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Details of Grant 

EPSRC Reference: EP/N033493/1
Title: Mathematical Modelling to Define a New Design Rationale for Tissue-Engineered Peripheral Nerve Repair Constructs
Principal Investigator: Shipley, Professor RJ
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Department: Mechanical Engineering
Organisation: UCL
Scheme: First Grant - Revised 2009
Starts: 01 September 2017 Ends: 31 August 2018 Value (£): 100,803
EPSRC Research Topic Classifications:
Mathematical & Statistic Psych Med.Instrument.Device& Equip.
Systems neuroscience Tissue Engineering
EPSRC Industrial Sector Classifications:
Related Grants:
Panel History:
Panel DatePanel NameOutcome
02 Jun 2016 Engineering Prioritisation Panel Meeting 1 and 2 June 2016 Announced
Summary on Grant Application Form
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.

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