Compact apparatus for noninvasive measurement of glucose through near-infrared spectroscopy Number:7,133,710 from the United States Patent and Trademark Office (PTO) owispatent The invention involves the monitoring of a biological parameter through a compact analyzer. The preferred apparatus is a spectrometer based system that is attached continuously or semi-continuously to a human subject and collects spectral measurements that are used to determine a biological parameter in the sampled tissue. The preferred target analyze is glucose. The preferred analyzer is a near-IR based glucose analyzer for determining the glucose concentration in the body.<H spectroscopy, measurement, Compact, apparat, 7133710.html, Patent, pto, 7133710

Title: Compact apparatus for noninvasive measurement of glucose through near-infrared spectroscopy

Abstract: The invention involves the monitoring of a biological parameter through a compact analyzer. The preferred apparatus is a spectrometer based system that is attached continuously or semi-continuously to a human subject and collects spectral measurements that are used to determine a biological parameter in the sampled tissue. The preferred target analyze is glucose. The preferred analyzer is a near-IR based glucose analyzer for determining the glucose concentration in the body.

Patent Number: 7,133,710 Issued on 11/07/2006 to Acosta, et al.

Inventors: Acosta; George M. (Phoenix, AZ), Henderson; James R. (Phoenix, AZ), Abul Haj; N. Alan (Mesa, AZ), Ruchti; Timothy L. (Gilbert, AZ), Monfre; Stephen L. (Gilbert, AZ), Blank; Thomas B. (Chandler, AZ), Hazen; Kevin H. (Gilbert, AZ)
Assignee: Sensys Medical, Inc. (Chandler, AZ)

Appl. No.: 10/472,856

Filed: March 7, 2003

PCT Filed: March 07, 2003

PCT No.: PCT/US03/07065

371(c)(1),(2),(4) Date: September 18, 2003

PCT Pub. No.: WO03/076883

PCT Pub. Date: September 18, 2003

Current U.S. Class: 600/316

Current International Class: A61B 5/00 (20060101)

Field of Search: 600/310,316,322,344

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Primary Examiner: Winakur; Eric F.
Attorney, Agent or Firm: Glenn; Michael A. Glenn Patent Group

Parent Case Text

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Patent Application Ser. Nos. 60/362,885, filed on Mar. 8, 2002, entitled Apparatus For Noninvasive Blood Analyte Determination; and 60/362,899, filed on Mar. 8, 2002 entitled Calibration Methods In Noninvasive Blood Analyte Determination; and 60/448,840, filed on Feb. 19, 2003, entitled Compact Apparatus for Noninvasive Measurement of Glucose through Near-Infrared Spectroscopy; and is a continuation-in-part of U.S. patent application Ser. No. 09/956,747, filed on Sep. 17, 2001.

Claims

The invention claimed is:

1. An apparatus for noninvasive measurement of glucose through near-infrared spectroscopy, comprising: a base module comprising a grating and a detector array, said base module further comprising: means for bias correcting one or more of spectral data collected in (X) and glucose concentration data (Y); a sampling module, securely and removeably attachable to a sample site, and coupled to said base module, said sampling module comprising an illumination source; and a communication bundle for carrying optical and/or electrical signals between said base module and said sampling module, and for carrying power to said sampling module from said base module, wherein said base module further comprises means for calibrating to an individual or a group of individuals based upon a calibration data set comprised of paired data points of processed spectral measurements and reference biological parameter values.

2. The apparatus of claim 1, further comprising: an optic system located before and/or after said sample site for coupling said illumination source to said sample and said sample to said detector array.

3. The apparatus of claim 2, said optic system comprising any of: an optical filter, a light blocker, and a standardization material.

4. The apparatus of claim 1, said sampling module further comprising at least one of: a low profile sampling interface; a low wattage stabilized source in close proximity to said sampled site; an excitation collection cavity or optics; a guide; a preheated interfacing solution; means for maintaining a temperature controlled skin sample; a mechanism for constant pressure and/or displacement of sampled skin tissue; a photonic stimulation source; and collection optics or fiber.

