Peripheral Nerve Regeneration in the Hand

Minh Hoang Nguyen, MD

Amy M. Moore, MD

Ryan W. Schmucker, MD

Dr. Nguyen or an immediate family member has stock or stock options held in BioNTech. Dr. Moore or an immediate family member has received research or institutional support from Checkpoint Surgical, Inc. Neither Dr. Schmucker nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter.

INTRODUCTION

Peripheral nerve injuries are common and result in devastating functional outcomes. Fortunately, the peripheral nervous system (PNS) has the capability to regenerate. Nerve regeneration is a highly coordinated phenomenon and understanding the complexity is essential to diagnosis and treatment of patients with nerve injuries. It is important to review the basic principles of nerve injury and regeneration, and also explore innovations in surgical techniques and orthobiologic advances that have continued to move the field of nerve surgery forward.

ANATOMY, PHYSIOLOGY, AND BASIC CONCEPTS OF PERIPHERAL NERVE INJURIES

Normal Peripheral Nerve Anatomy and Physiology

Peripheral Nerve Fiber and Fascicular Anatomy

A fundamental understanding of nerve anatomy and physiology is essential to guide surgeons in the diagnosis and surgical management of peripheral nerve injuries. The PNS is a complex network that encompasses the nerves outside the brain and spinal cord and allows communication between the central nervous system and the body. The PNS is composed of afferent sensory nerve fibers, whose cell bodies are in the dorsal root ganglia, and efferent motor nerve fibers, whose cell bodies are in the anterior (ventral) horn of the spinal cord.

There are two basic types of cells within the nervous system: neurons and glial cells. Neurons are responsible for sending and receiving motor and sensory input throughout the body, whereas glial cells play a supportive role by maintaining homeostasis and forming the myelin sheath crucial to nerve function. There are two distinct types of axons: unmyelinated and myelinated. The myelin sheath of axons in the PNS is formed by Schwann cells (a type of glial cell) that wrap tightly around a single axon using multiple layers of plasma membrane. The gaps in the myelin sheath are called the nodes of Ranvier, which allow action potentials to pass rapidly between nodes in myelinated axons (saltatory conduction). Unmyelinated axons conduct action potentials slower and are mainly made up of C fibers that mediate nociception, temperature, and mechanical sensibilities.

The individual axon together with the surrounding Schwann cells is encased in a bilayered connective tissue structure called endoneurium (Figure 1). A bundle of several axons encased in endoneurium forms a fascicle and this is enveloped by perineurium composed of concentrically oriented layers of perineural cells. The functions of the perineurium are to protect the endoneurium from stretching forces, to maintain constant intrafascicular pressure and to serve as a blood-nerve barrier.¹,² Epineurium, the outermost connective tissue layer, envelopes multiple fascicles and provides structural support. External to the epineurium is an areolar layer that contains extrinsic blood supply called mesoneurium, which is critical for nerve gliding.

FIGURE 1 Illustration of the anatomy of the peripheral nerve. (Reproduced with permission from Power HA, Moore AM: Basic science of nerve compression, in Skirven TM, Osterman AL, Fedorczyck JM, Amadio PP, Feldscher SB, Shin EK, eds: Rehabilitation of the Hand and Upper Extremity, ed 7. Elsevier, 2019.)

Nerve Blood Supply

Peripheral nerves are similar to any other tissue in the body in that they require adequate blood supply to maintain their integrity and function (Figure 1). Peripheral nerves rely on an intricate dual blood supply network, which consists of an extrinsic plexus that contains small vessels from major arteries running longitudinally in the epineural layer,³ termed the vasa nervorum. The extrinsic plexus crosses the epineurium and perineurium to anastomose with the intrinsic system. Reduction or disruption of either extrinsic or intrinsic blood supply can contribute to nerve injury through local ischemia. The magnitude and duration of the insult dictates the severity of injury and its ability to recover.⁴,⁵,⁶,⁷,⁸

Basic Concepts of Peripheral Nerve Injury

Classification of Nerve Injury

When evaluating peripheral nerve injuries, it is important to understand the classification of nerve injuries as well as the mechanism of injury, level at which the injury occurred, chronicity, and patient-specific factors that can affect recovery. All these factors can guide surgeons in selecting the appropriate treatment in the setting of an acute or chronic nerve injury. The original classification of nerve injuries was first proposed by Seddon and Sunderland in 1947 and 1951, respectively.³ In the original Seddon classification, the injuries are grouped as neurapraxia, axonotmesis, and neurotmesis. Sunderland categorized nerve injury as grade I to V based on the degree of injury and what structure was involved (Table 1). Mackinnon and Dellon introduced the sixth degree in 1988.

