Development of a Comprehensive Toolkit for Optimised Tissue Regeneration: Scaffold DOCTR

Although there has been an explosion of interest in the development of biomedical scaffolds over the past 15 - 20 years, the repair and regeneration of tissues is not always successful. The ability of the scaffolds to deliver cells to aid and guide the repair process, is limited their capacity to retain and encourage the appropriate cell types for optimised repair. Furthermore, the structural complexity and heterogeneity of many soft tissues demand matching scaffold architectures, which current technologies cannot produce.

We believe that is it possible to develop a "design Toolkit" for bespoke, personalised cell-based therapies to ensure optimised treatment of a range of different diseases. In order to test our hypothesis, we aim to address the specific issues in scaffold development for three contrasting, demonstrator applications: cardiovascular devices, dermal grafting and nerve guidance. Each of these applications presents different structural and biochemical challenges, which we aim to address using specifically designed three dimensional biomacromolecular environments.

The underlying technology will be based on ice-templated collagen-based scaffolds. The pathway through the project is the acquisition of knowledge, first about the three dimensional architectures required for optimised cell infiltration through the scaffold, then about the nature of the specific cell binding interactions with the scaffold surfaces. We will create cell-selective surfaces, by the incorporation of receptor-reactive collagen-derived triple helical peptide sequences to control cell reactivity and direct them towards specific regulatory receptors. We will investigate heterogeneity in scaffold architectures and then consider the creation of structures with spatially varying cell binding characteristics based on variations in the intrinsic chemistry of the scaffold struts. By considering optimised properties specific to each application, we will demonstrate the potential of the Toolkit for developing refined and targeted scaffolds with increasing levels of complexity.

The mechanism for this Fellowship is novel: for the first time, an EPSRC Fellowship will be based on a "job share" style arrangement with two PIs. For about 10 years the PIs have jointly run the Cambridge Centre for Medical Materials, both having part time contracts based on their family commitments. This joint which would be a 60% FTE fellowship split evenly between Professors Best and Cameron and reflects a forward-thinking approach by EPSRC based on Equality and Diversity considerations.

We propose a programme of underpinning science, which, once completed, will have huge potential economic and clinical impacts. At the end of the grant we plan to be in a position to apply for translation grants to take these forward. During the grant, we will take action to make sure that information is generated, protected and disseminated in ways appropriate and consistent with the needs of future regulatory approval, future commercialisation, and clinical translation.

Enhancing quality of life and health
We envisage that there will be downstream, post-grant benefits to patients in three demonstrator areas:
Heart failure:- One in four patients develop heart failure following myocardial infarction with ~50% mortality over 5 years contributing to the ~550,000 patients in the UK with heart failure in 2013. The development of a patch with the required combination of materials and biochemical properties to attract and retain stem cells will revolutionise cardiac repair.
Peripheral nerve repair:- Our neural repair strand is designed to create a conduit for axonal growth across a nerve gap. Clearly, the potential benefit to patients is huge, if control and movement can be restored.
Non-healing wounds:- A significant number of diabetic neuropathic ulcers, vascular insufficiency ulcers and pressure ulcers do not heal adequately with standard wound care lea to prolonged morbidity, limb amputation and increased risk of mortality. Dermal repair constructs, based on the appropriate materials structures and biochemistry will offer potential solutions.

Fostering global economic performance
Potential market size :- There is a substantial potential market in each demonstrator application. The current global cardiac patch market has been reported to be valued at $33m, and the total market opportunity for a time-of-surgery implant for heart failure is around 110,000 patients pa in the EU and US. Estimates suggest that around 700,000 peripheral nerve repair surgeries are performed every year worldwide, the global market being worth $4.1 billion in 2012. In the field of skin and soft tissue substitutes, the financial burden of venous ulcers alone is estimated to be $2 billion per year in the United States. The global market for wound-care was valued at over $15bn in 2014.
Exploitation of IP:- Protected IP will have the potential to be exploited, post project, through licensing or company spin out. We have a successful track record of two spin-out companies based on IP resulting from research undertaken in our group (including Orthomimetics (sold to Tigenix) and ApaTech (sold to Baxter)). We therefore realise the importance of creating a balance between undertaking sound, underpinning science published in the open literature and seeking potential impact from commercialisation. Our Advisory Team, including Dr Paul Mantle, a Departmental EPSRC funded Knowledge Transfer Facilitator, will offer guidance on clinical issues, regulatory matters, IP and potential for licensing and spin out. To take the Toolkit to a broader audience in an accessible form, we will explore links with Granta Design (see letter of support).

Increasing effectiveness of public services
The research has the potential to increase the effectiveness of the NHS in terms of improved patient outcomes, reduced care costs and enhanced cost effectiveness. We recognise that in order to drive market adoption the product would need to be recommended by NICE. With the advice of our Advisory Team we plan to ensure that data is generated the requirements of NICE approval in mind.

Public Engagement
We plan a broad programme of public engagement as outlined in our Pathways to Impact document. By highlighting the work of the grant, we plan to inspire and engage with the next generation of Materials Scientists and Tissue Engineers, and promote to the wider public the health and commercial benefits of the work.