5. The apparatus of claim 1, said sampling module further comprising: a guide that is securely and removeably attached to said sampling site, said guide continuously and/or periodically physically and optically locating said sampling module relative to said sample site in a repeatable manner and with minimal disturbance to said sampling site.

6. The apparatus of claim 5, further comprising: means for pretreatment of said sample site to provide appropriate contact of said sampling module to said sampling site to reduce specular reflectance, to approach and maintain appropriate sampling site temperature variation, and to minimize sampling site hydration changes.

7. The apparatus of claim 5, wherein said sampling module reversibly couples into said guide for reproducible contact pressure and/or sampling location.

8. The apparatus of claim 7, said guide further comprising: at least one magnet for aiding in positioning a sampling module probe to ensure proper penetration of said probe into a guide aperture, and to enable a constant pressure and/or displacement interface of said sampling site; wherein said magnet is optionally electrically activated to facilitate controlled movement into a guide aperture and to allow, through reversal of said magnet poles, withdrawal from said guide aperture without pulling.

9. The apparatus of claim 7, wherein said reversible coupling of said sampling module into said guide allows said sampling module to be removed and coupled to an intensity reference and/or a wavelength reference that have a same guide interface.

10. The apparatus of claim 9, wherein said intensity reference comprises a 99% reflective material, and wherein said wavelength reference is polystyrene.

11. The apparatus of claim 1, wherein said sampling module collects a diffusely reflected or transflected signal from said sampling site.

12. The apparatus of claim 1, either of said base module and said sampling module comprising any of: a wavelength reference standard; and an intensity reference standard.

13. The apparatus of claim 1, wherein said communication bundle is integrated between said sampling module and said base module.

14. The apparatus of claim 1, wherein said sampling module and said base module are integrated together into a handheld unit.

15. The apparatus of claim 1, said sampling module comprising: a housing a reflector; a lamp comprising a tungsten halogen source, coupled to said reflector; and a photodiode for monitoring said lamp and for maintaining said lamp's output stable by means of a lamp output controller.

16. The apparatus of claim 15, wherein said reflector, and hence incident light emanating therefrom, is centered on an angle off of a normal to said sample site to allow room for a collection fiber.

17. The apparatus of claim 15, wherein light is focused through a silicon window onto an aperture at said sample site, wherein said silicon window comprises a longpass filter.

18. The apparatus of claim 1, said sampling module further comprising: a heater for maintaining said sampling site at a constant temperature.

19. The apparatus of claim 1, said sampling module further comprising: a detection fiber for collecting diffusely reflected light.

20. The apparatus of claim 1, wherein said base module either resides on a support surface, or said base module may be worn by a person.

21. The apparatus of claim 1, wherein said sampling module couple to any of a hand, finger, palmar region, base of thumb, forearm, volar aspect of the forearm, dorsal aspect of the forearm, upper arm, head, earlobe, eye, tongue, chest, torso, abdominal region, thigh, calf, foot, plantar region, and toe.

22. The apparatus of claim 1, further comprising: a docking station for said base module.

23. The apparatus of claim 1, wherein said base module is coupled directly to said sampling module, with said communication bundle forming an integral part thereof.

24. The apparatus of claim 1, wherein said sampling module further comprises: a housing, providing light blocking in ultraviolet wavelengths, visible wavelengths, and near-infrared wavelengths from 700 to 1000 nm.

25. The apparatus of claim 24, wherein said housing is constructed of silicon, and has a thickness of about 1 mm.

26. The apparatus of claim 1, said illumination source comprising; a tungsten halogen source ranging in power from 0.05 W to 5 W.

27. The apparatus of claim 1, said illumination source comprising: at least one light emitting diode (LED).

28. The apparatus of claim 1, further comprising: a photodiode; and a feedback controller for allowing said illumination source to be driven at different levels at different points in time during and prior to data acquisition; wherein said photodiode is placed before an optional order sorter to detect visible light from said illumination source; and wherein said photodiode comprises any of a silicon, lnGaAs, lnPGaAs, PbS, and PbSe detector.

