Engineering the Future of Restorative Clinical Peripheral Nerve Surgery

Abstract

Peripheral nerve injury is a significant clinical challenge, often leading to permanent functional deficits. Standard interventions, such as autologous nerve grafts or distal nerve transfers, require sacrificing healthy nerve tissue and typically result in limited motor or sensory recovery. Nerve regeneration is complex and influenced by several factors: 1) the regenerative capacity of proximal neurons, 2) the ability of axons and support cells to bridge the injury, 3) the capacity of Schwann cells to maintain a supportive environment, and 4) the readiness of target muscles or sensory organs for reinnervation. Emerging bioengineering solutions, including biomaterials, drug delivery systems, fusogens, electrical stimulation devices, and tissue-engineered products, aim to address these challenges. Effective translation of these therapies requires a deep understanding of the physiology and pathology of nerve injury. This article proposes a comprehensive framework for developing restorative strategies that address all four major physiological responses in nerve repair. By implementing this framework, we envision a paradigm shift that could potentially enable full functional recovery for patients, where current approaches offer minimal hope.

Keywords: bioengineered tissue; nerve injury; nerve regeneration; neurological injury; tissue engineering.

Figure 1

Schematic of Uninjured and Injured Nerves. A) In healthy, uninjured nerves, axons extend from the proximal neurons either near or within the spinal cord and innervate the muscle and/or sensory end targets. Muscle targets are shown as an example in this schematic. Schwann cells are glial support cells within the nerve and are necessary for axon maturation and myelination. One major consideration for functional recovery prognosis is the nerve injury severity and the extent of damage to the underlying nerve architecture. B) Crush or compression nerve injury is the mildest form of nerve injury where the underlying nerve architecture remains intact, which either spares the axons (Neurapraxia) or results in axon degradation (axonotmesis). Immediately after injury, muscle function is diminished (as shown in yellow) and may return without surgical intervention. C) After nerve transection, Wallerian degeneration and surgical reconstruction are necessary for functional recovery. The most challenging clinical scenarios with the worst prognoses are cases with segmental nerve injury with gap lengths greater than 3 cm. Nerve reconstruction (in orange) can be achieved with various scaffolds, such as autograft, nerve guidance tube, or acellular nerve allograft. Distal nerve transfer is also an option.

Figure 2

Examples of various nerve injury locations. Another important consideration for functional recovery is the location of the nerve injury. In an uninjured nerve, Schwann cells surround the axons and provide support and myelination. Severe injury resulting in Wallerian degeneration leads to Schwann cell detachment, migration, and an elevated pro‐regenerative phenotype. Distance plays an important role in functional recovery because longer regenerative distances to the end target result in prolonged periods of denervation, which negatively impacts the regenerative capacity of the distal Schwann cells and muscles. Additionally, the location of the injury impacts proximal neuron survival. For example, the risk of motor neuron loss increases after ventral avulsion and/or increased proximal injury compared to distal injury.

Figure 3

Schematic of early nerve repair. A) Shortly after segmental injury, axons in the distal nerve undergo Wallerian degeneration and breakdown, and the Schwann cells align into a temporary pro‐regenerative phenotype. B) For nerve repairs completed in the acute injury phase, axons use the pro‐regenerative Schwann cells to extend through the otherwise denervated distal nerve. C) Early nerve repair increases the likelihood of greater muscle reinnervation, with an increased prognosis for functional recovery.

Figure 4

Schematic of delayed nerve repair. A) After the segmental injury, axons in the distal nerve undergo Wallerian degeneration. Schwann cells align in a temporary pro‐regenerative phenotype. B) While spontaneous recovery may occur in less severe trauma, surgical reconstruction is critical for functional recovery in severe cases with a defect. In this prolonged period without axonal contact, degradation of the distal pro‐regenerative environment and muscle atrophy may diminish the potential for recovery. C) Following delayed nerve repair, functional recovery depends on the location of the injury site (i.e., proximal muscles may have greater recovery than distal muscles).In cases of proximal nerve injury, functional recovery may be achieved in muscles with a shorter regenerative distance than a distal muscle target.

