Integrated microfluidic platform with MEMS cantilever for the early detection of prostate cancer using dry mass sensing

Lead Research Organisation: University of Warwick
Department Name: WMG

Abstract

Prostate cancer is the most prevalent cancer in men. In the UK alone, more than 40'000 cases are diagnosed every year (www.nhs.uk). The current accepted clinical gold standard for the diagnosis of prostate cancer is the measure of the prostate-specific antigen (PSA) levels in blood. However, it is now accepted that PSA test are unreliable and can lead to over-diagnosis. These false-positive results mean that many men are subjected to invasive and painful biopsies for no reason. Our pro-ject aims to address these limitations through the development of a minimally invasive, low-cost biosensing platform to detect PCA3, a promising urinary diagnosis biomarker for prostate cancer. In order to provide a viable alternative to ultra-sensitive, yet more complex and time-consuming assays, our platform should be capable of detecting, within 15 minutes, PCA3 down to concentra-tions of 1 ng/mL in urine.

This goal will be achieved through the implementation of a simple and novel concept to enable high-resolution measurement, using ultra-sensitive mechanical sensors integrated in microfluidic devices. The concept of measurement air pockets, proposed here for the first time, will permit the capture of the analyte molecules in the liquid phase and their measurement in the gas phase; through the introduction of air pockets as measurement chambers. The measurement of liquid borne analytes in air will minimize viscous damping losses and thereby enable high-resolution, high-sensitivity measurement.

In order to facilitate the deployment of the platform in clinical settings, we will test it using clinical samples from the early development stage and we will ensure that it can be fabricated using ac-cepted manufacturing methods. After a proof-of-principle device has been demonstrated we will seek further funding, in collaboration with prostate cancer clinicians, to evaluate the platform in clin-ical settings. It is noted that the platform could be adapted for the diagnosis of other conditions and that the simple concept proposed here could be applied to other sensor for a range of applications including environmental monitoring and food safety.

Planned Impact

The proposed project will ultimately achieve its main impact by enabling the use of ultra-sensitive MEMS flexural devices to measure and detect liquid borne analytes while retaining high measure-ment resolution through measurements in air pockets. These low-cost sensors, deployed at the point-of-care could transform healthcare systems around the world and have positive impact on the life of millions of patients. Indeed, these low-cost sensors will improve the patients quality of life by enabling earlier treatment, reducing stress and time spent at the practitioners/clinic. Cur-rently, prostate cancer is diagnosed by measuring the level of prostate-specific antigen (PSA) in blood. However, it is now accepted that PSA test are not reliable and can lead to over-diagnosis and the NHS recommends the development of other tests to diagnose prostate cancer. Our project addresses this issue through the development of a biosensing platform to detect PCA3, a long noncoding RNA (lncRNA), which has been identified as a promising new biomarker for pros-tate cancer. The smooth implementation of the project will be ensured by careful planning and management, including the consideration of ethical and regulatory matters. The development of such sensors that could also help reduce drastically healthcare costs is encouraged by the NHS.

The project is also designed to maximise the impact for UK industries as the integrated biosens-ing platforms proposed will be developed using a combination of accepted technologies compatible or easily transferable to medium scale manufacturing. We will use among others microfabrication foundries and moulding processes for the fabrication of the platform. Potential UK beneficiaries in-clude BAE system, through its Advanced Technology Centre that offers a comprehensive capability in MEMS and Barkley Plastics. Furthermore, the PI will benefit from an extensive network through his department WMG that has collaborated with over 1200 SMEs since 2007 and through his insti-tute, the Institute of Digital Healthcare (IDH), an institute specialised in translating healthcare re-search, for industrial engagement.

Academics from a range of disciplines will also benefit from a variety of advances that reflect the interdisciplinary nature of the project. In particular, the project offer the principal investigator a unique opportunity to develop a program that will give him the opportunity to build up the group and the network he needs to maximise the impact of his research.

Publications

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Farazmand MH (2019) Design and Development of a Disposable Lab-on-a-Chip for Prostate Cancer Detection. in Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

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Charmet J (2020) Low-Cost Microfabrication Tool Box. in Micromachines

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Bungon T (2021) Graphene FET Sensors for Alzheimer's Disease Protein Biomarker Clusterin Detection. in Frontiers in molecular biosciences

 
Description During the project, our fist challenge was the interfacing of the MEMS sensors (24 devices on a 1x1 cm chip) to the electronics (drive and sense) and the fluid (biological fluid). We have come up with an original idea, using a modular "plug-and-play" platform that does not require permanent electronic or fluidic integration. The platform, fabricated using an additive manufacturing, paves the way to low-cost disposable Lab on Chips for a range of applications.

