinsic to a photodetector, can adversely affect the = signal to=20 noise ratio of the measurement. To this end, in one aspect, the = photodetector=20 array of the instant invention exhibits a signal to noise ratio of = approximately=20 100 .mu.AU for a one-second collection. According to this aspect, the=20 time-averaged noise can be reduced to approximately 5 .mu.AU on the = order of 4=20 minutes. In still another aspect, the time-averaged noise can be in the = range of=20 from about 0.1 .mu.AU to about 20 .mu.AU, including such time averaged = noise=20 values of 0.5 .mu.AU, 1.0 .mu.AU, 5 .mu.AU, 10 .mu.AU, and 15 .mu.AU.=20

[0060] Detector noise can also be a limitation to achieving = high-quality=20 infrared absorption spectra in, for example, the near infrared = combination=20 region. Thus, to minimize detector noise and to increase signal to noise = ratios,=20 conventional spectrometer systems often utilize liquid nitrogen or = multi-stage=20 thermoelectric systems to cool the detector element. However, as one of = skill in=20 the art will appreciate, these techniques can in some circumstances be=20 problematic for use with a portable and/or implantable battery-operated = system.=20 Thus, in another aspect, the present invention comprises a photodetector = that=20 can operate successfully at ambient or body temperatures without the = need for a=20 cooling means to control the level of detector noise. For example, in = one=20 aspect, a photodetector of the present invention is capable of = substantially=20 continuous operation while maintaining a detector temperature less than = about=20 100.degree. F., less than 98.degree. F., less than 95.degree. F., or = even less=20 than 90.degree. F.

[0061] To this end, the level of noise = produced by a=20 detector element is typically proportional to the square root of its = surface=20 area. Thus, reducing the size of the detector, provided that the amount = of light=20 collected from the light source is held constant, can in one aspect = minimize the=20 level of detector noise. Accordingly, in another aspect of the present=20 invention, the impact of detector noise is minimized by reducing the = size of the=20 detector assembly while still maintaining a high brightness from the = light=20 source. For conventional instruments, the use of a low-brightness, = broadband=20 source (such as a tungsten lamp) means that small detector elements are = not as=20 practical. However, in the instant invention, by utilizing a = high-brightness=20 light source, such as an LED, and taking steps to substantially confine = the=20 light in a sub-millimeter optical cell, relatively small detector = elements can=20 be used with relatively high responsivity and minimal levels of detector = noise.=20

[0062] In still another aspect, the photodetector array of the = instant=20 invention can exhibit a specific detectivity (D*) in the range of from=20 approximately of approximately 10.sup.8 cm Hz.sup.1/2 watt to = approximately=20 10.sup.12 cm Hz.sup.1/2 watt, including specific detectivities of = 10.sup.9 cm=20 Hz.sup.1/2 watt, 10.sup.10 cm Hz.sup.1/2 watt, and 10.sup.11 cm = Hz.sup.1/2 watt.=20 In one aspect, a photodetector array according to the present invention = exhibits=20 a specific detectivity of approximately 10.sup.10 cm Hz.sup.1/2 watt. As = one of=20 ordinary skill in the art will appreciate, the specific detectivity can = be=20 calculated using equation (I) set forth below, wherein A is the area of = the=20 photosensitive region of the detector, .DELTA.f is the effective noise = bandwidth=20 and NEP is the noise equivalent power. D * =3D A .times. .times. .DELTA. = .times.=20 .times. f NEP , ( I ) In one exemplary and non-limiting aspect, the area = A of=20 the photosensitive region of the detector array can be in the range of = from=20 approximately 0.4 mm.times.50 .mu.m to approximately 3 mm.times.100 = .mu.m. In=20 another exemplary and non-limiting aspect, the area of the = photosensitive region=20 of the detector array can be 1 mm.times.50 .mu.m. Likewise, in one = exemplary and=20 non-limiting aspect, the NEP/ {square root over (.DELTA.f)} can be in = the range=20 from approximately 10 fW/Hz.sup.1/2 to approximately 10 pW/Hz.sup.1/2.=20

[0063] A stated above, a spatially variable bandpass filter can = be=20 mounted on the photodiode array. The filter can be configured such that = the=20 central wavelength of the passband varies along one of the dimensions of = the=20 filter. For example, a filter can have a passband width in the range of = from 12=20 cm.sup.-1 to 20 cm.sup.-1. Still further, in a configuration adapted for = the=20 analysis of glucose in interstitial fluid, a filter can have passband = width of=20 16 cm.sup.-1. Thus, it will be appreciated that by using a bandpass = filter, each=20 photodetector element, or photodiode, can be adapted to be sensitive to = a=20 different wavelength of light. An exemplary spatially variable filter is = the=20 JDSU LVF 14002500-3 and is commercially available from Optical Coating=20 Laboratory, Inc.

[0064] The electromagnetic radiation source = can, in one=20 aspect, comprise any conventional light source capable of providing=20 electromagnetic radiation in the waveband region corresponding to the = spectral=20 features of an analyte under investigation. In one aspect, and as = mentioned=20 above, the light source can be a high efficiency broad band LED. The LED = can,=20 for example, be comprised of GaInAsSb and based on a similar p-i-n = semiconductor=20 structure as described in connection with the exemplary photodiode = elements=20 discussed above. In an alternative aspect, the LED can comprise an = InAs/GaInSb=20 super lattice. Similar to the fabrication of the photodiode described = above, an=20 LED according to the present invention can also be fabricated using = conventional=20 molecular beam epitaxy.

[0065] Although LEDs can be very = efficient light=20 sources as compared with Globars or tungsten lamps, the LED can also = have the=20 largest power draw of any component in the system. This can mean that = the=20 efficiency of the LED can dominate the operation time available from a = single=20 battery. For example, a typical LED voltage requirement can be = approximately 0.7=20 V and the typical current draw can be approximately 140 mA. Further, = these=20 values can, in one aspect, be mismatched with the corresponding voltage = and=20 current values associated with a typical portable battery source as well = as the=20 other optional electronics components (.about.5 V and <10 mA) that = will be=20 described in detail in connection with the electronic support unit.=20

[0066] To this end, in one aspect, the present invention further = comprises a high efficiency LED assembly that can minimize or eliminate = the=20 mismatch in current and voltage discussed above. A conventional LED = typically=20 incorporates a single emitting layer in the center of a p-i-n diode = junction.=20 However, in a cascaded system, several p-i-n junctions can be cascaded = in series=20 within a single LED active region using, for example, Esaki tunnel = junctions.=20 Using a cascade of, for example, 5 emitter regions can therefore = increase the=20 voltage requirement of the light source and decrease the current draw by = a=20 factor of 5. Thus, using the typical exemplified voltage and current = values=20 discussed above, active cascading of 5 emitters can, for example, = provide a=20 light source having a net voltage requirement of 3.5V and total current = draw of=20 approximately 28 mA without altering the output optical power of the = light=20 source. As one of skill in the art will appreciate, this can, in one = aspect,=20 significantly extend battery life, which can be particularly well suited = for use=20 with portable, continuous and/or implantable analyte detection systems.=20 Accordingly, in view of the foregoing description, one of skill in the = art will=20 be able to readily determine the desired level of LED cascading needed = to=20 optimize the efficiency of a light source in a given system without = requiring=20 undue experimentation. In still another aspect, it is envisioned that = the light=20 source can comprise a tunable laser diode.

