Mathematical Modelling to Define a New Design Rationale for Tissue-Engineered Peripheral Nerve Repair Constructs
Lead Research Organisation:
University College London
Department Name: Mechanical Engineering
Abstract
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.
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.
Planned Impact
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.
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.
People |
ORCID iD |
Rebecca Shipley (Principal Investigator) |
Publications
Rayner MLD
(2018)
Developing an In Vitro Model to Screen Drugs for Nerve Regeneration.
in Anatomical record (Hoboken, N.J. : 2007)
Muangsanit P
(2018)
Vascularization Strategies for Peripheral Nerve Tissue Engineering.
in Anatomical record (Hoboken, N.J. : 2007)
Kayal C
(2019)
Physical and mechanical properties of RAFT-stabilised collagen gels for tissue engineering applications.
in Journal of the mechanical behavior of biomedical materials
Coy RH
(2018)
An integrated theoretical-experimental approach to accelerate translational tissue engineering.
in Journal of tissue engineering and regenerative medicine
Coy R
(2020)
Combining in silico and in vitro models to inform cell seeding strategies in tissue engineering.
in Journal of the Royal Society, Interface
Description | This funding enabled a new programme of research to be established, where we set up mathematical and computational modellers working alongside experimental tissue engineers. We made progress towards understanding the inter-relationship between tissue microenvironment (oxygen availability, growth factors that stimulate nerve regeneration) and therapeutic cell viability. We also made progress towards informing the design of engineered replacement tissues for peripheral nerve injury repair. |
Exploitation Route | We have ongoing funding for this research, which seeks to take this research to the next stage in testing the predictions of the computational models in in vitro and in vivo models. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
URL | https://www.nerve-engineering.ucl.ac.uk/ |
Description | This grant paved the way for establishing the Centre for Nerve Engineering at UCL, with the specific novelty of integrating approaches from the mathematical & engineering sciences, with the life and clinical sciences to better understand nerve injury repair and treatment options. This EPSRC funding established proof-of-concept of the use of mathematical models and integrating with experimental data to describe neurone regrowth after injury - this led to a further EPSRC Healthcare Technology Challenge Award, and subsequent funding (e.g. from the Rosetrees Trust) to accelerate translation of the resulting technologies. We also established a patient network/ engagement activity which continues to this day, in collaboration with our hospital partners (Royal National Orthopaedic Hospital, UCLH Trust). |
First Year Of Impact | 2018 |
Sector | Pharmaceuticals and Medical Biotechnology |
Impact Types | Societal |
Description | Improving nerve grafting using biomaterials(UCL Rosetrees Stoneygate Prize 2018) |
Amount | £245,568 (GBP) |
Funding ID | M827 |
Organisation | Rosetrees Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2019 |
End | 03/2022 |
Description | Mathematical Modelling Led Design of Tissue-Engineered Constructs: A New Paradigm for Peripheral Nerve Repair (NerveDesign) |
Amount | £1,080,646 (GBP) |
Funding ID | EP/R004463/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2018 |
End | 12/2023 |
Description | Collaboration with nervous system tissue engineers at the UCL School of Pharmacy |
Organisation | University College London |
Department | School of Pharmacy |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have collaborated by combining with data on outcomes of therapeutic cells for peripheral nerve injury repair, in vitro models. These data have incorporated response of cells to different oxygen environments representative of the range of microenvironments experienced by therapeutic cells in vivo. These data have informed mathematical models that predict inter-relationship between cell fate, oxygen environment and growth factor expression. |
Collaborator Contribution | The partner have provided the experimental facilities, expertise, therapeutic cells and analysis techniques. |
Impact | This is a multidisciplinary collaboration between mathematical modellers and engineers (myself), tissue engineers and cell biologists (UCL School of Pharmacy). This has resulted in joint research papers, conference presentations and engagement efforts, as reported in the full grant report. |
Start Year | 2017 |
Description | Nerve Injury Community Day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Centre for Nerve Engineering: Nerve Injury Community Day (16th November 2019) - an opportunity for people with nerve injuries and their loved ones to learn more, share experiences and meet researchers in the field. Interactive workshops including discussions around novel therapies, patient impacts, and presenting research stalls to attendees. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.eventbrite.co.uk/e/nerve-injury-community-day-with-ucl-centre-for-nerve-engineering-tick... |
Description | Podcast |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | I recorded two podcasts with the Naked Scientists on the role of interdisicplinary approaches to tissue engineering to address peripheral nerve injury repair. |
Year(s) Of Engagement Activity | 2017,2018 |
URL | https://mecheng.ucl.ac.uk/rebeccashipley/news/podcast-naked-scientists/ |