8,923,941
`
`A device and method for measuring the concentration of
`analytes in the blood of a portion of tissue. The device
`includes a sensor module, a monitor, and a processor
`(separate from or integral with the sensor module). The
`sensor module includes a radiation source for emitting
`radiation to the tissue; a collimator and narrow band filter for
`processing the radiation after it has transmitted through or
`been reflected by the tissue; and one or more sensors for
`sensing the transmitted or reflected radiation. The one or
`more sensors send a signal to the processor which algorith-
`mically converts the radiation using linear regression or
`orthogonal functions to determine the concentration of one
`or more blood analytes. The device self-calibrates to elimi-
`nate error caused by variables such as skin character. The
`sensor module is integrated to reduce size and weight such
`that it is inobtrusive, and the monitor is compact for trans—
`port
`
`(12) United States Patent
`US 6,898,451 B2
`(10) Patent No.2
`Wuori
`(45) Date of Patent:
`May 24, 2005
`
`U8006898451B2
`
`Wilke et al,
`Crowley
`Cook et a1.
`Braig et a1.
`Chan et a1.
`Haaland
`Amano et al.
`Coates et al.
`Alain et a1.
`Mansfield et a1.
`
`.............. .. 600/310
`600/310
`............... .. 600/310
`............... .. 600/310
`.
`600/323
`. 702/27
`600/500
`. 250,839.09
`600/310
`600/316
`
`.
`..
`
`3/2000
`9/2000
`1/2001
`3/2001
`4/2001
`1/2002
`3/2002
`9/2002
`4/2003
`10/2001
`
`AAE
`
`l
`B1
`B1
`B1
`B1 '
`Bl
`B1
`A1
`
`6,039,697
`6,119,031
`6,175,750
`6,198,949
`6,215,403
`6,341,257
`6,361,501
`6,452,179
`6,542,762
`2001/0034477
`
`(54) NON-INVASIVE BLOOD ANALYTE
`MEASURING SYSTEM AND METHOD
`UTILIZING OPTICAL ABSORPTION
`
`Inventor:
`
`Edward R.
`
`(75)
`
`VVuori, Mounds View, MN
`
`(US)
`
`Assignee:
`
`Minformed, L.L.C., Mounds View,
`MN (US)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`Appl. No.:
`Filed:
`
`10/104,782
`
`Mar. 2 l, 2002
`Prior Publication Data
`
`US 2003/0050541 A1 Mar. 13, 2003
`
`Related U.S. Application Data
`Provisional application No. 60/277,758, filed on Mar. 21,
`2001.
`
`Int. Cl.7 ................................................ .. A61B 5/00
`U.S. Cl.
`...................................... .. 600/322; 600/310
`Field of Search .............. ..
`..... .. 600/309—310,
`600/322—326, 316, 476, 473
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,596,057
`3,983,751
`4,271,358
`4,651,001
`5,069,214
`5,197,470
`5,348,003
`5,355,880
`5,361,758
`5,660,181
`5,755,226
`5,784,507
`5,817,007
`5,900,632
`
`>>>>>>>>>>>>>>
`
`7/1971
`10/1976
`6/1981
`3/1987
`12/1991
`3/1993
`9/1994
`' 10/1994
`11/1994
`8/1997
`5/1998
`7/1998
`10/1998
`5/1999
`
`.......... .. 600/323
`. 600/342
`.. (100/310
`........... .. 600/326
`
`Arntz ....................... .. 219/354
`Cipriano
`73/295
`Schwarz ................ .. 250/3381
`Harada et a1.
`Samaras et al.
`Helfer et a1.
`.
`Caro
`Thomas et a1.
`Hall et 81.
`.................. .. 600/408
`Ho et a1,
`Carim et a1.
`...... .. 600/323
`Holm-Kennedy et a1.
`385/31
`Fodgaard el al.
`Sterling et al.
`
`FOREIGN PATENT DOCUMENTS
`627250320
`
`* 10/1987
`
`............... .. 374/121
`
`OTHER PUBLICATIONS
`
`Tatsyi Tigawa, Patient Monitoring, Wiley Encyclopedia of
`Electrical and Electronics Engineering Online, 1999*
`Webster’s II New Riverside University Dictionary, Rlver—
`side Publishing Company,, 1994, p. 761.*
`
`* cited by examiner
`
`Primary Exatniner%ax F. Hindenburg
`Assistant Examiner—Matthew Kremer
`(74) Attorney, Agent, or Firm—Fredrikson & Byron, PA.