[0067] The = microspectrometer=20 further comprises an optical sampling cell having a cell housing that = defines a=20 fluid inlet port and a fluid outlet port, wherein the fluid inlet port = can be=20 configured to receive an optical sampling fluid from a test subject. = Still=20 further, in another aspect, the fluid inlet port can be adapted to = continuously=20 receive sampled fluid, such as an interstitial fluid, from a sampling = assembly.=20 In one aspect, the electromagnetic radiation source and the = electromagnetic=20 radiation detector can be aligned with the optical sampling cell such = that the=20 sampling fluid delivered to the optical cell can be irradiated with a = desired=20 waveband of electromagnetic radiation and so the detector can = subsequently=20 detect variations in the electromagnetic radiation resulting from the = interface=20 of the electromagnetic radiation with the interstitial fluid. =

[0068] The=20 desired geometry for the optical cell can depend, in part, upon the = particular=20 flow dynamics within the analyte detection system as well as the optical = configuration of the light source and photodetector assembly. To this = end, the=20 desired optical cell geometry can be readily derived and/or optimized by = one of=20 ordinary skill in the art without requiring any undue experimentation. = However,=20 in one aspect, and as exemplified herein without limitation, an optical = cell can=20 be substantially cylindrical in shape, comprising a diameter of = approximately=20 200 .mu.m, an optical path of approximately 1 mm and an interior volume = of=20 approximately 31 nL. In an alternative aspect, the optical sampling cell = or=20 chamber can be substantially rectangular, such as for example, the cell = provide=20 by a square capillary member. According to this aspect, a light source = such as=20 an LED can be mounted directly on one wall of the capillary and the = detector=20 assembly can be mounted directly on to the opposing wall of the = capillary=20 member.

[0069] In another aspect, the optical cell can be = configured to=20 provide a substantially laminar flow. To this end, one of ordinary skill = in the=20 art will appreciate that a substantially laminar flow within the optical = cell=20 can minimize the residence time of an interstitial fluid sample = delivered to the=20 optical cell. Minimizing residence time can therefore reduce the lag = time within=20 the detection system. For example, the vast majority of interstitial = fluid=20 volume present within the detection system at any given time can be in = the=20 optical cell region. Thus, in the exemplified aspect where the optical = cell has=20 a diameter of approximately 200 .mu.m and has an interior volume of=20 approximately 31 nL, if laminar flow conditions are achieved at a flow = rate of=20 approximately 100 nl/min, the approximate time needed to replace = substantially=20 all of the fluid in the optical cell will be less than approximately 20 = seconds.=20 To this end, it will be appreciated that higher and lower flow rates can = also be=20 used with the present invention. For example, and without limitation, a = suitable=20 flow rate can be in the range of from approximately 30 nl/min to = approximately=20 150 nl/min.

[0070] In still another aspect, the interior walls = of the=20 optical cell may be coated or metalized in order to maximize = electromagnetic=20 radiation throughput through the optical cell. This could, for example, = be=20 accomplished by photolithography using a conventional bi-level resist = lift off=20 scheme.

[0071] In still another aspect, and as further shown in = FIG. 2,=20 the optical cell 122 can be fabricated in a microfluidic chamber 180 = having a=20 micro fluidic inlet channel 182 and a micro fluidic outlet channel 184. = As=20 depicted, the inlet channel can be in fluid communication with a = sampling=20 assembly and the outlet channel can be in fluid communication with a = vacuum=20 source such that interstitial fluid can be drawn into the sampling = assembly and=20 propagated through the optical sampling cell.

[0072] The = microfluidic=20 chamber can be fabricated from a single substrate material using = conventional=20 means such as laser micromachining, chemical etching, diamond drilling, = and/or=20 ultrasonic drilling. In still another aspect, the microfluidic assembly = can be=20 molded from any suitable infrared transmitting polymer. For example, in = one=20 aspect, and without limitation, an infra red transmitting fluoropolymer = such as=20 TEFLON AF, commercially available from Dupont, can be used to mold a=20 microfluidic chamber according to the instant invention. As one of skill = in the=20 art will appreciate, TEFLON AF is transparent to certain wavebands of = infrared=20 radiation and has an index of refraction that is less than that of water = or ISF.=20 Thus, TEFLON AF or any similar polymer can in another aspect also serve = as a=20 waveguide for the IR radiation. To this end, the manufacturing = flexibility=20 offered by the fabrication strategies and materials set forth above can = provide=20 the added ability to customize the geometry of the optical cell to = virtually any=20 desired specifications.

[0073] Microfluidic tubes from the = sampling=20 assembly and vacuum source can, in one aspect, be coupled to the = microfluidic=20 chamber by fitting the tubing into, for example, a microfabricated = recess in the=20 distal ends of the inlet and outlet channels. The tubing can be secured, = for=20 example, using a UV curable silicone, commonly used in medical device=20 fabrication. In another aspect, the attachment of the sampling assembly = lead to=20 the optical cell can be accomplished using commercially available, low = dead=20 volume connectors. In another aspect, the entire microfluidic chamber = unit can=20 be closed by affixing infrared transmitting windows to the top and = bottom of the=20 chamber using any conventional adhesive, such as a uv photocurable = adhesive. It=20 should be understood that the size of the microfluidic chamber can be = scaled up=20 or down to any desired dimension. In one aspect, the optimal size of the = micro=20 fluidic chamber can depend on, for example, the structural strength = needed to=20 prevent breakage of the connection points to the ultrafiltration inlet = and=20 outlet lines.

[0074] As illustrated in FIG. 4, the = electromagnetic=20 radiation source 121 and detector assembly 127, mounted on respective = headers,=20 can be aligned with the optical sampling chamber and affixed or = connected=20 directly to a microfluidic chamber with, for example, a photo curable = adhesive.=20 The components can, for example, be bonded to the microfluidic chamber = substrate=20 using anodic bonding to ensure a long lasting hermetic seal for the main = assembly. Electrical connections from the source and detector can be = supplied=20 by, for example, by flexible ribbon cables that can be affixed to = metallic (i.e.=20 gold) pads on the headers. The ribbon cable can then be attached to the = system=20 control electronics discussed in detail below. This entire assembly can, = in=20 another aspect, be potted in a photocurable medical grade RTV silicone, = which=20 can protect the assembly from shock and ensure protection from the = surrounding=20 environment. It can also provide temperature insulation so that the = system can=20 operate under a relatively stable operating temperature profile. = Further,=20 according to this aspect, it will be appreciated that the source = radiation does=20 not emerge into air and can therefore maintain the brightness advantage=20 associate with the higher refractive indices associated with the = interstitial=20 fluid.

[0075] The analyte detection system further comprises a = sampling=20 assembly for obtaining a sample fluid, such as interstitial fluid. The = sampling=20 assembly can be positioned in fluid communication with the optical = sampling cell=20 of the micro-spectrometer via any conventional commercially available=20 microfluidic tubing and connectors. In one aspect, the microfluidic = tubing=20 connecting the sampling assembly to the optical cell can be constructed = and=20 arranged to minimize the amount of dead volume within the system. To = this end,=20 one of ordinary skill in the art will appreciate that having the optical = cell=20 positioned relatively close to the sampling assembly can minimize the = amount of=20 dead volume within the system and significantly decrease the lag time in = analyte=20 measurements. In one aspect, sampling lag times of less than 60 seconds = can be=20 achieved utilizing only a few centimeters of tubing between the sampling = assembly and the optical cell.

[0076] As one of skill in the art = will=20 appreciate, there are a variety of conventional techniques that can be = used to=20 access interstitial fluid from a test subject, including, for example, = the=20 implantation of subcutaneous sampling probes, extraction of interstitial = fluid=20 through intact skin by electrical current, drawing interstitial fluid = out of the=20 skin with a micro-cannula, insertion of a microdialysis probe into the = skin,=20 insertion of an ultrafiltration probe into the skin and the use of an = implanted=20 wick. The sampling assembly of the instant invention can comprise any = one or=20 more of these or any other conventional technique for obtaining a sample = of=20 interstitial fluid from a test subject.

[0077] In two exemplary = and=20 non-limiting aspects, microdialysis and ultrafiltration can be used in = the=20 instant invention as an effective means for sampling interstitial fluid. = Both=20 micro-dialysis and ultra-filtration involve mass transport of an analyte = of=20 interest across a conventional semi-permeable membrane that can be = implanted in=20 the subcutaneous tissue of a test subject. Because of the typical = hydrophobicity=20 and molecular weight limits of conventional semi-permeable membranes, = these=20 techniques can be well suited for sampling hydrophilic substances (i.e., = interstitial fluid) and can provide samples that are substantially free = of=20 extraneous proteins (enzymes), cells and/or other large molecular weight = substances.