29. The apparatus of claim 1, said illumination source further comprises: a reflector having any of a parabolic, elliptical, and spherical shape.

30. The apparatus of claim 29, wherein said source, said housing, and said reflector are arranged to bring in source light nearly parallel to said sample site surface.

31. The apparatus of claim 1, wherein said sampling module further comprising: folding optics for bringing light in at a low angle relative to said sampling site surface, wherein said folding optics optionally comprise any of a mirror and a focusing mirror.

32. The apparatus of claim 1, said communication bundle further comprising: quick connect optics which comprise; a first collection optic that is fixed into said communication bundle; and a connector in said communication bundle for accepting a second collection optic that in turn couples to said base module.

33. The apparatus of claim 32, further comprising: at least one optical device for coupling light by any of magnifying and de-magnifying lenses and folding mirrors.

34. The apparatus of claim 33, wherein said second collection optic is readily removed from said sampling module, allowing said sampling module to remain in contact with said sampling site.

35. The apparatus of claim 1, wherein said illumination source further comprises a heat source.

36. The apparatus of claim 1, further comprising: an optical filter located between said illumination source and said sampling site.

37. The apparatus of claim 36, wherein said optical filter is located after said illumination source but not in contact with any of said sampling site and a coupling fluid.

38. The apparatus of claim 36, wherein said optical filter comprises: at least two filters located between said illumination source and said sampling site, wherein a first filter removes heat, and wherein a second filter reduces spectral reflectance.

39. The apparatus of claim 36, wherein said optical filter comprises: a silicon filter for removing light under 1050 nm, wherein a grating can be used in the 1150 to 1850 nm region without detection of second or higher order light off of said grating, wherein said silicon filter is placed before the grating and after said sampling site.

40. The apparatus of claim 36, wherein said optical filter comprises: a filter comprising of any of the following: a filter that is a silicon longpass optic; a filter that is coated to block about 1900 to 2500 nm; a filter that is antireflection-coated to match refractive indices and increase light throughput, and/or used in combination with shortpass filters; a filter that is coated with a blocker for removing a largest intensity of a black body curve of a typical tungsten halogen source that is not blocked by silicon, wherein said blocking band may cover any region from about 1800 nm on up to 3000 nm; and a filter that is used in combination with an RG glass that cuts off at about 2500 nm to provide a bandpass filter passing light from approximately 1100 to 2500 nm, wherein said filter combination is optionally used in conjunction with a coating layer to provide a bandpass from 1100 to 1900 nm.

41. The apparatus of claim 1, said sampling module further comprising: a member shaped into a parabolic optic surrounding part of said illumination source, wherein an outside of said member is coated with a reflector.

42. The apparatus of claim 41, wherein said member comprises any of silicon and plastic parts.

43. The apparatus of claim 1, said sampling module further comprising: an illumination source filament that is wrapped around a collection fiber; and a reflector for directing light into an aperture for admission therethrough to said sampling site, wherein said reflector optionally is any of surface coated for reflectance on an incident light surface, and transmissive with an outer surface of said reflector being reflectively coated.

44. The apparatus of claim 43, further comprising: a window defined between said illumination source and said sampling site, said window optionally comprising a filter.

45. The apparatus of claim 1, said sampling module further comprising: a broadband source operatively combined with a single element detector.

46. The apparatus of claim 1, said sampling module further comprising: a Fabry-Perot interferometer.

47. The apparatus of claim 1, said sampling module comprising: a surface defining an aperture for providing optical pathlengths within a sample for indirectly monitoring glucose concentrations within a body, providing acceptable energy delivery to said sampling site, and providing appropriate heating/temperature control of said sampling site; wherein variation of said aperture affects a net analyte signal of a sampled tissue.

48. The apparatus of claim 47, further comprising: a fiber optic collection fiber placed in a center of an illumination area defined by said aperture.

