System for improving the sensitivity and stability of optical polarimetric measurements

Claims

What is claimed is:

1. A method for polarimetric measurement of optical rotation of light caused by a concentration of a substance contained in a sample, comprising:

(a) providing a laser beam passing through a polarizer and an optical modulator and split into a measurement beam and a reference beam, analyzing the measurement beam and directing it onto a first detector coupled to a first amplifier, and analyzing the reference beam and directing it onto a second detector coupled to a second amplifier;

(b) performing identical filtering at integral multiples of a modulation frequency, and performing multiplication and algebraic summing operations on outputs of the first and second amplifiers to produce a first .PSI..sup.2 /2 signal and a first 2.beta..PSI. signal in response to the measurement beam and a second .PSI..sup.2 /2 signal and a second 2.beta..PSI. signal in response to the reference beam, .PSI. representing a modulation level of light emanating from the optical modulator, and .beta. representing optical rotation from extinction of the measurement beam or reference beam;

(c) stabilizing the measurement beam by

i. comparing the second .PSI..sup.2 /2 signal to a first reference signal to produce a first error signal,

ii. comparing the second 2.beta..PSI. signal to a second reference signal to produce a second error signal,

iii. multiplying the first error signal by a modulation signal to produce a modulation feedback signal and adding it to the second error signal to produce a combined modulation and zeroing feedback signal, and

iv. driving the optical modulator in response to the combined modulation and zeroing feedback signal to minimize the first and second error signals; and

(d) computing a first value of .beta. from the first .PSI..sup.2 /2 signal and the first 2.beta..PSI. signal with no sample in a path of the measurement beam and a second value of .beta. from the first .PSI..sup.2 /2 signal and the first 2.beta..PSI. signal with the sample in the path of the measurement beam, and computing the difference between the first and second values of .beta..

2. The method of claim 1 wherein step (a) includes directing the measurement beam to an analyzer by means of a glass guide, and providing a compensation coil around the glass guide, measuring the temperature of the glass guide, and controlling a current in the compensation coil to compensate the temperature coefficient of the Verdet constant of the glass guide.

3. The method of claim 1 wherein each of the first and second 2.beta..PSI. signals has a value according to the expression

wherein .omega.t, 3.omega.t, 5.omega.t . . . represent odd harmonic frequencies, and Z.sub.1, Z.sub.3, Z.sub.5. . . represent odd harmonic coefficients.

4. The method of claim 3 wherein each of the first and second .PSI..sup.2 /2 signals has a value according to the expression

wherein 2.omega.t, 4.omega.t, 6.omega.t . . . represent even harmonic frequencies, and Y.sub.2, Y.sub.4, Y.sub.6. . . represent even harmonic coefficients.

5. The method of claim 4 wherein the magnitude of the modulation level of light .PSI. corresponds to a modulation angle .delta. substantially greater than 45 degrees, and wherein .PSI. cos(.omega.t) is the electrical signal applied to the optical modulator to produce the modulation angle .delta. of the polarized light.

6. The method of claim 4 wherein the magnitude of the modulation level of light .PSI. corresponds to a modulation angle .delta. in the range of approximately 30 degrees to 75 degrees, and wherein .PSI. cos(.omega.t) is the electrical signal applied to the optical modulator to produce the modulation angle .delta. of the polarized light.

7. The method of claim 1 wherein the filtering at integral multiples of the modulation frequency in step (b) is performed by fast Fourier transforms to be used in the multiplication and algebraic summing operations.

8. The method of claim 7 including performing a coherent averaging operation on the fast Fourier transforms to improve the signal-to-noise ratio of the polarimetric measurement.

