Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
  • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
  • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement

Definitions

• This invention involves a non-inVasive glucose measurement device and a process for determining blood glucose level in the human body using the device.
• the glucose measurement device is self-normalizing in that it does not employ an independent reference sample in its operation.
• the inventive device uses attenuated total reflection (ATR) infrared spectroscopy.
• ATR attenuated total reflection
• the device is used on a fingertip and compares two specific regions of a measured infrared spectrum to determine the blood glucose level of the user.
• this device is especially suitable for monitoring glucose levels in the human body, and is especially beneficial to users having diabetes mellitus.
• the device and procedure may be used for other materials which exhibit unique mid-IR signatures of the type described below and and that are found in appropriate regions of the outer skin.
• a cleaning kit for preparation of the skin surface is also included.
• Diabetes is a chronic disease having no cure.
• the complications of the disease include blindness, kidney disease, nerve disease, and heart disease, perhaps with stroke. Diabetes is said to be the leading cause of new cases of blindness in individuals in the range of ages between 20 and 74; from 12,000-24,000 people per year lose their sight because of diabetes. Diabetes is the leading cause of end- stage renal disease, accounting for nearly 40% of new cases. Nearly 60-70% of people with diabetes have mild to severe forms of diabetic nerve damage which, in severe forms, can lead to lower limb amputations. People with diabetes are 2-4 times more likely to have heart disease and to suffer strokes.
• Diabetes is a disease in which the body does not produce or properly use insulin, a hormone needed to convert sugar, starches, and the like into energy. Although the cause of diabetes is not completely understood, genetics, environmental factors, and viral causes have been partially identified.
• Type I diabetes (formerly known as juvenile diabetes) is an autoimmune disease in which the body does not produce any insulin and most often occurs in young adults and children. People with Type I diabetes must take daily insulin injections to stay alive.
• Type II diabetes is a metabolic disorder resulting from the body's inability to make enough, or properly to use, insulin. Type II diabetes accounts for 90-95%) of diabetes. In the United States, Type II diabetes is nearing epidemic proportions, principally due to an increased number of older Americans and a greater prevalence of obesity and a sedentary lifestyle.
• Insulin in simple terms, is the hormone that unlocks the cells of the body, allowing glucose to enter those cells and feed them. Since, in diabetics, glucose cannot enter the cells, the glucose builds up in the blood and the body's cells literally starve to death.
• Diabetics having Type I diabetes typically are required to self-administer insulin using, e.g., a syringe or a pin with needle and cartridge. Continuous subcutaneous insulin infusion via implanted pumps is also available. Insulin itself is typically obtained from pork pancreas or is made chemically identical to human insulin by recombinant DNA technology or by chemical modification of pork insulin. Although there are a variety of different insulins for rapid-, short-, intermediate-, and long-acting forms that may be used variously, separately or mixed in the same syringe, use of insulin for treatment of diabetes is not to be ignored.
• SMBG blood glucose
• individuals may make insulin dosage adjustments before injection. Adjustments are necessary since blood glucose levels vary day to day for a variety of reasons, e.g., exercise, stress, rates of food absorption, types of food, hormonal changes (pregnancy, puberty, etc.) and the like.
• SMBG blood glucose
• several studies have found that the proportion of individuals who self-monitor at least once a day significantly declines with age. This decrease is likely due simply to the fact that the typical, most widely used, method of SMBG involves obtaining blood from a finger stick. Many patients consider obtaining blood to be significantly more painful than the self-administration of insulin.
• Glucose may be measured by non-invasive or minimally-invasive techniques, such as those making the skin or mucous membranes permeable to glucose or those placing a reporter molecule in the subcutaneous tissue. Needle-type sensors have been improved in accuracy, size, and stability and may be placed in the subcutaneous tissue or peripheral veins to monitor blood glucose with small instruments. See, "An Overview of Minimally Invasive Technologies ", Clin. Chem. 1992 Sep.; 38(9):1596-1600.
