MicroTotal Pre Analytical Systems (MTPAS): Near-patient Approach to the Preparation of Circulating Biomarkers for Next-Generation Sensing
Lead Research Organisation:
Heriot-Watt University
Department Name: Sch of Engineering and Physical Science
Abstract
Increased demand on blood sampling requirements has arisen from prolong lifespan and ageing populations. The use of circulating cell-free nucleic acids (cfNAs) as biomarkers for cancer, non-invasive prenatal testing, organ transplant monitoring and more, has grown in popularity since it is non-invasive (simple blood draw) and easily repeated, allowing the possibility to rapidly establish a diagnosis, a prognosis and even used for theranostic applications. So called "liquid biopsies" and cfDNA analysis could for example allow the fourteen millions of cancer patients diagnosed globally each year to access earlier diagnosis and optimised treatments.
However, despite numerous translational research programs the detection of cfNA is not currently implemented clinically in daily practice. Several reasons have been emerged for this, including (i) the difficulty in controlling the different biological, environmental and logistic parameters from blood sampling to the analysis of biomarkers (ii) the cost of the currently available techniques, which limit accessibility (iii) the turn-around time needed to be useful for patients and clinicians. Current sample preparation solutions are multi-step which can introduce variations and lead to an erroneous diagnosis. Additionally these solutions are time consuming, not amenable to near-patient extraction following blood draw, and require highly trained technicians. The optimisation of the extraction of cell-free circulating markers is key to their translation from the research setting to clinical deployment. The lack of engineering solutions to address the specificities of circulating cell-free nucleic acid extraction, underpins this programme. To meet the requirements of future healthcare industry, the work proposed will integrate novel advanced materials such as electrospun fibres, packaged with on-chip reagents in a microfluidic cartridge to extract cfNAs from blood. Deployed near-patient, this technology will protect the biomarkers from enzymatic degradation and enrich them against the rest of the nucleic acids present in the sample, allowing an unparalleled standardisation and instant preservation of the true disease state until analysis.
The solution proposed involves the use of single-use cartridges, and could generate a significant amount of additional medical waste if implemented. Therefore this programme has a unique sustainable manufacturing component, looking into the use of a naturally-derived plastic (poly-lactic acid) to prototype and manufacture low carbon footprint, disposable, microfluidic cartridges, potential applicable to a large range of point-of-care devices.
The solutions developed in this programme have the potential to significantly reduce the overall cost of sample preparation in the field of circulating biomarkers, as well as increasing the robustness and reliability of a range of biomarkers with direct application in clinical diagnostic and biomarker and drug discovery, in a sustainable fashion. Hand-in-hand with novel sensing solutions, this work has the potential to increase life quality from earlier, quicker diagnosis through optimised treatment and better care management. With the global liquid biopsy market forecasts to reach $4.5 billion by 2020, front-end sample preparation constitutes an important area for the UK economy.
However, despite numerous translational research programs the detection of cfNA is not currently implemented clinically in daily practice. Several reasons have been emerged for this, including (i) the difficulty in controlling the different biological, environmental and logistic parameters from blood sampling to the analysis of biomarkers (ii) the cost of the currently available techniques, which limit accessibility (iii) the turn-around time needed to be useful for patients and clinicians. Current sample preparation solutions are multi-step which can introduce variations and lead to an erroneous diagnosis. Additionally these solutions are time consuming, not amenable to near-patient extraction following blood draw, and require highly trained technicians. The optimisation of the extraction of cell-free circulating markers is key to their translation from the research setting to clinical deployment. The lack of engineering solutions to address the specificities of circulating cell-free nucleic acid extraction, underpins this programme. To meet the requirements of future healthcare industry, the work proposed will integrate novel advanced materials such as electrospun fibres, packaged with on-chip reagents in a microfluidic cartridge to extract cfNAs from blood. Deployed near-patient, this technology will protect the biomarkers from enzymatic degradation and enrich them against the rest of the nucleic acids present in the sample, allowing an unparalleled standardisation and instant preservation of the true disease state until analysis.
The solution proposed involves the use of single-use cartridges, and could generate a significant amount of additional medical waste if implemented. Therefore this programme has a unique sustainable manufacturing component, looking into the use of a naturally-derived plastic (poly-lactic acid) to prototype and manufacture low carbon footprint, disposable, microfluidic cartridges, potential applicable to a large range of point-of-care devices.
