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`US 7,043,287 B1
`(10) Patent No.:
`(12) United States Patent
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`Khalil et a].
`(45) Date of Patent:
`May 9, 2006
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`USOO7043287B1
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`(54) METHOD FOR MODULATING LIGHT
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`PENETRATION DEPTH IN TISSUE AND
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`DIAGNOSTIC APPLICATIONS USING SAME
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`(75)
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`Inventors: Omar S. Khalil, Libertyville, IL (US);
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`Shu-Jen Yeh, Grayslake, IL (US);
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`X‘aofna" W“: Gumees IL (Us):
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`Stanislaw Kantor, Buifalo Grove, IL
`(US); Charles F. Hanna, LibertyVille,
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`IL (US); szy-Wen Jeng, Vernon Hills,
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`IL (US)
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`(73) Assignee: Abbott Laboratories, Abbott Park, IL
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`(US)
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`( * ) Notice:
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`Subject to any disclaimer, the term of this
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`patent is extended or adjusted under 35
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`U~S~C~ 154(b) by 0 days'
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`(21) APP1~ N05 09/412461
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`Flledi
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`(22)
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`Oct-15, 1999
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`Related US. Application Data
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`(63) Continuation-in-part of application No. 09/302,207,
`filed onApr. 29, 1999, HOW Pat. NO. 6,241,663, Wthh
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`is a continuation-in-part of application No. 09/080,
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`470, filed on May 18, 1998, now Pat. No. 6,662,030.
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`(51)
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`Int. Cl.
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`(2006.01)
`A613 5/00
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`....................................... 600/310; 600/316
`(52) US. Cl.
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`(58) Field of Classification Search ........ 600/31(L311,
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`600/316, 3227324, 326, 328, 334, 339; 356/39741
`See application file for complete search history.
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`(56)
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`Page 1
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`VALENCELL EXHIBIT 2015
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`IPR2017-00321
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`Page 1
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`VALENCELL EXHIBIT 2015
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`US 7,043,287 B1
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`Page 2
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`* cited by examiner
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`Primary ExamineriEric F. Winakur
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`(74) Attorney, Agent, or FirmiDavid L. Weinstein
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`(57)
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`ABSTRACT
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`Devices and methods for non-invasively measuring at least
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`one parameter of a sample, such as the presence of a disease
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`condition, progression of a disease state, presence of an
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`analyte, or concentration of an analyte,
`in a biological
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`sample, such as, for example, a body part. In these devices
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`and methods,
`temperature is controlled and is varied
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`between preset boundaries. The methods and devices mea-
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`sure light that is reflected, scattered, absorbed, or emitted by
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`the sample from an average sampling depth, dav, that is
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`confined within a region in the sample wherein temperature
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`is controlled. According to the method of this invention, the
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`sampling depth dav, in human tissue is modified by changing
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`the temperature of the tissue. The sampling depth increases
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`as the temperature is lowered below the body core tempera-
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`ture and decreases when the temperature is raised within or
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`above the body core temperature. Changing the temperature
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`at the measurement site changes the light penetration depth
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`in tissue and hence dav. Change in light penetration in tissue
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`as a function of temperature can be used to estimate the
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`US 7,043,287 B1
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`presence of a disease condition, progression of a disease
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`state, presence Of an analyte, or concentration Of an analyte
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`in a biological sample. According to the method of this
`invention, an optical measurement is performed on a bio-
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`logical sample at a first temperature. Then, when the optical
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`measurement is repeated at a second temperature, light will
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`penetrate into the biological sample to a depth that
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`different from the depth to which light penetrates at the first
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`temperature by from about 5% to about 20%.
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`30 Claims, 14 Drawing Sheets
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`U.S. Patent
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`May 9, 2006
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`Sheet 1 of 14
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`US 7,043,287 B1
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`a .
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`UHh
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`May 9, 2006
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`US 7,043,287 B1
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`U.S. Patent
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`May 9, 2006
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`Sheet 4 0f 14
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`US 7,043,287 B1
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`U.S. Patent
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`May 9, 2006
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`U.S. Patent
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`May 9, 2006
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`U.S. Patent
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`May 9, 2006
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`Sheet 7 of 14
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`US 7,043,287 B1
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`U.S. Patent
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`Page 11
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`U.S. Patent
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`May 9, 2006
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`Sheet 9 0f 14
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`Page 12
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`May 9, 2006
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`Sheet 10 0f 14
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`Page 13
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`May 9, 2006
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`Sheet 11 0f 14
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`US 7,043,287 B1
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`Page 14
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`May 9, 2006
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`Sheet 12 0f 14
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`Page 15
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`May 9, 2006
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`Sheet 13 0f 14
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`US 7,043,287 B1
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`
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`Page 16
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`May 9, 2006
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`Sheet 14 0f 14
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`US 7,043,287 B1
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`FIG.12
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`Page 17
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`US 7,043,287 B1
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`1
`
`METHOD FOR MODULATING LIGHT
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`PENETRATION DEPTH IN TISSUE AND
`
`
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`DIAGNOSTIC APPLICATIONS USING SAME
`
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`
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`This invention is a continuation-in-part of US. Ser. No.