• U.S. Patent No. 4,169,676 to Kaiser shows a method for the use of ATR glucose measurement by placing the ATR plate directly against the skin and especially against the tongue.
• the procedure and device shown there uses a laser and determines the content of glucose in a specific living tissue sample by comparing the IR absorption of the measured material against the absorption of IR in a control solution by use of a reference prism. See, column 5, lines 31 et seq.
• This invention is a glucose level measurement device utilizing IR-ATR spectroscopy and a method of using the device.
• the inventive device itself preferably made up of four parts: a.) an IR source for emitting an IR beam into the ATR plate, b.) the ATR plate against which the sampled human skin surface is pressed, and c.) at least two IR sensors for simultaneously measuring absorbance of two specific regions of the IR spectrum, i.e., a "referencing wavelength” and a "measuring wavelength.”
• the IR source must emit IR radiation at least in the region of the referencing wavelength and the measuring wavelength.
• the referencing wavelength is between about 8.25 micrometers and about 8.75 micrometers and the measuring wavelength is between about 9.50 micrometers and about 10. 00 micrometers.
• the IR sources may be broadband IR sources, non-laser sources, or two or more selected wavelength lasers.
• the ATR plate is configured to permit multiple internal reflections, perhaps 3-15 internal reflections, against said measurement surface prior to measurement by the IR sensors.
• the IR beam emitted from the ATR plate is split for the IR sensors using a beam splitter or equivalent optical device. Once the split beams are measured by the IR sensors, the resulting signals are then transformed using analog comparators or digital computers into readable or displayable values.
• the device It is usually important that the device have some accommodation for holding the body part against the ATR plate, preferably at some value which is constant and above a selected minimum pressure.
• the method for determining the blood glucose level, using the glucose measurement device comprises the steps of. a.) contacting a selected skin surface with the ATR plate, b.) irradiating that human skin surface with an IR beam having components at least in the region of the referencing wavelength and the measuring wavelength, and c.) detecting and quantifying those referencing and said measuring wavelength components in that reflected IR beam.
• the procedure ideally includes the further steps of maintaining the skin surface on said ATR plate at an adequate pressure which is both constant and above a selected minimum pressure and, desirably cleaning the skin surface before measurement. A step of actually measuring the pressure may also be included.
• a normalizing step practiced by simultaneously detecting and quantifying the referencing and measuring wavelength components prior to contacting the skin surface is also desirable.
• a final portion of this invention is a cleaning kit used for cleaning the object skin prior to testing.
• the kit usually is made up of sealed packets, preferably containing absorbent pads, of each of: a.) a glucose solvent, e.g., water or other highly polar solvent, b.) a solvent for removing the glucose solvent, e.g., isopropanol, and c.) a skin softener or pliability enhancer, e.g., various mineral oils such as "Nujol", not having significant IR wavelength peaks between about 8.25 micrometers and about 8.75 micrometers or between about 9.50 micrometers and about 10.00 micrometers.
• the solvent for removing the glucose solvent similarly should not have an interfering IR signal which persists after several minutes.
• Figures 1 A, IB, 1C, and ID show a side view of various ATR plates and their general operation.
• Figure 2 shows an IR spectrum of d-glucose.
• Figure 3 shows a schematicized layout of the optics of the inventive device.
• Figure 4 shows a packaged variation of the inventive glucose measuring device.
• Figure 5 shows a graph correlating glucose levels measured using a specific variation of the device with glucose levels in the blood determined using a commercial device.
• Figure 6 shows a pair of glucose IR curves (taken before and after eating) for an individual having diabetes made using the inventive glucose measuring device.
• Figure 7 shows a graph comparing glucose levels in a non-diabetic individual (taken before and after eating) made using the inventive glucose measuring device and direct blood measurement. This graph shows that the inventive procedure tracks blood glucose levels with minimum time lag.
• the device in this invention uses infrared (“IR”) attenuated total internal reflectance (“ATR”) spectroscopy to detect and ultimately to determine the level of blood glucose in the human body.
