Smith, Poppy Olivia; (2025) The application of endothelial cells in peripheral nerve tissue engineering. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Traumatic peripheral nerve injury has a sudden, debilitating effect on millions of people every year, resulting in loss of sensation and movement, significantly reducing quality of life. The standard clinical treatment to repair peripheral nerve injuries which result in a gap in the nerve tissue, is the nerve autograft. The autograft has multiple limitations including donor site morbidity and availability, donor-recipient nerve mismatches, and poor patient satisfaction. Tissue engineering offers a promising alternative, engineered neural tissue (EngNT) constructs comprised of aligned cells in an aligned collagen matrix. However, cell source and production time can limit the clinical translatability of EngNT constructs. Endothelial cells play a crucial role early in the nerve regeneration process, forming polarised vascular structures that bridge the gap in the nerve tissue and act as guidance tracks for migrating Schwann cells and regenerating axons. However, the benefit of mimicking these vascular structures in EngNT constructs is yet to be assessed due to the challenge of forming aligned endothelial tube-like structures within a stabilised construct. This project sought to advance EngNT constructs towards the clinic by automating the nerve repair construct fabrication process, achieved by integrating a robotic positioning system with a computer-controlled syringe pump. This technique produced nerve repair constructs from cellular collagen hydrogels in ~1 minute, with the potential to scale up production for commercialisation. Additionally, human induced pluripotent stem cells (hiPSCs), previously reprogrammed from clinical-grade neural stem cells, were successfully differentiated into endothelial cells, and characterised by immunocytochemistry, RT-qPCR and functional assays. These endothelial cells were used to produce viable and aligned EngNT constructs, capable of supporting neurite growth in vitro. Furthermore, the endothelial cells within the constructs developed into a 3D network of highly aligned tube-like structures after 4 days in culture, mimicking the polarised vascular structures seen in native regenerating nerve tissue.

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