[0078] In conventional microdialysis sampling, the = sampling=20 assembly can comprise an access probe that is implanted into = subcutaneous=20 tissue. The probe comprises a semi-permeable membrane. In use, the=20 semi-permeable membrane is perfused with a physiological solution. Water = soluble=20 substances in the interstitial fluid (ISF) can consequently diffuse = across the=20 semi permeable dialysis membrane and enter the perfusate, which can then = be=20 analyzed by the microspectrometer. With this technique, substances in = the ISF=20 can be monitored and, for example, the effects of locally delivered = drugs can be=20 studied.

[0079] The driving force for the diffusion of the = analyte from=20 the tissue and across the membrane wall is, in one aspect, the = concentration=20 gradient of the particular analyte of interest in the interstitial fluid = relative to the perfusate. Typically, the perfusate is selected to be=20 iso-osmotic with the surrounding tissue, the hydrostatic pressure is = relatively=20 minimal and there is no net fluid transfer between the perfusate and the = tissue.=20 To this end, additional techniques such as no-net flux and retrograde = dialysis=20 can also be used to ensure the exact determination of analyte = concentrations. As=20 one of ordinary skill in the art will appreciate upon practicing the = present=20 invention, in another aspect it may be desirable to utilize conventional = ultra-slow microdialyis.

[0080] It should be understood that = particular=20 aspects and parameters of a suitable microdialysis assembly, such as the = desired=20 flow rate, the composition of the semi-permeable membrane, and the = composition=20 of the perfusate, will be dependent, in part, upon the particular = analyte under=20 investigation and fluid dynamics of the analyte detection system. These=20 particular parameters can be optimized by one of ordinary skill in the = art=20 without the need for any undue experimentation. To that end, exemplary = and=20 conventional microdialysis systems and methods that can be used with the = instant=20 invention are disclosed and described by Rooyackers O., Thorell A., = Nygren J.,=20 Ljungqvist O. Microdialysis Methods for Measuring Human Metabolism = Current=20 Opinion in Clinical Nutrition & Metabolic Care. 7(5):515-21, 2004 = and by=20 Chaurasia C S. In vivo microdialysis sampling: theory and applications.=20 Biomedical Chromatography. 13(5):317-32, 1999, the entire disclosures of = which=20 are hereby incorporated by reference in their entirety for all purposes=20

[0081] As stated above, in another aspect, the sampling assembly = can=20 comprise a conventional ultra-filtration system. To this end, = ultra-filtration=20 similarly utilizes an implantable semi-permeable membrane. However,=20 ultra-filtration does not typically involve the use of a perfusate, but, = instead=20 relies on a pressure differential applied across the semi-permeable = membrane as=20 the driving force for the extraction of an analyte-containing sample of=20 interstitial fluid. Typically, the pressure differential is supplied in = the form=20 of a vacuum source. The reduced pressure provided by the vacuum source = results=20 in a hydrodynamic flux across the membrane, with water and one or more = permeable=20 solutes also being extracted from the tissue surrounding the membrane. = As one of=20 skill in the art will appreciate, ISF is rapidly replenished and the = amount of=20 fluid being sampled is small relative the entire pool of ISF available = for=20 sampling. Thus, in accordance with this aspect, ultra-filtration can be=20 particularly well suited for use in a sampling assembly constructed and = arranged=20 for extended and continuous removal of ISF. Furthermore, conventional=20 microdialysis typically involves the need to recalibrate the system = periodically=20 in order to account for changes in the diffusion properties of molecules = across=20 the membrane. In contrast, it will be appreciated upon practicing the = present=20 invention that ultra-filtration does not require periodic recalibration = of the=20 analytical system periodically in order to account for changes in the = diffusion=20 properties of molecules across the ultra-filtration membrane. =

[0082] Any=20 conventional vacuum source can be used in connection with a sampling = assembly of=20 the instant invention. Examples of suitable vacuum sources include, = without=20 limitation, an evacuated vial or vacutainer, a monovette, portable = battery=20 powered syringe pumps, and micro syringe pump systems. In one aspect, = power for=20 a battery powered pump unit can be controlled and supplied by the ESU = described=20 herein. The vacuum source can be used to draw the ISF across the = ultrafiltration=20 membrane. In one aspect, the vacuum source will be able to provide a = flow rate=20 in the range of from 30 nl/min to 150 nl/min. In another aspect, the = vacuum=20 source will be able to draw interstitial fluid at a flow rate of = approximately=20 100 nl/min. To this end, it should be understood that the desired flow = rate in=20 microdialysis and/or ultrafiltration can also depend, in part, upon the=20 configuration of the microfluidic chamber, dimensions of the probe and = the level=20 of negative pressure provided by the vacuum source.

[0083] As = one of=20 skill in the art will also appreciate, bubble formation within the = sampled=20 interstitial fluid can occur during the filtration process and can = result in an=20 inaccurate optical analysis of the sampled ISF. This typically results = as a=20 function of the negative pressure, with bubble formation increasing = proportional=20 to an increase in pressure. Further, bubble formation can also result as = a=20 function of increased flow rate. Thus, in another aspect, it should be=20 understood that minimization of bubble formation in the sampled ISF can = be=20 obtained by optimizing pressure and flow rate of the interstitial fluid = through=20 the sampling probe and subsequently through the micro-fluidic chamber = such that=20 bubble formation is minimized. To this end, one of ordinary skill in the = art=20 will be able to arrive at such optimized conditions without the need for = undue=20 experimentation.

[0084] In an exemplary aspect where glucose is = the=20 analyte under investigation, the sampling assembly is comprised of an=20 ultra-filtration probe such as the BAS UF-312 ultra-filtration probe=20 commercially available from Bioanalytical Systems. This exemplary=20 ultra-filtration probe is made from a polyacrylonitrile membrane and has = an=20 outer diameter of approximately 320 um and membrane wall thickness of=20 approximately 50 um. As will be appreciated by one of skill in the art, = prior to=20 implantation, the probe can be sterilized with, for example, ethylene = oxide. The=20 exemplified probe can then be implanted anywhere on the body having a = soft=20 tissue layer sufficiently thick to accommodate the protrusion of the = access port=20 into the subdermal space. In one aspect, the implant can be placed on = the wrist=20 or arm area for easy patient access and may include a device or = implement to=20 cover the port such as a wrist watch interface or skin colored bandage = to=20 improve patient acceptance of the aesthetic qualities of the device. = Further,=20 for durability, the access port can in another aspect be placed = somewhere on the=20 body that is not subject to a lot of exposure or contact such as the = abdomen.=20

[0085] It will be appreciated in view of the foregoing = description that=20 an implantable ISF access probe can provide a method for withdrawal of = body=20 fluids without requiring further breach of the skin barrier. The = implantable=20 access probe can also provide for filtration of interstitial fluid, = thereby=20 resulting in a sample of fluid containing an analyte of interest and=20 substantially free of extraneous proteins and/or cells. In another = aspect,=20 because of its porosity and fibrous structure, the implanted access port = can=20 form an infection-free, transcutaneous implant having a biological seal = around=20 the device. Therefore, the implant can be suitable for long term use. = Further,=20 since the implant can reside in the plane between the subcutaneous and = dermal=20 layers of tissue, subsequent removal can be relatively simple if = necessary.=20

[0086] The direct in situ sampling of interstitial fluid can in = one=20 aspect simplify the task of detecting an analyte as compared to other=20 conventional non-invasive measurement approaches that rely on detecting = an=20 analyte based on spectral data obtained from a more complex and/or = heterogeneous=20 skin matrix. More specifically, interstitial fluid is typically a clear = fluid=20 with relatively few or even no scattering particles (such as cells), and = thus=20 the optical throughput can be orders of magnitude higher than = transmission=20 measurements through skin or whole blood. Further, because the optical = geometry=20 of the method set forth above can be defined by the path length of the = sampling=20 chamber, the interpretation of measured spectra in terms of absolute = analyte=20 content can also be much more straightforward compared to methods that = rely on=20 diffuse reflection, transflection, or photoacoustic arrangements. =

