Method and apparatus for measuring the concentration of absorbing substances

• US 5,112,124 A
• Filed: 04/19/1990
• Issued: 05/12/1992
• Est. Priority Date: 04/19/1990
• Status: Expired due to Term

• Current Assignee: Worcester Polytechnic Institute
• Original Assignee: Worcester Polytechnic Institute
• Inventors: Harjunmaa, Hannu, Peura, Robert A., Mendelson, Yitzhak
• Primary Examiner(s): Rosenberger, Richard A.
• Application Number:
  US07/511,341
• Time in Patent Office: 754 Days
• Field of Search: 356/39, 356/41, 250/339, 250/341, 128/633
• US Class Current: 356/39
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/1455 using optical sensors, e.g. spectral photometrical oximeters

Abstract

A non-invasive system for measuring the concentration of an analyte in an absorbing matrix is described. The system directs a beam of radiation at the matrix. The beam consists of a series of successive alternate pulses of electro-magnetic radiation, one of which is highly absorbed by the analyte and the other of which is non-absorbed. The transmitted or reflected beam is optically detected and an electrical signal proportional to beam intensity is used to adjust the beam intensity and as a measure of analyte concentration.

Claims

1. A method for non-invasive in vivo determining and measuring in a living body matrix the concentration of an analyte which absorbs electromagnetic radiation of wavelength λ

₁, this method comprising the steps of;

a) generating said radiation of wavelength λ

₁ and another wavelength of electromagnetic radiation λ

₂ at which the absorption coefficient of the analyte is different from the one at λ

₁, and wherein the extinction coefficient of the matrix is the same at λ

₁ and at λ

₂ ;

b) combining said radiations into a probing beam which alternates in time at wavelengths λ

₁ and λ

₂, the intensity of the beam being controllable in at least one of the wavelength durations, and directing this beam, from a location outside the body, at the body to produce an incident beam;

c) detecting the incident beam after it has traversed a path in the body and exited the body and producing an alternating signal corresponding to the difference between the intensities of the two wavelength radiations in the incident beam and wherein the alternating signal is nulled when substantially no analyte, or minimal analyte, is present in the sample;

d) generating an intensity control signal from the said alternating signal;

e) using the said intensity control signal to control the intensity of one of the two wavelength radiations of the probing beam to reduce the alternating signal substantially to zero;

f) using the value of the intensity control signal needed to restore the alternating signal substantially to zero as a measure of the concentration of the analyte in the matrix.

2. The method according to claim 1 wherein one of the wavelengths λ

₁ and λ

₂ is tuned by the steps of;

a) changing periodically the relation of a calibration sample to the probing beam at a frequency substantially lower than the wavelength frequency, so that the sample is alternately in and out or the beam;

b) generating a wavelength control signal by rectifying the alternating component of the intensity control signal; and

c) using the wavelength control signal to tune the wavelength of one of the radiations to reduce the alternating component of the intensity control signal substantially to zero.

3. The method according to claim 1, where the matrix exhibits pulsatile variations of thickness or composition, and the instantaneous value of the intensity control signal is recorded at a constant phase of the pulsatile cycle.

4. The method according to claim 1 wherein the analyte is glucose and the matrix is the human body.

5. Measurement apparatus for non-invasive in vivo determination of an unknown concentration of an analyte that absorb electromagnetic radiation and is dissolved or dispersed in a living body matrix sample, comprising:

a) generating means external to the body matrix for generating a probe beam of the said radiation which contains, alternating in time, two different and substantially monochromatic wavelengths such that, at the two wavelengths, the extinction caused by the combined effects of absorption and scattering in the matrix is equal, but the absorption produced by the analyte is different at one wavelength;

b) optical means external to the body matrix for transmitting this beam into the body matrix;

c) collecting means for collecting the beam after it is has traversed at least a portion of the body matrix and exited the body matrix, said collecting means comprising a detector sensitive to both said wavelengths and providing in response an alternating-current signal;

d) electronic means to rectify and integrate the alternating current signal from the detector at the wavelength-alternating frequency to produce an intensity control signal;

e) control means for controlling the intensity of one of the wavelengths using the said intensity control signal so that the alternating-current signal from the detector is initially maintained substantially at zero with no analyte present in the body matrix and when analyte is present using the intensity control signal to force the alternating-current signal back to substantially zero; and

f) conditioning and display means to condition and display the value of the control signal required to maintain the signal from the detector substantially at zero in the presence of analyte.

