2D Mapping of Target Cellular Analytes in Real Time

An Integrated Electrochemical Imaging Platform

Unaltered Image from page 185 of “The Biological bulletin”
Male gametes of Ectocarpus (left), Laminaria (center), and Fucus (right).  Chemotaxis in Laminaria of spermatozoid movement in Laminaria digitata… It seems possible that the extremely long hind flagellum in Laminaria acts as a sensor for the chemical gradient along its axis.

Opportunity

Available for Licensing

IP Status

N/A

Inventor

Thomas Chen

At A Glance
  • An integrated platform containing 16,384 microelectrodes has been realized using a CMOS technology, with the hardware and software being tightly integrated to allow real-time capturing of 2D chemical images of metabolites and other chemical compounds
  • Ability to map target analytes in two dimensional maps in real-time
  • Markets include bioinstrumentation, such as biofilm formation and cancer cell metabolism

 

Licensing Director

Mandana Ashouri
Mandana.Ashouri@colostate.edu
970-491-7100

Reference No.: 19-017

Background

The ability to view biological events in real time contributes significantly to the understanding of critical life processes. Visualizing chemical changes at smaller dimensions and shorter timescales allows scientists to better understand the driving forces that regulate fundamental and obscure biological phenomena, such as chemotaxis and cancer metastasis. Traditional optical microscopy techniques provide a means of observing the movement of small molecules in live biological samples with spatial and temporal resolution, but have limitations. These methods are restricted to a library of inherently colored or fluorescent molecules and those that can be selectively labeled through genetic modifications, exogenous fluorophores, or quantum dots. In addition, these modifications add a considerable molecular weight when conjugated to small molecules such as neurotransmitters or pharmaceuticals, which can have a significant impact on behavior and function, making it difficult to visualize molecular changes in ways that replicate in vivo environments.

Electrochemical methods, such as scanning electrochemical microscopy (SECM) and microelectrode arrays (MEAs), have been previously explored as alternative methods for acquiring spatial and temporal chemical information from small molecules that cannot be reliably measured with existing microscopy techniques. SECM uses a microelectrode tip to scan the surface of a sample to measure the current generated by the reduction-oxidation (redox) of chemically active species, which can provide spatial chemical information, but is limited in its temporal resolution. On the other hand, the MEA system approach provides a means of taking measurements from multiple electrodes simultaneously, allowing for improved spatial and temporal resolution. One of the first biological applications of MEAs utilized an array of thirty nickel-gold-platinum electrodes on a glass substrate to gather bioelectric measurements on the cellular level .Over the years, the MEA system approach has substantially improved with the advancement of Complementary Metal-Oxide-Semiconductor (CMOS) manufacturing processes, which have allowed for the fabrication of higher density arrays capable of gathering spatially resolved electrical readings. Most of these CMOS-fabricated microchips have been used for bioelectric potential measurements and stimulation on electrogenic cells, such as neurons and cardiomyocytes. In addition, some CMOS-based MEA systems are capable of simultaneous electrochemical, impedimetric, potentiometric, and thermal measurements.

 

Technology Overview

An integrated electrochemical imaging platform was designed and implemented using a 600nm standard CMOS technology to realize an array of 16,384 microelectrodes supported by 16,384 integrated on-chip read channels (current-to-voltage converters) and other control logic. The design of the microelectrode and its array implementation presents a novel 3-electrode arrangement to optimize electron transfer while keeping the sensor pitch (27.5μm) to be spatially compatible with typical cellular dimensions to allow effective monitoring of cell-cell communication in an ex-vivo environment. The 16,384 on-chip read-channel circuits are pitch-matched with the microelectrodes to achieve the maximum density in order to fit everything into a 280-pin pin-grid-array (PGA) package. The read channel has a 3dB bandwidth of 3.56KHz and an input-inferred integrated noise of 21.01pA. The sensor platform is capable of scanning 16,384 electrodes at a speed of up to 244 frames per second (FPS). The sensor platform can be configured to perform amperometry, voltammetry, and impedance spectroscopy. Real-time temperature and pH monitoring is also integrated into the platform. The low level of noise from the on-chip read-channel circuits allows the detection of analytes, for instance, norepinephrine, as low as 4μM with a dynamic range of up to 512μM with excellent linearity. This platform provides the best overall sensitivity, dynamic range, speed, and the overall functionality for electrochemical experiments in existence to date.

Benefits
  • Ability to map target analytes in two dimensional maps in real-time
  • More compact and less expensive than what is currently in the market

Last updated on October 7, 2019.