We are still in the process of validating the platform (via a PhD studentship - as in-kind contribution from the Department). We are hoping to have a fully working proptotype by the end of the year, when we can validate it with clinical samples.

We have signed a number of NDA with potential industry stakeholder (will depend on the final outcomes) and we have engaged with clinicians and wider public.
Exploitation Route One paper has been published. It will enable an easier interfacing between MEMS based sensors and microfluidics.

More to come. We will be present the clinical results at the Clinical Challenges Forum and to our industry partners (NDAs already in place) to discuss potential next steps/expolitation.
Sectors Aerospace

Defence and Marine

Agriculture

Food and Drink

Chemicals

Electronics

Environment

Healthcare

Manufacturing

including Industrial Biotechology

Pharmaceuticals and Medical Biotechnology

 
Description Used in teaching material (in academic and other engagement activities - see details in relevant section) Enabled further collaborations and recognition
First Year Of Impact 2019
Sector Education,Healthcare
Impact Types Cultural

Policy & public services

 
Description Capacity Building for Prototyping Compatible Injection Moulding
Amount £236,753 (GBP)
Organisation High Value Manufacturing Catapult 
Sector Private
Country United Kingdom
Start 08/2020 
End 08/2022
 
Description Capital Award emphasising support for Early Career Researchers - University of Warwick
Amount £250,000 (GBP)
Funding ID EP/S017887/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 01/2019 
End 06/2020
 
Description Health Global Research Priorities
Amount £4,500 (GBP)
Organisation University of Warwick 
Sector Academic/University
Country United Kingdom
Start 05/2020 
End 07/2021
 
Description Access to clinical samples 
Organisation University Hospitals Coventry and Warwickshire NHS Trust
Department Arden Tissue Bank
Country United Kingdom 
Sector Academic/University 
PI Contribution Initially started a collaboration with the University of Birmingham, but never finalised the Materials Transfer Agreement due to the unrealistic requests (in terms of IP) of the clinicians involved. Then started a collaboration with the Arden Tissue Bank at University Hospital of Coventry and Warwickshire (UHCW) to gain access to urine samples. Discussion with a urologist (consultant) at UHCW to identify patients with prostate cancer and control group. The start of the testing was delayed due to issues with the fabrication of the sensors. Expected to resume in 2020 (June).
Collaborator Contribution Identification of patients. Preparation of MTA.
Impact Application Form for access to samples. Amendment of risk assessment.
Start Year 2020
 
Description Access to clinical samples 
Organisation University Hospitals Coventry and Warwickshire NHS Trust
Country United Kingdom 
Sector Academic/University 
PI Contribution Initially started a collaboration with the University of Birmingham, but never finalised the Materials Transfer Agreement due to the unrealistic requests (in terms of IP) of the clinicians involved. Then started a collaboration with the Arden Tissue Bank at University Hospital of Coventry and Warwickshire (UHCW) to gain access to urine samples. Discussion with a urologist (consultant) at UHCW to identify patients with prostate cancer and control group. The start of the testing was delayed due to issues with the fabrication of the sensors. Expected to resume in 2020 (June).
Collaborator Contribution Identification of patients. Preparation of MTA.
Impact Application Form for access to samples. Amendment of risk assessment.
Start Year 2020
 
Description NDA with M-Solv Ltd 
Organisation M-Solv
Country United Kingdom 
Sector Private 
PI Contribution NDA signed with M-Solv on microfabrication porcesses. It relates to the process we have developped through the project for low-cost prototyping-complatible injection moulding process.
Collaborator Contribution We have met and orgarnised a number of time. They have provided a letter of support for a recently submitted grant application (with in kind contribution up to £50k). The inkind contribution reported here is to account for the meeting times, visits, etc.
Impact Grant application (under review)
Start Year 2019
 