49. The apparatus of claim 47, further comprising: means for performing an indirect determination of glucose from sample constituents which comprise any of fat, protein, and water and that are distributed as a function of depth in a sample, wherein a magnitude of an indirect signal varies with said aperture.

50. The apparatus of claim 47, further comprising: a removable plug for placement in said aperture to stabilize tissue at said sampling site by providing a same tissue displacement as a probe.

51. The apparatus of claim 47, further comprising: a contact window for allowing a continuous barrier for hydration of said sampling site and a constant pressure interface.

52. The apparatus of claim 1, wherein said sampling module is semi-permanently attached to said sampling site with a replaceable adhesive.

53. The apparatus of claim 1, said sampling module further comprising any of: means for any of photonic stimulation, ultrasound pretreatment, mechanical stimulation, cooling, and, heating.

54. The apparatus of claim 1, said sampling module further comprising any of: an LED for providing photonic stimulation to induce capillary blood vessel dilation.

55. The apparatus of claim 1, further comprising: a coupling fluid disposed between said sampling module and said sampling site for coupling incident photons into a tissue sample, wherein said coupling fluid is optionally preheated to minimize changes to a surface temperature of said sampling site, and minimize spectral changes observed from said tissue sample, wherein said coupling fluid, if preheated, is preheated using any of illumination source energy, sampling site heater energy; and an auxiliary heat source.

56. The apparatus of claim 55, further comprising: means for automated delivery of said coupling fluid prior to sampling.

57. The apparatus of claim 1, said sampling module further comprising: a collection fiber placed into an aperture formed through a base, said collection fiber being in contact with a sampling site surface.

58. The apparatus of claim 1, further comprising: means for using any of a signal and an absence of observed intensity at large water absorbance bands near 1450, 1900, and 2500 nm to determine when said sampling module is in good spectral contact with a sampling site surface.

59. The apparatus of claim 1, wherein said base module further comprises: a two-way wireless communication system for transferring data between said base module and any of said sampling module and a data collection/processing system.

60. The apparatus of claim 1, further comprising: means for standardizing a near-infrared wavelength based on a comparative analysis of a master and slave spectra of a standardization material.

61. The apparatus of claim 60, said means for standardizing comprising: a material having absorption bands in a targeted wavelength region for determining said x-axis, said material comprising any of polystyrene, erbium oxide, dysprosium oxide, and holmium oxide.

62. The apparatus of claim 61, wherein said material used for standardization is any of: measured external to said base module; measured continuously and mounted within said base module in a separate light path, wherein said internal wavelength standard is measured simultaneously with said sample; moved through an actuator into a main optical train at an appropriate time; wherein a reference spectrum is collected in any of a transmittance mode, reflectance mode, or a diffuse reflectance mode.

63. The apparatus of claim 60, further comprising: means for measuring a reference spectrum and a (wavelength) standardization spectrum through spectroscopic measurement of a non-absorbing material and a material with known and immutable spectral absorbance bands, respectively.

64. The apparatus of claim 63, said means for measuring further comprising: a master spectrum of a standardization material, and means for determining a discrepancy between said master spectrum and an instrument standardization spectrum; wherein said master spectrum and wavelength regions are optionally stored in a nonvolatile memory.

65. The apparatus of claim 64, wherein at least one window across a spectrum of said x-axis phase shift between said master spectrum and an acquired spectrum are determined through a cross-correlation function after removing instrument related baseline variations, wherein said phase shift is used to correct (standardize) said x-axis of said acquired spectrum to said master spectrum.

66. The apparatus of claim 1, wherein for glucose measurement, said reference values comprise at least one of the following: finger capillary blood glucose, alternate site capillary blood glucose at a site on the body other than the finger, interstitial glucose, or venous blood glucose.

67. The apparatus of claim 1, wherein said base module is integrally connected to a docking station; wherein said docking station comprises a computer and a glucose management center; wherein said glucose management center keeps track of events occurring in time comprising any of glucose intake, insulin delivery, and determined glucose concentration.