The solutions developed in this programme have the potential to significantly reduce the overall cost of sample preparation in the field of circulating biomarkers, as well as increasing the robustness and reliability of a range of biomarkers with direct application in clinical diagnostic and biomarker and drug discovery, in a sustainable fashion. Hand-in-hand with novel sensing solutions, this work has the potential to increase life quality from earlier, quicker diagnosis through optimised treatment and better care management. With the global liquid biopsy market forecasts to reach $4.5 billion by 2020, front-end sample preparation constitutes an important area for the UK economy.
Planned Impact
This programme addresses the EPSRC Healthcare Challenge "optimising treatment". The faster extraction of cfNAs will preserve their integrity, preventing alterations and eventually reflecting better on the general health status of patients. Therefore, the miniaturised solution will greatly enhance the specificity, sensitivity and reliability of diagnostics whether in standard mode or POC devices, enabling optimised treatment. Furthermore the programme delivers on the EPSRC Mission and aligns to its strategy through the range of activities, from high quality applied research that meets industrial needs thereby contributing to building leadership and accelerating impact.
My programme is adaptable to a rapidly changing research landscape. The field of genomics is in exponential expansion, and by working with MRC-funded academics focusing on applied genomics, such as Nick Loman, or world leading companies such as Multiplicom-Agilent Technologies, I am best placed to understand and answer the industries immediate and future needs in terms of sample preparation for novel circulating cell-free markers.
Aside from realising academic impacts in my field and beyond, I aim to have a significant impact of the following aspects:
1. Commercial advantage for our industrial UK partner on advanced material, through developing, integrating and demonstration value of material
2. Developing an academic and industrial community around sample preparation to best answer the relevant needs
3. Developing students and staff in multi-disciplinary environments to answer complex real-world problems
4. Creating a pathway for a more sustainable research in micro-engineered medical devices and promoting EPSRC AREA approach
5. Creating technologies that will have tangible impact on patients' quality of life, such as reduced time to diagnosis, optimised treatment and ultimately better outcomes.
To deliver on these impact aims, I have put together a strong pathway to impact, which includes, additionally to normal academic dissemination routes, the following actions:
1. Creation of a clinical and industrial advisory group to monitor progress through-out the programme and advice on a rapidly changing field.
2. To organise proof-of-concept studies with biologists and clinicians to test early prototype outside my laboratory
3. To organise an international workshop on miniaturised sample preparation to build my leadership and galvanise the UK community efforts in this field.
4. To work with end-users and patient groups to disseminate research findings
My programme is adaptable to a rapidly changing research landscape. The field of genomics is in exponential expansion, and by working with MRC-funded academics focusing on applied genomics, such as Nick Loman, or world leading companies such as Multiplicom-Agilent Technologies, I am best placed to understand and answer the industries immediate and future needs in terms of sample preparation for novel circulating cell-free markers.
Aside from realising academic impacts in my field and beyond, I aim to have a significant impact of the following aspects:
1. Commercial advantage for our industrial UK partner on advanced material, through developing, integrating and demonstration value of material
2. Developing an academic and industrial community around sample preparation to best answer the relevant needs
3. Developing students and staff in multi-disciplinary environments to answer complex real-world problems
4. Creating a pathway for a more sustainable research in micro-engineered medical devices and promoting EPSRC AREA approach
5. Creating technologies that will have tangible impact on patients' quality of life, such as reduced time to diagnosis, optimised treatment and ultimately better outcomes.
To deliver on these impact aims, I have put together a strong pathway to impact, which includes, additionally to normal academic dissemination routes, the following actions:
1. Creation of a clinical and industrial advisory group to monitor progress through-out the programme and advice on a rapidly changing field.
2. To organise proof-of-concept studies with biologists and clinicians to test early prototype outside my laboratory
3. To organise an international workshop on miniaturised sample preparation to build my leadership and galvanise the UK community efforts in this field.
4. To work with end-users and patient groups to disseminate research findings
Organisations
- Heriot-Watt University (Lead Research Organisation)
- Liverpool School of Tropical Medicine (Collaboration)
- Nagoya University (Collaboration)
- microfluidic ChipShop (Collaboration)
- University of Birmingham (Project Partner)
- Agilent Technologies (Belgium) (Project Partner)
- The Electrospinning Company (Project Partner)
People |
ORCID iD |
Maiwenn Kersaudy-Kerhoas (Principal Investigator) |
Publications
Lety-Stefanska A.