Figure 5

Current clinical nerve repair strategies. To date, clinically available repair strategies focus on facilitating functional recovery by enabling axon regeneration across a defect via bridging strategies, preserving reinnervation capacity via babysitting, or enhancing regeneration via pro‐regenerative adjuncts. However, these approaches do not achieve adequate functionality, and additional work is necessary.

Figure 6

Potential strategies to enhance nerve regeneration and functional recovery. Current acellular approaches, including biomaterials, extracellular matrix, and growth factors, primarily focus on facilitating axonal extension and ignore the importance of the survival of injured neurons and the reinnervation capacity of denervated muscle. Novel pro‐regenerative and anti‐degenerative biological agents (e.g., small molecules, mRNA, siRNA, etc) are currently being developed to enhance functional recovery by enhancing regeneration and preventing atrophy. Engineered tissue serving as living scaffolds will likely be required to achieve greater restoration by replacing the lost nerve tissue with exogenous cells that can communicate with the endogenous host tissue.

Figure 7

Examples of potential tissue‐engineered medical products (TEMPs) and associated regenerative mechanisms of action. Several TEMPs are currently in development, aiming to address the major clinical challenges associated with functional restoration after peripheral nerve injury. For example, genetically modified xenografts can be utilized for nerve reconstruction without the need for harvesting a donor nerve. Alternatively, recellularized allografts and cell‐laden nerve conduits can provide a pro‐regenerative niche that promotes neuronal health and regeneration. Further advancements will lead to engineered replacement tissue that simultaneously serves as regenerative scaffolds while also providing functional benefits. For example, tissue‐engineered muscle caps may act as a surrogate end target for regenerating axons, thereby preserving regenerative capacity and preventing painful neuroma formation. Tissue‐engineered neuromuscular interfaces may be utilized to preserve the reinnervation capacity of denervated muscle with an exogenous source of axons. Tissue‐engineered nerve grafts may eventually become the gold standard for nerve reconstruction due to their ability to simultaneously preserve the regenerative capacity of the proximal neurons and denervated Schwann cells and maintain the reinnervation potential of denervated muscle.

Figure 8

Potential surgical algorithm for nerve injury management to maximize ceiling for potential recovery. The timing for nerve repair often depends on the severity of the injury. Clinicians will often “wait‐and‐see” if there is any spontaneous recovery before performing surgery. Although functional recovery often spontaneously occurs following crush injuries, more severe transection injuries require surgery to regain functionality. However, starting almost immediately after injury, the regenerative capacity of the injured proximal neurons diminishes without an appropriate end target, and the reinnervation potential of denervated muscle reduces without axonal contact. To address these issues, we propose early intervention using proximal babysitter grafts comprised of exogenous muscle/sensory tissue as a surrogate end target and distal babysitter grafts comprised of exogenous neurons as a surrogate axonal source. Delayed repairs can be subsequently performed using a bridging graft at a later time point following the removal of the babysitter grafts.

Figure 9

Potential clinical implementation of nerve fusion. Several clinical studies are currently underway testing the efficacy of nerve fusion. Although the exact mechanism remains unclear, it is believed that the direct reconnection of denucleated distal axons with proximal axons mitigates the harmful effects of prolonged denervation by rapidly restoring connectivity with the disconnected target muscles and/or sensory end organs. Although acute fusion is currently feasible, delayed fusion remains challenging due to catastrophic axonal fragmentation following Wallerian degeneration ≈3–7 days after injury. To address this issue, tissue‐engineered neuromuscular interfaces (TE‐NMI) can be deployed in the distal nerve to repopulate the denervated nerve sheath with exogenous axons. After the exogenous axons integrate with the denervated muscle/sensory end organ (based on clinical electrophysiological findings), the delayed fusion procedure will be completed during a second surgery that connects proximal axons with denucleated TE‐NMI axons. Similar to traditional repairs, tensionless coaptations will likely result in improved clinical recovery. However, TE‐NMI axon denucleation will create a non‐trivial segmental defect. Therefore, axon‐containing nerve grafts could be utilized for fusion across segmental defects greater than 5 mm long.