68. The apparatus of claim 1, said base module further comprising: means for estimating precision of measurement through a statistical analysis of repeated or successive measurements; and means for determining when a biological parameter is close to a preset level through a statistical estimate of confidence limits of a future analyte prediction made through a simple slope (change in said biological parameter over change in time) estimate based on an exponentially moving average, where said confidence limits are based upon said estimate of precision.

69. The apparatus of claim 1, said base module further comprising: means for determining when a biological parameter is close to a preset level through a standard time series analysis; wherein an alarm is invoked if an associated present alarm level is within a confidence interval of a future biological parameter prediction.

70. The apparatus of claim 1, either of said sampling module and said base module further comprising: means for taking any of continuous and semi-continuous measurements when said sampling module is in contact with said sampling site.

71. The apparatus of claim 1, said base module further comprising: means for using time based information and trends to perform various functions comprising any of: estimation of precision; estimation of a confidence intervals; and prediction of future events.

72. The apparatus of claim 1, further comprising: a link provided to an insulin delivery system to provide a feedback mechanism for control purposes.

73. The apparatus of claim 1, any of said base module and said sampling module comprising: a spectrometer system comprising LEDs to provide near-infrared radiation to said sample site over predefined wavelength ranges, wherein each of said LEDs provides near-infrared radiation over a band of wavelengths.

74. The apparatus of claim 73, wherein wavelengths of said LEDs are selected specifically to optimize a signal-to-noise ratio of a net analyte signal of a target analyte, and are arranged at various distances with respect to detection elements to provide a means for sampling various tissue volumes for purposes of averaging and determination of a differential measurement.

75. The apparatus of claim 73, wherein said LEDs are sequentially energized one at a time and/or in groups to obtain various estimates of diffuse reflectance of various tissue volumes at specific wavelengths or bands of wavelengths.

76. The apparatus of claim 73, wherein said LEDs are pulsed to provide short measurements with high signal-to-noise ratios to provide greater illumination intensity while avoiding photo heating of a sampled tissue volume.

77. The apparatus of claim 73, wherein said LEDs are modulated at a particular duty cycle and frequency to remove additive noise and to provide simultaneous measurement of multiple wavelengths.

78. The apparatus of claim 73, wherein said LEDs illuminate said sample site directly.

79. The apparatus of claim 73, further comprising: a mixing chamber with a reflective surface located between said LEDs and an optical window to provide a nearly uniform distribution onto a sample tissue region surrounding a detection fiber, wherein each LED is optionally recessed into a material having a reflective surface.

80. The apparatus of claim 73, wherein groups of LEDs are employed with each group associated with a single filter type, and wherein said LEDs are arranged at distances surrounding a detection fiber and energized to enable detection of light associated with different wavelength bands and different illumination to detection distances.

81. The apparatus of claim 80, wherein said groups of LEDs are arranged in any of: annuli (rings) at specific distances surrounding said detection fiber, wherein said filters are arranged in rings surrounding said detection fiber and covering associated LEDs; and wedges surrounding said detection fiber, wherein said filters are either of a wedged or triangular shape and are arranged to cover associated LEDs.

82. The apparatus of claim 80, wherein each LED or group of LEDs has an associated optical filter that is used to limit a bandwidth of emitted light wherein a different filter is mounted such that light emitted and delivered to said sampling site from said LED passes through said filter, wherein a filter associated with an LED has a specific bandwidth and is centered on a particular wavelength that is within a native bandwidth of said LED, wherein groups of LEDs are optionally associated with a same filter.

83. The apparatus of claim 80, wherein said LEDs have a bandwidth relatively broader than net analyte and interference signals.

84. The apparatus of claim 80, wherein said LED's are used in a spectrometer without a dispersive element and a single element detector, wherein thin dielectric films are used as in Fabry-Perot interference filters and a filter is associated with each LED.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to the noninvasive measurement of biological parameters through near-infrared spectroscopy. In particular, an apparatus and a method are disclosed for noninvasively, and continuously or semi-continuously, monitoring a biological parameter, such as glucose in tissue.