• IR infrared
• ATR total internal reflectance
• the inventive device uses an ATR procedure in which the size and configuration of the crystal permits a number of internal reflections before the beam is allowed to exit the crystal with its measured information.
• Figures 1 A and IB when an infrared beam (102) is incident on the upper surface of the ATR crystal (104) ⁇ or ATR plate — at an angle which exceeds a critical angle ⁇ c, the beam
• the incident beam (102) becomes reflected beam (106) as it exits crystal (104) as shown in Figure 1A.
• Higher refractive index materials are typically chosen for the ATR crystal to minimize the critical angle.
• the critical angle is a function of the refractive indices of both the sample and the ATR crystal and is defined as:
• nj is the refractive index of the ATR crystal and n 2 is the refractive index of the sample.
• the internally reflected beam (108) includes an evanescent wave (110) which penetrates a short distance into sample (112) over a wide wavelength range. In those regions of the IR spectrum in which the sample absorbs IR, some portion of the light does not return to the sensor. It is these regions of IR absorbance which provide information, in this inventive device, for quantification of the glucose level.
• the index of refraction of the ATR plate (104) should be significantly higher than that of the sample (112).
• the ATR crystal (104) shown in Figure 1 A is shown to be trapezoidal and having an upper surface (114) for contact with the sample, which sample, in this case, is skin from a living human body.
• this shape is only for the purposes of mechanical convenience and ease of application into a working commercial device.
• Other shapes in particular, a parallelogram (111) such as shown in Figure 1C and the reflective crystal (113) shown in Figure ID having mirrored end (115), are also quite suitable for this inventive device should the designer so require.
• the mirrored reflective crystal (113) has the advantage of, and perhaps the detriment of having both an IR source and the IR sensors at the same end of the crystal.
• the ATR crystal or plate (104) It is generally essential that the ATR crystal or plate (104) have a sample or upper surface (114) which is essentially parallel to the lower surface (116).
• the ATR plate (104) is preferably configured and utilized so that the product of the practical number of internal reflections of internal reflected beam (108) and the skin penetration per reflection of this product is maximized.
• EPL effective pathlength
• the information level in beam (106) as it leaves ATR plate (104) is significantly higher.
• the higher the value of the index of refraction, n 2 , of the ATR plate (104) the higher is the number of internal reflections.
• the sensitivity of the IR sensors also need not be as high when the EPL is maximized. We consider the number of total reflections within the crystal to be preferably from 3-15 or more for adequate results.
• a glucose measuring device made according to this invention is quite effective on the human skin of the hands and fingers.
• the glucose concentration as measured by the inventive devices correlates very closely with the glucose concentration determined by a direct determination from a blood sample.
• the glucose level as measured by the inventive device also is surprisingly found closely to track the glucose level of blood in time as well. This is surprising in that the IR beam likely passes into the skin, i.e., the stratum corneum, for only a few microns. It is unlikely in a fingertip that any blood is crossed by that light path.
• the stratum corneum is the outer layer of skin and is substantially unvascularized.
• the stratum corneum is the final outer product of epidermal differentiation or keratinization.
• corneocytes also known as squames. These cells overlap and interlock with neighboring cells by ridges and grooves. In the thin skin of the human body, this layer may be only a few cells deep, but in thicker skin, such as may be found on the toes and feet, it may be more than 50 cells deep.
• the plasma membrane of the corneocyte appears thickened compared with that of keratinocytes in the lower layers of the skin, but this apparent deposition of a dense marginal band formed by stabilization of a soluble precursor, involucrin, just below the stratum corneum.
• a glucose solvent e.g., water or other highly polar solvent
• a solvent for removing the water e.g., isopropanol
• a skin softener or pliability enhancer not having significant IR peaks in the noted IR regions, e.g., mineral oils such as those sold as "Nujol”.
• the inventive kit contains sealed packets of each of the three components, preferably each within an absorbent pad in the sealed packets.