(2021)
MICROFLUIDIC RARE ALLELE ENRICHMENT IN CIRCULATING DNA SAMPLE
in MicroTAS 2021 - 25th International Conference on Miniaturized Systems for Chemistry and Life Sciences
Haque M
(2021)
Effects of syringe pump fluctuations on cell-free layer in hydrodynamic separation microfluidic devices
in Physics of Fluids
Naeem N
(2022)
Current and Emerging Microfluidic-Based Integrated Solutions for Free Hemoglobin and Hemolysis Detection and Measurement.
in Analytical chemistry
Kersaudy-Kerhoas M
(2022)
Microfluidic system for near-patient extraction and detection of miR-122 microRNA biomarker for drug-induced liver injury diagnostics.
in Biomicrofluidics
Kersaudy-Kerhoas M
(2022)
Microfluidic system for near-patient extraction and detection of miR-122 microRNA biomarker for drug-induced liver injury diagnostics.
in Biomicrofluidics
Haque ME
(2022)
A microfluidic finger-actuated blood lysate preparation device enabled by rapid acoustofluidic mixing.
in Lab on a chip
Title | Cover page of Lab On Chip Perspective on Sustainaility of point-of-care devices |
Description | The cover compels the reader to think about the sustainability of point-of-care devices. It was created by a South African artist. ISSN 1473-0197 |
Type Of Art | Artwork |
Year Produced | 2022 |
Impact | The selection of this artwork for the cover page of Lab On Chip has helped broadening the reach of the work. |
URL | https://pubs.rsc.org/en/content/articlelanding/2022/lc/d2lc90080g |
Title | Micromixer photo |
Description | Photographic composition |
Type Of Art | Artwork |
Year Produced | 2019 |
Impact | This photo resulted in two prizes for a photographic competition. One public prize (400 voters). |
Description | - We have developed protocols to prototype and manufacture microfluidic chips in a sustainable biopolymer, Polylactic Acid (PLA). We have partially achieved this objective. We are capable of producing complex microfluidic network using laser-cut and laminated PLA sheets. A new collaborative research network is emerging from this research with University of Leeds, University of Palermo (Italy), University of Rome Tor Vergata (Italy) and several industrials. Together we are exploring the application of multi-layer PLA microfluidic devices to the organ-on-chip field. - We have developed protocols to electrospin PLA membranes and integrate those membranes in microfluidic devices. We have shown these membranes can be used as filters in blood plasma separation hybrid devices. We have shown that these filters do not bind DNA. - We have developed a platform for cfDNA extraction and reached similar levels of performance that the gold standard, manual bench extractions. We have demonstrated the quality of our eluates through sequencing experiments. We have demonstrated an ultrafast workflow for the detection of sepsis-causing pathogens via a cfDNA sequencing approach |
Exploitation Route | We are collaborating with academic in the field of biomedical sciences and industrials in the field of microfluidic manufacturing to develop the use of PLA-based laminated microfluidic devices. |
Sectors | Environment,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
Description | Our findings in the area of frugal diagnostics, have led to significant global interest and the creation of a new global network, funded by the Royal Academy of Engineering - Frontiers Champion programme We have demonstrated a microfluidic cartridge can be used for fast standardised extraction of nucleic acid extraction, compatible with nanopore sequencing, opening the doors for under six hours identification of sepsis -causing pathogens. Thanks to our findings on the use of PLA for prototyping and manufacturing microfluidic chips, a European leader in microfluidic manufacturing is promoting the use of sustainable polymers in the industry |
First Year Of Impact | 2019 |
Sector | Healthcare,Manufacturing, including Industrial Biotechology |
Impact Types | Societal,Economic |
Description | Frontiers Champions programme - Tranche 3 |
Amount | £10,000 (GBP) |
Funding ID | FC-2223-3-119 |
Organisation | Royal Academy of Engineering |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2023 |
End | 02/2024 |
Description | Organ-on-a-Chip Technologies Network (OOACT) Sabbatical Funding |
Amount | £15,100 (GBP) |
Organisation | Queen Mary University of London |
Sector | Academic/University |
Country | United Kingdom |
Start | 02/2019 |
End | 07/2019 |
Title | DLS data.xlsx |
Description | The size distribution of the particles presents in all the collected samples from inlet and both outlets at different flow rates were determined using Dynamic Light Scattering (DLS) (Nanozetasizer, Malvern). All the collected samples were diluted to 1:250 in PBS before the measurements and the analysis were performed at 20 °C. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | n/a too early |
URL | https://figshare.com/articles/dataset/DLS_data_xlsx/14627784 |
Title | Relative fluctuation.xlsx |
Description | Dataset for ArXiv Figure 3B |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | n/a too early |