2. Discussion of the Prior Art

Diabetes

Diabetes is a chronic disease that results in improper production and use of insulin, a hormone that facilitates glucose uptake into cells. Diabetes can be broadly categorized into four forms: diabetes, impaired glucose tolerance, normal physiology, and hyperinsulinemia (hypoglycemia). While a precise cause of diabetes is unknown, genetic factors, environmental factors, and obesity appear to play roles. Diabetics have increased risk in three broad categories: cardiovascular heart disease, retinopathy, and neuropathy. Diabetics may have one or more of the following complications: heart disease and stroke, high blood pressure, kidney disease, neuropathy (nerve disease and amputations), retinopathy, diabetic ketoacidosis, skin conditions, gum disease, impotence, and fetal complications. Diabetes is a leading cause of death and disability worldwide.

Diabetes Prevalence and Trends

Diabetes is a common and growing disease. The World Health Organization (WHO) estimates that diabetes currently afflicts one hundred fifty-four million people worldwide. Fifty-four million diabetics live in developed countries. The WHO estimates that the number of people with diabetes will grow to three hundred million by the year 2025. In the United States, 15.7 million people or 5.9% of the population are estimated to have diabetes. Within the United States, the prevalence of adults diagnosed with diabetes increased by six percent in 1999 and rose by thirty-three percent between 1990 and 1998. This corresponds to approximately eight hundred thousand new cases every year in America. The estimated total cost to the United States economy alone exceeds $90 billion per year (Diabetes Statistics. Bethesda, Md.: National Institute of Health, Publication No. 98-3926, November 1997).

Long-term clinical studies show that the onset of diabetes related complications can be significantly reduced through proper control of blood glucose concentrations (The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Eng J of Med 1993; 329:977 86; U.K. Prospective Diabetes Study (UKPDS) Group, "Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes," Lancet, vol. 352, pp. 837 853, 1998; Ohkubo, Y., H. Kishikawa, E. Araki, T. Miyata, S. Isami, S. Motoyoshi, Y. Kojima, N. Furuyoshi, and M. Shichizi, "Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study," Diabetes Res Clin Pract, vol. 28, pp. 103 117, 1995). A vital element of diabetes management is the self-monitoring of blood glucose levels by diabetics in the home environment. However, current monitoring techniques discourage regular use due to the inconvenient and painful nature of drawing blood through the skin prior to analysis (The Diabetes Control and Complication Trial Research Group, "The effect of intensive treatment of diabetes on the development and progression of long-term complications of insulin-dependent diabetes mellitus", N. Engl. J. Med., 329, 1993, 997 1036). Unfortunately, recent reports indicate that even periodic measurement of glucose by individuals with diabetes, (e.g. seven times per day) is insufficient to detect important glucose fluctuations and properly manage the disease. In addition, nocturnal monitoring of glucose levels is of significant value but is difficult to perform due to the state of existing technology. Therefore, a device that provides noninvasive, automatic, and nearly continuous measurements of glucose levels would be of substantial value to people with diabetes. Implantable glucose analyzers eventually coupled to an insulin delivery system providing an artificial pancreas are also being pursued.

Description of Related Technology

Common technologies are used to analyze the blood glucose concentration of samples collected by venous draw and with capillary stick approaches. Glucose analysis includes techniques such as colorimetric and enzymatic glucose analysis. Many of the invasive, traditional invasive, alternative invasive, and minimally invasive glucose analyzers use these technologies. The most common enzymatic based glucose analyzers use glucose oxidase, which catalyzes the reaction of glucose with oxygen to form gluconolactone and hydrogen peroxide, equation 1. Glucose determination may be achieved by techniques based upon depletion of oxygen in the sample, through the changes in sample pH, or via the formation of hydrogen peroxide. A number of colorimetric and electro-enzymatic techniques further use the reaction products as a starting reagent. For example, hydrogen peroxide reacts in the presence of platinum to form the hydrogen ion, oxygen, and current any of which may be used to determine the glucose concentration, equation 2. glucose+O.sub.2.fwdarw.gluconolactone+H.sub.2O.sub.2 eq. 1 H.sub.2O.sub.2.fwdarw.2H.sup.++O.sub.2+2e.sup.- eq. 2

