Surgery – Diagnostic testing – Measuring or detecting nonradioactive constituent of body...
Reexamination Certificate
1997-06-12
2001-06-12
Cohen, Lee (Department: 3739)
Surgery
Diagnostic testing
Measuring or detecting nonradioactive constituent of body...
C600S319000, C600S336000
Reexamination Certificate
active
06246893
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to techniques for non-invasive measuring of blood glucose concentration, especially in diabetics.
It is well known that glucose in solution is an optically active material. That is, it will cause the plane of polarization of light traversing the solution to be rotated. The quantitative relationship between the amount of polarization rotation, the glucose concentration, and the optical path length of the solution has been clearly established. It is known that this phenomenon offers the potential for developing a non-invasive blood glucose analyzer.
Diabetes is a disease which entails a large number of associated complications. Retinal deterioration leading to blindness and impaired circulation leading to limb amputation are just two of the more serious complications. Many of these complications result from the large excursions in blood glucose concentrations common to diabetics due to inadequate monitoring of the blood glucose levels. Current methods of diabetic monitoring of blood glucose involve the lancing or sticking of a finger and external measurement of the glucose content of the blood sample. This procedure leaves the diabetic with sore fingers, since the recommended frequency of testing is four or more times per day.
Although many diabetes patients should use the “finger sticking” test to obtain blood for glucose concentration measurements four or more times per day, studies show that very few patients do this unless they absolutely have to, and many patients only do it a few times at the beginning of their treatment until they establish what they think is a pattern in their required medication schedule. They then stop the finger sticking tests and simply take their insulin shots on the assumption that their body chemistry is thereafter constant. This leads to large changes in glucose concentration in the patient's blood, which in turn leads to a variety of serious medical consequences to the patient. For example, it is estimated that in 1996 there were over fifty thousand amputations of limbs due to complications of diabetes in the U.S.
Diabetics recover from cuts and bruises more slowly than do non-diabetics. This very real and basic discomfort causes many diabetics to shirk on the frequency of blood glucose testing, resulting in a higher frequency of complications than otherwise would be the case. A small device that could make blood glucose measurements on a non-invasive basis would be of great value to the diabetic in that it would greatly encourage frequent monitoring of blood glucose levels.
Glucose in solution is an example of an optically active substance. That is, the glucose solution will rotate the plane of polarization of polarized light passing through it in proportion to the path length in the solution and to the concentration of the glucose in the solution. This is expressed mathematically as:
&Dgr;&thgr;=&agr;*
L*C
Eq. 1
Where:
&Dgr;&thgr; is the polarization rotation in degrees;
&agr; is the specific rotation constant dependent on the specifics of the glucose type;
&agr;=56.5 (35.4) degrees per decimeter (dm) per gram per milliliter for glucose at a wavelength of 633 (780) nanometers
L is the path length in the solution in dm, (where 1 dm=10 centimeters (cm);
C is the glucose solution concentration in grams (gm) per milliliter.
For the clinically meaningful glucose concentration range from 50 to 500 mg/dL (milligrams per deciliter) and a path length of 1 cm, the observed rotation ranges from about 0.0028 degrees to about 0.028 degrees for a wavelength of 633 nanometers. As the wavelength is increased the specific rotation &agr; decreases, to a value of 26.3 at a wavelength of 900 nanometers. At that wavelength the rotation in the above case is reduced to 0.0013 and 0.013 degrees respectively. If the assumption is made that about 30% of the path length of radiation passing through living tissue is comprised of blood while the remainder is made up of fat, bone, sinew, etc. then a 1 cm path length through human tissue should produce about 0.001 to 0.01 degrees of polarization rotation. Thus, a useable system must have a basic sensitivity of the order of about 0.0003 degrees, i.e., 1 arc-second, or 5 micro radians.
It is known that human tissue is basically transparent in the wavelength range from about 750 nanometers to about 1800 nanometers. This is the spectral region known as the “overtone” region. It lies between the electronic, or atomic transition, wavelength region on the short wavelength side and the molecular vibrational-absorption region on the long wavelength side. Since there are no fundamental absorption processes in this region, it is found that organic materials basically have quite reasonable optical transmission in this region of the spectrum.
U.S. Pat. No. 5,209,231 by Cote et al. describes a non-invasive glucose sensor which utilizes a pair of polarizers, a quarter wave plate and a motor driven polarizer which produces a constant amplitude phase modulated beam. This beam is split into two beams, one of which passes through the sample and the other which is employed as a reference. By phase demodulation of the two beams, each incident on a different detector, a measure of glucose concentration in an optical cell is determined. Measurements are proposed to be made transversely through the eye's anterior chamber (e.g.,
57
in FIG.
3
). This approach suffers in sensitivity of measurement (according to the authors) which is probably due to noise problems associated with the motor driven phase modulator as well as other unidentified problems.
“Multispectral Polarimetric Glucose Detection using a Single Pockels Cell”, Optical Engineering, Vol. 33, pp 2746 (1994) by King et al. describes a system which employs a pair of polarizers, a quarter wave plate, and a Pockels cell modulator which are configured as a polarization spectrometer. They employed the output from a lock in amplifier which is “filtered using a leaky integrator” and then fed back to a compensator circuit which was eventually summed with the driver oscillator output and then input to the Pockels cell driver to null the AC signal in the system. Again, noise levels in the system represent the major problem in achieving the required sensitivity. The reported data show a scatter that is unacceptable for a working blood glucose sensor.
The angle of incidence of the input beam to the cornea and the exit angle therefrom as shown in FIG. 1 of the King et al. article are so large that the instrumentation, including small turning mirrors or the like, must be positioned very close to the patient's sclera or the soft tissue near the base of his/her nose and the soft tissue at the outer corner of the eye that it is difficult to provide the input beam and to intercept the exit beam, especially with a portable instrument. Furthermore, these angles are sufficiently large that it is difficult to “initialize” the apparatus by rotating the polarizer and analyzer sufficiently to produce the initial extinction of the beam required. The angles required of a prism which would provide the same angle of incidence and exit angle for initial alignment of the apparatus are so large that a suitable prism is very expensive. While the size and shape of the human eye does not vary substantially from person to person, the soft tissue structure surrounding the eye does vary greatly from person to person. This makes it difficult to design support structures for the turning mirrors required to provide the incidence beam and intercept the exit beam.
“Noninvasive Glucose Monitoring of the Aqueous Humor of the Eye: Part I. Measurement of Very Small Optical Rotations”, Diabetes Care, Vol. 5, pg 254, by Rabinovitch et al. describes a system having two polarizers, and two Faraday rotator/modulators. In this case there was no quarter wave plate employed in the apparatus. The absence of the waveplate means that their system is vulnerable to ellipticities of polarization which might be produced by mirror or optical surface r
Cahill Sutton & Thomas P.L.C.
Cohen Lee
Ruddy David M.
TecMed Incorporated
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