Novel bioengineering for auto-integration of advanced cell delivery substrates

Lead Research Organisation: University of Liverpool
Department Name: Institute of Ageing and Chronic Disease

Abstract

According to the World Health Organisation age-related macular degeneration (AMD) is the third most prevalent cause of blindness worldwide, and the leading cause of blindness in industrialised countries. There are two types, the neovascular - which contributes to 10% of cases - and atrophic - which contributes to 90% of cases. In AMD, a section of the retina called the Bruch's membrane thickens with age and can interfere with the waste/nutrient exchange between the retinal pigment epithelial (RPE) cells - the layer upon which photoreceptor cells attach and survive - and the choroid - the intricate network of vessels responsible for blood supply. This interference can cause the retinal pigment epithelial cells to die, which in turn can lead to photoreceptor cell death, eventually causing irreversible central vision loss. The sufferer loses their independence as this prevents them from carrying out everyday tasks such as reading and driving. The main risk factor for AMD is age and it, predominantly, affects people over the age of 50. It has already been reported by clinicians that cases of AMD have doubled between the years of 2000-2010, and with the population living longer the prevalence of this disease is anticipated to rise to more than double by the year 2030. Considering there is no current treatment for atrophic AMD and with its prevalence on the rise, this important issue needs to be addressed now.

A number of studies report the use of substrates to deliver healthy RPE cells under the photoreceptor cells before they begin to die. They discuss placing the substrate on top of the diseased Bruch's membrane to deliver a monolayer of RPE cells. I believe that simply placing a novel substrate on top of the diseased membrane could exacerbate the issue. The problem in AMD is the thickened Bruch's membrane, so adding a further layer could further increase the nutrient/waste exchange path leading to damage to the transplanted cells. I hypothesise that a cell transplant substrate can be designed that will unblock the diseased Bruch's membrane while providing support for the healthy RPE monolayer thus leading to improved nutrient/waste exchange between the photoreceptors and the choroidal blood vessels.

This project will develop a novel bioengineered persistent substrate with a bioactive layer that will deliver active molecules at a controlled rate. It will deliver the required monolayer of RPE cells in order to ensure photoreceptor cell survival while simultaneously removing and replacing the diseased native Bruch's membrane. These prerequisites address the necessity of having a permanent membrane upon which the retinal pigment epithelial cells can attach and survive, the removal of the diseased tissue, and the integration of the permanent substrate to replace the diseased Bruch's membrane in order to ensure that the optimal exchange pathway thickness is maintained.

I believe this novel approach will contribute to improving quality of life by reducing the number of people who lose their independence and require assistance/intervention due to AMD. The project aligns to the key Life Sciences Industrial Strategy challenge of developing advanced therapeutics under the theme of healthy ageing in the Health Advanced Research Programme and contributes to the EPSRC Healthy Nation delivery plan ambitions.

Planned Impact

This research will help people who develop AMD to maintain their independence and improve their quality of life. It will in turn contribute to the healthcare system by delivering a one-time treatment for people with AMD. The NHS is already under an immense amount of pressure pertaining to the on-going healthcare of the ageing population. This one-time treatment will give back the independence and freedom to these patients, and ease some of the pressure on the NHS by reducing the assistance and treatment required by those that suffer from AMD.

It will contribute to the UK's commercial sector by creating industrial collaborations and new jobs with expertise in medical devices. It will contribute to the economic growth of the UK, as this project will develop state of the art expertise and innovation based in the UK with a vision of exporting the product globally. This project requires many different experts to work together, therefore allowing the forging of multidisciplinary collaborations in order to develop the medical device. The translational nature of the project dictates that it will require the contribution of the commercial sector and hence will train people within the area of medical device development outside the academic profession. This project may also contribute to the development of a new spin-out company thereby commercialising novel scientific knowledge with application to other sectors in the medical field.