Due to the wide and somewhat loose terminology in the field, the terms traditional invasive, alternative invasive, noninvasive, and implantable are here outlined:

Traditional Invasive Glucose Determination

There are three major categories of traditional (classic) invasive glucose determinations. The first two methodologies use blood drawn with a needle from an artery or vein, respectively. The third group consists of capillary blood obtained via lancet from the fingertip or toes. Over the past two decades, this last method has become the most common method for self-monitoring of blood glucose at home, at work, or in public settings.

Alternative Invasive Glucose Determination

There are several alternative invasive methods of determining glucose concentrations.

A first group of alternative invasive glucose analyzers have a number of similarities to traditional invasive glucose analyzers. One similarity is that blood samples are acquired with a lancet. Obviously, this form of alternative invasive glucose determination may not be used to collect venous or arterial blood for analysis, but may be used to collect capillary blood samples. A second similarity is that the blood sample is analyzed using chemical analyses that are similar to the colorimetric and enzymatic analyses describe above. The primary difference is that in an alternative invasive glucose determination the blood sample is not collected from the fingertip or toes. For example, according to package labeling the TheraSense.RTM. FreeStyle Meter.TM. may be used to collect and analyze blood from the forearm. This is an alternative invasive glucose determination due to the location of the lancet draw.

In this first group of alternative invasive methods based upon blood draws with a lancet, a primary difference between the alternative invasive and traditional invasive glucose determination is the location of blood acquisition from the body. Additional differences include factors such as the gauge of the lancet, the depth of penetration of the lancet, timing issues, the volume of blood acquired, and environmental factors such as the partial pressure of oxygen, altitude, and temperature. This form of alternative invasive glucose determination includes samples collected from the palmar region, base of thumb, forearm, upper arm, head, earlobe, torso, abdominal region, thigh, calf, and plantar region.

A seond group of alternative invasive glucose analyzers are distinguished by their mode of sample acquisition. This group of glucose analyzers has a common characteristic of acquiring a biological sample from the body or modifying the surface of the skin to gather a sample without use of a lancet for subsequent analysis. For example, a laser poration based glucose analyzer would use a burst or stream of photons to create a small hole in the surface of the skin. A sample of basically interstitial fluid would collect in the resulting hole. Subsequent analysis of the sample for glucose would constitute an alternative invasive glucose analysis whether or not the sample was actually removed from the created hole. A second common characteristic is that a device and algorithm are used to determine glucose from the sample.

A number of methodologies exist for the collection of the sample for alternative invasive measurements including laser poration, applied current, and suction. The most common are summarized here: A. Laser poration: In these systems, photons of one or more wavelengths are applied to skin creating a small hole in the skin barrier. This allows small volumes of interstitial fluid to become available to a number of sampling techniques. B. Applied current: In these systems, a small electrical current is applied to the skin allowing interstitial fluid to permeate through the skin. C. Suction: In these systems, a partial vacuum is applied to a local area on the surface of the skin. Interstitial fluid permeates the skin and is collected.

For example, a device that acquires a sample via iontophoresis, such as Cygnus'.RTM. GlucoWatch.TM., is an alternative invasive technique.

In all of these techniques, the analyzed sample is interstitial fluid. However, some of the techniques can be applied to the skin in a fashion that draws blood. Herein, the term alternative invasive includes techniques that analyze biosamples such as interstitial fluid, whole blood, mixtures of interstitial fluid and whole blood, and selectively sampled interstitial fluid. An example of selectively sampled interstitial fluid is collected fluid in which large or less mobile constituents are not fully represented in the resulting sample. For this group of alternative invasive glucose analyzers sampling sites include: the hand, fingertips, palmar region, base of thumb, forearm, upper arm, head, earlobe, eye, chest, torso, abdominal region, thigh, calf, foot, plantar region, and toes. In this document, any technique that draws biosamples from the skin without the use of a lancet on the fingertip or toes is referred to as an alternative invasive technique.