9. A method for polarimetric measurement of the concentration of a substance contained in a sample, comprising:

(a) providing a laser beam passing through a polarizer and an optical modulator and split into a measurement beam and a reference beam, analyzing the measurement beam, and directing it onto a first detector coupled to a first amplifier, and analyzing the reference beam and directing it onto a second detector coupled to a second amplifier;

(b) performing identical filtering at integral multiples of a modulation frequency, and performing multiplication and algebraic summing operations on outputs of the first and second amplifiers to produce a first .PSI..sup.2 /2 signal and a first 2.beta..PSI. signal in response to the measurement beam and a second .PSI..sup.2 /2 signal and a second 2.beta..PSI. signal in response to the reference beam, .beta. representing a modulation level of light emanating from the optical modulator, and .PSI. representing optical rotation from extinction of the measurement beam or reference beam;

(c) stabilizing the measurement beam by

i. comparing the second .PSI..sup.2 /2 signal to a first reference signal to produce a first error signal,

ii. comparing the second 2.beta..PSI. signal to a second reference signal to produce a second error signal,

iii. multiplying the first error signal by a modulation signal to produce a modulation feedback signal and adding it to the second error signal to produce a combined modulation and zeroing feedback signal, and

iv. driving the optical modulator in response to the combined modulation and zeroing feedback signal to minimize the first and second error signals; and

(d) computing a first value of .beta. from the first 2.beta..PSI. signal with no sample in a path of the measurement beam and a second value of .beta. from the first 2.beta..PSI. signal with the sample in the path of the measurement beam, and converting the difference between the first and second values of .beta. to a value of concentration of the substance in the sample.

10. The method of claim 9 wherein each of the first and second 2.beta..PSI. signals has a value according to the expression

wherein .omega.t, 3.omega.t, 5.omega.t . . . represent odd harmonic frequencies, and Z.sub.1, Z.sub.3, Z.sub.5. . . represent odd harmonic coefficients.

11. The method of claim 10 wherein the magnitude of the modulation-level of light .PSI. corresponds to a modulation angle .delta. substantially greater than 45 degrees, and wherein .PSI. cos(.omega.t) is the electrical signal applied to the optical modulator to produce the modulation angle .delta. of the polarized light.

12. The method of claim 10 wherein the magnitude of the modulation level of light .PSI. corresponds to a modulation angle .delta. in the range of approximately 30 degrees to 75 degrees, and wherein .PSI. cos(.omega.t) is the electrical signal applied to the optical modulator to produce the modulation angle .delta. of the polarized light.

13. The method of claim 9 wherein the filtering at integral multiples of the modulation frequency in step (b) is performed by fast Fourier transforms to be used in the multiplication and algebraic summing operations.

14. The method of claim 13 including performing a coherent averaging operation on the fast Fourier transforms to improve the signal-to-noise ratio of the polarimetric measurement.

15. The method of claim 9 wherein step (a) includes directing the measurement beam to an analyzer by means of a first glass guide.

16. The method of claim 15 including providing a compensation coil around the first glass guide, measuring the temperature of the first glass guide, and controlling a current in the compensation coil to compensate for the temperature coefficient of the Verdet constant of the first glass guide.

17. The method of claim 15 including introducing the sample in the path of the measurement beam ahead of the first glass guide.

18. The method of claim 17 wherein the sample is an ear lobe, the method including placing a portion of the first glass guide behind the ear lobe.

19. The method of claim 9 wherein the substance is glucose, and the sample is human tissue.

20. The method of claim 19 wherein step (d) includes using a stored look-up table or an algorithm to convert the difference between the first and second values of .beta. to a value of glucose concentration in the sample.

21. The method of claim 9 including converting analog output signals produced by the first amplifier to digital measurement channel signals, and converting analog output signals produced by the second amplifier to digital reference channel signals.

22. The method of claim 21 including performing one of steps (b) and (c) in a digital signal processor operating in response to the digital measurement channel signals and the digital reference channel signals.

23. The method of claim 15 including zeroing a measurement channel including the measurement beam by driving the measurement beam to extinction by means of a compensation coil around the first glass guide with no sample in the measurement channel.

24. A system for polarimetric measurement of the concentration of glucose in a sample, comprising:

(a) a polarizer;

(b) an optical modulator;

(c) a laser producing a laser beam passing through the polarizer and then passing through the optical modulator;

(d) a beam splitter splitting the beam emanating from the optical modulator into a measurement beam and a reference beam;

(e) means for analyzing the measurement beam and the reference beam;

(f) a first detector detecting the analyzed measurement beam, and a second detector detecting the analyzed reference beam;

(g) a first amplifier amplifying an output of the first detector, and a second amplifier amplifying an output of the second detector;

