Biomimetic Strategies for Peripheral Nerve Injury Repair: An Exploration of Microarchitecture and Cellularization

Abstract

Injuries to the nervous system present formidable challenges to scientists, clinicians, and patients. While regeneration within the central nervous system is minimal, peripheral nerves can regenerate, albeit with limitations. The regenerative mechanisms of the peripheral nervous system thus provide fertile ground for clinical and scientific advancement, and opportunities to learn fundamental lessons regarding nerve behavior in the context of regeneration, particularly the relationship of axons to their support cells and the extracellular matrix environment. However, few current interventions adequately address peripheral nerve injuries. This article aims to elucidate areas in which progress might be made toward developing better interventions, particularly using synthetic nerve grafts. The article first provides a thorough review of peripheral nerve anatomy, physiology, and the regenerative mechanisms that occur in response to injury. This is followed by a discussion of currently available interventions for peripheral nerve injuries. Promising biomaterial fabrication techniques which aim to recapitulate nerve architecture, along with approaches to enhancing these biomaterial scaffolds with growth factors and cellular components, are then described. The final section elucidates specific considerations when developing nerve grafts, including utilizing induced pluripotent stem cells, Schwann cells, nerve growth factors, and multilayered structures that mimic the architectures of the natural nerve.

Keywords: Cellularized pathways; Nerve guidance conduit; Peripheral nerve regeneration; Synthetic scaffolds.

Fig. 1

Schematic of nerve anatomy. Nerves are protected by fat and other connective tissues. The outermost layer is the epineurium, which contains nerve fascicles, vasculature, and connective tissue. Nerve fascicles are surrounded by perineurium. Within fascicles, Schwann cells wrap around axons to increase nerve conduction and also play a protective role in axon regeneration following PNI. Adapted from Hendriks et al. [12]

Fig. 2

Schematic of Wallerian degeneration and peripheral nerve regrowth. At the time of nerve injury (a), biomolecular signals promote degeneration of the distal portion of the axon (b). As regeneration begins, Schwann cells support the growing axon (c), which must regrow from the injury site to its end destination (d). Adapted from Fix [21]

Fig. 3

Current interventions for peripheral nerve injury repair. Gap lengths between severed nerve endings are an important factor in determining the appropriate intervention. Direct sutures are recommended for very short gap injuries that span 0.0–0.5 cm in length. Nerve guidance conduits, currently, are recommended for gap injuries in the range of 0.5–1.5 cm. Allografts are indicated in longer PNI gap lengths 1.0–5.0 cm, and autografts are indicated for any nerve injury greater than 1.0 cm [30]. This diagram shows the paucity of intervention options, especially in patients with longer gap injury lengths

Fig. 4

E1001K Bioriented scaffold electro-spun from a tyrosine-derived polymer, E1001(1k), at high speed (2000 rpm) to obtain oriented fibers (a) and then at low speed (200 rpm) to obtain unoriented fiber (b) (unpublished)

Fig. 5

Primary Rat Schwann cells. A representative image of rat Schwann cells with highly aligned projections grown in vitro (unpublished)

Fig. 6

Schematic of various bio-engineered, functional conduits. Reproduced with the permission of the Authors from Carvalho et al. [4]

Fig. 7

Schematic of growth factors associated with Schwann cell response to axonal myelination and injury. During development and growth, Schwann cells form either myelinating or “bundling” (Remak) phenotypes. In response to injury, Schwann cells facilitate axonal and myelin debris degradation and removal. Specific growth factors participate in these processes, as shown above. Such growth factors may be critical for incorporation into nerve conduits. Reproduced from Salzer et al. [161]; this work is licensed under the Creative Commons Attribution-NonCommerical-ShareAlike 3.0 Unported Licence (http://creativecommons.org/licences/by-nc-sa/3.0/)