• the inventive device can be highly simplified compared to other known devices in that the device can be "self-normalizing" due to the specifics of the IR signature of glucose.
• Figure 2 shows the IR absorbance spectra of d-glucose. The family of curves there shows that in certain regions of the IR spectrum, there is a correlation between absorbance and the concentration of glucose. Further, there is a region in which the absorbance is not at all dependent upon the concentration of glucose.
• our device in its preferable method of use, uses these two regions of the IR spectra. These regions are in the so-called mid-IR range, between 2.5 and 14 micrometers.
• the "referencing wavelength” point is just above 8 micrometers (150), e.g., 8.25 to 8.75 micrometers, and the pronounced peaks (152) at the region between about 9.50 and 10.00 micrometers is used as a "measuring wavelength".
• the family of peaks (152) may be used to determine the desired glucose concentration.
• Use of the two noted IR regions is also particularly suitable since other components typically found in the skin, e.g., water, cholesterol, etc., do not cause significant measurement error when using the method described herein.
• FIG 3 shows an optical schematic of a desired variation of the inventive device.
• ATR crystal (104) with sample side (114) is shown and IR source (160) is provided.
• IR source ( 160) may be any of a variety of different kinds of sources. It may be a broadband
• IR source one having radiant temperatures of 300°C to 800°C, or a pair of IR lasers selected for the two regions of measurement discussed above, or other suitably emitted or filtered IR light sources.
• a single laser is usually not an appropriate light source in that a laser is a single wavelength source and the preferred operation of this device requires light sources simultaneously emitting two IR wavelengths.
• IR source (160) into ATR plate (104) is also shown. It may be desirable to include an additional mirror (163) to intercept a portion of the beam before it enters the ATR plate (104) and then to measure the strength of that beam in IR sensor (165). Measurement of that incident light strength (during normalization and during the sample measurement) assures that any changes in that value can be compensated for.
• the light then passes into ATR plate (104) for contact with body part (164), shown in this instance to be the desired finger.
• the reflected beam (106) exits ATR plate (104) and is then desirably spit using beam splitter (166).
• Beam splitter (166) simply transmits some portion of the light through the splitter and reflects the remainder.
• the two beams may then be passed through, respectively, lenses (168) and (170).
• the so-focussed beams are then passed to a pair of sensors which are specifically selected for detecting and measuring the magnitude of the two beams in the selected IR regions.
• the sensors will be made up of filter (172) and (174) with light sensors (176) and (178) behind.
• one filter (172), (174) will be in the region of the referencing wavelength and the other will be in that of the measuring wavelength.
• Figure 4 shows perhaps a variation of this device (200) showing the finger of the user (202) over the ATR plate (204) with a display (206). Further shown in this desirable variation (200) is a pressure maintaining component (208).
• a pressure maintaining component 208.
• we have determined for each design of the device it is much more appropriate that the design of a particular variation of the inventive device be designed with a specific sample pressure in mind.
• the appropriate pressure will vary with, e.g., the size of the ATR plate and the like. A constant pressure above that minimum threshold value is most desired.
• the variation shown in Figure 4 uses a simple component arm (208) to maintain pressure of the finger (202) on ATR plate (204).
• Other variations within the scope of this invention may include clamps and the like.
• the inventive device may include a pressure sensor, e.g., (210) as is shown in Figure
• Pressure sensor (210) may alternatively be placed beneath ATR plate (204). It is envisioned that normally a pressure sensor such as (210) would provide an output signal which would provide a "no-go/go" type of signal to the user.
• the inventive device described above is used in the following manner: a skin surface on a human being, for instance, on the skin of the finger, is placed on the ATR plate.
• the skin surface is radiated with an IR beam having components at least in the two IR regions we describe above as the "referencing wavelength” and the “measuring wavelength.”
• the beam which ultimately is reflected out of the ATR plate then contains information indicative of the blood glucose level in the user.
