In vivo electrochemistry computer system and method

• US 5,806,517 A
• Filed: 05/26/1995
• Issued: 09/15/1998
• Est. Priority Date: 05/26/1995
• Status: Expired due to Fees

• Current Assignee: The Board of Regents of the University of Colorado (University of Colorado System)
• Original Assignee: The Board of Regents of the University of Colorado (University of Colorado System)
• Inventors: Gerhardt, Greg Allen, Robinson, Steven Alan
• Primary Examiner(s): Bahr, Jennifer
• Assistant Examiner(s): GILBERT, SAMUEL G
• Application Number:
  US08/452,161
• Time in Patent Office: 1,208 Days
• Field of Search: 128/631-635, 128/639, 128/642, 128/731
• US Class Current: 600/345
• CPC Class Codes: A61B 5/14542 for measuring blood gases A61B5/14551 takes precedence
• CPC Class Codes: A61B 5/14546 for measuring analytes not otherwise provided for, e.g. ions, cytochromes
• CPC Class Codes: A61B 5/1468 using chemical or electrochemical methods, e.g. by polarographic means A61B5/1486 takes precedence
• CPC Class Codes: A61B 5/1495 Calibrating or testing of in-vivo probes

Abstract

A chemical detection and analysis system performs chemical measurements using microsensors. The in vivo or in vitro system records chemical concentrations of any substance that can be oxidized or reduced at the sensor surface in response to a voltage waveform applied to a reference electrode. The electrochemical technique has utility relative to molecules that are electroactive. Diffusion and metabolism of these chemicals are tracked in real time. A visual display of the measurements is provided in near real time. The system consists of: a 32 bit, digital computer; application software; an I/O board with analog to digital convertors, digital to analog converters, and digital input/output capability; a potentiostat; one to four microsensors; and a reference electrode. Calibrated microsensors, of carbon, platinum, or gold, are placed in brain tissue or other aqueous environments to detect chemical activity. A reference electrode is placed in the tissue at a location that is spaced from the sensors. A pulse cyclic or a constant electrical potential is generated and applied to the reference electrode to induce an oxidation or reduction current condition at the sensor surface. Calibration of the sensors, acquisition and storage of data, and auto-analysis of data, as well as user defined data analysis and modification, are performed under control of application software and hardware.

Claims

1. A method for measuring the concentration of a neurotransmitter in living tissue, said neurotransmitter providing oxidation and reduction chemical activity in the presence of a cyclic electrical potential, comprising the steps of;

A--placing a microsensor at a first physical location in said tissue, said sensor being responsive to said oxidation and reduction chemical activity in said tissue,

B--placing a reference electrode at a second physical location in said tissue,

C--applying a cyclic electric potential selected from the group consisting of chronoamperometry and fast-cycle voltammetry to said reference electrode to produce said oxidation chemical activity in said tissue at a location generally adjacent to said microsensor, and to produce said reduction chemical activity in said tissue at said location generally adjacent to said microsensor,

D--varying a frequency parameter of said cyclic electric potential a number of times,

E--measuring in real time a first electrical response of said microsensor to said oxidation chemical activity during said frequency parameter variation of said cyclic electric potential,

F--measuring in real time a second electrical response of said microsensor to said reduction chemical activity during said frequency parameter variation of said cyclic electric potential,

G--comparing said measurements of steps E and F,

H--generating an electrical signal as a result of step G, and

I--identifying said neurotransmitter concentration based upon steps E and F.

2. The method of claim 1 including the step of;

J--using said electrical signal of step H to energize a visual display in near-real time.

3. The method of claim 2 wherein said neurotransmitter is selected from the group consisting of dopamine, norepinephrine, or serotonin.

4. The method of claim 2 wherein said microsensor is responsive to a given neurotransmitter, including the step of;

K--calibrating said microsensor to determine a response of said microsensor to different concentrations of said given neurotransmitter,

L--storing said determined response of step K, and

M--utilizing said stored response of step L in step I implemented by a data processing system.

5. The method of claim 4 wherein said neurotransmitter is selected from the group consisting of dopamine, norepinephrine, or serotonin.

6. The method of claim 5 including the steps of;

N--determining a background electrical response of said microsensor, and

O--utilizing said background response as a subtraction parameter when executing said steps E, F and I.

7. A method for measuring neurotransmitter concentration in living tissue, comprising the steps of;

placing a microsensor at a first physical location in said tissue, said sensor being responsive to neurotransmitter chemical activity in said tissue,

placing a reference electrode at a second physical location in said tissue,

applying a first cyclic electric potential to said reference electrode for a first time period to produce a first chemical oxidation condition in said tissue at a location generally adjacent to said microsensor, and to produce a first chemical reduction condition in said tissue at said location generally adjacent to said microsensor,

applying a second cyclic electric potential to said reference electrode for a second time period to produce a second chemical oxidation condition in said tissue at said location generally adjacent to said microsensor, and to produce a second chemical reduction condition in said tissue at said location generally adjacent to said microsensor,

measuring a first electrical response of said microsensor to said first chemical oxidation condition during said first time period,

measuring a second electrical response of said microsensor to said second chemical reduction condition during said second time period,

identifying concentration of said neurotransmitter based upon said first and second electrical responses,

comparing said first and second electrical responses, and

generating an electrical signal in real time as a result of said comparing step.