`
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`
`
`09/080,470, filed May 18, 1998, now US. Pat. No. 6,662,
`
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`
`
`030, and is a continuation-in-part of US. Ser. No. 09/302,
`
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`207, filed Apr. 29, 1999, now US. Pat. No. 6,241,663.
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`5
`
`BACKGROUND OF THE INVENTION
`
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`10
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`2
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`Disease, 3’“ Edition, W.B. Saunders Company, Philadelphia,
`1984, p. 972). If uncontrolled, diabetes can result in a variety
`
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`of adverse clinical manifestations,
`including retinopathy,
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`atherosclerosis, microangiopathy, nephropathy, and neur-
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`opathy. In its advanced stages, diabetes can cause blindness,
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`coma, and ultimately death.
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`Non-invasive determination of glucose has been the sub-
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`ject of several patents. US. Pat. Nos. 5,082,787; 5,009,230;
`
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`4,975,581; 5,379,764; 4,655,225; 5,551,422; 5,893,364;
`
`
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`
`
`5,497,769; 5,492,118; 5,209,231; and 5,348,003 describe a
`
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`
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`variety of optical methods for the noninvasive determination
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`of glucose in the human body. However, all the previously
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`mentioned patents are silent as to the effect of different
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`layers of skin on optical measurements, or the effect of
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`temperature on light penetration through these various layers
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`of the skin. US. Pat. No. 5,935,062 recognizes the presence
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`of skin layers and describes means to detect diffusely
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`reflected light from the dermis and avoid light interacting
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`with the epidermis by using a black barrier on the skin to
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`separate specular reflectance and reflectance from the epi-
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`dermis from reflected light that penetrated to the dermis.
`
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`However, US. Pat. No. 5,935,062 is silent as to the effect of
`
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`temperature on light penetrating through these layers of
`
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`skin. The effect of temperature on the scattering and absorp-
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`tion properties of tissue has been of interest in the art.
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`Thermal effects of laser excitation, photocoagulation, and
`
`
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`temperature effect on skin optics have been described in the
`
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`art. See, for example, W-C. Lin et al., “Dynamics of tissue
`
`
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`
`
`
`reflectance and transmittance during laser irradiation”, SPlE
`
`
`
`
`
`
`
`Proceedings, 2134A Laser-Tissue lnteraction V (1994)
`
`
`
`
`
`2964303; and W4C. Lin, “Dynamics of tissue optics during
`
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`
`
`
`
`laser heating of turbid media”, Applied Optics (1996) Vol.
`
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`
`
`35, No. 19, 341343420; J. Laufer et al., “Effect of tempera-
`
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`
`
`
`ture on the optical properties of ex vivo human dermis and
`
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`
`
`
`
`
`subdermis”, Phys. Med. Biol. 43 (1998) 247942489; J. T.
`
`
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`
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`Bruulsema et al., “Optical Properties of Phantoms and
`
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`
`
`
`
`Tissue Measured in vivo from 0941.3 um using Spatially
`
`
`
`
`
`
`
`Resolved Diffuse Reflectance”, SPlE Proceedings 2979
`
`
`
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`
`
`(1997) 3254334.
`
`
`US. Pat. Nos. 3,628,525; 4,259,963; 4,432,365; 4,890,
`
`
`
`
`
`
`
`619; 4,926,867; 5,131,391; and European Patent Application
`
`
`
`
`
`
`
`EP 0472216 describe oximetry probes having heating ele-
`
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`
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`ments designed to be placed against a body part. US. Pat.
`
`
`
`
`
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`
`
`No. 5,148,082 describes a method for increasing the blood
`
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`
`
`flow in a patient’s tissue, during a photoplethsmography
`
`
`
`
`
`measurement, by heating the tissue with a semiconductor
`
`
`
`
`
`
`
`device mounted in a sensor. US. Pat. No. 5,551,422
`
`
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`
`
`describes a glucose sensor that is brought to a specified
`
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`
`
`temperature, preferably somewhat above normal body tem-
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`perature, with a thermostatically controlled heating system.