[0087]=20 One of skill in the art will appreciate that a microspectrometer as = described=20 and exemplified herein does not require the use of moving parts and/or = imaging=20 optics and can therefore occupy a relatively small volume of space. = Thus, in one=20 aspect, microspectrometer according to the present invention can occupy = as small=20 or as large a volume as is desired. For example, the microspectrometer = can=20 occupy a volume as small as the technology of the individual components=20 themselves will allow. In one aspect, and without limitation, a=20 microspectrometer according to the present invention can occupy a volume = in the=20 range of from approximately 0.01 cm.sup.3 to approximately 1.0 cm.sup.3, = including volumes of 0.02 cm.sup.3, 0.03 cm.sup.3, 0.04 cm.sup.3, 0.05 = cm.sup.3,=20 0.06 cm.sup.3, 0.07 cm.sup.3, 0.08 cm.sup.3, 0.09 cm.sup.3, 0.1 = cm.sup.3, 0.2=20 cm.sup.3, 0.3 cm.sup.3, 0.4 cm.sup.3, 0.5 cm.sup.3, 0.6 cm.sup.3, 0.7 = cm.sup.3,=20 0.8 cm.sup.3, 0.9 cm.sup.3, and any range derived from these values. In = still=20 another aspect, the microspectrometer can occupy a volume that does not = exceed=20 approximately 0.1 cm.sup.3.

[0088] In still another aspect, the = present=20 invention provides a method for the reagentless optical detection of an = analyte=20 in a fluid sample. The method can generally comprises providing an = analyte=20 detection system as described herein, comprising: (i) an optical = sampling cell=20 having a cell housing defining a fluid inlet port and a fluid outlet = port, the=20 fluid inlet port; (ii) an electromagnetic radiation source in = communication with=20 a first portion of the optical sampling cell housing; and (iii) an=20 electromagnetic radiation detector in communication with a second = portion of the=20 optical sampling cell housing. A fluid sample containing an analyte can = be=20 obtained from a test subject and conveyed through the inlet port in to = the=20 optical sampling cell. Electromagnetic radiation generated by the=20 electromagnetic radiation source can irradiate at least a portion of the = fluid=20 sample within the optical sampling cell and the electromagnetic = radiation=20 detector can optically detect electromagnetic radiation emanating from = the=20 optical sampling cell. Still further, if desired, at least a portion of = the=20 obtained fluid sample contained within the optical sampling cell can be = returned=20 to the source of the sample fluid, such as the test subject. =

[0089] It=20 should also be understood that the reagentless optical analyte sensor = and method=20 of the instant invention can also be used in a variety of applications. = For=20 example, as exemplified herein, the analyte sensor can be used to = monitor the=20 presence and concentration of one or more analytes in the interstitial = fluid of=20 a test subject. To this end, the microspectrometer can be used to=20 spectroscopically analyze interstitial fluid in either an in-vivo = configuration=20 or, alternatively, in an ex-vivo configuration.

[0090] In an = in-vivo=20 configuration, the microspectrometer can be implanted in the = subcutaneous tissue=20 of the test subject. The subcutaneously implanted sampling assembly = probe can=20 continually draw a small volume of interstitial fluid (ISF) from the = test=20 subject and pass the stream of ISF through the optical sampling cell = where it=20 can be analyzed spectroscopically for any number of targeted analytes. = By=20 providing a reagentless optical analyte sensor, the lack of reaction = byproducts=20 enables the sample fluid to then be returned to the body of the test = subject=20 without concern of contamination or poisoning. In one aspect, it is also = envisioned that a microspectrometer could be placed in the peritoneal = cavity of=20 a test subject and the sampling assembly probe can be imbedded in the=20 subcutaneous tissue bed surrounding the peritoneal cavity. =

[0091]=20 Alternatively, in an ex-vivo configuration, a sampling assembly probe = can be=20 implanted subcutaneously and can again continuously draw a relatively = small=20 sample volume of interstitial fluid (ISF) from the test subject and pass = the=20 stream of ISF through the optical sampling cell of a microspectrometer = where it=20 can be analyzed spectroscopically for any number of targeted analytes. = In=20 accordance with this configuration, the microspectrometer can be = positioned=20 external to the test subject, such as for example, by being affixed to = or worn=20 on the surface or skin of a test subject. By virtue of the = microspectrometer=20 being a reagentless optical analyte detector, even in an ex-vivo = arrangement the=20 sample can, if desired, be returned back to the subcutaneous tissue of = the test=20 subject. Alternatively, due to a potential fear of infection, the sample = fluid=20 obtained from an ex-vivo arrangement can also be externally collected = and=20 disposed. To this end, in an exemplary aspect where the sampling flow = rate is=20 approximately 150 nL/min, the system would generate approximately 216=20 microliters per day that could be externally collected and disposed of.=20

[0092] To this end, the reagentless optical analyte sensor can = in one=20 aspect be integrated into a nocturnal glucose monitoring system. In = another=20 aspect, the analyte sensor can be used in connection with a closed loop=20 automated biological delivery system, such as an artificial pancreas = adapted to=20 selectively deliver insulin to a test subject.

[0093] In still = another=20 aspect, the analyte sensor can be used to spectroscopically analyze = sample=20 fluids other than interstitial fluids. For example, the analyte sensor = can be=20 used in connection with traditional clinical analysis of biological = fluids such=20 as blood and/or urine. Thus, in one aspect, the analyte sensor can be = used to=20 enable the real-time optimization of hemodialysis treatments by = monitoring=20 analytes such as urea, lactate, creatinine, phosphate, and/or sulfate = present=20 within the blood of a test subject undergoing hemodialysis treatment. In = an=20 alternative aspect, the reagentless optical analyte sensor can also be = used in=20 connection with general blood chemistry, where, for example, the analyte = sensor=20 can be used to monitor the presence and concentration of one or more = analytes in=20 the blood of test subject.

[0094] In still another application, = the=20 reagentless optical analyte sensor of the instant invention can be used = to=20 monitor process chemistry. For example, and without limitation, the = reagentless=20 optical analyte sensor can be used on connection with a bioreactor to = monitor=20 the level of nutrients and/or cellular waste products to maximize = growth.=20 Additionally, the analyte sensor can be used to monitor industrial = chemical=20 processes and or environmental process monitoring.

[0095] As = briefly=20 stated above, in another aspect the present invention provides a an = electronic=20 support unit (ESU), for use in connection with a reagentless optical = analyte=20 detection system as described above. In one aspect the controller or = electronic=20 support unit is in communication with an analyte detection system and = can enable=20 the continuous and reagent-free optical analysis of interstitial fluid = (ISF)=20 present within a test subject. To this end, in one aspect, the = controller can=20 provide a physical interface between one or more optical sensing = elements=20 designed to obtained analyte related data.

[0096] An electronic = support=20 system 200 according to the instant invention can be constructed and = arranged so=20 as to comprise a battery powered primary or internal module that can be = affixed=20 to a test subject and an external or remote module that can be = positioned in a=20 remote location a predetermined distance from the internal module.=20

[0097] In one aspect, the primary or internal module can be = optionally=20 implanted in the subcutaneous tissue of a test subject. In an = alternative=20 aspect, the primary or internal module can be affixed to or worn on a = surface of=20 the test subject. For example, and without limitation, the primary = module can be=20 releasably affixed to or worn on the skin of a human test subject.=20

[0098] The electronic support system 200 can, in one aspect, = enable=20 continuous operation of a biological data sensor for extended durations = with=20 relatively minimal or even no user intervention. Further, the electronic = support=20 system 200 can operate from a battery based power supply capable of = remote=20 charging. To this end, the electronic support system 200 as configured = and=20 described herein can further operate at relatively low power supply = voltages=20 such as, for example, 3.3 volts. Such a power supply can provide = continuous=20 energy for up to and even exceeding 24 hours of system operability.=20

[0099] The primary or internal module comprises a data = acquisition unit=20 (DAU), a main controller unit (MCU) comprised of a dedicated = microcontroller=20 unit to control the sensor system; an internal power unit (IPU) to = supply power=20 to one or more of the components in the internal module, and a first = telemetry=20 unit (TU) for communicating analyte related data to the external or = remote=20 module. The external module can comprise a remote charger unit (RCU) = that can=20 transmit inductive power to the internal power unit, and a second = telemetry unit=20 that can receive sampled data that has been transmitted from the first = telemetry=20 unit of the internal module. Functionally, the ESU 200 in one aspect is = therefor=20 comprised of a Data Acquisition Unit (DAU) 300, Main Controller Unit = (MCU) 400,=20 Power Supply Unit (PSU) 500, and the Telemetry Unit (TU) 600 = respectively, as=20 shown in FIG. 5.

