Cell-impedance sensors

• US 8,642,287 B2
• Filed: 07/25/2007
• Issued: 02/04/2014
• Est. Priority Date: 04/25/2007
• Status: Active Grant

• Current Assignee: CapitalBio Corporation
• Original Assignee: CapitalBio Corporation
• Inventors: Wang, Lei, Wang, He, Cheng, Jing, Mitchelson, Keith
• Primary Examiner(s): Weber, Jon P
• Assistant Examiner(s): MARTIN, PAUL C
• Application Number:
  US12/532,992
• Publication Number:
  US 20100184115A1
• Time in Patent Office: 2,386 Days
• Field of Search: 435/29, 435/287.1, 703/14, 703/2, 324/692
• US Class Current: 435/29
• CPC Class Codes: G01N 27/06 of a liquid involving electrolysis G01N27/26
• CPC Class Codes: G01N 27/221 by investigating the dielectric properties using microwaves G01N22/00; measuring loss factors or dielectric constants per se G01R27/26
• CPC Class Codes: G01N 33/48707 by electrical means G01N33/49, G01N33/493 take precedence
• CPC Class Codes: G01N 33/48728 Investigating individual cells, e.g. by patch clamp, voltage clamp investigating individual particles in general G01N15/10
• CPC Class Codes: G01N 33/5438 Electrodes

Abstract

Methods and apparatus for designing and measuring a cell-electrode impedance sensor to detect chemical and biological samples, including biological cells. The method of designing a cell-electrode impedance sensor comprises: determining a cell free cell-electrode impedance and a cell-covered cell-electrode impedance; obtaining a sensor sensitivity of the cell-electrode impedance measurement system; and choosing one or more design parameters of the cell-electrode impedance sensor to maximize the sensor sensitivity. When the frequency of AC signal between electrodes ranges from 10 kHz to 40 kHz, the sensitivity of the sensor is maximized.

Claims

1. A method of designing a cell-electrode impedance sensor, comprising:

measuring a cell free cell-electrode impedance and a cell covered cell-electrode impedance based on a design model for the cell-electrode impedance sensor, wherein the design model is based on one or more factors, the factors including properties and elements of a cell-electrode impedance measurement system;

measuring a sensor sensitivity of the cell-electrode impedance measurement system based at least on the cell free cell-electrode impedance and the cell covered cell-electrode impedance;

computing, by a computer, one or more design values for one or more design parameters of the cell-electrode impedance sensor in the cell-electrode impedance measurement system to maximize the sensor sensitivity, and

generating a cell-electrode impedance sensor design having at least some physical dimensions based on the computed one or more design values.

2. The method of claim 1, wherein the cell-electrode impedance sensor comprises an interdigitated electrode array comprising a plurality of branch elements.

3. The method of claim 2, wherein the design parameters includes one or more of a width of the branch elements, a length of the branch elements, a surface area of the branch elements, and a number of the branch elements.

4. The method of claim 3, further comprising choosing an effective width lesser than the width chosen based on the design model, to account for a non-uniform electric field distribution over each branch element.

5. The method of claim 2, wherein the design model is based on a first equivalent circuit for the interdigitated array in absence of cells and a second equivalent circuit when the interdigitated array is covered with cells.

6. The method of claim 5, the design model further includes:

a parameter Rcell which represents a resistance of a mean gap distance between the cells which are attached on the electrodes,

a parameter Ccell which represents a capacitance of cells caused by insulating cell membranes to reflect changes in biophysical properties of the cell membranes,

a parameter Rgap which represents a resistance of a gap between attached cells and electrode surfaces; and

a parameter Cgap which represents a capacitance between attached cells and electrode surface substrate.

7. The method of claim 1, wherein the elements of the cell-electrode impedance measurement system include one or more of a cell culture vessel, a cell culture substrate, and circuitry.

8. The method of claim 7, wherein the properties of the cell-electrode impedance measurement system include one or more of a property of a cell culture medium and a property of the cell.

9. The method of claim 8, wherein measuring the cell free cell-electrode impedance and the cell covered cell-electrode impedance comprises:

identifying values for the properties of the cell-electrode impedance measurement system;

substituting the values in a first equation associated with the cell free cell-electrode impedance to measure the cell free cell-electrode impedance; and

substituting the values in a second equation associated with the cell covered cell-electrode impedance to measure the cell covered cell-electrode impedance.

10. The method of claim 1, wherein the cell free cell-electrode impedance is represented by a Helmholtz interfacial capacitance and a spreading resistance in the design model.

11. The method of claim 10, wherein the spreading resistance is associated with a proportionality coefficient.

12. The method of claim 1, wherein the cell covered cell-electrode impedance is represented by factors including one or more of a resistance between a plurality of cells, a capacitance between the plurality of cells, a resistance between a gap between a surface of a cell and a cell culture vessel substrate, and a capacitance between the gap between the surface of the cell and the cell culture vessel substrate.

13. The method of claim 12, wherein the resistance and capacitance between the plurality of cells, and the resistance and capacitance between the gap between the surface of the cell and the cell culture vessel substrate are each associated with a proportionality coefficient.

14. The method of claim 13, wherein the resistance and capacitance between the plurality of cells, and the resistance and capacitance between the gap between the surface of the cell and the cell culture vessel substrate depend on an extent of attachment between a surface of the cells and a surface of the sensor.

15. The method of claim 14, wherein the surface of the cells are completely attached to the surface of the sensor.

16. The method of claim 14, wherein the surface of the cells are partially attached to the surface of the sensor.

17. The method of claim 1, wherein obtaining the sensor sensitivity of the system further comprises measuring the cell density of the system.

18. The method of claim 1, further comprising:

determining a frequency to deliver an alternating current (AC) signal to the sensor, wherein delivering the AC signal at the determined frequency further improves sensor sensitivity.

19. The method of claim 18, wherein determining the frequency comprises determining a derivative of an equation for sensor sensitivity with respect to frequency and solving for the frequency by equating the derivative to zero.