Multi-Domain Self-Assembled Gels: From Multi-Component Materials to Spatial and Temporal Control of Multi-Component Biology

Lead Research Organisation: University of York
Department Name: Chemistry

Abstract

Stem cells - cells which are precursor cells to all other types of cells - open up radical new possibilities for the future of medicine as they can be encouraged to convert into different types of useful growing tissue. In particular, stem cell technology offers potential to encourage joint restoration, nerve tissue regeneration, bone reconstruction and cardiovascular repair in vivo. More complex, and potentially valuable, is the use of stem cells to grow whole organs ex vivo, suitable for transplantation into patients. This would potentially satisfy the unmet need for organs faced by many patients, who die waiting. Further, this would provide organs which, because of the use of stem cells, will be tailored to the patient's immune system preventing organ rejection, and hence avoiding the massive cost associated with anti-rejection medication. This project explores a new class of soft gel-phase materials which will be able to direct and control tissue growth in more precise and sophisticated ways than can currently be achieved.

We will create multi-domain gels in which different regions of the material have different chemical compositions and hence different properties. As a result, growing biological tissue will behave differently in different domains of the material. Although creating simple gels which are compatible with tissue growth is relatively straightforward, patterning multiple components in order to direct stem cells to do different things in different regions of the material is much harder. Progress has been made towards the goal of patterning gels for tissue growth using polymer gels, but our approach makes use of self-assembling small-molecule gelators, which have the potential to be much more programmable and responsive. Light will be used to pattern gel assembly, combining our technology with established polymer gels to create coherent patterned materials which have both rigid and soft domains. It would be expected that such materials would encourage stem cells to differentiate into different types - e.g. bone on the harder domains and fat on the softer domains.

Biologically active agents, such as tissue growth factors, will then be incorporated within specific domains of our new materials. The controlled release of these agents will then be able to influence the growing tissue - in principle, this can be achieved with both spatial and temporal control. In this way, the growing cells are exposed to specific stimuli at chosen times in specific locations. Conducting units will also be embedded into specific gel domains, so that conducting pathways can be assembled only in specific regions of the gel. We anticipate that these conducting pathways will enable parts of growing tissue culture to be electrically stimulated in a selective manner at a chosen time point - potentially encouraging cells to develop in unique and controllable ways.

The development of multi-domain gels is highly innovative and a number of important challenges will need to be solved in this project. Fundamental understanding will develop and control over multiple components within a single material will be achieved. Incoporating active agents into multi-domain gels for spatially and temporally controlled release, and the development of conducting pathways within such gels have never previously been achieved. As such, this project constitutes a step-change in multi-domain gel technology. We believe this approach may revolutionise approaches to tissue engineering and we will demonstrate its potential. Employing a supramolecular understanding of soft materials in order to control the ways in which they interact both with active agents, and biological organisms growing in their direct environment, moves the EPSRC Chemistry 'Grand Challenge' of Directed Assembly well beyond its current chemical state-of-the art by using the principles of supramolecular chemistry to interface with living systems biology.

Planned Impact

This proposal aims to develop self-assembled multi-domain gel materials, based on relatively cheap building blocks and move their applications into the next generation of tissue engineering technologies. It has been suggested that the global market for regenerative medicine will grow from $16.4bn in 2014 to ca. $65 by 2020 - there is vast potential market scope for innovative and disruptive technologies in this sector. Regenerative medicine offers the potential to encourage joint restoration, nerve tissue regeneration, bone reconstruction and cardiovascular repair (on 5-10 year timescales). More complex, and potentially valuable, is the use of gels as scaffolds to help grow whole organs from stem cells, suitable for transplantation into patients. This would potentially satisfy the unmet need for organs faced by many patients, who die waiting for a suitable organ donor as well as providing organs which could be tailored to the patient's immune system, avoiding problems of rejection, and avoiding the massive cost associated with anti-rejection medication (ca. £5-10k per patient per year, with ca. 4500 new organ recipients in the UK per year). There are thus significant medical and economic drivers for non-immunogenic organ development. Such a technology lies >>10 years in the future.

This is a hugely competitive and active field of research, but the potential for spatial and temporal control in the carefully designed self-assembled materials offers an exciting and unique approach for sophisticated intervention in tissue growth and differentiation. We believe our approach will become a powerful tool helping revolutionise this challenging area of research and has the potential to underpin a wide range of new regenerative medicine technologies. Key technologies developed in the project will be patented in order to enable commercial exploitation where appropriate. Support for this is provided by the Research and Innovation Office, University of York.

As a part of this project, there will be significant public engagement. Smith will develop a new outreach lecture aimed at members of the public and A' level students. This lecture will focus on Innovative Soft Materials, exploring real-world examples of gels, including their use of as scaffolds for tissue engineering, (e.g.) in transplantation, as directly relevant in this project. In collaboration with the PDRA, he will also develop a YouTube video supporting the research in the project in context, and disseminate it to the wider public. The PI has an exceptional track record in public outreach and education work (HEA National Teaching Fellowship, 2014; Times Higher Education Most Innovative Teacher nomination). He has given public and schools' lectures to ca. 50,000 people at venues ranging from the Royal Institution in London and Betty's Cafe in York to school students in rural India. He delivers highly personal contextualised lectures in which he discusses his husband's cystic fibrosis and double lung transplant and then explores how this personal connection has inspired medicinal chemistry in his lab such as gene delivery and nanoscale drugs for use in surgical therapies.