`
`(57)
`
`ABSTRACT
`
`31 Claims, 11 Drawing Sheets
`
`Apple Inc.
`APLl 054
`
`U.S. Patent No.
`
`Apple Inc.
`APL1054
`U.S. Patent No. 8,923,941
`
`0001
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`US 6,898,451 B2
`
`1
`NON-INVASIVE BLOOD ANALYTE
`MEASURING SYSTEM AND METHOD
`UTILIZING OPTICAL ABSORPTION
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`0013
`
`This invention relates to a non—invasive apparatus and
`methods for in vivo monitoring of the concentration levels
`of various blood analytes within a living subject, using
`optical absorption spectrophotometry. The device and meth-
`ods may be used to simultaneously monitor several analytes
`found in the blood outside of a laboratory setting. The device
`and methods are able to resolve analytes down to approxi-
`mately one mg/dL. Further, the device and methods are able
`to measure all blood analytes present at approximately one
`mg/dL, including glucose and lactate, for example.
`Information concerning the concentrations of blood ana-
`lytes is widely used to assess the health characteristics of
`people. For example, lactate is becoming the measurement
`of choice in sports and coaching to assess levels of condi-
`tioning for athletes and to prevent over-training. Lactate
`threshold and other related parameters are used to assess the
`aerobic and anaerobic status of athletes, are correlated to
`athletic performance, and may be used to “rank” athletes
`according to actual performance history. Lactate monitoring,
`as used in athletics, may also be useful for Military
`Academies, Army boot camps, and other physical training
`operations to assess the physical condition of trainees, to
`improve training programs, and to evaluate the e ectiveness
`of training regimens on specific individuals. Lactate is also
`widely used to assess the medical condition of injured
`people. When serum lactate elevates after an injury, whether
`or not the lactate clears is correlated strongly with mortality,
`thus, measurement of serum lactate levels is a key tool in
`assessing treatment.
`Likewise, the monitoring of blood glucose has long been
`an important tool in controlling diabetes in diabetic patients.
`Diabetes is a high maintenance disease, generally requiring
`several measurements of blood glucose daily. At present,
`this is typically accomplished using a glucometer, in which
`a fresh blood sample must be obtained for each measure—
`ment. Each measurement
`typically requires a new “test
`strip” for receiving the blood sample, the test strips charac-
`teristically being relatively expensive. Such measurements
`are often painful, cumbersome, and moderately time—
`consuming. The method of testing blood glucose using a test
`strip is generally referred to as the “finger stick” method. It
`specifically involves applying a drop of blood to the test
`strip, the test strip using molecular sieves to block molecules
`larger than molecular weight of about 200. The sieves
`consequently block, for example, large glycosylated pro-
`teins from being included in the blood glucose measure-
`
`2
`ment. Due to the inconvenience and expense, many diabetic
`patients do not monitor their blood glucose levels as often as
`recommended. About l6 million diabetic patients in the
`United States need to regularly monitor their blood glucose
`levels.
`A non-invasive device enabling painless and convenient
`monitoring of blood glucose would be of great benefit to
`diabetic patients. The relative ease of measurement may
`contribute to a more regular blood glucose monitoring
`regime by diabetic patients. Various attempts have been
`made at a blood glucose measurement device using spec-
`troscopy. However, those attempts have generally had prob-
`lems with “baseline drift” of unknown origin. It is hypoth-
`esized that the absorption method used in most spectroscopy
`devices for measuring glucose in the blood measures all
`glucose in the blood, both the bound glucose and the free
`glucose, For the purpose of diabetes management, measure-
`ment of the concentration of free glucose is desired. That is,
`the concentration of free glucose in the blood is generally
`recommended to be in the range of 80 mg/dL and 120
`mg/dL. A diabetic patient will measure their blood glucose
`level to determine whether the level is within the recom-
`mended range. If the blood glucose level is outside of the
`recommended range, the diabetic patient will typically inject
`insulin to reduce the blood glucose level. Again, it is the free
`glucose concentration level that is relevant to determining
`whether the patient’s blood glucose concentration is within
`the recommended range. Because absorption techniques
`may measure both free and bound glucose levels as one
`measurement, there may be an overstatement of the blood
`glucose level that results in faulty treatment by the patient.
