Method and apparatus to perform trans-cutaneous analyte monitoring

• US 5,628,310 A
• Filed: 05/19/1995
• Issued: 05/13/1997
• Est. Priority Date: 05/19/1995
• Status: Expired due to Fees

• Current Assignee: Joseph R. Lakowicz
• Original Assignee: Joseph R. Lakowicz
• Inventors: Rao, Govind, Lakowicz, Joseph R., Szmacinski, Henryk
• Primary Examiner(s): Cohen, Lee S.
• Assistant Examiner(s): WINAKUR, ERIC FRANK
• Application Number:
  US08/444,927
• Time in Patent Office: 725 Days
• Field of Search: 128/632, 128/633, 128/635, 604/890.1, 604/891.1, 604/19, 604/20, 604/21, 204/403, 204/415
• US Class Current: 600/317
• CPC Class Codes: A61B 5/0017 transmitting optical signals transmission by light H04B10/00
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/14539 for measuring pH
• CPC Class Codes: A61B 5/1459 invasive, e.g. introduced into the body by a catheter A61B5/1464 takes precedence

Abstract

An apparatus and method to enable minimally invasive transdermal measurements of the fluorescence lifetime of an implanted element without reagent consumption and not requiring painful blood sampling. The monitoring apparatus displays the quantity of a selected substance present in the skin and stores the data in memory. The stored information can be transmitted via modem, or antenna, to a master station for diagnostic purposes or clinical evaluation. The use of this method and apparatus improves control of blood monitoring, and therefore, enhances long-term disease management with fewer complications.

Claims

1. A trans-cutaneous analyte monitor, comprising:

a light emitting means for emitting an excitation light having predetermined wavelength and temporal characteristics;

a bio-compatible implant, said bio-compatible implant emitting fluorescence having predetermined wavelength and temporal characteristics upon absorption of said excitation light emitted from said light emitting means;

a detector means to detect said fluorescence from said bio-compatible implant, said detector means producing an electrical signal proportional to said fluorescence;

a comparison means to compare by means of lifetime-based sensing said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant said comparison means receiving input from said light emitting means and said detector means and having an output; and

a computing means to receive said output of said comparison means and relating said comparison of said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant to a quantity of a selected substance present.

2. The trans-cutaneous analyte monitor of claim 1, wherein:

said predetermined wavelength and temporal characteristics of said fluorescence is altered by collisional quenching caused by the presence of a predetermined substance.

3. The trans-cutaneous analyte monitor of claim 2, wherein:

said comparison means to compare said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant is by means of intensity based sensing.

4. The trans-cutaneous analyte monitor of claim 1, further comprising:

a display means for displaying said quantity of said substance present.

5. The trans-cutaneous analyte monitor of claim 1, further comprising:

a memory storage device for receiving said output of said computing means.

6. A trans-cutaneous analyte monitor, comprising:

alight emitting means for emitting an excitation light having predetermined wavelength and temporal characteristics;

a bio-compatible implant, said bio-compatible implant emitting fluorescence having predetermined wavelength and temporal characteristics upon absorption of said excitation light emitted from said light emitting means, said bio-compatible implant comprises a fluorescent donor and an analyte-dependent acceptor which spectrally overlaps said fluorescent donor, said bio-compatible implant emitting fluorescence of a predetermined wavelength and temporal characteristics upon absorption of said excitation light emitted form said light emitting means, said fluorescence wavelength and temporal characteristics being altered when a predetermined substance is present;

a detector means to detect said fluorescence from said bio-compatible implant, said detector means producing an electrical signal proportional to said fluorescence;

a comparison means to compare said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant said comparison means receiving input from said light emitting means and said detector means and having an output; and

a computing means to receive said output of said comparison means and relating said comparison of said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant to a quantity of a selected substance present.

7. The trans-cutaneous analyte monitor of claim 6, wherein:

said comparison means to compare said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant is by means of intensity based sensing.

8. The trans-cutaneous analyte monitor of claim 6, wherein:

said comparison means to compare said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant is by means of time domain lifetime-based sensing.

9. The trans-cutaneous analyte monitor of claim 6, wherein:

said comparison means to compare said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant is by means of frequency domain lifetime-based sensing.

