Mathematical Modelling to Define a New Design Rationale for Tissue-Engineered Peripheral Nerve Repair Constructs

Peripheral nerve injuries result from traumatic injury, surgery or repetitive compression, and their 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). The current clinical best practice for nerve gaps > 3 cm is to bridge the site of injury with a graft taken from the patient; however, this involves additional time, cost and damage to a healthy nerve, the amount of donor nerve is limited, and functional recovery of the main injury only occurs in ~50% of cases. For these reasons, research has focused on developing artificial nerve conduits to replace grafts, but to-date those available for clinical use can only bridge short (<3 cm) gaps and don't contain the living cells found in grafts. Stem cell technology provides a source of therapeutic cells for engineering living artificial nerve replacement tissue, but progress is limited due in part to a lack of consensus on the subtle interplay between the spatial arrangement of cells in engineered tissue and their survival outcome when implanted.

Cells require a critical oxygen concentration to retain their function; under oxygen-deprivation, cells produce chemical cues (growth factors) to promote the growth of a blood network into the tissue, and this is an essential component of the repair process. A denser population of cells will induce greater oxygen deprivation and associated growth factors with higher potential to generate a blood supply; however, the increase in oxygen deprivation may also induce cell death, and therefore a sub-optimal construct. Resolving this sensitive balance purely experimentally would require an unrealistic, costly and ethically-questionable level of animal experimentation; the aim of this proposal is to develop a mathematical model of the tension between oxygenation, cell viability and growth of a blood supply, providing a rational design base for distributing cells and materials within nerve repair conduits.

The above aim will be achieved through a carefully designed combination of mathematical modelling and experimentation. The mathematical work will be performed by the hired PDRA, whilst UCL Mechanical Engineering will fund a PhD student to perform the experimental work. The mathematical models will track, for example, the density of different cell populations, and the concentration field of oxygen and related growth factors in a nerve repair construct. Key biological relationships must be quantified for these models to have predictive capabilities; examples include the rate of oxygen uptake by a cell population, and the resulting proliferation rate of the cells. The interplay between modelling and experiment is a key feature of the proposal. The flow of information is a two-way process: the mathematical models will utilise experimentally-derived data, but will also inform the experimental work by highlighting the experiments that will produce the most meaningful data, and by predicting the cell distributions and chemical/ physical gradients to be tested. The resulting experimentally-parameterised mathematical model will predict the sensitive interplay between oxygenation, cellular viability and blood vessel growth, providing significant insight into the biology that would not be possible using an experimental approach in isolation. The mathematical model will inform spatial distributions of cells and materials in a construct, that promote cell survival and growth of a vascular supply. These construct designs will provide a platform to underpin generation of new repair devices in the future, and the modelling-experimental framework developed will be ripe for application to a host of repair scenarios in the cell therapy field.

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. The proposed research 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 ~5-10 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 strong links with nerve repair clinicians at the Royal National Orthopaedic Hospital, and National Hospital for Neurology and Neurosurgery (specifically Mr Tom Quick and David Choi - see attached Letters of Support). Additionally, the IBME at UCL facilitates the translation of academic research into clinical practice by bringing together 6 academic faculties with 6 hospital trusts. Through her positions within the Tissue and Cell Engineering Society and In Vitro Toxicology Societies, the PI also has strong links with interested commercial sector parts (e.g. ReNeuron Ltd, TAP Biosystems). These clinical and industrial links will be engaged throughout the project, providing a pipeline for application of the new models within the translational commercial arena in the future.

Research Staff: The project will provide the hired PDRA with detailed training in the use of state-of-the-art mathematical & computational modelling, and translational tissue engineering approaches, specifically through training courses in both areas. The PDRA will also benefit from being part of a thriving and growing interdisciplinary group at UCL working on peripheral nerve repair (the PI has 3 PhD students in this area), with the opportunity to interact weekly with relevant tissue engineers and biologists. The PDRA will also benefit from publishing in high-impact journals, and presenting their work at key national and international meetings.

3Rs: The aim of this combined mathematical-experimental approach is to provide a predictive framework to systematically direct experimentation, thereby avoiding 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 final in vivo experiment, to be completed by the linked PhD student, and the dissemination plans will make the framework available to academic and industrial communities.