`The molecular sieves of the test strip glucometers described
`above correct for the possibility of measuring bound and
`free glucose by preventing the bound glucose, with a rela-
`tively high molecular weight, from passing through the
`sieve.
`
`It is notable, however, that the finger stick methods take
`only one measurement of the glucose concentration level in
`the blood and, for a series of measurements, require a series
`of blood samples, generally obtained by a series of finger
`pricks. Consequently, the finger stick methods do not ofier
`an appealing method of continuous measurement of blood
`glucose concentration in the blood. Continuous measure—
`ment of blood glucose levels enable near instant recognition
`of abnormal blood glucose levels whereas a series of iridi-
`Vidual measurements inevitably includes periods of time
`where the precise blood glucose level is unknown. Thus, a
`diabetic patient may be better able to control blood glucose
`levels.
`It may also assist
`the person in adjusting their
`lifestyle, diet, and medication for optimum benefits. Provid-
`ing the easy, non-invasive, and optionally continuous moni-
`toring provides a great improvement in the treatment of the
`diabetes and allows the treatment
`to be tailored to the
`individual.
`
`Many other blood analytes with concentrations similar to
`or greater than lactate and glucose are of fundamental
`importance; for example, hemoglobin and its sub-types,
`albumin, globulins, electrolytes, and others. Hemoglobin is
`important especially in the monitoring of anemia caused by
`various various factors such as HIV infection and chemo-
`therapy. Anemia treatments need frequent monitoring of
`hemoglobin to assess effectiveness of various treatments
`such as Epoetin—Alpha therapy.
`Spectrophotometry provides a useful method for deter-
`mining the presence of analytes in a system. A typical
`spectrometer exposes a dissolved compound to a continuous
`wavelength range of electromagnetic radiation. The radia-
`
`I
`
`,
`
`1
`
`This application is entitled to the benefit of Provisional
`Patent Application Ser. No. 60/277,758 entitled “Noninva-
`sive Infrared Blood Analyte Measuring System and Meth-
`ods” by Edward Wuori, filed Mar. 21, 2001.
`
`FIELD OF THE INVENTION
`
`The present invention relates to a method and apparatus
`for non-invasive monitoring of various blood analytes in
`humans and other animals in the fields of medicine, sports
`medicine, military hardware, anemia treatment, diabetes
`treatment, and traumatic injury treatment.
`
`BACKGROUND OF THE INVENTION
`
`
`
`
`0013
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`4
`before analysis. Invasive procedures are undesirable because
`they cause pain and increase the risk of spread of
`communicable, blood-borne diseases. Further, after the
`invasive collection of body samples,
`these samples may
`need to be further prepared in the laboratory by adding water
`or ions to the samples to increase the accuracy of the
`spectrophotometry readings. Thus, these commonly known
`devices and methods are often only suitable for use under
`laboratory in vitro conditions and are too difficult to be
`practically applied in athletic training and military situa—
`tions. It is noted, of course, that the finger stick method of
`measuring blood glucose concentration levels using a glu-
`cometer has been adapted for home use.
`Recently, non-invasive devices for monitoring levels of
`blood analytes using infrared spectroscopy have been devel—
`oped. For example, U.S. Pat. No. 5,757,002 by Yamasaki
`relates to a method of and an apparatus for measuring lactic
`acid in an organism in the field of sports medicine or
`exercise physiology. Also, U.S. Pat. No. 5,361,758 by Hall
`relates to a non—invasive device and method for monitoring
`concentration levels of blood and tissue constituents within
`a living subject.
`Previous non-invasive devices and methods typically
`require time—consuming custom calibrations to account for
`the differences between individuals and environmental fac-
`tors which cause variation in energy absorption. There are
`several factors that may result in variation in energy absorp-
`tion; for example, environmental factors such as tempera—
`tures and humidity that may affect
`the equipment, and
`individual factors such as skin coloration, skin weathering,
`skin blemishes or other physical or medical conditions. This
`need for custom calibration to each individual makes it
`impractical to use previous devices on demand in training
`situations or at
`the scene of accidents. A universal or
`self-calibrating device that is capable of taking into account
`these variations would be useful.