6. Apparatus according to claim 5, in which the analyte is glucose to be measured in human or animal body tissue, the two different wavelengths being between about 1 to 2.5 μ

m.

7. A non-invasive measurement system for determining in vivo the concentration of an analyte in an absorbing matrix of a living body comprising:

a) generating means external to the body for generating a beam of radiation at said matrix, said beam comprising pulses of energy at different wavelengths λ

₁ and λ

₂ wherein λ

₁ is highly absorbed by said analyte and λ

₂ is substantially non-absorbed by said analyte and the extinction coefficient of the matrix is the same at λ

₁ and λ

₂ ;

b) detector means external to the body for detecting the intensity of the beam after it has been subjected to said analyte and exited the body and generating an electrical signal which is substantially zero when minimum analyte is present in the matrix;

c) processing means external to the body for processing the electrical signal to form a control signal;

d) control means external to the body responsive to said control signal for adjusting the intensity of one of said energy pulses in accordance with said control signal to maintain said electrical signal at zero.

8. The system of claim 7 wherein the generating means comprises pulsed laser sources, one of which emits energy at λ

₁, the other at λ

₂ and wherein said sources are energized and de-energized, such that when one source is energized, the other is de-energized and vice versa.

9. The system of claim 8, including a reference signal, and wherein the control signal is compared with the reference signal and display means wherein the difference between the compared signals is displayed as a measure of the concentration of said analyte.

10. The system of claim 9 wherein the analyte is glucose and the absorbing matrix is the human body.

11. A method for non-invasive determining and measuring in a living body matrix the concentration of an analyte which absorbs electromagnetic radiation of wavelength λ

₁, this method comprising the steps of;

a) generating said radiation of wavelength λ

₁ and another wavelength of electromagnetic radiation λ

₂ at which the absorption coefficient of the analyte is different from the one at λ

₁, and wherein the extinction coefficient of the matrix is the same as λ

₁ and at λ

₂ ;

b) combining said radiations into a probing beam with alternate half-periods at λ

₁ and λ

₂, the intensity of the beam being controllable in at least one of the half-periods, and directing this beam at the matrix from a location external to the matrix;

c) detecting the beam after it has traversed a path in the matrix and exited the matrix to produce an alternating-current signal corresponding to the alternation of the two wavelength radiations in the incident beam which alternating current signal is substantially nulled when the concentration of analyte in the matrix is nulled;

d) generating an intensity control signal from the said alternating-current signal;

e) using the said intensity control signal to control the intensity ratio of the two wavelength radiations of the probing beam to maintain the ratio at unity and thereby maintain the alternating-current signal substantially at zero;

f) using the intensity control signal as a measure of the concentration of the analyte in the matrix.

12. The method according to claim 11 wherein one of the wavelengths λ

₁ and λ

₂ is tuned by the steps of;

a) changing periodically the relation of a calibration sample to the measuring beam at a frequency substantially lower than the wavelength alternating frequency, so that the sample is alternately in and out of the beam;

b) generating a wavelength control signal by rectifying the alternating component of the intensity control signal;

c) using the wavelength control signal to tune the wavelength of one of the lasers so as to reduce the alternating component of the intensity control signal substantially to zero.

13. The method according to claim 11, where the matrix exhibits pulsatile variations of thickness or composition, and the instantaneous value of the intensity control signal is recorded at a constant phase of the pulsatile cycle.

