Developing functionalised electrospun scaffolds to exploit neural–stromal interactions in wound healing (Industry Project)

The ABM CDT is a partnership between The Universities of Manchester and Sheffield. ALL APPLICATIONS should however, be submitted via the Manchester application system only.

The skin and other epithelial surfaces such as the oral mucosa play a critical role as a barrier to pathogens and other environmental insults. These epithelial surfaces are vulnerable to injury, necessitating efficient wound-healing responses. These responses can be affected by many factors, including diseases such as diabetes, as well as cancer therapy and ageing. Defective wound healing is a major cause of ill health and poor quality of life, and poses a huge economic burden on the NHS. Peripheral neuropathy, the loss of neurons from the connective tissue underlying epithelial barriers, is strongly implicated in defective wound healing associated with disease and ageing. Our preliminary in-vivo data (using an ear denervation model) demonstrate that denervation significantly impairs wound healing, and our in-vitro studies have elucidated potential mechanisms underpinning this impaired response. These data provide evidence that fibroblasts, the predominant cell type found in connective tissue, are stimulated to differentiate into myofibroblasts, a process critical for effective wound healing, by secreted neural mediators such as soluble and/or extracellular vesicle-associated neuropeptides and growth factors, generated by sensory neurons.

Effective treatments for chronic wounds are limited and present a significant unmet clinical need. This project aims to further understanding of biological pathways underpinning neural interactions in wound healing and develop advanced functionalised electrospun scaffolds to deliver neural factors and promote and control healing. These materials will provide therapeutic tools for rapid clinical translation.

Project Description (max 1,000 words):

The skin and other epithelial surfaces such as the oral mucosa play a critical role as a barrier to pathogens and other environmental insults. These epithelial surfaces are vulnerable to injury, necessitating efficient wound-healing responses. These responses can be affected by many factors, including diseases such as diabetes, as well as cancer therapy and ageing. Defective wound healing is a major cause of ill health and poor quality of life, and poses a huge economic burden on the NHS. Peripheral neuropathy, the loss of neurons from the connective tissue underlying epithelial barriers, is strongly implicated in defective wound healing associated with disease and ageing. Our preliminary in-vivo data (using an ear denervation model) demonstrate that denervation significantly impairs wound healing, and our in-vitro studies have elucidated potential mechanisms underpinning this impaired response. These data provide evidence that fibroblasts, the predominant cell type found in connective tissue, are stimulated to differentiate into myofibroblasts, a process critical for effective wound healing, by secreted neural mediators such as soluble and/or extracellular vesicle-associated neuropeptides and growth factors, generated by sensory neurons. Effective treatments for chronic wounds are limited and present an unmet clinical need, which can be addressed by combining emerging advanced biomaterials with increased understanding of the cell biology of wound healing to develop novel, readily-translatable therapeutic tools.

In this project, we propose to use functionalised electrospun scaffolds to deliver neural factors to promote wound healing. This project brings together an interdisciplinary team with the expertise in cell biology, advanced biomaterials and neuroscience required to deliver its objectives.

Main questions to be answered:

Aim 1 (0–6m): Generate and characterise electrospun scaffolds

Electrospun membranes (PLA, PCL) will be manufactured using a commercially-available rig (Bionicia) and characterised as previously optimised in Dr Ortega’s laboratory.1

Aim 2 (0–12m): Assess effects of neural mediators on wound healing in vitro

We have previously reported endothelin-1 is able to promote wound-healing responses in vitro.2 Here we will expand these observations to test the effect of a panel of other neural mediators (eg CGRP, substance P) and extracellular vesicles derived from primary neurons on wound-healing responses.

Aim 3 (6–18m): Functionalise scaffolds with neuronal mediators

We will use our experience in modification of electrospun scaffolds to incorporate neural mediators. We will assess their incorporation and release kinetics using techniques well-established in our laboratory.

Aim 4 (18–24m): Assess the effect of functionalised scaffolds on wound healing in vitro

We will assess the effect of functionalised scaffolds on wound-healing responses in vitro.

Aim 5 (24–38m): Assess the influence of functionalised scaffolds on wound healing in vivo. We have preliminary evidence of defective wound healing in mice with experimentally-induced denervation of the affected area (using an ear denervation model). Here, we will use this model to examine the efficacy of the functionalised electrospun scaffolds from Aims 1–4.