`Further, many previous non-invasive devices and meth-
`ods accurately measure only a single blood analyte at a time.
`Most typically, the devices are designed to measure blood
`glucose. To measure a di ‘erent analyte, the device must be
`reprogrammed or otherwise altered. Even with such repro-
`gramming or alteration, the devices may not typically mea—
`sure the results of two or more analytes at the same time
`without significant inaccuracies. Each analyte in the blood
`sample contributes a unique absorption pattern to the overall
`infrared spectrum, governed by the unique set of molecular
`vibrations characteristic of each distinct molecular species.
`The infrared spectral range extends from 780 nm to 25,000
`nm and is commonly subdivided further into the near-
`infrared and mid-infrared regions. Most devices obtain an
`measurement of an analyte by using only a small portion of
`the IR spectrum reflecting the particular analyte of interest.
`In those devices that do attempt to use a wider spectrum to
`obtain multiple analyte readings, relatively ineffective meth-
`ods are used to separate and account for multiple analyte
`spectral interferences, leading to decreased accuracy. Thus,
`there exists a need for a device that may successfully use a
`wider spectrum to accurately and simultaneously isolate and
`determine the concentrations of multiple analytes.
`IR spectroscopy typically involves radiating light onto a
`portion of tissue for either transmission through the tissue or
`reflection from the tissue. The transmitted or reflected radia-
`tion is then analyzed to determine concentrations of ana-
`lytes. However, the radiation that is transmitted or reflected
`is not just transmitted through or reflected from the blood,
`but instead includes transmissions or reflection from the
`skin, subdermal tissue, and blood. Thus, the received radia-
`
`US 6,898,451 B2
`
`3
`tion is selectively absorbed by the compound, and a spec—
`trograph is formed of radiation transmitted (or absorbed) as
`a function of wavelength or wave number. Absorption peaks
`are usually plotted as minima in optical spectrographs
`because transmittance or reflectance is plotted with the
`absorbance scale superimpose, creating IR absorption
`bands.
`
`At a given wavelength the absorption of radiation follows
`Beers’ Law, an exponential law of the form:
`A=er Where: A=absorbance=—log10(r,
`I.
`
`
`
`
`
`
`
`'
`
`.
`
`t=fraction of radiation transmitted (or reflected).
`e=molar extinction coeflicient, cmZ/mol.
`C=concentration, mol/cc.
`b=thickness presented to radiation, cm.
`The wavelengths of maximum absorption, km“, and the
`corresponding maximum molar extinction coe icient, em“,
`are identifying properties of a compound. Radiation causes
`excitation of the quantized molecular vibration states. Sev—
`eral kinds of bond stretching and bond bending modes may
`be excited, each causing absorption at unique wavelengths.
`Only vibrations that cause a change in dipole moment give
`rise to an absorption band. Absorption is only slightly
`affected by molecular environment of the bond or group.
`Nevertheless,
`these small c1emical shifts may aid in
`uniquely identifying a compound. A “fingerprint region”
`exists between 42 and 24 THz (1400 and 800 cm’l) because
`of the many absorption peaks hat occur in this region. It is
`virtually impossible for two di erent organic compounds to
`have the same infrared (IR) spectrum, because of the large
`number of peaks in the spectrum. While the peaks and
`valleys are the traditional features used in this type of
`spectrophotometry, the overall shape of the spectra may also
`provide useful
`information, especially in mathematically
`separating mixed spectra where more than one analyte is
`present.
`In addition to the IR absorption bands, absorption peaks
`also occur in the near-IR region (700—2500 nm). Absorp-
`tions in this region are most often associated with the
`overtone and combination bands of the fundamental molecu-
`lar vibrations of 70H, iNH, and 7CH functional groups
`that are also seen in the mid IR region. As a result, most
`biochemical species will exhibit unique absorptions in the
`near-IR. In addition, a few weak electronic transitions of
`organometallic molecules, such as hemoglobin, myoglobin,
`and cytochrome, also appear in the near—IR. These highly
`overlapping, weakly absorbing bands were initially per-
`ceived to be too complex for interpretation and too weak for
`practical application. However, recent
`improvements in .