• the beam leaving the ATR plate is split using an optical beam splitter into at least two beams.
• Each of the two beams may be then focussed onto its own IR sensor.
• Each such IR sensor has a specific filter. This is to say that, for instance, one IR sensor may have a filter which removes all light which is not in the region of the referencing wavelength and the other IR sensor would have a filter which remove all wavelengths other than those in the region of the measuring wavelength.
• the referencing wavelength is typically in the range of about 8.25 to 8.75 micrometers.
• the measuring wavelength is typically between about 9.5 and 10.0 micrometers.
• analyte materials which have both referencing wavelengths and measuring wavelengths in the mid-IR range and that are found in the outer regions of the skin may also be measured using the inventive devices and procedures described herein.
• Respective signals may be compared using analog or digital computer devices.
• the signals are then used to calculate blood glucose concentration using various stored calibration values, typically those which are discussed below.
• the resulting calculated values may then be displayed.
• periodic at least an initial calibration of the device, using typical blood sample glucose determinations may be necessary or desirable.
• a baseline is first determined by measuring the level of infrared absorbance at the measuring and referencing wavelengths, without a sample being present on the sample plate. The skin is then placed in contact with the ATR plate and the two specified absorbance values are again measured. Using these four values, the following calculation is then made.
• T 01 measured value at reference spectral band w/o sample
• T 02 measured value at measuring spectral band w/o sample
• Ti measured value at reference spectral band w/ sample
• T measured value at measuring spectral band w/ sample
• a g i absorbance of glucose at reference spectral band
• a g2 absorbance of glucose at measuring spectral band
• a b i absorbance of background at reference spectral band
• a b2 absorbance of background at measuring spectral band
• d effective path length through the sample.
• C g measured concentration of glucose
• IR spectrometer (Nicolet 510) having a ZnSe crystal ATR plate (55mm long, 10mm wide, and 4mm thick) we tested the inventive procedure.
• the inventor used a blood stick known as "Whisper Soft” sold by Amira Medical Co. and "Glucometer Elite" blood glucose test strips sold by Bayer Corp. of Elkhart, Ind. On each of the various test days, the inventor took several test sticks and measured the glucose value of the resulting blood; the IR test was made at the same approximate time.
• curve 6 shows the IR absorbance spectrum of the test subject's finger before eating (and after fasting overnight) and curve 2 shows IR absorbance spectrum of the same individual after having eaten. Incidentally, insulin was administered shortly after the measurement of curve 2. In any event, the significant difference in the two peak heights at the 9.75 micrometer wavelength and the equality of the two IR absorbance values at the 8.50 micrometer value shows the effectiveness of the procedure in measuring glucose level.
• Example 3 That the inventive glucose monitoring device non-invasively determines blood glucose level and quickly follows changes in that blood glucose level is shown in Figure 7.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Physics & Mathematics (AREA)
• Medical Informatics (AREA)
• Surgery (AREA)
• Biophysics (AREA)
• Pathology (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Heart & Thoracic Surgery (AREA)
• Veterinary Medicine (AREA)
• Molecular Biology (AREA)
• Optics & Photonics (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Spectroscopy & Molecular Physics (AREA)
• Emergency Medicine (AREA)
• Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)
• Investigating Or Analysing Materials By Optical Means (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=22297534

Family Applications (1)

Country Status (8)

Cited By (2)

Families Citing this family (29)

Family Cites Families (8)

• 1999
  • 1999-10-12 WO PCT/US1999/023823 patent/WO2000021437A2/en not_active Application Discontinuation
  • 1999-10-12 EP EP99951963A patent/EP1137364A2/en not_active Withdrawn
  • 1999-10-12 JP JP2000575421A patent/JP2002527136A/ja active Pending
  • 1999-10-12 AU AU64286/99A patent/AU761110B2/en not_active Ceased
  • 1999-10-12 IL IL14254599A patent/IL142545A0/xx unknown
  • 1999-10-12 CN CNA998134066A patent/CN1555242A/zh active Pending
  • 1999-10-12 CA CA002347482A patent/CA2347482C/en not_active Expired - Fee Related
• 2001
  • 2001-04-10 NO NO20011815A patent/NO20011815L/no not_active Application Discontinuation

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events