Translational bioengineering strategies for peripheral nerve regeneration: opportunities, challenges, and novel concepts

Abstract

Peripheral nerve injuries remain a challenging problem in need of better treatment strategies. Despite best efforts at surgical reconstruction and postoperative rehabilitation, patients are often left with persistent, debilitating motor and sensory deficits. There are currently no therapeutic strategies proven to enhance the regenerative process in humans. A clinical need exists for the development of technologies to promote nerve regeneration and improve functional outcomes. Recent advances in the fields of tissue engineering and nanotechnology have enabled biomaterial scaffolds to modulate the host response to tissue repair through tailored mechanical, chemical, and conductive cues. New bioengineered approaches have enabled targeted, sustained delivery of protein therapeutics with the capacity to unlock the clinical potential of a myriad of neurotrophic growth factors that have demonstrated promise in enhancing regenerative outcomes. As such, further exploration of combinatory strategies leveraging these technological advances may offer a pathway towards clinically translatable solutions to advance the care of patients with peripheral nerve injuries. This review first presents the various emerging bioengineering strategies that can be applied for the management of nerve gap injuries. We cover the rationale and limitations for their use as an alternative to autografts, focusing on the approaches to increase the number of regenerating axons crossing the repair site, and facilitating their growth towards the distal stump. We also discuss the emerging growth factor-based therapeutic strategies designed to improve functional outcomes in a multimodal fashion, by accelerating axonal growth, improving the distal regenerative environment, and preventing end-organs atrophy.

Keywords: Schwann cells; bioengineering; biomaterials; growth hormone; insulin-like growth factor 1; nanotechnology; neurobiology; peripheral nerve regeneration; translational research.

Figure 1

Engineering biomaterials with specific regenerative cues. (A) Topographical cues provide a surface for regenerating axons, mimicking the Bands of Büngner of peripheral nerve tissue. (B) Biochemical cues (growth factors) activate the senescent Schwann cells in the distal stump and maintain the motor endplates in the denervated target muscle. (C) Electrically conductive biomaterial scaffolds stimulate nerve regeneration and guide the growth of the leading cone.

Figure 2

Minimizing scarring at the repair site. (A) A novel nanofiber nerve wrap made of nonwoven electrospun polycaprolactone fibers was created with specific design principles to polarize the invading macrophages into a pro-regenerative phenotype. (B) When compared to the gold standard simple epineural repair, the use of this wrap resulted in decreased fibrosis at the repair site as evidenced by gross surgical examination (scale bars: 1 mm in a and b) and Masson’s Trichrome collagen staining (scale bars: 100 μm in c and d). There was also an increased number of regenerating myelinated axons (scale bars: 10 μm in e and f), and an attenuation of target muscle atrophy (scale bars: 50 μm in g, and h) as a result of an earlier and more robust reinnervation. Reprinted with permission from Sarhane et al. (2019a).

Figure 3

Improving the regenerative environment in the distal stump. (A) A chronic denervation tibial nerve model in rats was used. (B) Twelve weeks following the denervation surgery, a peroneal to tibial nerve transfer was performed. The distal stump was injected with the corresponding growth factors embedded in fibrin glue, glial-derived neurotrophic factor (GDNF), and chondroitinase (CDN). (C) Five weeks following nerve transfer, (i) immunofluorescent staining was performed to understand the mechanisms through which GDNF and CDN promote axonal growth. The injection of GDNF resulted in the upregulation of Ki67 in Schwann cells (i.a). The injection of CDN in resulted in the degradation of chondroitin sulfate proteoglycans (ii.b). In addition, retrograde labeling of neurons regenerating their axons was performed eight millimeters distal to the coaptation site. Sensory neurons in the dorsal root ganglia (ii), and ventral horn cells in the spinal cord (iii) were counted to assess motor and sensory neuron regeneration, respectively. The distal stump (iv) was sent for nerve histomorphometry. Reprinted with permission from Sarhane et al. (2019b). a: Proximal common peroneal nerve; b: distal stump of the common peroneal nerve; c: injection into the denervated tibial nerve; d: tibial nerve; n.: nerve.