Cell-impedance sensors

• US 9,664,632 B2
• Filed: 02/03/2014
• Issued: 05/30/2017
• Est. Priority Date: 04/25/2007
• Status: Active Grant

• Current Assignee: CapitalBio Corporation
• Original Assignee: CapitalBio Corporation
• Inventors: Cheng, Jing, Wang, Lei, Mitchelson, Keith, Wang, He
• Primary Examiner(s): Long, Scott
• Assistant Examiner(s): MARTIN, PAUL C
• Application Number:
  US14/171,757
• Publication Number:
  US 20140285215A1
• Time in Patent Office: 1,212 Days
• Field of Search: 324649
• 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

Systems, apparatus and methods for designing and operating a cell-electrode impedance sensor to detect chemical and biological samples, including biological cells. In one implementation, a method of designing a cell-electrode impedance sensor includes determining 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, using the cell free cell-electrode impedance and the cell covered cell-electrode impedance to obtain a sensor sensitivity of the cell-electrode impedance measurement system, and choosing one or more design parameters of the cell-electrode impedance sensor in the cell-electrode impedance measurement system to maximize the sensor sensitivity.

Claims

1. An apparatus for measuring cell-electrode impedance in biological cells, comprising:

a cell-culture vessel comprising electrodes structured in an interdigitated array of electrode branch elements, the cell-culture vessel operable to hold a cell-culture medium having biological cells attachable to the electrodes and the electrode branch elements arranged to be staggered with a non-uniform distance between each of the electrode branch elements; and

circuitry electrically coupled to the electrodes and comprising a detection resistor and a stimulator to apply an alternating current (AC) signal at different frequencies to the electrodes and configured to control a frequency range of the AC signal to be between a low frequency and a high frequency;

wherein

the electrodes have an equivalent electrical circuit that is dominated by interface capacitance at the low frequency and is dominated by spreading resistance at the high frequency.

2. The apparatus of claim 1, wherein the electrodes are located in the cell-culture vessel at a location to be immersed in the cell culture medium in the cell-culture vessel when the cell culture medium is present.

3. The apparatus of claim 1, wherein the electrode branch elements include first electrode branch elements connected to a first electrical terminal of the circuitry and second electrode branch elements connected to a second electrical terminal of the circuitry, wherein the first and second electrode branch elements are interleaved and the circuitry applies the AC signal at the first and second electrical terminals.

4. The apparatus of claim 1, wherein each branch element has a width from 10 μ

m to 100 μ

m.

5. The apparatus of claim 1, wherein the cell-culture vessel comprises a bio-compatible insulating material.

6. The apparatus of claim 5, further comprising a vessel substrate that is manufactured from a same material as the cell-culture vessel.

7. The apparatus of claim 1, further including:

a digital signal processor that collects and stores values of at least one of the AC signal and a voltage difference between electrodes.

8. The apparatus of claim 1, wherein the interdigitated array of electrode branch elements includes a first electrode comprising interleaved branch elements and a second electrode comprising second interleaved branch elements.

9. The apparatus of claim 1, wherein the sensitivity of the electrodes corresponds to smallest impedance caused by presence of cells in the cell-culture vessel that can be measured by the apparatus.

10. The apparatus of claim 1, wherein the sensitivity is a function of a cell-free impedance of the electrodes, a cell-covered impedance of the electrodes and a density of the biological cells.

11. The apparatus of claim 1, wherein the sensitivity of the electrodes is a function of frequency of the AC signal.

12. A cell-electrode impedance sensor for use in a cell-electrode impedance measurement system, comprising:

an interdigitated electrode array comprising a plurality of branch elements that have non-uniform actual widths and are separated by non-uniform distances, the plurality of branch elements characterized by design parameters including one or more effective widths of the branch elements, a length of the branch elements, a surface area of the branch elements, and a number of the branch elements;

wherein the design parameters are determined based on a design model for the cell-electrode impedance sensor, the design model predicting a cell free cell-electrode impedance and a cell covered cell-electrode impedance; and

wherein each of the non-uniform actual widths of the branch elements is less than each of the effective width of the branch elements obtained based on the design parameters, to account for a non-uniform electric field distribution over each branch element;

wherein the interdigitated electrode array has an equivalent electrical circuit that is dominated by interface capacitance at a low frequency and is dominated by spreading resistance at a high frequency.

13. The cell-electrode impedance sensor of claim 12, wherein the cell-electrode impedance measurement system includes one or more of a cell culture vessel, a cell culture substrate, and circuitry.

14. The cell-electrode impedance sensor of claim 12, wherein the cell-electrode impedance sensor is fabricated using various materials such as glass, silicon and plastics.

15. The cell-electrode impedance sensor of claim 12, wherein the cell-electrode impedance measurement system includes:

a digital signal processor that collects and stores values of at least one a current signal and a voltage difference signal of the cell-electrode impedance sensor.

16. The cell-electrode impedance sensor of claim 12, wherein the interdigitated electrode array includes a first electrode comprising interleaved branch elements and a second electrode comprising second interleaved branch elements.

17. The cell-electrode impedance sensor of claim 12, wherein the sensor sensitivity corresponds to smallest impedance caused by presence of cells in the cell-culture vessel that can be measured by the apparatus.