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Peripheral nerve injuries (PNI) affect millions of patients worldwide and cause motor and sensory dysfunction leading to reduced quality of life and increased healthcare costs. The primary treatment option for repairing large PNIs is to use patient’s own nerve graft – an autograft, which is limited by availability and donor site morbidity. In this study, we aim to prepare an off-the-shelf advanced nerve guidance conduit (NGC) with capacity to regenerate critical-sized PNI as effectively, but overcoming the associated limitations of utilising autografts.
Advanced NGCs were composed of two phases – an outer tubular shell composed of collagen type I (Coll) and internal matrix composed of Coll, chondroitin-6-sulphate (CS) that was enriched by adding series of extracellular matrix derived molecules, namely fibronectin, laminin 1 and laminin 2 (Coll-CS-ECM). NGCs with Coll-CS and Coll-CS-ECM were tested for their neurotrophic and immunomodulatory potential in vitro using rat dorsal root ganglia (DRGs) explant culture. Following this, NGCs with Coll-CS (n=16) and Coll-CS-ECM (n=16) and autografts (n=16) were implanted in a large (15 mm) critical-sized rat sciatic nerve defect model.
In vitro analysis showed that in comparison to Coll-CS conduits, Coll-CS-ECM significantly decreased DRGs’ secretion of inflammatory markers such as interferon gamma-induced protein 10, monocyte chemoattractant protein 1 and macrophage inflammatory protein 1a and significantly increased DRGs’ production of nerve growth factor, vascular endothelial growth factor and interleukin-6.
In vivo analysis showed that sensory and motor function recovery improved significantly over time in all animals. Notably, the response of the two NGCs to electrical stimulation was similar to the autograft group and no differences were seen in recordings of compound nerve action potential and compound muscle action potential either. Consistent with these results, no significant differences in muscle weight loss were observed between either NGC and autograft group. Importantly, the total area of neurofilament positive staining and the number of myelinated axons within both NGCs was similar to autografts. However, in agreement with our in vitro results, Coll-CS-ECM significantly increased vascularisation inside the conduit when compared to Coll-CS and autograft. This demonstrates the ability of the ECM molecules to direct early regeneration across a large nerve defect.
Collectively, our results demonstrated that enrichment of a NGC with ECM derived molecules such as fibronectin, laminin 1 and laminin 2 resulted in a biomaterial capable of modulating immune response and increasing secretion of pro-repair molecules that ultimately resulted in bridging large PNIs to a level equivalent to an autograft indicating its potential as a new clinical therapy for repairing large nerve defects.
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