Engineering a multimodal nerve conduit for repair of injured peripheral nerve

Abstract

Injury to nerve tissue in the peripheral nervous system (PNS) results in long-term impairment of limb function, dysaesthesia and pain, often with associated psychological effects. Whilst minor injuries can be left to regenerate without intervention and short gaps up to 2 cm can be sutured, larger or more severe injuries commonly require autogenous nerve grafts harvested from elsewhere in the body (usually sensory nerves). Functional recovery is often suboptimal and associated with loss of sensation from the tissue innervated by the harvested nerve. The challenges that persist with nerve repair have resulted in development of nerve guides or conduits from non-neural biological tissues and various polymers to improve the prognosis for the repair of damaged nerves in the PNS. This study describes the design and fabrication of a multimodal controlled pore size nerve regeneration conduit using polylactic acid (PLA) and (PLA):poly(lactic-coglycolic) acid (PLGA) fibers within a neurotrophin-enriched alginate hydrogel. The nerve repair conduit design consists of two types of PLGA fibers selected specifically for promotion of axonal outgrowth and Schwann cell growth (75:25 for axons; 85:15 for Schwann cells). These aligned fibers are contained within the lumen of a knitted PLA sheath coated with electrospun PLA nanofibers to control pore size. The PLGA guidance fibers within the nerve repair conduit lumen are supported within an alginate hydrogel impregnated with neurotrophic factors (NT-3 or BDNF with LIF, SMDF and MGF-1) to provide neuroprotection, stimulation of axonal growth and Schwann cell migration. The conduit was used to promote repair of transected sciatic nerve in rats over a period of 4 weeks. Over this period, it was observed that over-grooming and self-mutilation (autotomy) of the limb implanted with the conduit was significantly reduced in rats implanted with the full-configuration conduit compared to rats implanted with conduits containing only an alginate hydrogel. This indicates return of some feeling to the limb via the fully-configured conduit. Immunohistochemical analysis of the implanted conduits removed from the rats after the four-week implantation period confirmed the presence of myelinated axons within the conduit and distal to the site of implantation, further supporting that the conduit promoted nerve repair over this period of time. This study describes the design considerations and fabrication of a novel multicomponent, multimodal bio-engineered synthetic conduit for peripheral nerve repair. AbstractInjury to nerve tissue in the Peripheral Nervous System (PNS) results in long-term impairment of limb function, dysaesthesia and pain, often with associated psychological effects. Whilst minor injuries can be left to regenerate without intervention and short gaps up to 2 cm can be sutured, larger or more severe injuries commonly require autogenous nerve grafts harvested from elsewhere in the body (usually sensory nerves). Functional recovery is often suboptimal and associated with loss ...

Peripheral Nerve Regeneration by Secretomes of Stem Cells from Human Exfoliated Deciduous Teeth

“…BDNF promotes motor neuron survival and differentiation [54,55]. NT-3 supports myelin formation by enhancing SC motility and migration [56,57]. CNTF is a neuroprotective agent that facilitates remyelination [58,59].…”

Scaffolds for Peripheral Nerve Regeneration, the Importance of In Vitro and In Vivo Studies for the Development of Cell-Based Therapies and Biomaterials: State of the Art

“…These conduits require a second surgery in order to remove the non-resorbable material. The original idea was to provide support, structure to guide axonal regrowth and form a stable barrier against connective tissue infiltration [73,100,101]. Synthetic nerve conduits made of ePTFE were successfully applied in a 4-cm nerve gap, in human [102].…”

Speculations on the Use of Marine Polysaccharides as Scaffolds for Artificial Nerve ‘Side-’Grafts

“…Alginate hydrogels have been used as lumen fillers in association with growth factors such as LIF, a pleiotrophic protein [74,153], fibroblastic growth factor 2 (FGF2) [154] and glial derived growth factor (GGF) [155,156]. Alginate hydrogels have been used as lumen fillers in association with cells, such as Schwann cells [58,157], allogenic Schwann cells [158] and olfactory ensheathing cells (OECs), Schwann cells (SCs) and bone marrow stromal cells (BMSCs) [159].…”