Scaffolds for Neural Tissue Engineering

Within the European Union in 2007 there were three times more patients on the waiting list than there were organ transplantations (28.009 essential organ transplantations - 60.141 people on waiting list). Given this substantial and chronic shortage in donor organs, medical scientists have been searching for alternative treatments. Surgical reconstruction is often used to regain some organ function, but this treatment suffers from a lack of available donor tissue but it also can lead to longer term problems. For example, a surgical procedure to treat incontinence redirects urine into the colon, but this treatment increases the risk of colon cancer. Mechanical devices, such as kidney dialysers, are good alternatives to transplants, but these devices do not mimic all the functions of the organ and do not prevent progressive deterioration of the patient. Additionally, there is always chance of rejection of the transplant or implant and the patient will have to take immunorepressive drugs throughout her/his life to avoid organ rejection.A general solution to these problems is proposed by the discipline tissue engineering in which methods are developed to provide tailor-made living tissue 'spare parts' of damaged or diseased tissue. This field, founded in the late 1980's, is currently maturing and starting to provide a real alternative to standard transplantation. This has been exemplified by recent high profile case studies; in one case 7 patients received tissue engineered bladders. Nowadays, skin, cartilage and bone tissue engineering products are commercially available. The main tissue engineering approach to grow a complex 3D tissue is to provide a 3D environment or scaffold for the cells to grow in.However, far less progress has been made in developing tissue engineering solutions for neural tissue (such as brain tissue and peripheral nerve tissue), although the number of patients that would benefit from these is substantial. For example, (i) in England in 2007/8 a total of 5,521 surgical peripheral nerve repairs were undertaken in the NHS, (ii) at least 500.000 people in the UK are affected by macular degeneration and (iii) yearly there are 140.000 people in the UK who suffer a stroke. The slow progress in neural tissue engineering is partly due to the complex structure of the neural tissue itself; e.g. the structure of a peripheral nerve can be compared to a co-axial cable, in which the neurons align themselves along one axis. These nerves are structured on the micrometer level (1 micrometer is ~1/100 of the thickness of an average human hair). To grow cells in an organised manner, we need to provide a well-structured scaffold for the cells to grow in. This scaffold needs to be itself 3D structured on the micrometer scale, providing severe demands on the manufacturing technique. Currently used methods for scaffold manufacture typically do not provide control on the microstructural architecture of the scaffold to build up complex tissues.This proposal is investigating an innovative laser-based scaffold manufacturing technique which is expected to comply with the aforementioned demands. The laser beam is focussed into a material that hardens (or cures) upon irradiation. When the laser is scanned through the material, it leaves cured regions within the liquid non-cured matrix. Once the liquid matrix is washed away, the cured pattern remains and can be used as a tissue engineering scaffold. For this proposal we have carefully selected materials that do not invoke any adverse reaction of the immune system when implanted (biocompatible materials). Additionally, these materials provide the initial scaffold, but then slowly degrade while the cells build up the tissue. These materials will be investigated for neural tissue engineering and a fast route into clinical use will be explored throughout the project via collaborations with clinicians.

This project will investigate a novel polymer microstructuring route and will apply this technique to produce biocompatible and biodegradable polymer constructs for healthcare. The produced polymers will be in particular investigated as scaffolds for neural tissue engineering solutions. The wide potential application of our research means that a number of groups will benefit. These include: (i) the commercial sector; (ii) the public sector (in particular the NHS); and (iii) the general public. I am particularly keen to engage actively with industry to commercially exploit any possible research outcomes and to maximize the impact of our work. The industrial sectors I will seek to engage with are biomaterials and polymers companies (e.g. Biocompatibles and Xiros). Additionally, I will aim to engage with companies that are working towards stem cell therapies for neural repair (e.g. ReNeuron, gained recently approval for a clinical trial to investigate stem cell based stroke therapy). To ensure that the aforementioned companies are aware of our work we will work closely together with regional research clusters (e.g. N8 and METRC) and the Sheffield-based Polymer Centre (www.polymercentre.org.uk, an organisation specifically aimed at enhancing the interaction between academia and industry) to translate our technology to industry. Where appropriate spin-off projects will be created with industry for which funding will be sought through programmes such as Knowledge Transfer Projects, Case PhD studentships, ESPRC and BBSRC industrial partnerships and Wellcome Technology Transfer programme. I envisage that this work will have a significant impact on healthcare. To ensure this I am continuing to establish collaborations with clinicians. For this particular project I will produce microstructured scaffolds to be investigated in collaboration with two medical teams, i.e. the teams of Prof. Andrew Dick (Professor of Ophthalmology and Head of Academic Unit of Ophthalmology at the University of Bristol) and Prof. Peter Robinson (Oral Neuroscience Research Group Leader at the School of Clinical Dentistry at the University of Sheffield). These collaborations, and other clinical collaborations that I will subsequently develop, will investigate our scaffolds for clinical use and they will also play an active role in the project via advice given in bi-annual progress meetings. Where the results of our work are appropriate we will apply for early stage funding from the National Institute for Health Research (NIHR) and the Medical Research Council (MRC) to begin to translate healthcare solutions into the NHS. The lay public will benefit in the longer term via implementation of any healthcare solution that is founded on this project. Additionally, in the shorter term the wider public will also be informed and engaged during our project. This project and its clear applications (regenerative medicine solutions for peripheral nerve injury, macular degeneration and stroke) will have the power to engage the public. I will seek involvement in a limited number of high impact public engagement opportunities (such as the Royal Society Summer Exhibition) to inform the wider public of the goals and the implications of this project.