10. A trans-cutaneous analyte monitor, comprising:

a light emitting means for emitting an excitation light having predetermined wavelength and temporal characteristics;

a bio-compatible implant, said bio-compatible implant emitting fluorescence having predetermined wavelength and temporal characteristics upon absorption of said excitation light emitted from said light emitting means, said bio-compatible implant includes an analyte-free and an analyte-bound form of a fluorescent emitter and wherein the ration of the signals at two excitation emission wavelengths is used for quantitative measurements of a predetermined substance;

a detector means to detect said fluorescence from said bio-compatible implant, said detector means producing an electrical signal proportional to said fluorescence;

a comparison means to compare said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant said comparison means receiving input from said light emitting means and said detector means and having an output; and

a computing means to receive said output of said comparison means and relating said comparison of said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant to a quantity of a selected substance present.

11. The trans-cutaneous analyte monitor of claim 10, wherein:

said comparison means to compare said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant is by means of intensity based sensing.

12. The trans-cutaneous analyte monitor of claim 10, wherein:

said comparison means to compare said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant is by means of time domain lifetime-based sensing.

13. The trans-cutaneous analyte monitor of claim 10, wherein:

said comparison means to compare said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant is by means of frequency domain lifetime-based sensing.

14. A trans-cutaneous analyte monitor, comprising:

a light emitting means for emitting an excitation light having predetermined wavelength and temporal characteristics;

a bio-compatible implant, said bio-compatible implant emitting fluorescence having predetermined wavelength and temporal characteristics upon absorption of said excitation light emitted from said light emitting means;

a detector means to detect said fluorescence from said bio-compatible implant, said detector means producing an electrical signal proportional to said fluorescence;

a comparison means to compare said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant said comparison means receiving input from said light emitting means and said detector means and having an output;

a computing means to receive said output of said comparison means and relating said comparison of said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant to a quantity of a selected substance present;

a memory storage device for receiving said output of said computing means; and

a data transfer means, said data transfer means configured to receive input from said memory storage device and whereby said quantity of said substance present stored in said memory storage device is transferred to a remote receiving station.

15. The trans-cutaneous analyte monitor of claim 14, wherein said data transfer means is a modem for data transfer to a computer.

16. The trans-cutaneous analyte monitor of claim 14, wherein said data transfer means is an antenna and transmitter to transmit said data to a receiver.

17. The trans-cutaneous analyte monitor of claim 14, wherein said data transfer means is a satellite relay.

18. A trans-cutaneous analyte monitor, comprising:

a light source capable of emitting an excitation light having predetermined wavelength and temporal characteristics;

a bio-compatible implant, said bio-compatible implant emitting fluorescence having predetermined wavelength and temporal characteristics upon absorption of said excitation light emitted from said light source;

a detector means to detect said fluorescence from said bio-compatible implant, said detector means producing an electrical signal proportional to said fluorescence;

a comparison means to compare said wavelength and temporal characteristics of said light emitted from said light source and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant by means of time domain lifetime-based sensing, said comparison means receiving input from said light source and said detector means and having an output;

a computing means to receive said output of said comparison means and relating said comparison of said wavelength and temporal characteristics of said light emitted from said light source and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant to a quantity of a selected substance present.

19. The trans-cutaneous analyte monitor of claim 18, wherein said light source emits an excitation light in the infrared wavelength.

20. The trans-cutaneous analyte monitor of claim 20, wherein said light source emits an excitation light of a wavelength greater than about 600 nm.

21. A trans-cutaneous analyte monitor, comprising:

a light emitting means capable of emitting an excitation light having predetermined wavelength and temporal characteristics;

a bio-compatible implant, said bio-compatible implant emitting fluorescence having predetermined wavelength and temporal characteristics upon absorption of said excitation light emitted from said light emitting means;

a detector means to detect said fluorescence from said bio-compatible implant, said detector means producing an electrical signal proportional to said fluorescence;

a comparison means to compare said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant by means of frequency domain lifetime-based sensing, said comparison means receiving input from said light emitting means and said detector means and having an output;

a computing means to receive said output of said comparison means and relating said comparison of said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant to a quantity of a selected analyte present.

22. A trans-cutaneous analyte monitor, comprising:

a light emitting means for emitting an excitation light having predetermined wavelength and temporal characteristics;

a bio-compatible implant, said bio-compatible implant emitting fluorescence having predetermined wavelength and temporal characteristics upon absorption of said excitation light emitted from said light emitting means;

a detector means to detect said fluorescence from said bio-compatible implant wherein said detector measures the wavelength and temporal characteristics of said bio-compatible skin implant fluorescence, and further wherein said detector emits an electrical signal which is proportional to the fluorescence wavelength and temporal characteristics received;

a comparison means to compare said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant;

a computing means to relate said comparison of said wavelength and temporal characteristics of said intensity modulated light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible to a quantity of a biologically significant substance present;

a display means for displaying said quantity of biologically significant substances;

a memory storage device for receiving said output of said computing means; and

a data transfer means, said data transfer means receiving input from said memory storage device and whereby said quantity of said biologically significant substance present stored in said memory storage device.