Title Injection moulded clamping device for low-cost prototyping 
Description We have developed a novel prototyping injection moulding process. It will be used to develop a clamp, to be integrated into the final platform, to hold the sensor (instead of using a 3D printed clamp). The mould (tool) was fabricated using rapid tooling (using additive manufatcuring). We are still evaluating the method (on various test samples to evaluate the wear/tear of the moulds, and the reproducibility and accuracy of the moulded parts as a function of number of cycles). We are hoping to submit a paper (target Lab On Chip or Advanced Materials Technology) in July 2020. 
Type Of Technology Systems, Materials & Instrumental Engineering 
Year Produced 2019 
Impact We have demonstrated the possibility to fabricate injection moulded parts based on low-cost 3D printing moulds. Typically, moulds for injection moulding cost >£20k and therefore seriously limit the developments of injection moulded parts for research and development in biomedical/microfluidic applications, despite the many advantages of the fabrication method (including robustness, wide range of materials and easy route to manufacture). The method can have applications beyond the project itself. 
 
Title low-cost modular electrical and fluidic integration platform for MEMS-based biosensors 
Description We have designed and fabricated a low-cost modular electrical and fluidic integration platform for MEMS-based biosensors, paving the way for a disposable, low-cost Lab-on-a-Chip. We have demonstrated seamless integration using an additive manufacturing enabled "plug-and-play" platform that does not require permanent electronic or fluidic integration. 
Type Of Technology Physical Model/Kit 
Year Produced 2018 
Impact Submitted full papers for the IEEE Engineering in Medicine and Biology Society Annual conference in Berlin (July 2019) and abstract for the BioMedEng conference in London (September 2019). Once we obtain more results with biological samples, we will submit a manuscript (targeted journals Lab on a Chip, Biosensors and Bioelectronics, or Analytical Chemistry) 
 
Title shared files to fabricate low cost microfabrication toolbox 
Description share file (design, code, process parameters, bill of material) to complement the publication Low Cost Microfabrication Toolbox (www.mdpi.com/2072-666X/11/2/135) 
Type Of Technology New/Improved Technique/Technology 
Year Produced 2020 
Impact The low cost photolothography system (bill of material, code provided via GitHub) was put together and installed at Universitas Indonesia (YW lab). It was also installed at the Warwick Medical School (DK Lab) 
 
Description Masterclass as part of the Global Partnership Scholar Program (GPS Program) from Universitas Indonesia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Masterclass on microfabrication processes. Organised by Universitas Indonesia as part of the Masterclass as part of the Global Partnership Scholar Program (GPS Program). Engaged with > 50 students
Year(s) Of Engagement Activity 2020
 
Description Public engagement at University of Warwick Familly day 
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 Set-up a small demonstration based on the pump / imaging devices developed during the project to showcase the world microdevices.
Year(s) Of Engagement Activity 2019
URL https://warwick.ac.uk/about/community/warwickfamilydays/dropin/#show2
 
Description Surgical Research Forum 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Co-organisation, with colleagues clinicians, of the Surgical Research Forum that aims to bring together clinicians and academic researchers to share ideas/initiate collaborations. The quarterly meetings take place at the University of Warwick and the University Hospital of Coventry and Warwickshire (alternatively). It is though this forum that we got to meet with the urologist who is now collaborating on the project.
Year(s) Of Engagement Activity 2017,2018,2019,2020
 
Description University Alliance of the Silk Road (UASR) - Virtual Summer Courses 2020 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact International Summer School as part of the MEMS Series Talks (organised by Xi'an Jiaotong University). 1 hours presentation, including on recent projects. Interactive discussion with students/facilitators.
Year(s) Of Engagement Activity 2020
URL http://uasr.xjtu.edu.cn/info/1172/2294.htm
 
Description Workshop on Biosensing, Microfluidics, Liquid biopsies, Fabrication technologies in Ankara, Turkey 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact ~20 people attended, including students, proefssoionals from various institutions (mostly universities in Ankara), 2 companies and clinicians. We presented some of the outcomes of the project and discuss further challenges. It has generated new collaborations (in preparation) and press release on the University of Cankaya's website and in regional news. As a consequence of one articles, we were contacted by a clinician from the Turkish Thoracic Society. Followed up by colleagues in Cankaya university.
Year(s) Of Engagement Activity 2019
URL http://www.cankaya.edu.tr/duyuru/4285/Akci%C4%9Fer_Kanseri_Te%C5%9Fhisi_Birka%C3%A7_Dakikaya_%C4%B0n...