(h) means for performing identical filtering at integral multiples of a modulation frequency, and performing multiplication and algebraic summing operations on outputs of the first and second amplifiers to produce a first .PSI..sup.2 /2 signal and a first 2.beta..PSI. signal in response to the measurement beam and a second .PSI..sup.2 /2 signal and a second 2.beta..PSI. signal in response to the reference beam, .PSI. representing a modulation level of light emanating from the optical modulator, and .beta. representing optical rotation from extinction of the measurement beam or reference beam;

(i) means for stabilizing the measurement beam by

i. comparing the second .PSI..sup.2 /2 signal to a first reference signal to produce a first error signal,

ii. comparing the second 2.beta..PSI. signal to a second reference signal to produce a second error signal,

iii. multiplying the first error signal by a modulation signal to produce modulation feedback signal and adding it to the second error signal to produce a combined modulation and zeroing feedback signal, and

iv. driving the optical modulator in response to the combined modulation and zeroing feedback signal to minimize the first and second error signals; and

(j) means for computing a first value of .beta. from the first 2.beta..PSI. signal with no sample in the path of the measurement beam and a second value of .beta. from the first 2.beta..PSI. signal with the sample in the path of the measurement beam, and converting the difference between the first and second values of .beta. to a value of glucose concentration in the sample.

25. A system for polarimetric measurement of the concentration of an optically active substance in a sample, comprising:

(a) a polarizer;

(b) an optical modulator;

(c) a laser producing a laser beam passing through the polarizer and then through the optical modulator;

(d) a splitter splitting the beam emanating from the optical modulator into a measurement beam and a reference beam;

(e) a first analyzer in the path of the measurement beam and a second analyzer in the path of the reference beam;

(f) a first detector detecting the analyzed measurement beam, and a second detector detecting the analyzed reference beam;

(g) a first amplifier amplifying an output of the first detector, and a second amplifier amplifying an output of the second detector; and

(h) a digital signal processor adapted to

i. perform identical filtering at integral multiples of a modulation frequency, and performing multiplication and algebraic summing operations on digital representations of outputs of the first and second amplifiers to produce a first .PSI..sup.2 /2 signal and a first 2.beta..PSI. signal in response to the measurement beam and a second .PSI..sup.2 /2 signal and a second 2.beta..PSI. signal in response to the reference beam, .PSI. representing a modulation level of light emanating from the optical modulator, and .beta. representing optical rotation from extinction of the measurement beam or reference beam,

ii. stabilize the measurement beam by comparing the second .PSI..sup.2 /2 signal to a first reference signal to produce a first error signal, comparing the second 2.beta..PSI. signal to a second reference signal to produce a second error signal, multiplying the first error signal by a modulation signal to produce a modulation feedback signal and adding it to the second error signal to produce a combined modulation and zeroing feedback signal, and driving the optical modulator in response to the combined modulation and zeroing feedback signal to minimize the first and second error signals, and

iii. compute a first value of .beta. from the first 2.beta..PSI. signal with no sample in the path of the measurement beam and a second value of .beta. from the first 2.beta..PSI. signal with the sample in the path of the measurement beam, and converting the difference between the first and second values of .beta. to a value of glucose concentration in the sample.

26. The system of claim 25 wherein the substance is glucose, and the sample is human tissue.

27. The system of claim 25 including a first analog-to-digital converter having an input coupled to the output of the first amplifier and an output coupled to a digital input of the digital signal processor, and a second analog-to-digital converter having an input coupled to the output of the second amplifier and an output coupled to the digital input of the digital signal processor.

28. The system of claim 25 including a Faraday glass guide guiding the measurement beam to the first analyzer with a compensation coil around the glass guide, a temperature sensor adapted for measuring the temperature of the glass guide, an analog-to-digital converter coupled between the temperature sensor and the digital signal processor and adapted to convert an output signal produced by the temperature sensor to a digital signal, the digital signal processor compensating the first and second values of .beta. for the temperature coefficient of the V erdet constant of the glass guide during computing of the first and second values of .beta..

29. The system of claim 28 wherein the system is packaged in a housing including a first section containing a portion of the glass guide, the first section bounding a first side of a recess for receiving an earlobe, finger or the like as the sample, the glass guide guiding the measurement beam through the sample in the recess.

30. The system of claim 29 wherein the housing includes a moveable second section bounding a second side of the recess, to provide a measurement of the width of the sample.