`
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`
`
`US. application Ser. No. 09/080,470, filed May 18, 1998,
`
`
`
`
`
`
`
`
`assigned to the assignee of this application, describes a
`
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`
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`non-invasive glucose sensor employing a temperature con-
`
`
`
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`
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`trol. One purpose of controlling the temperature is to mini-
`
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`mize the effect of physiological variables. US. application
`
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`
`
`Ser. No. 09/098,049, filed Nov. 23, 1998, assigned to the
`
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`
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`assignee of this application, describes methods for deter-
`
`
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`
`
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`mining optical properties of tissue having a plurality of
`
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`
`
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`layers. Both applications teach the use of temperature con-
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`trolled optical element that is brought in contact with the
`
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`skin.
`
`Although a variety of detection techniques have been
`
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`disclosed in the art, there is still no commercially available
`
`
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`
`
`
`device that provides non-invasive glucose measurements
`
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`
`
`with an accuracy that is comparable to the current commer-
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`cially available invasive devices. Signals obtained by prior
`
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`art methods reflect the analyte information of the tissue as if
`
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`15
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`20
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`
`35
`
`
`1. Field of the Invention
`
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`This invention relates to devices and methods for the
`
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`noninvasive determination of in vivo concentrations of
`
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`
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`analytes or evaluation of a disease state, and more particu-
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`
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`larly, the noninvasive determination of in vivo concentra-
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`tions of analytes or evaluation of a disease state wherein
`
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`temperature is controlled and varied between preset bound-
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`aries.
`
`2. Discussion of the Art
`
`
`
`
`Non-invasive monitoring of concentrations of analytes in
`
`
`
`
`the human body by means of optical devices and optical
`
`
`
`
`
`
`
`
`methods is an important tool for clinical diagnosis. “Non-
`
`
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`
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`invasive” (alternatively referred to herein as “Nl”) monitor-
`
`
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`
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`ing techniques measure in vivo concentrations of analytes in 25
`
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`
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`the blood or in the tissue without the need for obtaining a
`
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`blood sample from the human body. As used herein, a
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`“non-invasive” technique is one that can be used without
`
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`removing a sample from, or without inserting any instru-
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`mentation into, the human body. The ability to determine the 30
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`
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`concentration of an analyte, or a disease state, in a human
`
`
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`subject without performing an invasive procedure, such as
`
`
`
`
`
`
`removing a sample of blood or a biopsy specimen, has
`
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`
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`several advantages. These advantages include ease in per-
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`
`
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`forming the test, reduced pain and discomfort to the patient,
`
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`and decreased exposure to potential biohazards. These
`
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`advantages tend to promote increased frequency of testing,
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`accurate monitoring and control of a disease condition, and
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`improved patient care. Representative examples of non-
`
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`invasive monitoring techniques include pulse oximetry for 40
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`oxygen saturation (US. Pat. Nos. 3,638,640; 4,223,680;
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`5,007,423; 5,277,181; and 5,297,548). Another example of
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`a non-invasive monitoring technique is the use of laser
`
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`Doppler flowmetry for diagnosis of circulation disorders (J.
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`E. Tooke et al., “Skin Microvascular Blood Flow Control in 45
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`Long Duration Diabetics With and Without Complications”,
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`Diabetes Research (1987) 5, 1894192). Other examples of
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`NI techniques include determination of tissue oxygenation
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`(WO 92/20273), determination of hemoglobin (US. Pat.
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`No. 5,720,284), and determination of hematocrit (US. Pat. 50
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`Nos. 5,553,615; 5,372,136; 5,499,627; and WO 93/13706).
`
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`Determination of bilirubin was also described in the art (R.
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`E. Schumacher, “Noninvasive Measurements of Bilirubin in
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`the Newborn”, Clinics in Perinatology, Vol. 17, No. 2 (1990)
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`4174435, and US. Pat. No. 5,353,790).
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`Non-invasive diagnosis and monitoring of diabetes may
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`be the most important non-invasive diagnostic procedure.
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`Diabetes mellitus is a chronic disorder of carbohydrate, fat,
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`and protein metabolism characterized by an absolute or
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`relative insulin deficiency, hyperglycemia, and glycosuria.
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`At least two major variants of the disease have been iden-
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`tified. “Type 1” accounts for about 10% of diabetics and is
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`characterized by a severe insulin deficiency resulting from a
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`loss of insulin-secreting beta cells in the pancreas. The
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`remainder of diabetic patients suffer from “Type 11”, which 65
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`is characterized by an impaired insulin response in the
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`peripheral tissues (Robbins, S. L. et al., Palhologic Basis of
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`55
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`Page 18
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`Page 18
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`US 7,043,287 B1
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`3
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`the tissue comprised a single uniform layer that has a single
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`uniform temperature. As a result, current approaches to
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`non-invasive metabolite testing, such as glucose monitoring,
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`have not achieved acceptable precision and accuracy.
