Team:UParis BME/Implementation
Implementation
The medical device
Our team has always envisioned the ExoSwitch prototype as a compact and accessible cancer screening device that can be used with minimal training. With this goal in mind, we looked for ways to streamline our exosomal miRNA detection protocol, hoping to find inspiration from existing point-of-care testing strategies. Naturally, our attention was drawn to microfluidic devices. As we explored the advantages of the “lab-on-chip” strategy and learned about commercialised diagnostic medical devices, our implementation strategy has evolved to utilise both the strengths and the weaknesses of our technology.
Microfluidics is a powerful tool to simplify and streamline an experiment, but that’s far from all it has to offer. By exploiting the behaviour of liquids in microscale channels, we can significantly reduce the reagent use and the cost per reaction.1 Furthermore, minimisation of the laboratory setup allows the experimenter to run multiple protocols in parallel.2 For is it means that we can engineer ExoSwitch to “split” the sample between multiple chambers and detect several target miRNAs in parallel.
Screening targets
Altered expression of a single miRNA is not sufficient to detect a cancer with high specificity. Instead, researchers are establishing groups of cancer-associated miRNAs, termed signatures, to test for a particular cancer type.3 Instead of tailoring the panel of our targets to detect a single cancer, the ExoSwitch picked a different approach. Our device is designed to screen for multiple cancer types with high sensitivity and low specificity, efficiently adopting a “whistle-blower” position. Like rapid HIV testing4, ExoSwitch is not offering definitive diagnosis, but a simple and quick screening solution to redirect potentially ill people for further testing at an oncologist’s office. Thus, we can focus on just 3-4 miRNAs per cancer instead of a complete signature, and screen for multiple cancer types in parallel. We think this solution will be especially impactful to supplement/replace existing controversial cancer screening strategies, such as in prostate, lung and breast cancers.5
In theory, a microfluidic device can be made as accessible as we want – even sold over the counter next to the pregnancy tests in a nearby convenience store.6 However, during our work with La Ligue Contre le Cancer, the leading non-governmental organization supporting cancer research in France, cancer diagnosis is a very complex topic. Some patients can develop trauma after receiving the bad news.7 Furthermore, our device will be designed in order to feature acute sensitivity, which could produce false positive results. Therefore, the according likelihoods for such results should be assessed and indicated before implementation of the product on the market. Moreover, the patient undertaking the test should understand the diagnostic efficiency/ accuracy of the product and get referred to an appropriate follow-up examination. This efficiently crosses out a purely over-the-counter (OTC) approach; however, we still have multiple ways of integrating the ExoSwitch into healthcare systems worldwide.
Reaching the patient
Based on the insights from one of the team members, we took inspiration from the HIV screening strategies. The HIV diagnosis is also known to be a potentially traumatic experience8, which is why the self-diagnosis tests remain illegal in certain countries, e.g. Ireland9. However, there are multiple alternative campaigns and strategies utilised by countries across the globe to expand the HIV testing coverage. First and foremost comes integration of the rapid HIV tests into other medical procedures, for example during pregnancy support10 or blood donation11, especially for the populations at an elevated infection risk10. The screens are always complemented by a pre-test and a post-test consultation to educate the patient and address their concerns (legally mandated in multiple countries12) and sometimes performed on the “opt-out” basis13.
Furthermore, different healthcare systems and non-profit charities sometimes employ the “field work” approach to expand the coverage of HIV testing. They employ mobile testing stations inside special vehicles (e.g. “blue buses” in Saint Petersburg14) that bring the medical stuff and necessary equipment to festivals and events, or known places with aggregation of individuals from high risk groups for the HIV infection. While the latter may not be directly translatable to ExoSwitch implementation, it is possible to create similar field laboratories to target regions with undeveloped healthcare infrastructure.
Finally, one other strategy we have considered is unique to our prototype design. Multiple-chamber design of the ExoSwitch chip makes it complicated to interpret the result without some expertise and/or access to an interpretation guide. This offers an opportunity for a semi-self-diagnosis system. In this scenario, patients may have an option to perform the test at home by themselves, but they will not immediately learn the results. Instead, the patients would have to visit a doctor’s / nurse’s office, where they would receive all necessary information alongside the test results and further instructions. Perhaps, we will even be authorised to develop a virtual consultation software with a test to ensure a patient understands all details ahead of the access to the results.
Global outlook
We have already mentioned the low cost per reaction among other advantages of microfluidic solutions.1 Of course, depending on the final reagents put on our chips, they may require certain storage and transportation conditions. For instance, cell-free systems are known for their sensitivity to the temperature regimens.15 Although we intend to avoid this set of problems by utilizing a freeze-dried paper-based system16,17, logistical questions are nonetheless important to consider. We expect ExoSwitch to become an affordable cancer screening solution that can be implemented in countries with less advanced economies and medical systems. By making our device more accessible, we expect to improve global coverage of the cancer screening programs and have a pronounced impact on the global community.