31. The system of claim 30 including a transducer coupled to the moveable second section and adapted to provide a signal representative of the width of the sample to the digital signal processor for use in computing the second value of .beta..

BACKGROUND OF THE INVENTION

The invention relates to polarimetry, especially as applied to noninvasive measuring of blood glucose concentration in diabetics. It is known that this phenomenon offers the potential for developing a noninvasive 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, kidney failure and heart disease are just some of the more serious complications. Many of these complications result from the large excursions in blood glucose concentrations common to diabetics due to dietary intake, inadequate exercise, genetic predisposition, and complicated by infrequent and inaccurate monitoring of the blood glucose levels. Current methods of in home monitoring of blood glucose involve the lancing or sticking of a finger and external measurement of the glucose content of the blood sample and or urine sampling by use of a litmus strip test comparing a color change relative to glucose concentrations.

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 regular and frequent finger sticking tests and simply take their insulin injections or oral medications 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 nondiabetics. This very real and basic discomfort also causes many diabetics to minimize the frequency of or altogether ignore blood glucose testing, resulting in a higher frequency of complications than otherwise would be the case. A small accurate 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 without pain.

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. This is expressed mathematically as: ##EQU1##

Where:

.alpha. is the polarization rotation in degrees;

{.alpha.}is the specific rotation constant of glucose; ({.alpha.}=45.1 degrees per decimeter (dm) per gram per milliliter for glucose at a wavelength of 633 nanometers);

L is the path length in the solution in dm, (where 1 dm=10 centimeters (cm);

C is the glucose concentration in grams (g) per 100 milliliter of solution or g/dL. (From "Sugar Analysis", 3rd Edition, Browne & Zerban, John Wiley & Sons, 1941, page 263.)

For the clinically meaningful glucose concentration range from 25 to 500 mg/dL (milligrams per deciliter) and a path length of 1 cm, the observed rotation ranges from about 0.00113 degrees to 0.02255 degrees at a wavelength of 633 nanometers.

It is known that human tissue has an absorption minima in the wavelength range from about 750 nanometers to 900 nanometers. Because there are no fundamental absorption processes in this region, human tissue has a reasonable optical transmission in this region of the spectrum. Light scattering by tissue remains a problem, which may limit the path length to less than 4 mm, dependent upon the type of tissue.

All of the prior art systems using crossed polarizers use only a single frequency, usually in conjunction with a null control system and a lock in amplifier that operates only at that single frequency. The prior art null compensation techniques all involve inserting a sample between the first and second polarizers and driving a Faraday modulator to reestablish the extinction condition. The problem with the prior techniques of establishing a null condition at extinction in a system using crossed polarizers is that the laser, optical modulator, and other components have parameters which drift from the time that the null condition or extinction is initially established and the time at which the sample to be measured is placed between the polarizers and an extinction condition is reestablished to determine the phase rotation caused by the sample.

According to the article "Non-Invasive Optical Glucose Sensing--An Overview" by Gerard L. Cote, PhD. Journal of Clinical Engineering, Vol. 22, No. 4, July/August 1997, a path length of 4 mm through human soft tissue (other than the eye) attenuates or scatters 95% of the signal. We conducted tests to confirm the general claims by Cote and found that both scattering and absorption are strongly wavelength dependent.

Because of the impracticality of using prior art devices and techniques to accurately measure such a small signal, the prior art use of polarimetry to measure glucose concentration levels in human tissue has been based primarily on passing light through the transparent tissue of the anterior chamber of the human eye.

The prior art fails to provide any practical, workable polarimeter system which can consistently provide accurate measurements of the glucose level in human tissue because of the inadequate sensitivity and the large degree of instability of the prior art devices. There is a strong but unmet need for a practical, reliable system which overcomes the problems of the prior art to provide a practical, reasonably priced, noninvasive system for measurement of human glucose levels.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the invention to provide a device capable of consistently and accurately measuring the concentration of an optically active ingredient in a sample.

It is another object of the invention to provide a practical, economical device for noninvasive measurement of glucose levels in diabetics.

It is another object of the invention to avoid instrument instability problems which have in part prevented success of prior attempts to provide a practical system using polarimetry to noninvasively measure blood glucose levels in diabetics.

