Ultrasonic cell handling and manipulation for microfluidic detection and analysis systems.
Lead Research Organisation:
University of Southampton
Department Name: Faculty of Engineering & the Environment
Abstract
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.
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.
Planned Impact
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.
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.
People |
ORCID iD |
Peter Glynne-Jones (Principal Investigator / Fellow) |
Publications
Baron VO
(2020)
Real-time monitoring of live mycobacteria with a microfluidic acoustic-Raman platform.
in Communications biology
Devivier C
(2015)
Time-resolved full-field imaging of ultrasonic Lamb waves using deflectometry
in Experimental Mechanics
Elkington PT
(2021)
A Personal Respirator to Improve Protection for Healthcare Workers Treating COVID-19 (PeRSo).
in Frontiers in medical technology
Hammarström B
(2019)
Acoustic focussing for sedimentation-free high-throughput imaging of microalgae
in Journal of Applied Phycology
Jonnalagadda US
(2018)
Acoustically modulated biomechanical stimulation for human cartilage tissue engineering.
in Lab on a chip
Khedr MMS
(2019)
Generation of functional hepatocyte 3D discoids in an acoustofluidic bioreactor.
in Biomicrofluidics
Lei J
(2016)
Modal Rayleigh-like streaming in layered acoustofluidic devices
in Physics of Fluids
Lei J
(2017)
Transducer-Plane Streaming Patterns in Thin-Layer Acoustofluidic Devices
in Physical Review Applied
Lei J
(2017)
Comparing methods for the modelling of boundary-driven streaming in acoustofluidic devices.
in Microfluidics and nanofluidics
Title | Curious replicas |
Description | An installation exhibited as part of the British Art Show 8 in Southampton civic centre. A collaborative project with funding from the Arts council. Curious Replicas is an immersive audio experience which explores the uncharted territory of the human voice by creating an intimate voice salon for audiences to experience. Visitors sit at a hair salon-style booth in front of a microphone into which they can talk and sing: by pressing and turning a variety of buttons and knobs they can manipulate their voices into something entirely different and unusual which they invent. By doing so, visitors can reimagine their vocal selves and literally touch their vocal creativity. |
Type Of Art | Artistic/Creative Exhibition |
Year Produced | 2016 |
Impact | Engagement with several thousand visitors. |
URL | http://tractandtouch.com/portfolio/curious-replicas/ |
Description | We have discovered that we can use forces created by ultrasonic fields to enhance the growth of cartilage and liver cells outside of the body. This has the potential to lead to more effective tissue engineering for creating replacement body parts, and also for studying the functions functions of the body in in-vitro experiments (which could also reduce the need for animal experiments). We have also demonstrated the potential for acoustically focussed imaging cytometers to be of use in monitoring populations of marine phytoplankton. |
Exploitation Route | Bioreactors for tissue engineering could be taken up towards commercialisation by interested companies. Imaging cytometers for monitoring phytoplankton could be implemenented. |
Sectors | Environment Healthcare Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
Description | (TechOceanS) - Technologies for Ocean Sensing |
Amount | € 8,975,662 (EUR) |
Funding ID | 101000858 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 09/2020 |
End | 09/2024 |
Description | Consumables funding |
Amount | £30,000 (GBP) |
Organisation | Rosetrees Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2015 |
End | 09/2018 |
Description | Diagnostics for the future: Combining optical tomography with microfluidic systems for high throughput 3D imaging of single cells |
Amount | £12,000 (GBP) |
Funding ID | IES\R3\170399 |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2018 |
End | 03/2020 |
Description | International exchanges |
Amount | £12,000 (GBP) |
Funding ID | IES\R3\170399 |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2020 |
Description | PhD studentship |
Amount | £80,000 (GBP) |
Organisation | Wessex Medical Research |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2015 |
End | 09/2019 |
Title | Data underpinning: Real-time monitoring of live mycobacteria with a microfluidic acoustic-Raman platform |
Description | |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://research-portal.st-andrews.ac.uk/en/datasets/data-underpinning-real-time-monitoring-of-live-... |
Description | Cheltenham Science Festival |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | ~6000 visitors interacted with our exhibit each year, which was focussed on the biological applications of acoustic particle manipulation. |
Year(s) Of Engagement Activity | 2015,2016 |
URL | http://www.cheltenhamfestivals.com/science |
Description | Galstonbury festival science tent |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | 5000 visitors interacted with our exhibits each year, which were focussed on the biological applications of acoustic particle manipulation. |
Year(s) Of Engagement Activity | 2015,2016 |
Description | Radio and podcast interview "Thresholds of Audibility" |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Prof Salomé Voegelin and Mark Wright from London College of Communication, UAL interviewed me to create a podcast and radio broadcast aired Tues 1st March, 2022 at 18.30 on Resonance 104.4fm. This was part of their project, "Listening Across Disciplines II" The podcast explored the way I relate to sound in my research, and how language is used in this context. Discussion included ways in which the realities of how I experienece ultrasound in my work can be related to by a wider audience. |
Year(s) Of Engagement Activity | 2021,2022 |
URL | https://www.mixcloud.com/Resonance/listening-across-disciplines-1-march-2022-episode-7-thresholds-of... |