23. The trans-cutaneous analyte monitor of claim 22, further comprising:

a frequency synthesizer, wherein said frequency synthesizer products a modulated electrical output;

wherein said light emitting means receives said modulated electrical output of said frequency synthesizer causing said light emitting means to emit an intensity modulated excitation light of predetermined wavelength and temporal characteristics;

wherein said detector measures the wavelength and temporal characteristics of said bio-compatible implant fluorescence, and further wherein said detector emits an electrical signal which is directly proportional to the fluorescence wavelength and temporal characteristics received;

wherein said comparison means compares the phase angle difference between said excitation light predetermined wavelength and temporal characteristics and said wavelength and temporal characteristics of said fluorescence of said bio-compatible implant; and

wherein said computing means computes the quantity of said biologically significant substance present from said comparison of said light emitted form said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant.

24. The trans-cutaneous analyte monitor of claim 23, wherein:

said light emitting means is a light emitting diode.

25. The trans-cutaneous analyte monitor of claim 23, wherein:

said light emitting means is a laser diode.

26. A method to trans-cutaneously monitor analytes, comprising:

emitting a modulated excitation light from a light emitting means, said excitation light having predetermined wavelength and temporal characteristics;

implanting a bio-compatible implant, said implant emitting fluorescence having predetermined wavelength and temporal characteristics upon absorption of said excitation light emitted from said light emitting means;

detecting said fluorescence wavelength and temporal characteristics from said bio-compatible implant;

comparing said wavelength and temporal characteristics of said excitation light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant; and

computing said wavelength and temporal characteristics of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence form said bio-compatible implant to quantify an amount of an analyte.

27. The method to trans-cutaneously monitor analytes of claim 26, comprising:

displaying said quantity of said analyte.

28. The method to trans-cutaneously monitor analytes of claim 27, further comprising:

storing in a memory storage device said output of said computing means.

29. The method to trans-cutaneously monitor analytes of claim 28, further comprising:

transferring said data from said memory storage device to a remote receiving station.

30. The method to trans-cutaneously monitor analytes of claim 26 wherein:

said bio-compatible implant comprises a fluorophore wherein said bio-compatible implant emits fluorescence of a predetermined wavelength and temporal characteristics, said fluorescence of a predetermined wavelength and temporal characteristics being altered by collisional quenching caused by the presence of a predetermined analyte.

31. The method to trans-cutaneously monitor analytes of claim 26 wherein:

said bio-compatible implant comprises an analyte-free and an analyte-bound form and wherein the ratio of the signals at two excitation or emission wavelengths is used for quantitative measurements.

32. The method to trans-cutaneously monitor analytes of claim 26 wherein:

said bio-compatible implant comprises a fluorescent donor and an analyte-dependent acceptor which spectrally overlaps said fluorescent donor, said bio-compatible implant emitting fluorescence of a predetermined wavelength and temporal characteristics upon absorption of said excitation light emitted from said light emitter, said fluorescence wavelength and temporal characteristics being altered when a predetermined analyte is present.

33. A method to trans-cutaneously monitor analytes, comprising:

synthesizing a modulated electrical output by means of a frequency synthesizer;

inputting said modulated electrical output of said frequency synthesizer means into a light emitting means whereby said light emitting means emits an intensity modulated excitation light, said excitation light having predetermined wavelength and temporal characteristics;

implanting a bio-compatible implant wherein said bio-compatible implant emits fluorescence of a predetermined wavelength and temporal characteristics upon absorption of said excitation light emitted from said light emitter, said fluorescence wavelength and temporal characteristics being altered when a predetermined biologically significant substance is present;

detecting said bio-compatible implant emitted fluorescence of a predetermined wavelength and temporal characteristics by detection means wherein said detection means emits an electrical signal which is directly proportional to the fluorescence wavelength and temporal characteristics received;

comparing said wavelength and temporal characteristics of said excitation light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescence from said bio-compatible implant;

computing the phase angle difference between said comparison of said light emitted from said light emitting means and said wavelength and temporal characteristics of said fluorescent light from said bio-compatible implant to a quantity of said biologically significant substance present and relating said phase angle difference to the quantity of a biologically significant substance present; and

displaying the quantity of said biologically significant substance present.