Optical detector for enzyme activation

• US 8,003,373 B2
• Filed: 05/28/2008
• Issued: 08/23/2011
• Est. Priority Date: 04/25/2003
• Status: Expired due to Fees

• Current Assignee: Medtronic Incorporated (Medtronic Plc)
• Original Assignee: Medtronic Incorporated (Medtronic Plc)
• Inventors: Donovan, Maura G., Soykan, Orhan
• Primary Examiner(s): YANG, NELSON C
• Application Number:
  US12/127,908
• Publication Number:
  US 20080227083A1
• Time in Patent Office: 1,182 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 system comprising:

a first implantable medical device comprising;

a reservoir that contains a tagged 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 a processor of the first implantable medical device is configured to control the pump to present the substrate to the bodily fluid via the catheter,

wherein the first implantable medical device is configured to optically detect activation of an enzyme and to determine a concentration of activated enzyme that cleaves the substrate within a bodily fluid of a patient; and

a second medical device configured to deliver a therapy to the patient based on the detection of enzyme activation.

2. The system of claim 1, wherein the first medical device comprises:

an emitting element configured to emit energy at a first wavelength into the bodily fluid; and

a detector configured to detect energy emitted at a second wavelength and a third wavelength by products of the substrate in the bodily fluid in response to the energy at the first wavelength, and

wherein the processor is further configured to control the emitting element to emit energy at the first wavelength, to receive indications of intensities of energy detected by the detector, and to determine a concentration of activated enzyme that cleaves the substrate within the bodily fluid based on the indicated energy intensities, wherein the second medical device delivers the therapy to the patient based on the determined concentration.

3. The system of claim 1, wherein the second medical device comprises a drug pump configured to deliver a drug based on the detection of enzyme activation.

4. The system of claim 1, wherein the second medical device comprises a neurostimulation device configured to deliver neurostimulation therapy based on the detection of enzyme activation.

5. The system of claim 1, wherein the first and second medical devices are integrated within a single housing.

6. The system of claim 1, wherein the second medical device comprises an implantable medical device.

7. The system of claim 2, wherein first medical device further comprises an optical fiber optically coupled to the emitting element and the detector, wherein a distal end of the optical fiber is locatable in the bodily fluid of the patient, and further wherein the emitting element is configured to emit energy into the bodily fluid via the optical fiber and the detector is configured to detect energy via the optical fiber.

8. The system of claim 1, wherein the first medical device further comprises an alarm configured to be activated upon the detection of enzyme activation.

9. The system of claim 1, wherein the enzyme is a protease enzyme.

10. The system of claim 9, wherein the enzyme is one of thrombin and kallikrein.

11. The system of claim 1, wherein the second medical device is configured to deliver anticoagulation therapy to the patient based on the detection of enzyme activation.

12. An implantable medical device system comprising:

a first implantable medical device comprising;

a reservoir that contains a tagged 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 a processor of the first implantable medical device is configured to control the pump to present the substrate to the bodily fluid via the catheter,

wherein the first implantable medical device is configured to optically detect activation of an enzyme and to determine a concentration of activated enzyme that cleaves the substrate within a bodily fluid of a patient,

wherein the first implantable medical device further comprises;

an emitting element configured to emit energy at a first wavelength into a bodily fluid, and

a detector configured to detect energy emitted at a second wavelength and a third wavelength by products of the substrate in the bodily fluid in response to the energy at the first wavelength; and

a second medical device configured to deliver a therapy to the patient based on the detection of enzyme activation.

13. The system of claim 12, wherein first medical device further comprises an optical fiber optically coupled to the emitting element and the detector, wherein a distal end of the optical fiber is locatable in the bodily fluid of the patient, and further wherein the emitting element is configured to emit energy into the bodily fluid via the optical fiber and the detector is configured to detect energy via the optical fiber.

14. The system of claim 12, wherein the enzyme is a protease enzyme and the substrate is enzymatically cleavable by activation of the protease enzyme.

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

16. The system of claim 12, wherein the second medical device is configured to deliver anticoagulation therapy to the patient based on the detection of enzyme activation.