Bartlett, Richard D; (2020) Tissue Engineering & Regenerative Medicine to Repair the Spinal Cord. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

Spinal cord injury (SCI) affects between 250,000 and 500,000 new people each year worldwide. It commonly leads to severe disability, yet current treatments are limited. Cell therapies offer one promising approach to repair the damaged spinal cord. Specifically, olfactory ensheathing cells (OECs) have demonstrated convincing efficacy in animal models and they can be safely harvested from human patients to facilitate autologous transplant. However, approximately only 1 % of OECs remain viable at the lesion site after transplantation. This project aimed to enhance the delivery of OECs using biomaterial and tissue engineering approaches. Mechanical properties play a critical role in determining cellular behaviour and rat spinal cord tissue was first comprehensively characterised using compressive dynamic mechanical analysis. Biomaterials suitable for clinical use and scalable for good manufacturing practice (GMP) production were then tuned to match the mechanical properties of the spinal cord and their suitability for OEC transplantation assessed. Low concentration fibrin hydrogels conferred the highest levels of OEC survival in vitro, and both collagen and fibrin hydrogels significantly increased the proportion of cells expressing a key repair marker (p75NTR). In vivo testing using a rat model of cervical SCI showed that fibrin OEC hydrogels significantly improved forepaw posturing and function relative to collagen OEC hydrogels. This was corroborated by increased OEC survival and a more favourable host cell response. An emerging magneto-responsive system was then explored to create aligned OEC hydrogels in situ, with the aim of developing a cell delivery technology capable of promoting organised neuroregeneration at the spinal cord lesion. The response of OECs in low oxygen environments was also explored, in order to assess the effect of OEC transplantation into the hypoxic spinal cord lesion site microenvironment. Overall, tissue engineering approaches enhanced the delivery of OECs for spinal cord repair, facilitating early functional improvement and effective cell retention.

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