14. A measurement system for non-invasively determining the concentration of glucose in an absorbing matrix of a living body comprising:

a) generating means external to the body for generating a beam of light at said matrix, said beam comprising light pulses of energy at different wavelengths λ

₁ and λ

₂ wherein λ

₁ is highly absorbed by glucose and λ

₂ is substantially non-absorbed by glucose and wherein the extinction coefficient of the matrix is the same at λ

₁ and λ

₂ ;

b) detector means external to the body for detecting the intensity of the beam after it has been subjected to glucose in the matrix and has exited the matrix and generating an electrical signal proportional to the ratio of the intensities of the radiation at the two different wavelengths, which ratio is pre-set to unit with minimum glucose in the matrix;

c) process means external to the body for processing the electrical signal to form a control signal;

d) control means external to the body responsive to said control signal for adjusting the intensity of one of said energy pulses in accordance with said control signal to maintain the ratio of the intensities at unity and thereby force the electrical signal to zero.

15. The system of claim 14 wherein the generating means comprises pulsed laser sources, one of which emits energy at λ

₁, the other at λ

₂ and wherein said sources are energized and de-energized, such that when one source is energized, the other is de-energized and vice versa.

16. The system of claim 15, including a reference signal, and wherein the control signal is compared with the reference signal and display means wherein the difference between the compared signals is displayed as a measure of the concentration of said glucose.

17. A method for determining and measuring in a sample matrix the concentration of an analyte which absorbs electromagnetic radiation of wavelength λ

₁, this method comprising the steps of;

a) generating said radiation of wavelength λ

₁ and another wavelength of electromagnetic radiation λ

₂ at which the absorption coefficient of the analyte is different from the one at λ

₁, and wherein the extinction coefficient of the matrix is the same at λ

₁ and at λ

₂ ;

b) combining said radiations into a probing beam which alternates in time at wavelengths λ

₁ and λ

₂, the intensity of the beam being controllable in at least one of the wavelength durations, and directing this beam at the sample to produce an incident beam;

c) detecting the incident beam after it has traversed a path in the sample and producing an alternating signal corresponding to the difference between the intensities of the two wavelength radiations in the incident beam and wherein the alternating signal is nulled when substantially no analyte, or minimal analyte, is present in the sample;

d) generating an intensity control signal from the said alternating signal;

e) using the said intensity control signal to control the intensity of one of the two wavelength radiations of the probing beam to reduce the alternating signal substantially to zero;

f) using the value of the intensity control signal needed to restore the alternating signal substantially to zero as a measure of the concentration of the analyte in the matrix; and

g) tuning the wavelengths of one of the radiations by the steps of;

(i) changing periodically the relation of a calibration sample to the probing beam at a frequency substantially lower than the wavelength frequency, so that the sample is alternately in and out of the beam;

(ii) generating a wavelength control signal by rectifying the alternating component of the intensity control signal; and

(iii) using the wavelength control signal to tune the wavelength of one of the radiations to reduce the alternating component of the intensity control signal substantially to zero.

18. A method for determining and measuring in a sample matrix the concentration of an analyte which absorbs electromagnetic radiation of wavelength λ

₁, this method comprising the steps of;

a) generating said radiation of wavelength λ

₁ and another wavelength of electromagnetic radiation λ

₂ at which the absorption coefficient of the analyte is different from the one at λ

₁, and wherein the extinction coefficient of the matrix is the same at λ

₁ and at λ

₂ ;

b) combining said radiations into a probing beam with alternate half-periods at λ

₁ and λ

₂, the intensity of the beam being controllable in at least one of the half-periods, and directing this beam at the sample;

c) detecting the beam after it has traversed a path in the sample to produce an alternating-current signal corresponding to the alternation of the two wavelength radiations in the incident beam which alternating current signal is substantially nulled when the concentration of analyte in the matrix is nulled;

d) generating an intensity control signal from the said alternating-current signal;

e) using the said intensity control signal to control the intensity ratio of the two wavelength radiations of the probing beam to maintain the ratio at unity and thereby maintain the alternating-current signal substantially at zero;

f) using the intensity control signal as a measure of the concentration of the analyte in the matrix; and

g) tuning one of the wavelengths λ

₁ and λ

₂ by the steps of;

(i) changing periodically the relation of a calibration sample to the measuring beam at a frequency substantially lower than the wavelength alternating frequency, so that the sample is alternately in and out of the beam;

(ii) generating a wavelength control signed by rectifying the alternating component of the intensity control signal;

(iii) using the wavelength control signal to tune the wavelength of one of the radiations so as to reduce the alternating component of the intensity control signal substantially to zero.