[0100] The main controller unit or MCU 400 can, = in one=20 aspect, provide one or more functions including, without limitation, = obtaining=20 sampled analyte data from the data acquisition unit, storing the = obtained data=20 in memory, packaging the data along with a time stamp, and/or = subsequently=20 transmitting the data through the telemetry unit (TU) 600. The main = controller=20 can also be responsible for coordinating the communication between the = internal=20 and external modules and ensuring proper operation of one or more units = within=20 the system.

[0101] An exemplary schematic of an MCU 400 = according to the=20 instant invention is illustrated in FIG. 6. As depicted, the MCU = comprises a=20 memory component 410 and a microcontroller component 420. While any = conventional=20 memory device can be used with the MCU, the commercially available = Dallas=20 Semiconductor DS1644 NVRAM memory, equipped with a real time clock (ETC) = and=20 back-up Li-ion battery can be used for data storage in an exemplary = aspect. As=20 one of skill in the art will appreciate, the NVRAM with an integrated = circuit=20 can provide fast access to data and a real time clock for time-stamping = the=20 data. Further, the memory and real time clock combination can, in one = aspect,=20 eliminate the need for additional time keeping hardware. An alternative = memory=20 device which is suitable for use in the instant invention can be the = Ramtron=20 FM31256 32 KB FRAM memory, also equipped with a real time clock. The = FRAM can=20 offer virtually unlimited read/write cycles, relatively fast access to = data, and=20 as mentioned, a real time clock for time stamping the data. =

[0102] In=20 one aspect, it is desired for the memory capacity to be sufficient to = store up=20 to approximately 24 hours of sampled data. According to this aspect, at = an=20 exemplary sampling rate of one sample every 5 minutes and approximately = 3 bytes=20 of memory needed per sample per channel, an additional 6 bytes per = sample for=20 timestamp and error detection, a data memory capacity of at least 29.4 = KB can be=20 needed to store 24 hours of data obtained from a 32 photodiode array. To = this=20 end, one of skill in the art can appreciate that any desired memory = capacity can=20 be used in the instant invention and further, the desired memory = capacity can be=20 calculated according to the following equation: Memory Capacity=3DdRSn = where d is=20 the duration in hours, R is the sampling rate in samples per hour; S is = the=20 sample size in bytes per channel per sample, n is the number of = channels.=20

[0103] To enable data collection, light source control, data = processing,=20 and/or operation of the telemetry generation, a microcontroller 420 is=20 incorporated into the Main Control Unit. According to this aspect, since = the=20 microcontroller can in one aspect be accessing data stored in external = memory, a=20 microcontroller that supports external memory can be used. To this end, = as one=20 of ordinary skill in the art will appreciate, it can also be desired, = although=20 not required, for a single microcontroller unit to support one or more = of the=20 other instrumental requirements, while maintaining as small of a size as = possible with as low power consumption as possible.

[0104] In = still=20 another aspect, it can be further desired, although it is not required, = for the=20 microcontroller to comprise an instruction set supporting multiplication = and=20 division instructions such that it is capable of performing floating = point=20 operations. Additionally, a suitable microcontroller can comprise either = an=20 internal program flash or an external flash memory. Any conventional and = commercially available microcontroller capable of performing one or more = feature=20 set forth above can be used in accordance with the present invention. = However,=20 the specific features described above can typically be provided in an = exemplary=20 conventional 8-bit microcontroller such as those tested and indicated in = Table 1=20 below. While any one of the microcontrollers listed in Table 1 is = suitable for=20 use in the instant invention, a comparison of these four commercially = available=20 8-bit microcontrollers indicates that in one aspect, a suitable = microcontroller=20 for use in the Main Controller Unit is the Atmel AT89C51ID2. = TABLE-US-00001=20 TABLE 1 Exemplary Microcontrollers Features AT89LS53 ATtiny26L MC68HC805 = AT89C51ID2 Architecture 8051 AVR 68 8051 Supply Voltage 2.7 V 2.7 V 5 V = 3.3 V=20 Program Memory 12 kB 2 kB 8 kB 64 kB RAM (bytes) 256 128 192 2048 IO = Pins 32 16=20 20 32 Clock Speed (Max) 12 MHz 16 MHz 4 MHz 160 MHz ISP Yes Yes No Yes = MUL, DIV=20 Inst Yes No No Yes Interrupts 9 11 10 9 Timers 3, 16-bit 2, 8-bit = 16-bit, 8-bit=20 3, 16-bit UART Module Yes No No No SPI Module Yes No No No =

[0105] In=20 still another aspect, a suitable microcontroller can typically supply=20 multiplexed address-data lines. Thus, in order to access the external = memory, a=20 transparent octal D-type latch 430 with tri-state outputs can be used. = To this=20 end, a suitable latch for the multiplexing can, in one aspect, have a = latch=20 switching delay that is negligible as compared to the memory access = time, which=20 is typically of the order of 120 ns for the DS1644 NVRAM memory = described above.=20 An exemplary D-type latch that is suitable for use in the instant = invention is=20 the Texas Instrument SN74AC373 octal D-type latch with a switching delay = of=20 approximately 15 ns.

[0106] The microcontroller unit is also = provided=20 with a telemetry unit interface 440 to interface the telemetry unit with = the=20 main controller. The telemetry unit interface can be any communication = interface=20 such as, for example, USB, serial, firewire, parallel, and the like In = one=20 aspect, the telemetry unit interface can comprise an RS-232 serial port. = The=20 RS-232 serial port can provide added debugging functionality as well. = Virtually=20 any conventional and commercially available RS-232 serial port can be = used to=20 provide the telemetry interface. While any transceiver known in the art = can be=20 used, in one aspect, a suitable RS-232 transceiver can provide true = RS-232=20 signal levels with minimum board space, low power consumption, and = suitable=20 operating voltage. To this end, the Maxim MAX3233EWE dual RS-232 = transceiver=20 with internal charge pumps is a non-limiting example of a RS-232 = transceiver=20 that is suitable for use in the instant invention. The MAX3233E can = operate in=20 the voltage range of 3.0-3.6V DC with 1 uA supply current. Additionally, = the=20 MAX3233E is capable of entering into a sleep mode when either the RS-232 = cable=20 is disconnected or when the UART driving the transmitter inputs is = inactive for=20 more than 30 seconds. From the sleep mode, the MAX3233E can turn on = again when=20 it senses a valid transition at any transmitter or receiver input. As = one of=20 skill in the art will appreciate, this feature can help to conserve = power in the=20 system.

[0107] The microcontroller can further comprise one or = more=20 peripheral support interfaces such as, for example, a jumper for a light = source=20 connector 450, an ISP jumper 460, and other serial interfaces to = facilitate=20 connectivity of other controller modules and/or other system components. =

[0108] As stated above, the electronic support system further = comprises=20 a data acquisition unit (DAU) 300 that can obtain sampled data from a = biological=20 data sensor, such as for example, data detected by the optical sensing = component=20 of an analyte sensor. In one aspect, the data acquisition unit can = obtain data=20 in a first format and can transform that sample data into a second = format. For=20 example, the DAU 300 can obtain sampled voltage data from a photodiode = array in=20 an analog format and can transform the analog data into digital format = having a=20 predetermined level of precision.

