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

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.

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.