Surgery – Diagnostic testing – Measuring or detecting nonradioactive constituent of body...
Reexamination Certificate
2000-04-19
2002-08-27
Winakur, Eric F. (Department: 3736)
Surgery
Diagnostic testing
Measuring or detecting nonradioactive constituent of body...
C600S336000, C600S310000
Reexamination Certificate
active
06442411
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the detection and measurement of the concentration of constituents of a solution or suspension using radiation, preferably near-infrared radiation. More particularly, methods have been developed for the noninvasive measurement of the concentration of constituents such as hemoglobin and its variants and derivatives, glucose, cholesterol and its combined forms, drugs of abuse, and other analytes of clinical and diagnostic significance. Because these methods do not require the withdrawal of blood in order to perform these measurements, they are particularly suitable for home testing of glucose levels in diabetics and of urea or creatinine levels in patients undergoing home dialysis. The present invention provides a method of calibrating these measurements to obtain an absolute concentration without the requirement of obtaining extensive calibration data for each subject.
In addition to home testing, development of noninvasive clinical testing procedures has become an important goal, due to the widespread fear of AIDS and other diseases, such as hepatitis, which can be spread through the use of invasive procedures.
In the published research, a major issue in the in vivo quantification of blood analyte concentrations is the problem of how to take the signals generated by the apparatus and create from those signals an absolute value for the constituent concentration of interest. Current methods for the evaluation of concentration levels involve conversion of the signals to an estimated constituent concentration by some arbitrary algorithm using values generated by a contemporaneous set of invasive measurements from appropriately generated samples of blood or tissue. If the concentrations estimated by the converted signals and the concentrations estimated by the invasive measurements are highly correlated, then the correlation thus found is accepted as a “calibration curve” for the constituent of interest. However, the calibration curve thus generated is not necessarily valid over a wider range of subjects or physiological conditions than the range used to generate the curve.
In cases where only a relative trend in the data is of interest an accurate calibration is less critical and the foregoing method is adequate. However, in many cases, either calibration data are unavailable or a more accurate estimate of the constituent concentration is required. For these cases, a calibration method applicable to all subjects under all conditions is desirable.
A number of related publications suggest the use of water as an internal standard. Since water is an absorber in the near infra-red, the general approach is to measure the optical effect of water and to compare it with the optical activity of the constituent of interest. For example, Matcher et al. (Phys. Med. Biol., 38, 177, 1993) discusses the use of certain features of the water absorption spectrum to estimate the “differential path length” traveled by radiation in a scattering medium which includes water. However, their calculation for the concentration of water in the tissue studied (the human forearm) varies by approximately 12% around the mean value. Other publications (Documenta Geigy, 7
th
edition, 1970) indicate that, depending on the tissue of interest, water concentrations can vary between 60% and 90%.
Jobsis (U.S. Pat. No. 4,805,623) describes a method in which an unknown concentration is estimated using the presence in the sample of an absorber having a known concentration. However, in the Jobsis disclosure, the absorber of known concentration is water in tissue. Jobsis states that the variability is about 15%. Thus the concentration of water is subject to the same lack of constancy as in the disclosures by Matcher et al. Jobsis does not discuss the use of any water concentration having a level sufficiently constant to employ as a universal calibration or reference level. In fact, Jobsis states that “the practice of the present invention depends strongly on the development of either a means of translating the results in terms of accepted standards, such as spectrophotometric data in clear solutions, or on the de novo development of an extensive data base where accepted standards are not relevant, i.e., in heterogeneous systems such as the brain.”
Pologe (U.S. Pat. No. 5,297,548) discloses the use of simultaneous measurement on a common optical path using pulsatile signals to determine the relative amounts of the dominant absorbers: water, deoxyhemoglobin, and oxyhemoglobin. Pologe does not indicate the possible use of such an apparatus to generate a universal calibration method applicable across multiple subjects. In fact, Pologe indicates that calibration of such an apparatus is intended to be performed empirically.
Other workers, such as Carim et al. (U.S. Pat. No. 5,553,615) and Kuestner (U.S. Pat. No. 5,377, 674), also disclose the use of optical measurements for noninvasive analysis in which one or more detectors are sensitive to wavelengths in which water is the primary absorbing species. However, neither of these disclosures attempts to create a universal calibration or reference level.
As the above discussion suggests, the difficulty of in vivo calibration problem results from a combination of two factors. First, the physical pathlength over which any absorber is present in the tissue or blood is unknown and varies from person-to-person. Second, the intense scattering in tissue and its variation from person-to-person causes the unknown pathlength to be multiplied by an unknown factor that varies with wavelength as well as with subject. A successful solution to this problem requires consideration of both of these issues.
Several patents from the laboratory of the present inventor disclose various procedures which can assist in diminishing some sources of variability and provide better precision. These include U.S. Pat. No. 5,334,287, which describes the basic procedure now known as Kromoscopy, and U.S. Pat. Nos. 5,434,412, 5,424,545, 5,818,048 and 5,672,875, all of which describe improvements and variants on the basic Kromscopic system and methods. The disclosures of all the above-referenced patents are incorporated herein by reference. While many of these patents relate to methods of improving sensitivity and precision of the assays, the biological system is so complex that additional modifications and processes are helpful.
SUMMARY OF THE INVENTION
The method of the present invention makes use of the physiological fact that the kidneys and their associated regulatory systems maintain a virtually constant water concentration in the blood. These regulatory systems maintain the osmotic pressure difference across the filtration systems of the kidney at a stable level and thereby provide the renal system with maximal control over the critical function of solute filtration.
As a result of this regulation, the water concentration in the blood, as measured by a variety of techniques, varies from approximately 830-860 grams per milliliter of blood, a variation of ±1.8% around the average level. In contrast, the concentration of water in tissues can vary by as much as ±20% around the average level. This exceptionally high stability of blood water concentration can be used to calculate concentrations of other constituents in the blood.
In the present invention, this highly stable value for the concentration of water in blood is employed in a universal calibration scheme by combining optical measurements performed at two or more wavelengths in such a way as to eliminate the dependence of concentration on either the thickness of the body part, on the thickness of the absorbing regions within the body part, and on the scattering properties within the body part.
This is accomplished, in a general sense, by employing several types of normalization of the detection channel outputs. For each detection channel the output signals are scaled to fractional modulations by comparing the differential output produced by the cardiac pulse to the background output pro
Kremer Matthew
Lahive & Cockfield LLP
Optix LP
Winakur Eric F.
LandOfFree
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