Suannun, Titinun; (2022) Development of Tethered Aligned Engineered Neural Tissue Containing Elongated Neurons for Peripheral Nerve Regeneration. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Following peripheral nerve injury, the axons in the distal nerve between the injury site and the muscle degenerate. When the injured site is very proximal, functional recovery from nerve repair is a clinical challenge since neuronal regeneration rate is limited, resulting in muscle atrophy due to the delay in reinnervation, even where the ‘gold standard’ autograft is used. Much research focuses on developing biomaterial scaffolds that mimic the autograft and promote host neurite regeneration from proximal to distal stump, whereas here, we aim to improve long distance repair by populating constructs with functional neurons and glial cells. With an engineered living scaffold populated with neurons exhibiting long neurite extensions supported by glial cells, the gap between proximal stump and muscle could potentially be reconnected promptly once the challenge of integration is overcome. To test the concept, a method was developed using tethered aligned engineered neural tissue (TaeNT) formed from simultaneous self-alignment of Schwann cells and collagen fibrils in a fully-hydrated tethered gel resulting in an anisotropic tissue-like structure. The in vitro results showed neurite elongation and alignment in the co-culture of neurons and Schwann cells in TaeNT, indicating that TaeNT could be an appropriate substrate for growing long neurites with a view to generating therapeutic constructs containing long functional neurons. The implantation of TaeNT containing neurons and Schwann cells in a 10mm-gap rat sciatic nerve for 3 weeks provided information about host-transplant cell interaction including Schwann cell migration and alignment inside the conduit, and neurite elongation across the conduit interface. Furthermore, in an attempt to induce longer neurite growth, TaeNT was proposed as a substrate that could be combined with mechanical tension application using a 3D-printed mould developed to stretch the cellular gels in a controlled manner. A series of newly designed protocols for mechanical tension application to induce growth response for enhanced neural regeneration was developed and discussed correspondingly. In summary, the findings represent the development and investigation of the regenerative potential for engineered living scaffolds containing neurons and Schwann cells suitable for stretch-growth to provide an elongated functional nerve graft. With a view to translation for clinical use, investigating the source of therapeutic cells in the conduit and the functional integration of host and transplanted cells is an important step towards optimising the regenerative potential of the engineered living scaffold.

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