It is another object of the invention to provide a device capable of measuring an optically sensitive ingredient in biological tissue in a noninvasive manner more accurately than has been achieved in the prior art.

It is another object of this invention to provide a new very sensitive and very stable polarization spectrometer which has applications in certain types of chemical analysis.

It is another object of the invention to provide a device capable of measuring optical rotation in the presence of large percentages of more than about 95% scattered light.

It is another object of the invention to provide an improved polarimeter which is more sensitive and more stable than prior art polarimeters.

Briefly described, and in accordance with one embodiment thereof, the invention provides a system for polarimetric measurement of the concentration of a substance, such as glucose, in a sample, including a laser beam passing through a first polarizer and an optical modulator and then split into (1) a measurement beam which is analyzed and directed to a first detector coupled to a first amplifier, and (2) a reference beam which is analyzed and directed to a second detector coupled to a second amplifier. Identical multiple filtering and summing operations are performed on outputs of the first and second amplifiers to produce a first .PSI..sup.2 /2 signal and a first 2.beta..PSI. signal in response to the measurement beam and a second .PSI..sup.2 /2 signal and a second 2.beta..PSI. signal in response to the reference beam. The measurement beam is stabilized by a first control loop that compares the second .PSI..sup.2 /2 signal to a first reference signal to produce a first error signal and a second control loop that compares the second 2.beta..PSI. signal to a second reference signal to produce a second error signal. The first error signal is multiplied by a modulation signal to produce a modulation feedback signal and adding it to the second error signal to produce a combined modulation and zeroing feedback signal. The optical modulator then is driven in response to the combined modulation and zeroing feedback signal to minimize the first and second error signals. A first value of .beta. is computed from the first .PSI..sup.2 /2 signal and the first 2.beta..PSI. signal with no sample in the path of the measurement beam, and a second value of .beta. is computed from the first .PSI..sup.2 /2 signal and the first 2.beta..PSI. signal with the sample in the path of the measurement beam. The difference between the first and second values of .beta. is converted to a value of concentration of the optically active substance in the sample by reference to a look-up table or algorithm. Both a primarily hardware implementation of the invention and a primarily sofware/firmware DSP implementation of the invention are disclosed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an optical schematic of a basic prior art polarimeter system.

FIG. 2 shows a modulating sinusoidal signal applied to the sin.sup.2 .delta. curve of 90.degree. crossed polarizers; also shown is the resulting doubled frequency output signal.

FIG. 3 is a graph comparing the sensitivity of a single frequency lock in amplifier, cos (.omega.t), the derivative dT/d.delta., and Algorithm 1.

FIG. 4 is a graph showing the distribution of light energy detected at the output of the polarimeter between all even frequencies, the DC term, along with the total energy, sin.sup.2 .delta., for a range of optical modulation.

FIG. 5 is a graph depicting the distribution of light energy detected at the output of the polarimeter for even frequencies and Algorithm 2, (.PSI..sup.2 /2), and the total energy, sin.sup.2 .delta..

FIG. 6 shows the shape of the waveform of light energy detected at the output of the polarimeter at 75.degree. modulation.

FIG. 7 is similar to FIG. 2 with the addition of sample rotation signal .beta., and it also illustrates graphically the optical instabilities that are corrected by feedback loop stabilization methods.

FIG. 8 is a graph useful in comparing the sensitivity of the stabilization loop of the present invention to that of the prior art.

FIG. 9 is a graph of the known relationship of specific rotation of glucose to wavelength.

FIG. 10A is a simplified optics diagram of a presently preferred polarimeter system of the invention.

FIG. 10B is a detailed optics diagram of one preferred embodiment of the polarimeter system of FIG. 11A.

FIG. 10C is a side view diagram of a portion of the system of FIG. 10B.

FIG. 11A is a block diagram of an analog implementation of the present invention.

FIG. 11B is a block diagram of digital circuitry for producing the digital signals required as inputs to the system shown in FIG. 11A.

FIG. 12 is a block diagram of a frequency domain implementation using a digital signal processor (DSP) of the present invention.

FIG. 13 is a flow chart of the operation of the digital signal processor in the diagram of FIG. 12.

FIG. 14 is an optical diagram of an alternative embodimen