URL | https://figshare.com/articles/dataset/Relative_fluctuation_xlsx/14627778 |
Description | Collaboration with Liverpool School of Tropical Medicine |
Organisation | Liverpool School of Tropical Medicine |
Department | Parasite Immunology Liverpool |
Country | United Kingdom |
Sector | Public |
PI Contribution | We proposed a new workflow for the identification of sepsis-causing pathogens via a cfDNA sequencing approach |
Collaborator Contribution | We received patient samples from the Liverpool School of Tropical Medicine, and accessed clinical expertise |
Impact | n/a (too early) |
Start Year | 2021 |
Description | Collaboration with Microfluidic Chip Shop |
Organisation | microfluidic ChipShop |
Country | Germany |
Sector | Private |
PI Contribution | We provided information about transparency, auto-fluorescence and adsorption properties of polylactic acid |
Collaborator Contribution | The partner provided 600 chips in polylactic acid and in Durabio, another biopolymer product |
Impact | This collaboration is multi-disciplinary: microfluidic, material science, manufacturing |
Start Year | 2018 |
Description | Collaboration with Nagoya University |
Organisation | Nagoya University |
Country | Japan |
Sector | Academic/University |
PI Contribution | We proposed a new workflow for the detection of sepsis-causing pathogens. We extracted and sequenced various samples |
Collaborator Contribution | Nagoya University brought bioinformatic expertise |
Impact | Nagoya University brings in bioinformatics experience. As a result, Nagoya University has developed a long-read option to their online Bioinformatics tool, Pathdet. |
Start Year | 2020 |
Description | Collaboration with Nagoya University |
Organisation | Nagoya University |
Country | Japan |
Sector | Academic/University |
PI Contribution | We proposed a new workflow for the detection of sepsis-causing pathogens. We extracted and sequenced various samples |
Collaborator Contribution | Nagoya University brought bioinformatic expertise |
Impact | Nagoya University brings in bioinformatics experience. As a result, Nagoya University has developed a long-read option to their online Bioinformatics tool, Pathdet. |
Start Year | 2020 |
Title | FLUIDIC DEVICE |
Description | A fluidic device (10) is described. The fluidic device (10) comprises the first part (110) and the second part (120). The first part (110) comprises a first inlet (111) and a first outlet (112), mutually spaced apart. The second part (120) comprises a first chamber (121) arranged to contain a predetermined first amount A1 of a first fluid F1 therein and a first wall portion (122) arranged to contain, at least in part, the first fluid F1 in the first chamber (121). The fluidic device (10) is arrangeable in a first configuration, wherein the first part (110) is fluidically isolated from the first chamber (121). The fluidic device (10) is arrangeable in a second configuration, wherein the first inlet (111) and the first outlet (112) are fluidically coupled via the first chamber (121), whereby increasing a first pressure P1 in the first chamber (121) via the first inlet (111) urges at least a part of the predetermined first amount A1 of the first fluid F1 through the first outlet (112). |
IP Reference | US2021031195 |
Protection | Patent granted |
Year Protection Granted | 2021 |
Licensed | No |
Impact | Other patents applied for/granted: PCT application US and Europe |
Title | MICROFLUIDIC DEVICE |
Description | A microfluidic device (200) for separating a liquid L into first and second liquid components L1, L2 thereof is described. The microfluidic device (200) comprises an inlet (230) for receiving the liquid therethrough. The microfluidic device (200) comprises a first outlet (210) for the first liquid component L1, wherein the first outlet (210) is fluidically coupled to the inlet (230) via a first passageway (240). The microfluidic device (200) comprises a second outlet (220) for the second liquid component L2, wherein the second outlet (220) is fluidically coupled to the first passageway (240A) via a first set of N conduits 250 (250A, 250B, 250C, 250D, 250E), wherein N is a positive integer greater than 1, wherein respective conduits 250A, 250B, 250C, 250D, 250E of the first set of N conduits 250 divide from the first passageway 240A at respective divisions 252 (252A, 252B, 252C, 252D, 252E) from the inlet 230 therealong 240. The respective conduits 250A, 250B, 250C, 250D, 250E of the first set of N conduits 250 are arranged to, at least in part, equalize flowrate ratios at the respective divisions 252 (252A, 252B, 252C, 252D, 252E). |
IP Reference | US2021016284 |
Protection | Patent application published |
Year Protection Granted | 2021 |
Licensed | No |
Impact | n/a |
Description | Interview for National News |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Interview with BBC News, for diffusion on BBC News website and radio interview on BBC Good Morning Scotland (largest Scottish Radio audience) |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.bbc.co.uk/news/uk-scotland-50345522 |