Gregory, Holly Nicole; (2023) Nanofibrous biomaterials with encapsulated therapeutics and aligned architecture for peripheral nerve regeneration. Doctoral thesis (Ph.D), UCL (University College London).

Text HGregory thesis.pdf - Accepted Version Access restricted to UCL open access staff until 1 November 2024. Download (5MB)

Abstract

Traumatic damage to peripheral nerve often requires surgical intervention for sensory and motor recovery. When a large defect in the nerve tissue is evident this usually involves implanting an autologous nerve graft as a bridge, but liberating this donor tissue has a number of shortcomings. Nerve-mimicking biomaterials would be valuable alternatives to this technique, and the incorporation of regenerative therapeutics and aligned topography may further improve patient outcomes. This thesis aims to fabricate these scaffolds using electrospinning and investigate their functional characteristics and interactions with neuronal cell types. Tacrolimus is an immunosuppressive macrolide which potently promotes nerve regeneration. Here, tacrolimus-loaded poly-ε-caprolactone (PCL) fibres were developed and drug release profiles over one month were achieved. Schwann cells adhered to the fibres and displayed upregulated expression of key neurotrophic factors. Tri-layered materials with aligned outer fibres and a tacrolimus-loaded interior were also fabricated and formed into three-dimensional constructs, where drug release was sustained over six weeks. Glial cell line-derived neurotrophic factor (GDNF) is a critical protein that encourages regeneration after nerve injury. GDNF-loaded PCL nanofibres were manufactured with uniform morphology and controlled release of protein over six weeks. Nanofibre eluents were not detrimental to cultures of primary neurons and glial cells, and so the material was used as the central component of a tri-layered scaffold. The outer aligned layers of this formulation significantly increased the alignment and length of neurites extending from primary rat neurons seeded on the surface. The tri-layered material released GDNF continuously for six weeks, and could support the attachment and outgrowth of primary rat neurons. This work has generated robust formulations of multi-layered electrospun biomaterials, which display sustained release of either a protein or a small molecule in addition to aligned architecture. These biomaterials have the potential to improve regeneration in the context of peripheral nerve injury.

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