Mathematical Modelling Led Design of Tissue-Engineered Constructs: A New Paradigm for Peripheral Nerve Repair (NerveDesign)

Peripheral nerve injury is debilitating, causing loss of sensation and muscle control, chronic pain and permanent disability. In addition to the serious impact on patients and their families, nerve injuries impact society economically through reduced productivity (nerve injuries predominantly affect young people) as well as the cost of healthcare and rehabilitation. Transected peripheral nerves have the potential to regenerate following surgical repair, but there are serious limitations for injury sites >3cm, because regeneration requires a supportive microenvironment. The current best option is a nerve autograft harvested from another part of the patient's body, but donor site morbidity, limited availability and poor outcome mean there is a clear clinical need to develop effective alternatives. Advances in tissue engineering together with stem cell technologies provide promising routes for engineering living artificial nerve replacement tissues, but progress is limited due in part to a lack of consensus on how to arrange materials and cells in space to maximize nerve regeneration. This is compounded by a reliance on experimental testing, which precludes elaborate investigations due to time and cost limitations.

NerveDesign will address this log-jam, by combining mathematical modelling with state-of-the-art in vitro and in vivo experimentation for the first time, to bring about a paradigm shift in the approach used for neural repair. NerveDesign will focus on the chemical and physical stimuli that promote growth of blood vessels and regenerating nerves through a damaged nerve site. Mathematical models will be developed that incorporate the key mechanisms at play - these mechanisms will be quantified through carefully designed experiments that test them in the laboratory. Computer simulations with then be used to test different potential peripheral nerve repair construct designs, and the leading contenders will be fabricated and then tested. This multidisciplinary approach to nerve repair is entirely novel, and delineates an ambitious approach with significant potential for human health impact.

To facilitate the uptake of the approach by clinicians, NerveDesign will create and test a user-friendly software tool that enables end users to set construct design parameters according to individual repair requirements. All computational models will be formulated in Systems Biology Mark-Up Language, and published on our websites (alongside an example experimental dataset) to encourage their uptake in a range of nerve tissue engineering applications. Finally, NerveDesign will work with its clinical and commercial Project Partners to directly engage patient groups, and pave the way for translation and commercialisation of the new repair constructs designs.

Economic & Societal Impacts: Peripheral nerve injuries (PNI) result from traumatic injury, surgery or repetitive compression, and are reported in 3-5% of all trauma patients. The impact ranges from severe (leading to major loss of function or intractable neuropathic pain) to mild (some sensory and/or motor deficits affecting quality of life). PNI affect ~1M people in Europe and the US p.a. of whom 600,000 have surgery but only 50% regain function. PNI has high healthcare, unemployment, rehabilitation and societal costs and because it more often affects young people (mean age ~30) their disability greatly impacts lifetime productivity. NerveDesign will improve fundamental understanding of the nerve repair process and accelerate the development and optimisation of effective new cellular conduit designs for future uptake by clinicians and industry (timescale ~2-10 years). This will lead to patient benefit through new treatment options, with improved health and quality of life, less disability and pain, and improved return to work. The UK economy will benefit from lower burden on healthcare, rehabilitation, social and welfare systems; patients who return to work increase the tax base. Furthermore, the UK is a leading player in the regenerative medicine sector, so new tools that can improve the efficacy and reduce the cost of new cell-based therapies will boost development leading to greater UK employment and investment.

Clinicians & Industry: The PI has excellent links with nerve repair clinicians, including Mr Quick at the RNOH who is Project Partner. As part of NerveDesign, Mr Quick will complete a clinical survey of around 40-60 patients over 2 years to assess the impact of current peripheral nerve surgeries, provide concrete data to motivate clinical translation of our tissue-engineered alternatives, and engage patient groups in the NerveDesign plans. Secondly, UCL's commercial sector partners are currently poised to move into the PNR market using EngNT (developed by the co-I) technology, and NerveDesign will facilitate this through improving the efficacy of the device (2-5 years). This potential new product area will enable them to grow their businesses, leading to more investment and employment in the UK, increasing activity and strengthening the UK Regenerative Medicine sector in a globally relevant market. Finally, a dedicated feasibility study using commercially-available synthetic biomaterials (Biogelx, Project Partner) will provide proof-of-concept data for commercialisation and translation of alternative construct designs (5-10 years). Finally, NerveDesign will develop and test a software tool to enable end users (including clinicians) to tailor design parameters for engineered constructs, paving the way for translation of the mathematical-experimental approach (5 years).

Research Staff: NerveDesign will hire three PDRAs and train them in state-of-the-art mathematical & computational modelling, in vitro and in vivo experimental methodologies and translational tissue engineering. The team will benefit from membership of a thriving, interdisciplinary group at UCL, including regular interactions with academic, commercial and clinical representatives (through the Project Partners).

3Rs: NerveDesign will combine mathematical modelling with in vitro and in vivo approaches, providing a predictive framework to systematically direct experimentation, thereby avoid animal experiments that are least likely to produce informative results. This is particularly pertinent in the field of peripheral nerve repair, where rat experimentation is currently the standard for exploring and developing clinical alternatives to the autograft approach. These benefits will be evident within the timescale of the grant - the mathematical models will direct a reduced number of in vivo experiments, and the dissemination plans will make the framework available to academic and industrial communities.