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MRC DiMeN Doctoral Training Partnership: In vitro characterisation of a novel Engineered Micro-Pancreas (EMP) and identification of prognostic biomarkers towards evidence-based, safe, and effective clinical implementation.


MRC DiMeN Doctoral Training Partnership

Dr William E Scott III , , Dr Nikolai Kunicher Wednesday, January 27, 2021 Competition Funded PhD Project (Students Worldwide)
Newcastle United Kingdom Biomedical Engineering Biotechnology Cell Biology Endocrinology Immunology Molecular Biology Pathology

About the Project

Existing islet-transplantation techniques focus on addressing hypoglycaemia unawareness in patients suffering from severe Type-1 Diabetes (T1D), but struggle to eliminate the need for exogenous insulin therapy (the ultimate therapeutic objective) due to poor engraftment and function following transplantation.

BetalinUK has developed an innovative regenerative therapy: a biologically engineered micro pancreas (EMP) that promotes islet engraftment; improving transplantation outcomes. This is based on a unique scaffold that provides a supportive microenvironment for insulin-producing β-cells.

Objectives:

This project will build on existing evidence to further characterise the EMP in vitro before evaluating a diabetic rodent transplant model to identify and characterise circulating biomarkers indicative of transplant success and harvesting EMP for histological evaluation.

Novelty:

The EMP technology offers a novel tissue-engineered solution, avoiding direct-blood interactions and promoting rapid islet engraftment. Initial data has indicated significant potential to reverse diabetes with fewer islets than gold standard islet-transplantation. This project will evaluate islet-scaffold interactions throughout the transplantation journey and work to identify prognostic biomarkers to be monitored in patient blood-samples during transplantation. Further understanding of islet-EMP engraftment will be established from explant tissue. Improved understanding of this process will help clinicians better manage treatment.

Timeliness:

This project will be carried out in parallel with planned phase-1 clinical trials of EMP-technology. Project will benefit from parallel commercial studies providing synergy. Project success will offer the opportunity to monitor identified biomarkers in a human clinical transplant model; generating future impact. 

Experimental Approach: 

Human-islets will be isolated and loaded into MOM scaffolds to form EMPs. EMPs will be characterised in vitro to establish viability and function; evaluating changes in EMP islets vs control preservation. Islets/EMPs will be shipped to Leeds for implantation into a diabetic nude-rat model comparing intraportal islet delivery with the EMP. Blood will be collected from the tail-vein, processed, and stored during the immediate posttransplant period and at day 1-7, 14, 21, and 28 before animals are sacrificed and grafts harvested for histopathology. Levels of circulating cell-free DNA will be monitored and compared with outcomes.  Technologies such as ELISA or the next-generation Mesoscale Multiplex platform will be leveraged to assess shifts in circulating proteins. Histopathology will be evaluated, including Transmission Electron Microscopy to evaluate islet engraftment with EMP vs control and native islets. 

Key Objectives: 

OB1.1 Literature-review (Months 1-6)

OB1.2 Human islet-isolation training (M7-12; 3 months)

OB1.3 Combine and assess islets and MOM in vitro (M9-24; Viability, function, biomarker identification)

OB1.4 In vivo assessment (M18-36; Evaluate circulating biomarkers/explant-tissue)

OB1.6 Thesis write-up (M36-42)

Student Experience:

Applicants will gain experience working within a cross-disciplinary team spanning the NHS, Industry and Academia (Newcastle-Leeds-BetalinUK consortium). Exposure to each of these environments; including working to industry standards and under regulatory quality systems will provide unique experience beyond the PhD. Access to a wide-variety of techniques will add further value providing students key-skills for career-progression. This project should yield opportunities to present at relevant national/international meetings and publication(s) in peer-reviewed journals.

iCASE Industrial Partner

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:

https://bit.ly/3lQXR8A 


Funding Notes

Funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner.

Funding will cover UK tuition fees and an enhanced stipend (around £17,785) only. We aim to support the most outstanding applicants from outside the UK. We are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2021.
Good luck!

References

1. Materials Science & Engineering C: Materials for Biological Applications i. (2018) 91: 236-246.
2. Cytotechnology. (2020); 72: 715–730.
3. Horm Metab Res. (2019); 51(12): 805-811.

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