In addition, it is recognized that the alternative invasive systems each have different sampling approaches that lead to different subsets of the interstitial fluid being collected. For example, large proteins might lag behind in the skin while smaller, more diffusive, elements may be preferentially sampled. This leads to samples being collected with varying analyte and interferent concentrations. Another example is that a mixture of whole blood and interstitial fluid may be collected. Another example is that a laser poration method can result in blood droplets. These techniques may be used in combination. For example the Soft-Tact, SoftSense in Europe, applies a suction to the skin followed by a lancet stick. Despite the differences in sampling, these techniques are referred to as alternative invasive techniques sampling interstitial fluid.

Sometimes, the literature refers to the alternative invasive technique as an alternative site glucose determination or as a minimally invasive technique. The minimally invasive nomenclature derives from the method by which the sample is collected. In this document, the alternative site glucose determinations that draw blood or interstitial fluid, even_microliter, are considered to be alternative invasive glucose determination techniques as defined above. Examples of alternative invasive techniques include the TheraSense.RTM. FreeStyle.TM. when not sampling fingertips or toes, the Cygnus.RTM. GlucoWatch.TM., the One Touch.RTM. Ultra.TM., and equivalent technologies.

Biosamples collected with alternative invasive techniques are analyzed via a large range of technologies. The most common of these technologies are summarized below: A. Conventional: With some modification, the interstitial fluid samples may be analyzed by most of the technologies used to determine glucose concentrations in serum, plasma, or whole blood. These include electrochemical, electroenzymatic, and colorimetric approaches. For example, the enzymatic and colorimetric approaches described above may also be used to determine the glucose concentration in interstitial fluid samples. B. Spectrophotometric: A number of approaches, for determining the glucose concentration in biosamples, have been developed that are based upon spectrophotometric technologies. These techniques include: Raman and fluorescence, as well as techniques using light from the ultraviolet through the infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000 cm.sup.-1), and infrared (2500 to 14,285 nm or 4000 to 700 cm.sup.-1)].

In this document, an invasive glucose analyzer is the genus of both the traditional invasive glucose analyzer species and the alternative invasive glucose analyzer species.

Noninvasive Glucose Determination

There exist a number of noninvasive approaches for glucose determination. These approaches vary widely, but have at least two common steps. First, an apparatus is used to acquire a reading from the body without obtaining a biological sample. Second, an algorithm is used to convert this reading into a glucose determination.

One species of noninvasive glucose analyzers are those based upon the collection and analysis of spectra. Typically, a noninvasive apparatus uses some form of spectroscopy to acquire the signal or spectrum from the body. Used spectroscopic techniques include but are not limited to Raman, fluorescence, as well as techniques using light from ultraviolet through the infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000 cm.sup.-1), and infrared (2500 to 14,285 nm or 4000 to 700 cm.sup.-1)]. A particular range for noninvasive glucose determination in diffuse reflectance mode is about 1100 to 2500 nm or ranges therein (Hazen, Kevin H. "Glucose Determination in Biological Matrices Using Near-infrared Spectroscopy", doctoral dissertation, University of Iowa, 1995). It is important to note, that these techniques are distinct from the traditionally invasive and alternative invasive techniques listed above in that the sample analyzed is a portion of the human body in-situ, not a biological sample acquired from the human body.

Typically, three modes are used to collect noninvasive scans: transmittance, transflectance, and/or diffuse reflectance. For example the light, spectrum, or signal collected may be light transmitting through a region of the body, diffusely transmitting, diffusely reflected, or transflected. Transflected here refers to collection of the signal not at the incident point or area (diffuse reflectance), and not at the opposite side of the sample (transmittance), but rather at some point or region of the body between the transmitted and diffuse reflectance collection area. For example, transflected light enters the fingertip or forearm in one region and exits in another region. When using the near-IR, the transflected radiation typically radially disperses 0.2 to 5 mm or more awa