The financial matters
While our “ultimate'' clients are the patients getting a cancer screening with ExoSwitch, they are not the only elements of the chain. As a team based in France, we envision primary clinical trials and commercialisation registration with the European Medical Agency (EMA). Once ExoSwitch becomes a registered medical device, our plan will vary depending on the country-specific context. For instance, we intend to interact with national providers in countries with universal healthcare, for example the NHS in the UK and Securité sociale in France. Furthermore, different private laboratories and hospitals could also be interested in purchasing our medical device to offer to their patients. Finally, we plan to reach out to the non-profit organisations, such as Ligue contre le cancer, whose support would facilitate the rollout and access to regular screening using ExoSwitch for, for example, high-risk individuals. We hope to partner with regional and global trusts and authorities to expand our product’s access into areas that have less advanced healthcare systems.
- Pandey CM, Augustine S, Kumar S, et al. Microfluidics Based Point-of-Care Diagnostics. Biotechnol J. 2018;13(1):1700047. doi:https://doi.org/10.1002/biot.201700047
- Klatt J-N, Schwarz I, Hutzenlaub T, et al. Miniaturization, Parallelization, and Automation of Endotoxin Detection by Centrifugal Microfluidics. Anal Chem. 2021;93(24):8508-8516. doi:10.1021/acs.analchem.1c01041
- Zhou X, Lu Z, Wang T, Huang Z, Zhu W, Miao Y. Plasma miRNAs in diagnosis and prognosis of pancreatic cancer: A miRNA expression analysis. Gene. 2018;673:181-193. doi:https://doi.org/10.1016/j.gene.2018.06.037
- World Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Clin Guidel HIV Diagnosis. 2016. https://www.ncbi.nlm.nih.gov/books/NBK374310/%0A.
- Miller DP, Reuland DS. Controversies in Cancer Screening. N C Med J. 2014;75(4):253 LP - 256. doi:10.18043/ncm.75.4.253
- Kumar S, Bhushan P, Agarwal AK, Bhattacharya S. A Historical Perspective on Paper Microfluidic Based Point-of-Care Diagnostics. Bhattacharya S, Kumar S, Agarwal AK, eds. Pap Microfluid Theory Appl. October 2019:1-5. doi:10.1007/978-981-15-0489-1_1
- Gieseler F, Gaertner L, Thaden E, Theobald W. Cancer Diagnosis: A Trauma for Patients and Doctors Alike. Oncologist. 2018;23(7):752-754. doi:10.1634/theoncologist.2017-0478
- Nightingale VR, Sher TG, Hansen NB. The impact of receiving an HIV diagnosis and cognitive processing on psychological distress and posttraumatic growth. J Trauma Stress. 2010;23(4):452-460. doi:10.1002/jts.20554
- Youngs J, Hooper C. Ethical implications of HIV self-testing. J Med Ethics. 2015;41(10):809 LP - 813. doi:10.1136/medethics-2014-102599
- Arora DR, Maheshwari M, Arora B. Rapid Point-of-Care Testing for Detection of HIV and Clinical Monitoring. ISRN AIDS. 2013;2013:287269. doi:10.1155/2013/287269
- Stoyanov E, Gozlan Y, Wax M, et al. HIV-1/2 screening in blood centers: implementing a two-step serological screening assay approach to reduce donor deferral. Transfusion. 2019;59(6):2054-2060. doi:https://doi.org/10.1111/trf.15245
- World Health Organization. HIV Testing and Counselling in Prisons and Other Closed Settings: Technical Paper. 2009. https://www.ncbi.nlm.nih.gov/books/NBK305392/.
- Gebrezgi MT, Mauck DE, Sheehan DM, et al. Acceptance of Opt-Out HIV Screening in Outpatient Settings in the United States: A Systematic Review and Meta-Analysis. Public Health Rep. 2019;134(5):484-492. doi:10.1177/0033354919860510
- Petrova A. HIV prevention in key populations: an overview of service-delivery projects in Russia. AFEW. 2017. https://afew.org/eecaaids2018/service-delivery-projects-eng/.
- Karig DK, Bessling S, Thielen P, Zhang S, Wolfe J. Preservation of protein expression systems at elevated temperatures for portable therapeutic production. J R Soc Interface. 2017;14(129):20161039. doi:10.1098/rsif.2016.1039
- Pardee K, Green AA, Ferrante T, et al. Paper-based synthetic gene networks. Cell. 2014;159(4):940-954. doi:10.1016/j.cell.2014.10.004
- Pardee K, Green AA, Takahashi MK, et al. Rapid, Low-Cost Detection of Zika Virus Using Programmable Biomolecular Components. Cell. 2016;165(5):1255-1266. doi:https://doi.org/10.1016/j.cell.2016.04.059