Ultrasonic cell handling and manipulation for microfluidic detection and analysis systems.

Miniaturisation of electronic devices has been matched in recent years by a drive to create miniature Lab-on-Chip systems that can handle and analyse chemical and biological materials in tiny volumes.

Ultrasonic standing-wave fields are a promising technology that can potentially achieve many of the functions required for Lab-on-Chip systems, including: pumping, mixing, cell lysis, cell sorting, and sonoporation (opening pores in cell walls to allow drugs or genetic material to enter). Most importantly, by establishing and shaping the acoustic field bacteria and other biological cells can be manipulated and levitated within fluidic devices. In contrast to other technologies, it is possible to manipulate thousands of cells at once without harming them.

However, controlling these various functions and preventing interactions in the confines of a microfluidic system is challenging and prevents wider uptake of these technologies. Research is required to better understand how secondary effects interfere with the primary functions. One example is the disruption of manipulation by acoustic streaming (a movement of the fluid itself induced by the ultrasound). Using novel techniques such as surface structuring I will enable the streaming flows to be controlled, and put to practical use (e.g. to enhance diffusion for cell perfusion, and analyte diffusion in sensor systems). Initial modelling suggests that this approach could enhance streaming by a factor of 10, leading to applications in other domains such as micro-cooling systems.

I will be researching several other key areas: The mechanical stimulation of cells with acoustic forces to direct the development of mechanically responsive cells such as stem cells; the integration of ultrasonic arrays into microfluidic devices for enhanced flexibility of manipulation; and ways to integrate multiple acoustic functions within a single disposable device.

The fundamental research will both enable and be driven by the second focus of the fellowship, applications. Two applications that each have the potential to transform existing technologies will be developed:

1) Bacterial detection in drinking water: My team has recently proven that bacteria (who typically experience forces 1000x smaller than human cells) can be successfully concentrated in flow-through ultrasonic devices. As part of a European project we have used this to concentrate the bacteria in samples of water to enhance the detection efficiency. However, I believe that we could deliver around a 100-fold increase in sensitivity by using the ultrasound to drive bacteria directly towards an antibody coated sensor surface where they will be captured and optically detected. Deploying such devices widely would be very beneficial for detecting contamination of drinking waters, rivers, and industrial waste streams.
2) Drug screening system: I will create a system that forms arrays of tiny clusters of human cells. Cells cultured in this 3D environment behave more naturally than those grown on a petri dish. The cells will be held in place by acoustic forces, both levitated away from contaminating surfaces, and also held against a steady flow of nutrients over a period of several days. Drugs will be introduced into the flow, and an integrated laser based detection system will monitor the resulting metabolites produced by the cells. The advantage of this is that large numbers of drugs can be tested in parallel, identifying those that could be further developed. A strong motivation for this application is that by providing a representative model of human tissues it could reduce the number of animal experiments required for drug testing.

Given the huge potential impacts of these and other related systems I will work closely with industrial companies that have experience of creating detection and analytical systems to bring our technologies into widespread use.

I believe that this Fellowship will make a major contribution to realising the vision of cheap, ubiquitous microfluidic devices that bring chemical and biological analysis tools into our everyday lives. My research will create a new generation of fluidic devices that use ultrasound to perform diverse functions.

The potential societal impacts of the advances I will deliver include:
Better drinking water security through widely distributed bacterial sensors, and on-line monitoring of effluent streams (See case for support, Application A).
More accurate and faster drug discovery, and a reduction in animal experiments (See case for support, Application B).
Increased longevity and quality of life due to more accurate and widespread point-of-care diagnostic devices.

It is both feasible and commercially attractive to mass produce systems based on the applications I will be pursuing. Thus, with my partners dstl, Leica Microsystems and Agilent we are in a position to enhance the UK's already strong position in the medical diagnostics, and fluidic sensors market.

Ultrasonic manipulation has several key features that make it likely to have wide impact:
i. The ability to manipulate or levitate thousands of particles simultaneously is unique, and opens classes of devices in which transported particles do not interact with channel walls.
ii. Very low cost (a plastic device with PZT transducer can cost less than £1 in materials), enabling devices that can be disposable, distributed (in the sense of distributed sensor networks) or point-of-care. This is exampled by the disposable acoustic concentration devices that I recently developed for Prokyma Ltd.
iii. Multiple functionality: functions such as manipulation, mixing, pumping, cell lysis, etc can all be created using suitable geometry and electronic control to achieve the required acoustic fields. By pursuing the integration of these functions in the fellowship, I aim to be able to reduce the complexity and size of current microfluidic systems that often require numerous external pumps and actuators.