`instrumentation and advances in multivariate chemometric
`data analysis techniques, which may extract vast amounts of
`chemical information from near-IR spectra, allow meaning-
`ful results to be obtained from a complex spectrum. Absorp-
`tion bands also occur in the visible range (400—700 nm). For
`example, hemoglobin and bilirubin absorb strongly in this
`region.
`Traditionally, Near Infrared Spectroscopy (NIRS) has
`been used to estimate the nutrient content of agricultural
`commodities. More recently NIRS has become widely
`applied in the food processing, chemical, pulp and paper,
`pharmaceutical, polymer, and petrochemical industries.
`Invasive devices and methods of quantifying and classi-
`fying blood analytes using IR and other optical spectropho-
`tometry methods are very commonly known. Invasive pro—
`cedures are those where a sample such as blood is taken
`from the body by puncture or other entry into the body
`
`
`
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`US 6,898,451 B2
`
`5
`tion is a mixture of absorption signals from skin and tissues
`and blood. The signals contributed by the skin and tissues
`make it difl‘lcult to accurately measure the presence of blood
`analytes. These signals need to be separated to eliminate the
`effects of skin and tissue in order to measure the analytes in
`the blood. Previous non—invasive devices and methods were
`unable to separate blood-related readings from body tissue
`readings. Therefore, there is a need for a device capable of
`separating the blood-related component of the signal from
`the tissue component.
`One method of achieving the separation of a blood—related
`component of the signal is to accept only the portion of the
`mixed signal which has a pulse synchronized with the heart
`pulse, known as a pulsatile technique or synchronous detec-
`tion. The pulsatile signal is the time varying portion of the
`whole signal that is synchronized with the heart beat. This
`method presumes that the pulsations come from the move-
`ment of arterial blood or closely related volume and allows
`a signal associated with the blood to be separated from that
`of tissue. The synchronous method is widely used for
`separating blood-related components in pulse oximeters.
`Another possible method for achieving separation of the
`blood related components of the signal from tissue and skin
`related components uses a hematocrit—type method to deter—
`mine the portion of the signal associated with the blood. The
`hematocrit is the proportion, by volume, of the blood that
`consists of red blood cells. The hematocrit
`is typically
`measured from a blood sample by an automated machine
`that makes several other measurements at the same time.
`Most of these machines do not directly measure the
`hematocrit, but instead calculate it based on the determina-
`tion of the amount of hemoglobin and the average volume of
`the red blood cells. Using a hematocrit method generally is
`faster than using a synchronous method because there is no
`need to wait for heart beats. Further, there is less signal loss
`associated with hematocrit methods than with the synchro-
`nous method,
`the synchronous method removing some
`blood associated signal unnecessarily.
`Finally, many non-invasive devices for in vivo monitoring
`of blood analyte concentrations do not allow for an ambu-
`latory application. They typically utilize permanent equip-
`ment set up in a laboratory or other test site, which makes
`it impossible to use while away from the laboratory or other
`test site. Thus, there is a need for a device that may be easily
`transported and used away from the laboratory. The device
`would preferably not interfere with the user’s normal func-
`tioning and would greatly increase the utility and range of
`analyte concentration monitoring beyond the laboratory
`setting.
`
`SUMMARY OF THE INVENTION
`
`6
`The present invention also provides a method and appa—
`ratus with increased sensitivity and accuracy. A problem
`encountered in the area of blood an alyte measurement Via IR
`spectroscopy is accuracy and drift. In general, other analytes
`and various other substances present interfere with the IR
`measurement of the desired analyte. These analytes vary in
`concentration and thus vary the IR spectrum in the regions
`being used to determine specific analyte concentration. The
`present invention corrects for all other analytes with con-
`centrations sufficient to interfere in the determination of the
`concentration of the analyte or analytes of interest. Measur—
`ing the entire Visible and IR spectrum provides enough data
`to simultaneously determine all of the analytes and thereby
`compensate for any accuracy or drift problems their con-
`centration may cause in measuring the concentration of the
`analyte(s) of interest. Data processing using orthogonal
`functions is used to accomplishing this task. Other proper-
`ties of blood may also effect the IR measurement of the
`desired analyte. For example, turbidity of the blood, as may
`v be caused by elevated white cell count or high blood lipids,
`may affect the measurement. These factors appear in the
`spectra and are compensated for by the present invention.
