A biomaterials approach to peripheral nerve regeneration: bridging the peripheral nerve gap and enhancing functional recovery

Abstract

Microsurgical techniques for the treatment of large peripheral nerve injuries (such as the gold standard autograft) and its main clinically approved alternative--hollow nerve guidance conduits (NGCs)--have a number of limitations that need to be addressed. NGCs, in particular, are limited to treating a relatively short nerve gap (4 cm in length) and are often associated with poor functional recovery. Recent advances in biomaterials and tissue engineering approaches are seeking to overcome the limitations associated with these treatment methods. This review critically discusses the advances in biomaterial-based NGCs, their limitations and where future improvements may be required. Recent developments include the incorporation of topographical guidance features and/or intraluminal structures, which attempt to guide Schwann cell (SC) migration and axonal regrowth towards their distal targets. The use of such strategies requires consideration of the size and distribution of these topographical features, as well as a suitable surface for cell-material interactions. Likewise, cellular and molecular-based therapies are being considered for the creation of a more conductive nerve microenvironment. For example, hurdles associated with the short half-lives and low stability of molecular therapies are being surmounted through the use of controlled delivery systems. Similarly, cells (SCs, stem cells and genetically modified cells) are being delivered with biomaterial matrices in attempts to control their dispersion and to facilitate their incorporation within the host regeneration process. Despite recent advances in peripheral nerve repair, there are a number of key factors that need to be considered in order for these new technologies to reach the clinic.

Figures

Figure 1.

Regenerative sequence occurring within a hollow NGC. Figure adapted from Belkas et al. [7]. This regenerative process occurs in five main phases: (1) the fluid phase: plasma exudate fills the conduit resulting in accumulation of neurotrophic factors and ECM molecules; (2) the matrix phase: an acellular fibrin cable forms between the proximal and distal nerve stumps; (3) the cellular phase: Schwann cells, endothelial cells and fibroblasts migrate (from the proximal and distal nerve stumps), align and proliferate along the fibrin cable forming a biological tissue cable; (4) axonal phase: re-growing axons use this biological tissue cable to reach their distal targets; (5) myelination phase: Schwann cells switch to a myelinating phenotype and associated with regenerated axons forming mature myelinated axons.

Figure 2.

Summarized schematic of the structural repair strategies used for improving existing hollow nerve guidance conduits. Repair strategies include the use of intraluminal guidance structures and micro-grooved luminal designs to provide additional structure support and topographical guidance to regenerating axons and migrating Schwann cells. A similar strategy involves using electrospun fibrous conduits with the advantages of high flexibility and porosity, a high surface area-volume and fibres that can be aligned for guided Schwann cell migration and proliferation and axonal growth. Variations in conduit design include the use of multi-channel conduits for control of axonal dispersion, as well as designs which optimize nutrient exchange or introduce external stimuli. These designs may be used alone or in combination, but also require further surface functionalization. These surface modifications can increase cell adhesion, migration, alignment and proliferation.

Figure 3.

Schematic of cellular and molecular-based therapies used for the creation of a more conductive nerve microenvironment. Examples of molecular therapies include growth factors (VEGF and bFGF) and neurotrophic factors (NT3 and NGF). Likewise cell therapies involve the use of SCs, stem cells (ASCs and MSCs) and genetically modified cells (SCs overexpressing GDNF). These can be delivered by a number of means including: (i) suspension within solution or a biomaterial matrix (hydrogel, sponge), (ii) released via a diffusion-based systems (controlled released via cross-linking, slow degrading polymer coatings etc. from luminal wall), (iii) the use of affinity-based delivery systems (factors conjugated to a fibrin matrix), and (iv) microsphere (e.g. collagen, fibrin) encapsulation which can either be suspended within the lumen or released from the luminal wall.