8. The method of claim 7 including the step of;

using said electrical signal to energize a visual display to visually show concentration in near-real time.

9. The method of claim 8 wherein said neurotransmitter is selected from the group consisting of dopamine, norepinephrine, apomophine, serotonin, acetaminophen, oxygen, ascorbic acid, hydrogen peroxide and nitric acid.

10. A method for measuring the chemical activity of chemicals that aid in the transmission of impulses between two living cells within a living tissue mass, comprising the steps of;

placing a microsensor at a first physical location in said tissue mass, said sensor being responsive to chemical activity within said tissue mass,

placing a reference electrode at a second physical location in said tissue mass,

applying a variable frequency square wave electric potential to said microsensor,

said square wave having a first wave portion and a second wave portion,

said first wave portion producing a chemical oxidation condition in said tissue mass at a location generally adjacent to said microsensor,

said second wave portion producing a chemical reduction condition in said tissue mass at said location generally adjacent to said microsensor,

varying said frequency of said square wave in N number of steps,

measuring a first electrical response of said microsensor to said chemical oxidation condition for certain ones of said N steps of said square wave frequency variation,

measuring a second electrical response of said microsensor to said chemical reduction condition for said certain ones of said N steps of said square wave frequency variation,

said steps of measuring said first and second electrical responses of said microsensor being operable for all but a first number of said N steps of said square wave frequency variation,

comparing said first and second electrical responses, and generating an electrical signal as a result of said comparing step.

11. The method of claim 10 including the step of;

using said electrical signal to energize a visual display.

12. The method of claim 11 wherein said chemicals include the group consisting of dopamine, norepinephrine, and serotonin.

13. A method for measuring neurotransmitter chemical activity in living tissue, comprising the steps of;

placing a microsensor at a first physical location in said tissue, said microsensor being responsive to neurotransmitter chemical activity within said tissue,

placing a reference electrode at a second physical location in said tissue,

connecting a first cyclic electric source of a first phase to said microsensor to alternately produce a first chemical oxidation condition in said tissue at a location generally adjacent to said microsensor, and a first chemical reduction condition in said tissue at said location generally adjacent to said microsensor,

measuring a first electrical response of said microsensor to said first chemical oxidation condition produced by said first electric source,

measuring a second electrical response of said microsensor to said first chemical reduction condition produced by said first electric source,

connecting a second electric source to said microsensor to produce a second chemical reduction condition in said tissue at said location generally adjacent to said microsensor,

measuring a third electrical response of said microsensor to said second chemical reduction condition produced by said second electrical source, and

identifying neurotransmitter chemical activity based upon said first, second and third electrical responses.

14. The method of claim 13 including the steps of;

comparing said first, second and third electrical responses, and

generating an electrical signal as a result of said comparison.

15. The method of claim 14 including the step of;

using said electrical signal to energize a visual display.

16. The method of claim 15 wherein said neurotransmitter is selected from the group consisting of dopamine, norepinephrine, and serotonin.

17. The method of claim 14 including the steps of;

calibrating said microsensor to determine response of said microsensor to different known concentrations of said neurotransmitter, and

utilizing said determined response when comparing said first, second and third electrical responses.

18. The method of claim 17 wherein said neurotransmitter is selected from the group consisting of dopamine, norepinephrine, and serotonin.

19. Apparatus for use in measuring electrochemical activity within a living tissue mass, comprising;

a microsensor adapted to be placed at a first location within the tissue mass,

said microsensor being responsive to reduction and oxidation chemical states of neurotransmitters generally adjacent to said microsensor,

a reference electrode adapted to be placed at a second physical location within the tissue mass,

computer means having a first input port connected to said microsensor, and having a second input port connected to said reference electrode,

voltage generating means connected to said reference electrode and operable to apply a cyclic electrical voltage to said reference electrode,

said voltage generating means being operable to produce an oxidation condition during a first time period, and then a reduction condition during a second time period,

means including said computer means connected to said microsensor to measure a first electrochemical response of said microsensor to said oxidation condition during said first time period, and to measure a second electrochemical response of said microsensor to said reduction condition during said second time period,

a visual output device connected to said computer means and controlled by said computer means,

said visual output device being adapted to provide a first visual output curve in response to said first electrochemical response, and to provide a second visual output curve in response to said second electrochemical response,

said first and second visual output curves having a common time origin point,

impedance means adapted to be temporarily connected between said first and second input ports,

manual control means operable to adjustably control timing of said computer means when said impedance means is temporarily connected between said first and second input ports, and

said manual control means being adapted for manual adjustment to achieve a computer system timing wherein said first and second visual output curves overly each other to form a common curve.