This grant will deliver a PDRA who will be a highly skilled individual, with expertise in synthetic, materials, supramolecular and biological chemistry. They will develop highly interdisciplinary skills at the interface between materials and life sciences which will make them highly employable either in Biotech or academia. The PDRA will also develop skills in organisation and time management, presentations, IT, critical thinking and problem solving. This will ensure that the people pipeline is maintained.

The UK has produced world-leading supramolecular materials and biotech research both in academia and industry, but fewer examples in which the two are combined in a synergistic way - as such, there is significant potential for disruptive impact.

Publications

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Chivers P (2019) Shaping and structuring supramolecular gels in Nature Reviews Materials

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Okesola BO (2019) Supramolecular Self-Assembly To Control Structural and Biological Properties of Multicomponent Hydrogels. in Chemistry of materials : a publication of the American Chemical Society

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Piras C (2019) Self-Assembling Supramolecular Hybrid Hydrogel Beads in Angewandte Chemie

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Piras CC (2020) Self-Assembling Supramolecular Hybrid Hydrogel Beads. in Angewandte Chemie (International ed. in English)

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Piras CC (2020) Multicomponent polysaccharide alginate-based bioinks. in Journal of materials chemistry. B

 
Description We have developed a significantly enhanced understanding of how to assemble gels from multiple components. This provides us with materials that are much more precisely tailored for tissue engineering applications. For example, by mixing different gelators we can generate materials with different stiffnesses, that encourage stem cells to differentiate into different type of human tissue. Our photo-patterning methods allow us to achieve spatial resolution over this process and create patterned gels. Cells behave differently in different domains of these gels. We have also created a new class of microbead structured gels and are investigating the growth of stem cells within these well-defined constructs. We have demonstrated that microgel beads loaded with bioactive agents can encourage stem cell growth - such materials can be injected and might be suitable for use in regenerative medicine applications. In addition to applications in tissue engineering, we have developed simple gel beads that exhibit activity against drug resistant bacteria. We have also employed our gel beads as recyclable catalysts in reaction processes of importance to the pharmaceutical industry,
Exploitation Route The gel platforms that we are developing could easily be applied by others working in regenerative medicine or drug delivery. We suspect that the photopattering ideas we have been developing will be applied by others in this area of research.
Sectors Pharmaceuticals and Medical Biotechnology

URL https://www.york.ac.uk/chemistry/news/deptnews/2021/injectableself-assembledmicrogelsenhancestemcellgrowth/
 
Description At this point, the primary impacts have been on the general public, with TV interviews, schools lectures, news articles and exhibitions being used to disseminate the concept of gel technology and the ways in which it can impact on regenerative medicine. Myself as PI and the researcher have both been heavily engaged personally in these activities. The educational impact has been significant - gels/materials are well-aligned with the school curriciulum and the impact of engagement on school students at all levels has been large.
First Year Of Impact 2020
Sector Education
Impact Types Cultural

 
Description RSC Travel Grant
Amount £4,200 (GBP)
Funding ID 1117461 
Organisation Royal Society of Chemistry 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2020 
End 01/2021
 
Description 3D Printing of Low Molecular Weight Gelators 
Organisation Paul Sabatier University (University of Toulouse III)
Country France 
Sector Academic/University 
PI Contribution We have an active collaboration to 3D print some of the gelators we have developed in our lab. Our expertise is in provision of te gelators and understanding of self-assembly.
Collaborator Contribution Our collaborators, led by Dr Juliette Fitremann ( in the lab of Profs Marty and Mingotaud), have expertise in 3D printing.
Impact A funded research visit is being made to the labs in Toulouse (see future funding section).
Start Year 2019
 
Description ITV (Regional) News Feature 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Media interview describing my husband's healthcare problems and our research in tissue engineering with a long term goal of engineering organs from a patient's own stem cells.
Year(s) Of Engagement Activity 2018
URL https://www.youtube.com/watch?v=LMncP04j5Qc
 
Description News Story (Departmental Homepage) 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact News story on our gel beads with antimicrobial activity explaining the research and its potential impact.
Year(s) Of Engagement Activity 2020
URL https://www.york.ac.uk/chemistry/news/deptnews/2020/doughnuts-drug-resistant-bacteria/
 
Description News Story (Departmental Homepage) 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact A news story was written up about our research paper on microgels. This was published on the departmental webpage and was on the front homepage for a considerable period of time. Most likely engagement is with school students browsing the webpages, researchers at other institutes etc.
Year(s) Of Engagement Activity 2020
URL https://www.york.ac.uk/chemistry/news/deptnews/2021/injectableself-assembledmicrogelsenhancestemcell...
 
Description Schools Lectures (London/Manchester - 2 per year) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact A major schools lecture about medical applications of chemistry, featuring the concept of engineered materials for regenerative medicine. The lecture is given to groups of 500-1000 students at a time as part of a major day of Chemistry outreach organised by The Training Partnership. It is given, ca. two times per year in London and/or Manchester. I appear in the video advertising the Chemistr Study Days online.
Year(s) Of Engagement Activity 2018,2019,2020
URL https://thetrainingpartnership.org.uk/study-days/subjects/chemistry/
 
Description YorNight - Public Understanding of Science - Exhibition 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact We exhibited our research on gels at 'YorNight', which is a major public outreach event in York. It is an ehibition-style event visited by the general public, with a paricularly large number of families with primary school age children (7-11) attending. At the 2020 event, Carmen Piras led the SMith group exhibit. ca. 750 members of the public engaged with the exhibit over a 4 hour period.
Year(s) Of Engagement Activity 2018,2020
URL https://www.york.ac.uk/news-and-events/events/yornight/2020/activities/silly-jelly/