[0109] In one aspect, the data = acquisition unit (DAU) 300 can comprise a current integrator and an=20 analog/digital (A/D) converter. The A/D converter can be interfaced to = the main=20 controller unit through any conventional interface, such as for example = a serial=20 peripheral interface (SPI). The level of precision for A/D conversion = can vary=20 as desired and can in one aspect be in the range of from at least 8 bits = up to=20 and even exceeding 128 bits, including additional precision values of = 16, 20,=20 24, 32, 64 and any range derived from these values. In another aspect, = the=20 precision for the A/D converter is at least 20 bits. The data obtained = can be=20 transmitted to the MCU 400 through an SPI interface, where they can be = stored in=20 memory and subsequently transmitted through the first telemetry unit = interface=20 to the remote telemetry unit for analysis of the particular analyte = levels.=20 Thus, in the above-exemplified glucose sensor, the DAU can, for example, = perform=20 the task of sampling the photo diode currents from the 32 photodiodes = depicted=20 in FIG. 3. The 32 photodiode array provides 32 channels of the optical = sensor,=20 with each channel corresponding to different regions in an NIR spectrum. = The DAU=20 300 can also convert the 32 channels into high precision voltage values, = such as=20 for example, 16, 20, or even 24 bit voltage values. An exemplary data=20 acquisition from one photodiode of the 32 photodiode array is = illustrated in=20 FIG. 7.

[0110] FIG. 8 illustrates an exemplary schematic diagram = of a=20 data acquisition unit 300 for one channel of a photo diode. As shown, = the data=20 acquisition unit comprises a current integrator 310, such as the IVC102, = in=20 communication with a channel of a photodiode array. An analog digital = converter=20 320, such as the ADS1241, is positioned in communication with the = integrator 310=20 and interfaced with the main controller unit via an interface 330, such = as an=20 SPI interface. As one of ordinary skill in the art will appreciate, the=20 extension of this schematic diagram to any number of photodiode = channels, such=20 as the 32 photodiode array depicted in FIG. 3, is straight forward and = can be=20 constructed by one of ordinary skill in the art without requiring undue=20 experimentation. It will also be appreciated by one of ordinary skill in = the art=20 that due to the possible limitation of the number of I/O pins on a=20 microcontroller of the Main Controller Unit, port expanders 340 can also = be used=20 to generate control signals for the integrator 310. For example, each = optional=20 port expander can provides as many as 8 extra I/Os and can also be = controlled by=20 the microcontroller of the Main controller unit through an I.sup.2C = interface=20 350.

[0111] In an alternative aspect, and as depicted in the = schematic=20 diagram of FIG. 9, the data acquisition unit can comprise one or more = current=20 integrating analog to digital converters 360, such as the Texas = Instruments=20 DDC118. According to this aspect, the photo detector current from a = photo diode=20 in the analyte sensor can be converted to a voltage by the current = integrating=20 analog to digital converter. As one of skill in the art will appreciate, = the=20 photo detector current will depend, in part, on the responsivity of the=20 particular photo detector used. Thus, as responsivity of the photo = detector is=20 increased, the photo detector current will also increase. In one aspect, = a photo=20 detector current will typically be of the order of 10 nA. If a photo = detector=20 current is not within the measurable range of an analog to digital = converter, an=20 appropriately-selected integrating capacitor can be used to adjust the = output=20 voltage of the amplifier to a level that is within the measurable range = of the=20 analog to digital converter. To this end, the integrating capacitor = needed, will=20 depend on the particular level of the photocurrent and the measurable = limits of=20 the analog to digital converter. One of skill in the art will readily be = able to=20 optimize the integrating capacitor gain without requiring any undue=20 experimentation. In one aspect, an exemplary integrating capacitor will = be 3,=20 12.5, 25, 37.5, 50, 62.5, 75, or 82.5 pF.

[0112] The DDC118 is = an=20 exemplary and commercially available current-integrating analog to = digital=20 converter that can be used with a photo diode as described herein. The = DDC118=20 has integrating capacitors along with a field effect transistor (FET) = op-amp=20 which can provide precision voltage corresponding to a particular photo = diode=20 current. The signal level can be varied to a desired level by varying = the=20 integrating capacitance values and integration times. The DDC118 can=20 periodically sample and convert to a digital value the integrated = current from=20 the photo diode and the resulting value can be stored in the memory of = the=20 microcontroller of the Main Controller Unit.

[0113] Once again, = the=20 extension of the schematic diagram of FIG. 9 to any number of photodiode = channels, such as the 32 photodiode array depicted in FIG. 3, is = straight=20 forward and can be constructed by one of ordinary skill in the art = without=20 requiring undue experimentation. It will also be appreciated by one of = ordinary=20 skill in the art that due to the possible limitation of the number of = I/O pins=20 on a microcontroller of the Main Controller Unit, port expanders can = also be=20 used to generate control signals for the current-integrating analog to = digital=20 converter. Each optional port expander can provides as many as 8 extra = I/Os and=20 can also be controlled by the microcontroller of the Main controller = unit=20 through an I.sup.2C interface.

[0114] FIGS. 10 and 11 illustrate = exemplary sampled absorption data indicating normalized infrared = absorption=20 spectra for a representative glucose containing solution. As depicted, = each=20 normalized data point corresponds to the data generated by each channel = of a 32=20 channel photodiode array. The particular data sets were obtained from a = current=20 integrating digital analog converter, as described herein, using an = exemplary 90=20 Hz sampling frequency, alternating with 2.5 ms of integration with the = infrared=20 LED on and 2.5 ms with the LED off. FIG. 10 indicates raw data obtained = from the=20 digital analog converter and FIG. 11 indicates the same data after = having been=20 filtered with a digital filtering algorithm designed to increase the = signal to=20 noise ratio. These exemplary data point are further indicative of the = data which=20 can be time stamped and stored in the main controller unit of the = electronic=20 support system and transmitted to the remote telemetry unit for further=20 evaluation.

[0115] The electronic support system 200 can further = comprise a Power Supply Unit 500 that can provide a regulated power = supply to=20 one or more modules and/or components of the electronic support module. = It=20 should be understood that the power supply unit can be configured to = provide any=20 desired level of regulated voltage, depending on the operational = requirements of=20 the individual components present within the analyte sensor and = electronic=20 support unit. For example and without limitation, in one aspect the = power supply=20 can provide a regulated voltage in the range of from approximately 1.0V = to=20 approximately 5.0 volts, including voltages of 1.1, 1.2, 1.3, 1.4, 1.5, = 1.6,=20 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, = 3.1, 3.2,=20 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.5, 4.6, 4.7, 4.8, 4.9 and any = range=20 derived from these values. In another aspect, the power supply provides = a=20 regulated voltage ranging from approximately 3.3 V-5V to one or more = modules=20 and/or components of the electronic support module.

[0116] = Additionally,=20 the power supply unit 500 can also provide power for recharging the = batteries.=20 Thus, in one aspect, the PSU 500 can be constructed and arranged to = comprise an=20 external remote charger unit 510 and an internal inductive power unit = 560.=20

[0117] According to this aspect, power can be transmitted=20 electromagnetically by the remote charger unit (RCU) 510 to the = inductive power=20 unit (IPU) 560 using transcutaneous inductive coupling.

[0118] = The IPU=20 560 can supply regulated power to one or more of the units of the = internal=20 module. Again, it should be understood that the internal power unit can = be=20 configured to provide any desired level of regulated voltage to the = internal=20 module depending on the operational requirement of the internal module. = In one=20 aspect, the internal power unit can provide regulated voltage in the = range of=20 from approximately 1.0 V to approximately 5.0 volts, including voltages = of 1.1,=20 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, = 2.6, 2.7,=20 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.5, = 4.6, 4.7,=20 4.8, 4.9 and any range derived from these values. In another aspect, and = without=20 limitation, the internal power unit power supply can provide a regulated = voltage=20 ranging from approximately 3.3 V-5V to the internal module. =

[0119] In=20 one aspect, the IPU power source is comprised of two or more battery = packs 580,=20 with each pack containing a pair of rechargeable batteries. According to = the=20 exemplified aspect in which the IPU supplies a regulated 3.3 V to the = internal=20 module, the pair of rechargeable batteries can be, for example, 1.2 V = NiMH=20 batteries having 1600 mAh capacity and being connected in series. In = use, at any=20 given time a first battery pack can source electrical power to the = internal=20 module while the IPU can recharge the second or plurality of second = battery=20 packs. The remote charging unit or RCU can also facilitate the charging = of the=20 batteries by using transcutaneous inductive coupling through the use of = FET=20 switches 520 and a transcutaneous energy transmission inductor 530. The = FET=20 switches can generate square waveforms and can be turned ON and OFF=20 alternatively by a microcontroller 540. A schematic of an exemplary RCU = 510 is=20 shown in FIG. 12.

