Electrophysiology chip on a microfluidic platform

Lead Research Organisation: University of Glasgow
Department Name: School of Engineering

Abstract

The action of the heart can be simplified by considering it as a set of large muscles, whose synchronised contractions draws blood in the chambers and forces it out again. This timing of the muscle's contractions are crucial to its correct functioning. One method for testing the activity of the heart is known as 'patch clamping', in which it is possible to measure the electrical activity of the cell. This is a technically difficult, time consuming technique which often needs to be performed by skilled scientists, and which we believe we can address by making new instruments. The project aims to create a Lab-on-a-Chip, where highly functional measurements, which collect information on both the mechanical contraction and the electrical activity of the single cell, will be implemented on such chips. These chips will either make general measurements of how well the cell contractsor more specific measurements on the flow of voltages and currents as the cell contracts, or both, at the same time. The project will benefit the scientific community by providing an easy to use instrument, that can quickly, and at low cost, measure both the mechanical and the electrical activity of the heart or muscle cell. The nature of the platform will be such that we can not only use the chip to examine intracellular signalling, but also inter-cellular signalling, between cells. In order to demonstrate the more generic nature of the chip for use with other electrically active cell types, we will also investigate the use of primary smooth muscle as well as human embryonic stem cells (hESC) derived cardiomyocytes and smooth muscle in our chip systems.

Technical Summary

There has been a recent interest in the development of microfluidic cell based chips for performing assays in lower volumes and with higher throughputs. To date the majority of such cell chips has involved the use of cultured adherent and non-adherent non-electrically active cells, which are generally characterised by having smooth plasma membranes, and being relatively small (10-30 microns). In this proposal, we wish to develop a new microfluidic platform to provide functional information concerning about the mechanism of electrical and contractile activities (EC coupling) in healthy primary cells, particularly the heart muscle cell (the cardiomyocyte). We will develop the platform so that we can, for the first time, produce arrays of multiplexed voltage and current clamped primary heart and smooth muscle cells, providing electrophysiologists with a high throughput tool for measuring the action potential directly with extracellular metal microelectrodes. The nature of the platform will be such that we can not only use the chip to examine intracellular signalling, but also inter-cellular signalling, between cells. In order to demonstrate the more generic nature of the chip to use with other electrically active cell types, we will also investigate the use of smooth muscle and human embryonic stem cells (hESC) derived cardiomyocytes in our chip systems.

Planned Impact

Who will benefit from the research: Electrophysiologists and cell biologists, whether they be in academic or commercial research will benefit from the development of a new technique to patch clamp primary heart and smooth muscle cells, and to explore cell-cell transfer. If validated successfully when exploring normal cell functionality, in the future the instruments may also be of value to scientists within the drug discovery industry including biotechnology and pharmaceutical companies. As part of the programme we also wish to make direct comparisons between primary cell(s) and hESC preparations of both cardiomyocytes and smooth muscle to explore the efficacy of using these materials for functional biological (electrophysiological) assays. Scientists working in any part of the biosciences industry which uses animal models will benefit, if we are able to demonstrate a reduced dependence on animal models (as experimentation may be considered more ethical and cheaper if the phenotype of the stem cell derived model is similar). How will they benefit: The microfluidic formats will have practical advantages over existing technologies, namely: (i) their ease of use, even for an untrained electrophysiologist (making these measurements more widely available within medicine and biology); (ii) the cell and the electrodes are fixed in position, relative to each other, such that the technique will not require elaborate micromanipulators and vibration isolation; and (iii) the amplifiers and circuitry for the voltage clamp will be mounted within a very short distance of the cardiac cell, perhaps as little as 1 mm, thus delivering superior noise and bandwidth characteristics, in this compact design, when compared with traditional patch clamp instrumentation. Aside from the novelty, with the microfluidic configuration enabling new measurements, the chip-based format also increases the throughput of experiments, improving the statistical information associated with measurements. What will be done to ensure that they have the opportunity to benefit: Novel IP will be identified before research is published. Glasgow University have an agreement with IP Group, who help with the establishment of commercial spin outs, including the priming of the venture with capital, recruitment of management and the development of a business plan. If spin-out is not appropriate, we will use our Research and Enterprise Office to help identify key industrial partners to explore opportunities for co-development projects or licensing (including, in this case, Cellartis, who are a collaborative partner in the project).

Publications

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Description Methods have been developed to trap single heart cells in microfluidic devices so as to perform optical and electrophysiology measurements. Amongst other things, we have discovered that it is possible to create tight seals between heart cells and features in the microfliudic structure, although as yet these are not quite as tight as those that can be obtained with the best glass patch clamp methods. Work is however continuing in order to improve this, using novel lithograthic methods we have developed in this project.
In addition, a variety of optical platform assay methods have been developed, refined and evaluated and these are contributing to the IP associated with Clyde Biosciences spin out.
Exploitation Route As indicated on the impact page, these findings are being taken forward though our spin out Clyde Biosciences in order to develop platforms for cardiomyocyte drug testing
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description Collaboration between Prof Cooper and Godfrey Smith, Professor of Cardiovascular Physiology (Institute of Cardiovascular and Medical Sciences) at the University of Glasgow resulted in the formation of Clyde Biosciences Ltd in August 2012. In partnership with the IP Group, the University secured Scottish Enterprise Proof of Concept funding in 2011 to further develop the tools created by PDRAs during the BBSRC grant. The next stage in commercialisation saw Dr Margaret-Ann Craig secure an RSE Enterprise Fellowship to develop the Clyde Bioscieces business plan. The following year Dr Craig won the prestigious Royal Academy of Engineering ERA Foundation Entrepreneurship Award for her research into new optical instrumentation, bespoke software and microsystems technologies for evaluating new drugs validation and testing their toxicity. Clyde Biosciences Ltd, launched in 2012 has developed cell preservation technology and CellOPTIQ, a system designed to make it easier for pharmaceutical firms to assess the efficacy of new compounds as potential medicines and reduce late-stage failure of candidate drugs as they move from the lab into later stage trials. Following several VC investments and having sold instruments and established a services revenue stream, Clyde Biosciences is now having a significant impact in the field of assessing of cardiotoxicity potential for the global pharmaceutical industry, as can be judged from their website https://www.clydebio.com.
First Year Of Impact 2011
Sector Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Economic