Biohacking Nerve Repair: Novel Biomaterials, Local Drug Delivery, Electrical Stimulation, and Allografts to Aid Surgical Repair

Abstract

The regenerative capacity of the peripheral nervous system is limited, and peripheral nerve injuries often result in incomplete healing and poor outcomes even after repair. Transection injuries that induce a nerve gap necessitate microsurgical intervention; however, even the current gold standard of repair, autologous nerve graft, frequently results in poor functional recovery. Several interventions have been developed to augment the surgical repair of peripheral nerves, and the application of functional biomaterials, local delivery of bioactive substances, electrical stimulation, and allografts are among the most promising approaches to enhance innate healing across a nerve gap. Biocompatible polymers with optimized degradation rates, topographic features, and other functions provided by their composition have been incorporated into novel nerve conduits (NCs). Many of these allow for the delivery of drugs, neurotrophic factors, and whole cells locally to nerve repair sites, mitigating adverse effects that limit their systemic use. The electrical stimulation of repaired nerves in the perioperative period has shown benefits to healing and recovery in human trials, and novel biomaterials to enhance these effects show promise in preclinical models. The use of acellular nerve allografts (ANAs) circumvents the morbidity of donor nerve harvest necessitated by the use of autografts, and improvements in tissue-processing techniques may allow for more readily available and cost-effective options. Each of these interventions aid in neural regeneration after repair when applied independently, and their differing forms, benefits, and methods of application present ample opportunity for synergistic effects when applied in combination.

Keywords: allograft; autograft; electrical stimulation; nerve conduit; nerve regeneration; peripheral nerve injury.

Figure 1

The five phases of neural regeneration across a gap and selected implants to enhance regeneration in each. (A) Healing across a nerve deficit begins with (i) the secretion of ECM precursors, which (ii) coalesce to a matrix of ECM proteins, allowing (iii) cellular traversal of the deficit. (iv) These cells guide axonal growth, which is followed by (v) myelination [8,9,10,11]. (B) The current gold standard of repair across a deficit, autologous nerve graft, obtained through harvest of a patient sensory donor nerve. (C,D) Implantable scaffolds [25] and hydrogel systems [26] may be preloaded with cultured SC or SC-like cells [27]. (E) The incorporation of functional polymers that enhance electrical stimulation and conductivity allows for the preservation of denervated SC populations [27]. (F) Precise 3D printing of biocompatible scaffolds allows for the design of bifurcating and irregular scaffolds for improved topographic guidance [28]. (G–I) Topographic guidance features within walls [29] or intraluminal channels [30] and filaments [31] of a conduit encourage migration along its length. (J) Decellularization of allografts and xenografts allows for the removal of immunogenic components, leaving behind an ECM scaffold [32,33]. (K) The embedding of bioactive substances within conduit walls allows for the controlled, local release of the substance within the repair site [34]. (L) Porous, hollow conduits permit nutrient exchange while preventing cellular invasion [35].

Figure 2

Schematic representation of potential synergistic approaches to nerve repair. (A) Intraoperative electrical stimulation is applied proximal to the nerve repair site, commonly by hook electrodes. (B) Bioactive wraps and conduits can be fashioned around joined nerve stumps for the delivery of therapeutics such as drugs and neurotrophic factors and have shown promise in preclinical models. Wraps and conduits can also provide protection and topographic guidance cues to regenerating axons. (C) At this time, the use of acellular nerve allografts serves as a suitable method to avoid the donor morbidity associated with autografts.