[0120] The switching rate of the FET's can in = one=20 aspect correspond to the optimal transmission frequency of the inductive = power=20 unit. To this end, the optimal FET switch rate can be obtained by one of = ordinary skill in the art without any undue experimentation. To this = end, in the=20 exemplified aspect set forth herein, the optimal switch rate for the = FET's can=20 be approximately 4.7 kHz.

[0121] In an exemplary aspect, the IPU = 560 can=20 comprise the Linear Technology LTC1325 battery management integrated = circuit=20 570. The LTC1325 is capable of charging a NiMH, Li-ion, and NiCd = rechargeable=20 batteries. It is also capable of measuring and/or monitoring battery = voltage,=20 battery temperature and/or ambient temperature thereby providing battery = status=20 data. The IPU can also comprise its own microcontroller that supervises = the=20 LTC1325 through a serial port interface. In use, a fully charged battery = pack=20 can have any desired voltage, such as, for example, a voltage of = approximately=20 2.5 V. If needed according to the voltage requirements of the particular = system,=20 this voltage can be boosted using an integrated voltage booster circuit = and then=20 supplied to a voltage regulator to output a desired voltage, such as, = for=20 example, 3.3 V as exemplified above. Accordingly, in one aspect, the IPU = is=20 capable of supplying any desired regulated voltage at any desired = current load,=20 such as, for example, 700 mAh, in order to power any device within the=20 electronic support unit. A schematic of an exemplary IPU is shown in = FIG. 13.=20

[0122] In order to receive the transmitted inductive power, the = IPU can=20 use an inductor 590 that is similar or identical to the one used for the = RCU. In=20 use, the received waveform can be rectified by a rectifier 592 and fed = to a=20 voltage booster unit 594, which boosts the voltage to a desired voltage, = such=20 as, for example, approximately 5 V. This voltage can then be used to = charge a=20 battery pack 580 and to power a battery management integrated circuit = 570 such=20 as the LTC1325 battery management integrated circuit described above. = The=20 microcontroller of the IPU can also communicate with the battery = management=20 circuit and, based upon the varying state of the battery, determine = which phase=20 of the charging cycle to enter. Exemplary determinations that can be = performed=20 by the IPU microcontroller are depicted in a flow chart as illustrated = in FIG.=20 14. As illustrated, the IPU microcontroller can switch to a charging = mode when=20 it detects transmission of power. If no power is being transmitted, the = battery=20 pack with lower voltage can be switched to the charging mode and the = other=20 battery pack can drive the system. Additionally, while the battery is = being=20 charged, the battery temperature can also be monitored in order to = prevent=20 overheating during the charge cycle.

[0123] More specifically, = as=20 exemplified in FIG. 14, at block 1205 a first internal battery pack can = provide=20 power to the primary module in an output state while a second battery = pack can=20 receive a charge from the RCU in a charge state. For the purpose of the=20 exemplified system the method begins with battery pack one in the output = state=20 and battery pack two in the charge state. At block 1210 a voltage = booster output=20 of the charging inductor is read. The system then proceeds to perform a = check at=20 block 1215 to determine if the voltage read is high enough for charging. = If the=20 system determines that voltage is high enough for charging, the system = proceeds=20 to block 1220, to identify the battery pack with lowest voltage. Then at = block=20 1225, the system reads the temperature of the pack. At block 1230, the = system=20 can perform another check to determine if the temperature is too high. = If the=20 system determines that the temperature is too high, the system proceeds = to block=20 1235 and can stand by for a predetermined period of time, such as for = example 20=20 minutes. After the predetermined period of time has lapsed, the system = returns=20 to block 1210.

[0124] If at block 1215 the voltage booster = output is not=20 high enough for charging, the system can then proceed to block 1240. At = block=20 1240, the system can read the voltage of battery pack one and battery = pack two.=20 Then, at block 1245, the system performs a check to determine the = relative=20 voltages of the battery packs, i.e., if the voltage of battery pack one = is less=20 than the voltage of battery pack two. If the voltage of battery pack one = is less=20 than the voltage of battery pack two the system proceeds to block 1250 = and swaps=20 the states of battery packs one and two. If at block 1245 the voltage of = battery=20 pack one is not less than the voltage of battery pack two, the system = proceeds=20 to block 1235 and can standby for a predetermined period of time before=20 returning to block 1210.

[0125] The electronic support system = further=20 comprises a telemetry unit 600 or (TU) that can provide a wired or = wireless=20 interface between the internal module and the external module. Examples = of=20 wireless telemetry connections can include RF, Infrared, 802.xxx, = satellite,=20 cellular, and the like. The external module can in one aspect be = integrated into=20 a user's personal computer or PDA. Alternatively, the external module = can also=20 be a stand alone device. In one aspect, RF telemetry can enable reliable = transmission of sensor data on a full-duplex wireless link from the = mobile=20 implanted sensor to an external base station. Data can then be collected = and=20 sent as packets using a radio protocol that incorporates error detection = in=20 order to ensure data accuracy. These packets can also be transmitted to = the=20 receiver in any desired frequency, such as, for example, in five minute=20 intervals.

[0126] The telemetry unit also comprises a receiving = unit=20 that is capable of receiving the data, acknowledging the receipt of = valid data,=20 decoding data, and checking for transmission errors. The receiving unit = can be=20 interfaced to a PC based system, which can also be integrated into an = internet=20 Web based application that can permit local and or remote data analysis = by the=20 patient and/or one or more medical health professionals.

[0127] = The RF=20 telemetry system can also comprise a first internal or primary telemetry = unit=20 610 which forms a part of the primary module. A remote telemetry unit = 620 can=20 also be provided and can be integrated into the remote or external = module.=20 Schematic diagrams of an exemplary internal 610 and external telemetry = unit 620=20 are illustrated in FIGS. 15 and 16 respectively. The internal telemetry = unit can=20 be similar to or the same as the external unit but is powered by the=20 rechargeable battery power supply. The TU can also be interfaced to both = the=20 main controller unit and the power supply unit through conventional = interrupt=20 driven protocols.

[0128] As will be appreciated upon practicing = the=20 invention disclosed herein, the external telemetry unit can enable user = access=20 to data through a base station. The external telemetry unit can = therefore=20 comprise a microcontroller based system and an RS-232 transceiver. To = this end,=20 the block diagram shown in FIG. 16 illustrates an exemplary external = telemetry=20 unit comprised of an Atmel Atmega8L AVR microcontroller 630 interfaced = to a=20 radio transceiver EWM-900-FDTC 640 through a 3-wire serial interface. If = desired, an antenna input can act as the transmitting and the receiving=20 conductor. In one aspect, the antenna input has an impedance of = approximately 50=20 ohms. Digital signals can also be sent to the RF transmitter through the = 3-wire=20 serial interface and subsequently converted to radio signals using = FM/FSK=20 modulation and then transmitted using the antenna.