`The analyte measurement apparatus of the present invention
`is sufficiently sensitive to detect blood glucose or lactate
`with accuracy within, approximately, 10% of the level
`actually present, and may do so in a short period of time (e.g.
`5 seconds or less). Due to the non-intrusive nature of the
`measurement and its relative rapidity, it is also possible to
`monitor blood analyte levels essentially continuously.
`The blood analyte measurement apparatus of the present
`invention includes a radiation source for generating and
`transmitting a spectrum of radiation onto a portion of tissue
`(for transmission theretlirougli or reflection therefrom), one
`or more sensors for detecting the radiation either transmitted
`through or reflected from the tissue over a broad spectrum
`and generating an output
`in response to the detected
`radiation, and a processor for receiving output from the
`sensors to determine the concentration of blood analytes in
`the portion of tissue. In a preferred embodiment, the appa-
`ratus also makes use of a mounting device to position the
`radiation source and the sensors relative to a portion of tissue
`so the one or more sensors may receive a substantial portion
`of the radiation produced by the radiation source and trans-
`mitted through or reflected by the portion of tissue. In a
`further preferred embodiment,
`the information regarding
`absorption of the radiation is then algorithmically processed
`to clarify the signal(s) of the desired blood analytes. Thus,
`the invention, in a typical configuration, includes a sensor
`module which is preferably attached to an earlobe, a pocket
`, monitor for immediate readout and data logging, and a data
`link to a PC for long term storage and compilation of data.
`Thus, blood analyte levels may be continuously monitored
`without the constraints of attachment wires or bulky appa-
`ratus.
`
`0015
`
`The present invention provides an improved apparatus
`and method for the rapid, non-intrusive determination of the
`concentration of blood analytes,
`In one embodiment,
`it
`provides a portable tabletop unit for measurement of blood
`analyte concentrations where the subject may walk up to the
`device for measurement from a body part, such as a finger.
`However, there are many situations Where blood analyte
`measurement must be done outside of a domestic or labo-
`ratory environment. Thus, another embodiment of the
`present invention provides a portable system which may be
`positioned on body tissue and transported on the user’s
`person. Features such as small size, a wireless sensor, battery
`operation, portability, and downloadability demonstrably
`increase the utility and range of the analyte measurement
`apparatus of the present invention beyond the hospital or
`laboratory setting.
`
`The blood analyte sensor module is integrated as much as
`possible to reduce the size and weight. In one embodiment,
`the sensor module is completely self-contained. The sensor
`module illuminates the measurement site with a built-in
`radiation source tailored to the spectral region of interest.
`The radiation source and the sensors are each positioned on
`a chip. The radiation source may be integrated onto a custom
`chip in transmission mode, or onto the same chip as the
`sensors in reflection mode, That is, when it is desired to
`receive and interpret radiation transmitted through the
`tissue, the apparatus is working in transmission mode and
`the radiation source is positioned on a chip separate from the
`chip on which the sensors are positioned. In contrast, when
`
`0015
`
`FITBIT, Ex. 1054
`
`

`

`US 6,898,451 B2
`
`8
`the one or more sensors in response to the detected radiation,
`communicating the signal
`to the processor, and finally
`interpreting the signal communicated to the processor to
`determine the concentration of one or more blood analytes.
`Preferably, the method of the present invention also includes
`the step of displaying the results so they may be perceived
`by the user.
`The preferred tissue exposed to the radiation in the
`method is either an earlobe or a finger. Preferably,
`the
`positioning of the tissue is carried out so that the sensors and
`the radiation source have minimal or no contact with the
`tissue itself. While any analyte which has infrared absorp-
`tion may be measured by this method, specific examples are
`lactate/lactic acid, glucose, insulin, ethanol, triglycerides,
`albumin, proteins, hemoglobin,
`immunoglobulins,
`cholesterol, and urea.