Publications

10 25 50
 
Description We have been able to reproducibly form sub-micron scale fibre structures and have also developed sub-micron scale nanoparticles successfully.
We have produced nanoparticles with FITC encapsulated dye which exhibit sustained release of the dye over 1 month period.
Nanoparticles are not toxic to the cells.
Cells show typical native phenotype and protein expression when cultured on the intended membrane- cells function in their native state.
Cell do not invade the bulk architecture of the membrane - this is a desirable characteristic,
We have begun the set-up of a disease model in vitro.
Exploitation Route Our finding can be used by other research groups to develop something similar. It will eventually be used to deliver cells and specific biologically active moieties to the site of interest.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

URL https://www.biorxiv.org/content/10.1101/2019.12.20.884635v1
 
Description Findings have been used to diseminate the data. at conferences TERMIS 2019- EU chapter was attended in June 2019, and TCES-UKSB 2019 was also attened in June 2019 to present the work in an oral presentation. The data has also been submitted to a journal to publish an original article. A new collaboration was forged with InoCure s.r.o based in Prague. InoCure are a company that specialise in upscaling electrospinning, electrospraying and encapsulation of drugs for long-term sustained release.
First Year Of Impact 2019
Sector Education,Healthcare,Other
 
Description Industrial Strategy Challenge Pump-Priming Fund
Amount £10,000 (GBP)
Organisation University of Liverpool 
Sector Academic/University
Country United Kingdom
Start  
End 06/2020
 
Description MRC Proximity to Discovery (P2D) award
Amount £10,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2019 
End 09/2019
 
Description National Eye Research Centre 2020 grants - Application for Maor Project
Amount £69,976 (GBP)
Organisation National Eye Research Centre 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2020 
End 10/2021
 
Description Non-antibiotic antimicrobial agents for microbial keratitis
Amount £170,000 (GBP)
Organisation Fight for Sight 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2018 
End 06/2021
 
Description Collaboration with The Electrospinning Company Ltd 
Organisation The Electrospinning Company
Country United Kingdom 
Sector Private 
PI Contribution We have been in touch with The Electrospinning Company and have had conference calls updating them on the progress of the project so far. We have organised regular update calls with them to disucss progress. We are going to organise a touching base visit with them soon to view their facilities. We are due to see them at TERMIS 2019 in May this year as they are holding an exhibition stand there, while we are presenting a podium talk on the progress of the work so far.
Collaborator Contribution They have mentioned the commercial regulations we need to research and read up on for medical devices. They have invited us to their facilities for a visit of their commercial laboratories.
Impact Touch-base visit of their facilities to organise a working visit to spend time at their laboratories.
Start Year 2018
 
Description InoCure s.r.o. 
Organisation InoCure
Country Czech Republic 
Sector Private 
PI Contribution I approached InoCure s.r.o following seeing a presentation by Mr Matej Buzgo at TERMIS-EU chapter conferences in June 2019. They specialise in electrospinning/electrospraying, encapsulation of drugs for long-term sustained release, which is ideal for the next stages of the project. I visited the company in October 2019 to work with them and inititate a technology transfer to being the fabrication of the membrane. I have since organised a 2x1month placement for my PDRA Dr Veronica Hidalgo-Alvarez to work under their guidance and expertise to further develop the technology. Since the initial collaboration we have written for further funding together to maintain the collaboration and we have also submitted a PhD studentship in collaboration which will entail a 1 year placement at InoCure s.r.o. for the PhD student. We will be bringing back the technology to test in in vitro models and by the end of the project will have a pre-clinical trial ready technology.
Collaborator Contribution I have worked with InoCure s.r.o. in a new collaboration to develop and upscale the production of the membranes/bioactive nanoparticesl being developed. They will be hosting PDRA Dr Veronica Hidalgo-Alvarez for two months' placement to work in their laboratory to further develop our technology. InoCure s.r.o. are providing some in-kind training and consumables towards the project and will be developing GMP-like fabrication methods to enable us to bring back commericial expertise to the university. We have also written a PhD studentship to enhance our partnership, where they have offered to host and contribute to the expenses of the student including travel, accommodation, subsistence, conference attendance and teaching business know-how. We will be undertaking meetings with Business Strategy to underpin IP rights within the project.
Impact none as yet.
Start Year 2019
 
Description School participation on outreach event - Meet the Scientist (recurring) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Outreach activity demonstrating scientific experiments to children and the wider public based on the human body. Children were allowed to provide feedback from the experience and a vast majority of them expressed an interest in aspiring to become a future scientist. Parents/carers of the children also got involved and asked questions on the background of the science being demonstrated and also asked questions regarding their own health.
Year(s) Of Engagement Activity 2018