[0129] The = internal=20 telemetry unit is capable of sending sensor data to the external = telemetry unit=20 and can also be configured to wait for acknowledgments from the external = unit.=20 The internal unit can, in one aspect, transmit 24-bit sensor data along = with=20 time stamp information, 16-bit CRC and protocol overhead to the external = unit.=20 The radio signals transmitted from the internal telemetry unit can then = be=20 received by the external unit through an antenna and converted to = digital=20 signals compatible with the CMOS levels for the microcontroller using = I/Q=20 demodulation. The received data can also be sent through the UART to a = PC or PDA=20 and made accessible to the user. Depending on the choice of components = used in=20 the telemetry unit, baud rates of at least 9600 can be used for the data = transmission described above. In another aspect, the baud rate can be at = least=20 14400, at least 19200, at least 38400, at least 56000, at least 128000, = or at=20 least 256000. To this end, any baud rate capable of providing the data=20 transmission described above can be used in accordance with the present=20 invention.

[0130] In another aspect, the internal telemetry unit = can be=20 configured to communicate with a remote web server via a network = connection,=20 such as over the Internet. The network connection can be, for example, a = wired=20 or wireless connection. Examples of wireless connections can include RF, = Infrared, 802.xxx, satellite, cellular, and the like. Still further, the = internal telemetry unit can be configured to communicate by any one or = more of=20 the foregoing exemplary wired or wireless connections. For example, a = primary=20 module of the instant invention can be configured to connect to any = available=20 802.xxx connection and transmit sampled biological data to a remote = server.=20 Additionally, the sampled data can be encrypted or decrypted as needed. = When the=20 primary module is not in range of an available 802.xxx connection, the = telemetry=20 can be programmed to automatically switch to a subsequently available=20 communication network.

[0131] As described, the ESU can be = constructed=20 and arranged to operate continuously and unobtrusively for extended = durations=20 with minimal or even no user intervention. Owing to the conditions and = the=20 environment in which the sensor and ESU operate, as stated above, in one = aspect,=20 a battery based power supply capable of remote charging can be used. It = will be=20 also be appreciated upon practicing the present invention that data = loss, which=20 can occur when, for example, a user is out of communicable range from = the base=20 station for an extended period of time, can be prevented by features = implemented=20 in firmware. For example, the ESU can be configured to operate at a = relatively=20 low power supply voltage, such as 3.3 V, for reduced power consumption. = To this=20 end, a power supply according to this aspect can typically provide more = than 24=20 hours of continuous energy in between successive battery recharge cycles = at=20 constant maximum discharge current of, for example, approximately 100 = mA.=20 Further, a low power operation mode or sleep mode can be supported as = described=20 above in order to conserve the battery energy when the analyte data is = not being=20 sampled.

[0132] Exemplary and non limiting system specifications = concerning data memory capacity, power supply voltage, battery capacity, = sampling rate, and data transfer rate are listed in Table 2 below for = one aspect=20 of the instant invention. TABLE-US-00002 TABLE 2 Specifications Units = Target=20 Value Memory Capacity kB 32 Power Supply V 3.3 Battery Capacity mAh 3200 = Sampling Rate (max) Hz 15 Data Transfer Rate kbps 13 Serial Interface = Type SPI,=20 I.sup.2C, RS-232

[0133] FIG. 17 illustrates an exemplary = physical=20 implementation of an analyte sensor 1510 into a test subject 1520. In = use, the=20 sensor can be implanted in the subcutaneous tissues of, for example, the = human=20 body. The ESU can enable the sensor to operate for months with minimal = user=20 intervention. During operation, the interstitial fluid from subcutaneous = space=20 can be sampled through an embedded ultra filtration probe and can then = enter=20 into a micro fluidic chamber, which can be physically isolated from the=20 biological environment. If, for example, glucose is the analyte under=20 investigation, then the sample can be carried to an optimized = spectrometer cell,=20 where a 16 cm.sup.-1 resolution near infrared spectrum is collected over = a=20 spectral range of from approximately 4600 to approximately 4200 = cm.sup.-1=20 (2.17-2.38 .mu.m). The uniqueness of the glucose spectrum in this = waveband is=20 illustrated in FIG. 18. The concentration of the glucose can then be = obtained=20 from direct analysis of the collected absorbance data in the selected = waveband.=20 As one of ordinary skill in the art will appreciate, the spectral range=20 illustrated above is optimized for use in connection with glucose. Thus, = the=20 desired spectral range will be dependent upon the particular analyte = under=20 investigation.

[0134] The electronic support unit described and=20 disclosed herein can be used in a variety of applications. As such, in = another=20 aspect, the present invention provides a method for performing any one = or more=20 of the applications disclosed herein, wherein the method further = comprises=20 utilization of an ESU as described herein. For example, the ESU can be = used in=20 connection with analyte concentration measurement, analysis, data = logging,=20 storage, and/or transmission. In one aspect, the analysis of an analyte=20 concentration in a test subject can be accomplished by using an order = derivative=20 of the absorption data collected by the data acquisition unit, including = zero=20 order, optionally combined with other forms of data pre-processing. Any=20 statistical technique may be used to derive the primary calibration = algorithm,=20 for example, which should not be considered limiting in any way, simple = linear=20 regression, multiple linear regression and multivariate data = determination.=20 Examples of multivariate data analysis, which should not be considered = limiting=20 in any way, are principle component analysis, principle component = regression,=20 partial least squares regression, and neural networks. Examples of data=20 pre-processing, which should also not be considered limiting in any way, = can=20 include smoothing, deriving a first higher order derivative of = absorbance,=20 interpolation of absorbance, multiplicative scatter correction, = photometric=20 correction, and data transformation, such as Fourier Transform. =

[0135]=20 In one aspect, a computing apparatus for computing and analyzing the = analyte=20 concentration from the data transmitted to the external telemetry unit = can=20 comprise a processor such as a microprocessor, a hybrid/software system, = controller, computer, neural network circuit, digital signal processor, = digital=20 logic circuits, or an application specific integrated circuit, and = memory. The=20 computing apparatus can be electronically coupled to the data received = by the=20 external telemetry unit and can contain circuits programmable to perform = mathematical functions such as, for example, waveform averaging, = amplification,=20 linearization, signal rejection, differentiation, integration, network = or fuzzy=20 logic, addition, subtraction, division, multiplication, and the like = where=20 desired.

[0136] In an alternative aspect, and apart from = assisting a=20 user, physician or other medical professional in monitoring analyte = levels, such=20 as blood glucose levels of patients in real time, the sensor unit = comprising an=20 ESU as described herein can in another aspect be used as a feedback = element in=20 an insulin delivery system, where, for example, the entire system can = function=20 as an artificial pancreas. Thus, in another aspect, the present = invention=20 provides an artificial biological delivery system comprising an ESU as = described=20 herein.

[0137] In still another aspect, the electronic support = system=20 can be adapted for use with a plurality of other sensor units involving = the=20 measurement of biological data. For example, individual sensor units can = be=20 adapted to function as nodes of a larger network through the use of the = ESU's=20 adaptable telemetry unit. For example, use of a ZigBee 802.15.4 protocol = based=20 microcontroller 1610 and transceiver 1620 can be used in the instant = invention.=20 IEEE 802.15.4 is a wireless technology protocol standard targeted at = home=20 networking and sensor networks and, when used, can permit up to, for = example,=20 255 nodes to exist in one network. It is an ultra low power technology = with=20 relatively low system hardware requirements and can provide up to 250 = kbps of=20 bandwidth. Thus, the use of 802.15.4 technology in the instant invention = can=20 provide an ESU having reduced power consumption and increased security = in=20 transmissions. Still further, any desired number of such networks could = be set=20 up in, for example, a hospital and the nodes (individual sensor units) = could all=20 be controlled remotely from a central location. FIGS. 19 and 20 = illustrate=20 alternative aspects of the instant invention comprised of components = using the=20 802.15.4 based ZigBee protocol.

[0138] In view of the foregoing, = it will=20 be apparent to those skilled in the art that various modifications and=20 variations can be made in the present invention without departing from = the scope=20 or spirit thereof. As such, other aspects of the present invention will = become=20 apparent to those skilled in the art from consideration of the instant=20 specification and practice of the invention disclosed herein.

* * * * *

=20

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U.S. Current = Class:	600/315 =
U.S. Class at = Publication:	600/315 =
Intern'l Class: =	A61B 5/00 20060101=20 A61B005/00