`invention is the
`An important aspect of the present
`interpreting of the signals communicated to the processor by
`V an algorithm. One type of algorithm used to interpret this
`data is linear regression. A more preferred algorithm makes
`use of orthogonal functions. The concept
`is to use the
`reference spectrum for each blood analyte as basis functions
`and determine a weighting function or functions that create
`an orthogonal set. This permits easy separation algorithms
`for mixed spectra. The use of algorithms is very helpful for
`self—calibrating to eliminate data artifacts caused by indi—
`vidual variation in tissue character.
`
`'
`
`
`
`0016
`
`7
`it is desired to receive and interpret radiation that is reflected
`from the tissue, the apparatus is working in reflection mode
`and the radiation source may be positioned on the same chip
`as the chip on which the sensors are positioned. Preferably,
`the radiation source is a thermal radiator made up of
`tungsten or tantalum positioned over a reflective he at shield.
`The blood analyte measurement apparatus also optionally
`includes a focusing device for focusing the radiation from
`the radiation source onto a point on the tissue. Afresnel lens,
`for example, works well in this capacity. The apparatus also
`optionally includes a collimator to compensate for
`the
`scattering that typically occurs when the radiation passes
`through tissue. The beam divergence of the collimator, if
`used, should be approximately 5 degrees or less.
`A filter may also be included to separate the radiation
`received by the sensors into various wavelengths subsequent
`to collimation. The preferred filter for this separation is a
`Fabry-Perot narrow band interference filter comprising a
`dielectric film between two metal films, where the dielectric
`film has a graded thickness running from a short wavelength
`end with a thickness of about 100 nm to a long wavelength
`end with a thickness of about 2.5 microns. Between the
`narrow band interference filter and the sensors is a planariz-
`ing layer. The spectrophotometer bears sensors which are
`preferably sensitive to radiation from wavelengths of about
`700 nm to about 2500 nm.
`The sensors within the sensor module are divided into two
`groups: direct silicon sensors sensitive to radiation of a
`wavelength range from about 0.4 to 1.1 microns, and infra-
`red sensors sensitive to radiation of a wavelength range from
`1 to 10 microns. Using both types of sensors, the apparatus
`of the present invention preferably uses an array of approxi-
`mately 1024 elements, for an overall filter passband of about
`0.22 percent of its center wavelength or frequency. The
`direct silicon sensors may be, for example, either 3hoto-
`
`diodes or charge coupled devices. A charge coupled cevice
`array made up of multiple elements sensitive to di ering
`portions of the wavelength range is preferred. The in rared
`sensors making up the rest of the array may, for exam ale, be
`extrinsic silicon, pyroelectric, photoconductor, or thermo-
`couple sensors. Thermocouples comprising two layers of
`metal with an additional layer of gold black are pre erred,
`where the two metal layers may be either nickel—chromium
`alloy on nickel-copper alloy, for example. The sensor mod-
`ule may include a replaceable, rechargeable battery and use
`a unique ID code if desired.
`Aprocessor is provided for processing the output from the
`sensors. If desired, an RF transmitter or other device may be
`provided for Wirelessly transmitting the signals from the p
`sensors to the processor. This processor is preferably a
`CMOS microprocessor, which uses a Boolean algorithm to
`process the output from the sensors. Various processing
`algorithms are used to enhance the value of the data obtained
`from the sensors. The blood analyte measurement apparatus
`may also include a display, typically a liquid crystal display,
`for the immediate display of data to the user. The data may
`be downloaded to a computer or other device via an I/O port,
`typically an RS-232 port.
`The present invention also discloses a method for mea—
`suring the concentration of one or more blood analytes in a
`portion of tissue with a non-invasive measuring apparatus.
`The method involves positioning a portion of tissue approxi-
`mately adjacent one or more sensors and a radiation source,
`exposing the tissue to radiation from the radiation source,
`detecting radiation transmitted through or reflected from the
`tissue with the one or more sensors, generating a signal from
`
`The least squares method of orthogonal functions is
`preferably used to separate the concentrations of the indi-
`vidual analytes from the total spectrum measured. This is
`also referred to as “principle component analysis” and is
`similar to “Fourier series decomposition.” Separating the
`various analyte concentrations is statistically challenging
`because of an overlap of the spectra whic