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`Thus, there is a continuing need for improved NI instru-
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`ments and methods that are unaffected by variations in skin
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`structures and layers or account for the effect of skin layers
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`and the effect of temperature on the optical properties of
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`these layers.
`SUMMARY OF THE INVENTION
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`4
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`least one optical parameter of the
`(c) determining at
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`the first
`temperature,
`the first
`biological sample at
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`temperature corresponding to a first depth in the bio-
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`logical sample;
`(d) changing the first temperature of the biological sample
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`to at least a second temperature, the at least second
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`temperature being within the physiological temperature
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`range of the biological sample;
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`(e) performing an optical measurement on the biological
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`sample at the at least second temperature;
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`(f) determining the at least one optical parameter of the
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`biological sample at the at least second temperature, the
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`at least second temperature corresponding to a second
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`depth in the biological sample; and
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`(g) determining the at least one parameter of the biologi-
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`cal sample from the functional dependence of the at
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`least one optical parameter on depth in the biological
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`sample.
`Parameters of biological samples include, but are not limited
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`to, the presence of a disease condition, the progression of a
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`disease state, the presence of an analyte, or the concentration
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`of an analyte.
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`In another aspect, the present invention provides a method
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`of measuring at least one parameter of a biological sample
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`having a plurality of layers, the method comprising the steps
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`of:
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`(a) setting the temperature of the biological sample to a
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`temperature,
`temperature being within the
`the first
`first
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`physiological temperature range of the biological sample;
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`(b) performing an optical measurement on the biological
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`sample at the first temperature;
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`(c) determining at least one optical parameter of a first
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`layer of the biological sample, the first layer being located
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`at a first depth of the biological sample, the first temperature
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`corresponding to a first depth in the biological sample;
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`(d) changing the temperature of the biological sample to
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`at least a second temperature, the at least second temperature
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`being within the physiological temperature range of the
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`biological sample;
`(e) performing an optical measurement on the biological
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`sample at the at least second temperature;
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`(f) determining the at least one optical parameter at at
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`least a second layer of the biological sample, the at least
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`second layer being located at at least a second depth of the
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`biological sample, the at least second temperature corre-
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`sponding to the second depth of the biological sample; and
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`(g) determining the at least one parameter of the biologi-
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`cal sample from the functional dependence of the at least one
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`optical parameter on depth in the biological sample.
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`The method of this invention can be used to determine a
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`disease state or screen a population of individuals for a
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`disease state.
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`light,
`is
`i.e.,
`In the preferred embodiments, radiation,
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`introduced into the surface of a biological sample, such as a
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`body part, at a light introduction site. The diffusely reflected
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`light collected at one or more light collection sites located on
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`the surface of the sample at different distances, r, from the
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`light introduction site is measured. For a given light collec-
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`tion site at a specific distance r from the light introduction
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`site (sampling distance), the average light penetration depth
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`in the biological sample varies with temperature. Light
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`penetrates deeper into the biological sample as temperature
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`is lowered below the body core temperature.
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`This invention involves increasing the penetration depth
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`of radiation, i.e., light, into a biological sample by decreas-
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`ing the temperature of the biological sample below the body
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`10
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`15
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`20
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`25
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`30
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`35
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`40
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`45
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`55
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`60
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`65
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`This invention provides devices and methods for non-
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`invasively measuring at least one parameter of a sample,
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`such as the presence of a disease condition, progression of
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`a disease state, presence of an analyte, or concentration of an
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`analyte, in a biological sample, such as, for example, a body
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`part. In these devices and methods, temperature is controlled
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`and is varied between preset boundaries.
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`The methods and devices of the present invention mea-
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`sure light that is reflected, scattered, absorbed, or emitted by
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`the sample from an average sampling depth, dav, that is
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`confined within a region in the sample wherein temperature
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`is controlled. According to the method of this invention, the
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`sampling depth dav, in human tissue is modified by changing
`the temperature of the tissue. The sampling depth increases
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`as the temperature is lowered below the body core tempera-
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`ture and decreases when the temperature is raised within or
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`above the body core temperature. As used herein, the phrase
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`“body core temperature” means the temperature of the
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`interior of the body remote from the extremities of the body.
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`Rectal temperature and esophageal temperature represent
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`body core temperature. For normal human beings, body core
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`temperature is 3711° C. Changing the temperature at the
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`measurement site changes the light penetration depth in
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`tissue and hence dav. Change in light penetration in tissue as
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`a function of temperature can be used to estimate the
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`presence of a disease condition, progression of a disease
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`state, p