Surgery – Diagnostic testing – Measuring or detecting nonradioactive constituent of body...
Reexamination Certificate
1999-07-07
2001-09-11
Winakur, Eric F. (Department: 3736)
Surgery
Diagnostic testing
Measuring or detecting nonradioactive constituent of body...
C600S316000
Reexamination Certificate
active
06289230
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The invention relates to methods for noninvasive spectroscopic examination of blood and/or other tissues. More particularly, the invention relates to methods for obtaining Raman spectroscopic features associated with both mobile and immobile tissues, including a method for determining blood volume and analyte concentration, and a method for detecting Raman spectroscopic features associated with skin.
BACKGROUND
There has long been considerable interest in the non-invasive monitoring of body chemistry. There are 16 million Americans with diabetes, all of whom would benefit from a method for non-invasive measurement of blood glucose levels. Using currently accepted methods for measuring blood glucose levels, many diabetics must give blood five to seven times per day to adequately monitor their health status. With a non-invasive blood glucose measurement, closer control could be imposed and the continuing damage, impairment and costs caused by diabetes could be minimized.
Blood oximetry is an example of an application of electronic absorption spectroscopy to non-invasive monitoring of the equilibrium between oxygenated and deoxygenated blood (U.S. Pat. No. 5,615,673, issued Apr. 1, 1997). Similarly, vibrational spectroscopy is a reliable mode of quantitative and qualitative ex vivo analysis for complex mixtures, and there are reports of in vitro applications of this method to metabolically interesting analytes (A. J. Berger et al., 1999, Multicomponent blood analysis by near infrared spectroscopy, Applied Optics 38(13):2916-2926 ; S. Y. Wang et al, 1993, Analysis of metabolites in aqueous solution by using laser Raman spectroscopy, Applied Optics 32(6):925-929; A. J. Berger et al., 1996, Rapid, noninvasive concentration measurements of aqueous biological analytes by near-infrared Raman spectroscopy, Applied Optics 35(1):209-212). Infrared measures, such as vibrational absorption spectroscopy, have been applied to skin tissue, but with success limited by unavailability of suitable light sources and detectors at crucial wavelengths, and by heating of the tissue due to the absorption of incident radiation (U.S. Pat. No. 5,551,422, see also R. R. Anderson and J. A. Parrish, 1981, The Optics of Human Skin, J. Investigative Dermatology 77(1):13-19). Previous attempts to provide methods for noninvasive blood glucose monitoring are summarized in U.S. Pat. No. 5,553,616, issued on Sep. 10, 1996, and in O. S. Khalil, 1999, Spectroscopic and clinical aspects of noninvasive glucose measurement, Clinical Chemistry 45:165-177.
Application of noninvasive techniques for blood analysis will require improved methods for isolating signals attributable to blood versus surrounding tissues.
SUMMARY OF THE INVENTION
The invention provides methods for noninvasively measuring blood volume and analyte concentration and for obtaining spectroscopic information relating to immobile tissues, such as skin. In one embodiment, the invention provides a noninvasive method of determining concentration of an analyte in blood of a subject. Examples of an analyte include, but are not limited to, glucose, urea, total protein, free fatty acids, monoglycerides, diglycerides, triglycerides, creatinine, exchangeable protein associated amide protons or cholesterol. Preferably, the analyte is glucose. The method comprises irradiating a region of tissue, such as a fingertip, of the subject with a light source; collecting fluorescence spectra emitted by the region of tissue, the quantity of fluorescence spectra being indicative of blood volume; and collecting Raman spectra emitted by the region of tissue at a wavelength range that corresponds to the analyte, the quantity of Raman spectra being indicative of the amount of analyte. The method further comprises dividing the collected Raman spectra by the collected fluorescence spectra to obtain a number that is proportional to the concentration of analyte per unit blood volume.
In a preferred embodiment, the fluorescence and Raman spectra are collected while the region of tissue is in a blood-replete state and collected while the region of tissue is in a blood-depleted state. The method further comprises determining the integral of net collected spectra, net collected spectra being a difference between spectra collected while the region of tissue is in a blood-replete state and spectra collected while the region of tissue is in a blood-depleted state. In this embodiment, the integral of the net collected Raman spectra at the wavelength range corresponding to the analyte is divided by the integral of the net collected fluorescence spectra.
In one embodiment, the net collected Raman spectra is determined by:
I
(&lgr;)
unp
−I
(&lgr;)
pre
={{(
e
I
s
)+
(
f
I
s)+(
r
I
s)}+{(
e
I
bu
)+(
f
I
bu
)+(
r
I
bu)}}
e
−[b
unp
]d
−{{(
e
I
s
)+(
f
I
s
)+(
r
I
s
)}+{(
e
I
bp
)+(
f
I
bp
)+(
r
I
bp
)}}
e
−[b
pre
]d
where:
I(&lgr;)=incident light intensity at wavelength &lgr;
unp or u refers to an unpressed or blood-replete state
pre or p refers to a pressed or blood-depleted state
(
e
I
s
)=intensity of light scattered by elastic processes from skin
(
f
I
s
)=intensity of fluorescence from skin
(
r
I
s
)=intensity of Raman scattering from skin
(
e
I
b
)=intensity of light scattered by elastic processes from blood
(
f
I
b
)=intensity of fluorescence from blood
(
r
I
b
)=intensity of Raman scattering from blood
[b]d=volume of blood-related signal multiplied by the depth of the region of tissue
The method can further comprise enhancing the spectra collected by performing a 61-501 point adjacent averaging smoothing operation on the net collected spectra; subtracting the smoothed spectra from the net collected spectra; and performing a 3-27 point adjacent averaging smoothing operation on the result. Preferably, the adjacent averaging smoothing operation of the first step is a 85-201 point smoothing operation, and more preferably, a 101 point smoothing operation. The adjacent averaging smoothing operation of the third step is preferably a 7 point smoothing operation.
In preferred embodiments, the light source emits light having a wavelength of about 785 nm to about 850 nm. One example of a light source is a laser.
The blood-depleted state can be achieved by tissue modulation, including by applying a tourniquet to the tissue, by pressing the tissue against a surface, or by applying an ultrasonic transducer to the region of tissue.
The invention also provides a noninvasive method of determining concentration of an analyte in blood of a subject that comprises irradiating a region of tissue of the subject with a light source; collecting Raman spectra emitted by the region of tissue at a wavelength range that corresponds to the analyte, the quantity of Raman spectra being indicative of the amount of analyte; and measuring absorption of incident light by the region of tissue, the amount of absorbed light being indicative of blood volume. The method further comprises dividing the collected Raman spectra by the amount of absorbed incident light to obtain a number proportional to the concentration of analyte per unit blood volume. The method can be performed while the region of tissue is in a blood-replete state and while the region of tissue is in a blood-depleted state. The net collected Raman spectra is divided by the net absorbed light, wherein net refers to the difference between the blood-replete and blood-depleted states.
The spectra collected can be further enhanced by the adjacent averaging smoothing operations described above. The method can further comprise irradiating the tissue with a second light source having a wavelength that corresponds to an isosbestic point for oxy-deoxyhemoglobin. The second light source can be, for example, a laser, a black body source or a light emitting diode (LED). In a preferred embodiment, the first light source ha
Chaiken Joseph
Peterson Charles M.
Gates & Cooper LLP
LighTouch Medical, Inc.
Winakur Eric F.
LandOfFree
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