Optical detector for enzyme activation

• US 7,473,548 B2
• Filed: 04/25/2003
• Issued: 01/06/2009
• Est. Priority Date: 04/25/2003
• Status: Expired due to Fees

• Current Assignee: Medtronic Incorporated (Medtronic Plc)
• Original Assignee: Medtronic Incorporated (Medtronic Plc)
• Inventors: Thompson, Amy E., Soykan, Orhan, Donovan, Maura G.
• Primary Examiner(s): Weber; Jon P
• Assistant Examiner(s): Shen; Bin
• Application Number:
  US10/423,112
• Publication Number:
  US 20040215134A1
• Time in Patent Office: 2,083 Days
• Field of Search: None
• US Class Current: 435/287.1
• CPC Class Codes: A61B 5/0071 by measuring fluorescence emission
• CPC Class Codes: A61B 5/0075 by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy A61B5/0071 takes precedence
• CPC Class Codes: A61B 5/0084 for introduction into the body, e.g. by catheters A61B5/1459 takes precedence
• CPC Class Codes: A61B 5/14546 for measuring analytes not otherwise provided for, e.g. ions, cytochromes
• CPC Class Codes: A61B 5/4839 combined with drug delivery
• CPC Class Codes: A61B 5/7203 for noise prevention, reduction or removal
• CPC Class Codes: C12Q 1/37 involving peptidase or proteinase
• CPC Class Codes: C12Q 1/56 involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen
• CPC Class Codes: G01N 2021/6415 with two excitations, e.g. strong pump/probe flash
• CPC Class Codes: G01N 2021/6441 with two or more labels
• CPC Class Codes: G01N 2021/6484 Optical fibres
• CPC Class Codes: G01N 2021/8528 Immerged light conductor
• CPC Class Codes: G01N 21/6428 Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" in vivo A61B5/00; immunoassay G01N33/53
• CPC Class Codes: G01N 21/8507 Probe photometers, i.e. with optical measuring part dipped into fluid sample
• CPC Class Codes: G01N 33/86 involving blood coagulating time or factors, or their receptors

Abstract

Activation of an enzyme in a bodily fluid is detected based on the amount of cleavage of a substrate for the enzyme. The substrate is tagged with two fluorescent dyes—a donor and an acceptor. The tagged substrate is presented to the bodily fluid. A device emits energy at a first wavelength into the bodily fluid, and detects energy at second and third wavelengths emitted by the dyes in response to the energy at the first wavelength. Prior to enzymatic cleavage of the substrate, the acceptor emits energy at the third wavelength in response to energy at the second wavelength received through fluorescent resonant energy transfer (FRET) from the donor. After enzymatic cleavage of the substrate, the donor emits energy at the second wavelength. The device can determine the concentration of activated enzyme within the bodily fluid based on the relative intensities of energy at the second and third wavelengths.

Claims

1. An implantable medical device comprising:

an emitting element to emit energy at a first wavelength into a bodily fluid that contains an enzyme and a substrate tagged with at least two fluorescent dyes;

a detector to detect energy emitted by a first one of the dyes at a second wavelength based on fluorescent resonant energy transfer from a second one of the dyes in response to the emitted energy at the first wavelength; and

a processor to control the emitting element to emit energy at the first wavelength, receive an indication of an intensity of energy detected by the detector, and detect enzyme activation based on the indicated energy intensity.

2. The device of claim 1, wherein the detector detects energy emitted by the second one of the dyes at a third wavelength in response to the emitted energy at the first wavelength, and

wherein the processor receives an indication of an intensity of energy detected by the detector at the second and third wavelengths, determines a ratio between a first detected intensity at the second wavelength and a second detected intensity at the third wavelength, and determines a concentration of activated enzyme within the bodily fluid based on the ratio.

3. The device of claim 2, wherein the substrate includes a first product and a second product, the first product tagged with the first one of the dyes, and the second product tagged with the second one of the dyes, and

wherein the enzyme cleaves the substrate, and the first one of the dyes absorbs energy received from the second one of the dyes at the third wavelength via fluorescent resonant energy transfer and emits energy at the second wavelength in response to receiving the energy at the third wavelength prior to cleavage of the substrate by the enzyme.

4. The device of claim 2, wherein the detector comprises a first detector to detect energy emitted at the second wavelength and a second detector to detect energy at the third wavelength, the device further comprising:

a first filter to pass energy at the second wavelength to the first detector; and

a second filter to pass energy at the third wavelength to the second detector.

5. The device of claim 1, further comprising an optical fiber optically coupled to the emitting element and the detector, wherein a distal end of the optical fiber is located in the bodily fluid, the emitting element emits energy into the bodily fluid via the optical fiber, and the detector detects energy emitted by the first one of the dyes via the optical fiber.

6. The device of claim 5, wherein the fluid is blood and the distal end of the optical fiber is located within a blood vessel of a patient.

7. The device of claim 5, wherein the optical fiber includes a cladding, and wherein the optical fiber includes a region at which the cladding is removed from the optical fiber, and wherein the substrate is linked to the region of the optical fiber where the cladding is removed.

8. The device of claim 7, wherein the region is a distal region of the fiber.

9. The device of claim 5, further comprising:

a first reel;

a second reel; and

a reel rotation mechanism to move a tape between the first reel and the second reel along a path that is substantially parallel and proximate to the optical fiber,

wherein the substrate is linked to the tape, the optical fiber includes a cladding, the cladding is removed from a portion of the optical fiber, and the processor controls the reel rotation mechanism to move the tape such that uncleaved substrate is proximate to the unclad portion of the optical fiber.

10. The device of claim 9, wherein at least one of the first and second reels is coupled to the optical fiber.

11. The device of claim 1, further comprising:

a reservoir that contains the substrate;

a pump in fluid communication with the reservoir; and

a catheter that includes a proximal end in fluid communication with the pump and a distal end located in the bodily fluid,

wherein the processor controls the pump to present the substrate to the bodily fluid via the catheter.

12. The device of claim 11, wherein the bodily fluid is blood and the distal end of the catheter is located in a blood vessel of a patient.

13. The device of claim 1, wherein the energy is visible light.

14. The device of claim 1, wherein the enzyme is a protease enzyme.

15. The device of claim 14, wherein the enzyme is one of thrombin and kallikrein.

16. The device of claim 1, further comprising:

a memory to store information relating to the detection of enzyme activation; and

a telemetry circuit,

wherein the processor delivers the information to a user via the telemetry circuit.

17. The device of claim 1, further comprising an alarm, wherein the processor activates the alarm based on the detection of enzyme activation.

18. The device of claim 1, further comprising:

a reservoir containing a drug;

a pump in fluid communication with the reservoir; and

a catheter with a proximal end in fluid communication with the pump and a distal end located within a patient,

wherein the processor controls the pump to deliver the drug to the patient via the catheter based on the detection of enzyme activation.

19. The device of claim 18, wherein the drug comprises one of an anticoagulant and a pain relieving drug.

20. The device of claim 1, wherein the device is implanted in a patient.