TABLE 1 Classification of Nerve Injury (Sunderland and Seddon)

Classification		Histologic Changes	Wallerian Degeneration	Spontaneous Recovery
Sunderland	Seddon	Histologic Changes	Wallerian Degeneration	Spontaneous Recovery
I	Neurapraxia	Segmental demyelination without axonal injury	No wallerian degeneration	Fast Expect full recovery
II	Axonotmesis	Axonal injury	Wallerian degeneration of the nerve distal to the injury	Slow Expect full recovery
III	Axonotmesis	Axonal injury + endoneurium fibrosis	Same as second degree	Slow Partial recovery depending on severity
IV	Axonotmesis	Axonal injury + endoneurium and perineurium injury	No	None Surgery needed
V	Neurotmesis	Complete transection (damage to axon, endoneurium, perineurium, and epineurium)	No	None Surgery needed
Adapted with permission from Wood MD, Johnson PJ, Myckatyn TM: Anatomy and physiology for the peripheral nerve surgeon, in Mackinnon SE, ed: Nerve Surgery. Thieme, 2015.

Wallerian Degeneration

After incurring traumatic injury, the peripheral nerve stump distal to the injury undergoes changes at the cellular level referred to as wallerian degeneration. Axon degeneration does not begin immediately after the injury, with axonal segments distal to the injury able to conduct action potentials for up to 3 days after the insult.⁹,¹⁰ The hallmark of this degeneration process is the proteolysis and degeneration of the axonal cytoskeleton starting with sudden influx of mostly Ca⁺ ions.¹¹,¹²,¹³ This eventually leads to the fragmentation, disintegration, and removal of axons and their myelin sheath by both Schwann cells and macrophages.⁹,¹⁴,¹⁵ In addition to changes at the distal nerve stump, there are also changes that happen at the proximal stump, which usually are limited to the first node of Ranvier.

NERVE REGENERATION

Nerve regeneration is complex. After injury, there is activation of many signaling pathways and transcription factors that promote cellular changes from the injury site to the soma allowing for regeneration. These complex coordinated events include membrane sealing, growth cone assembly, protein synthesis, and activation of signaling molecules and transcription factors. Neurotrophic factors also play a significant role in promoting a regenerative environment. There are three major groups of neurotrophic factors: neurotrophins, neuropoietic cytokines (ciliary neurotrophic factor and interleukin 6), and fibroblast growth factors.¹⁶

At a cellular level, macrophages are critical in the myelin degradation part of wallerian degeneration as
well as in nerve regeneration. Nerve growth factor production is induced by the release of interleukin 1β by macrophages.¹⁷,¹⁸ The production of nerve growth factor and other growth factors such as insulinlike growth factor 1, ciliary neurotrophic factor, and brain-derived neurotrophic factor are promoted by Schwann cells following nerve transection. In addition, nerve growth factor receptors are also upregulated on the surface of the Schwann cells¹⁷ forming bands of Büngner.¹⁹ Bands of Büngner are columns that serve as pathways for growing sprouts. At the end of each sprout, there is a growth cone that sends out filopodia. The growth cones are essential in determining the growth direction of the sprout.

CLASSIC AND ALTERNATIVE APPROACHES TO NERVE REPAIR

Principles of Nerve Repair

Decisions regarding timing of nerve repair are multifactorial and must consider mechanism of injury (sharp, crush, avulsion), closed or open nature of the injury, patient stability and comorbidities, and ability to determine zone of injury. Early nerve repair has the advantages of less nerve end retraction, an unscarred field, and the ability to stimulate the distal nerve stump up to 72 hours after injury, which can be useful for aligning fascicles and determining topography. Given the slow regeneration rate, early repairs allow for earlier, and potentially improved recovery as motor end plate viability is typically only maintained for 12 to 18 months after the initial injury.²⁰,²¹ Because nerves are estimated to grow approximately 1 to 3 mm per day,²² earlier repair can help regenerating axons reach the muscle before muscle fibrosis occurs.

In general, open wounds with lack of nerve function should be explored for presumed nerve transection. Although often accompanied by an open wound, gunshot wounds are considered closed injuries as the blast mechanism allows the nerve to be moved out of the way. Thus, time for spontaneous recovery (6 months) should be allowed in the setting of gunshot wounds. In the setting of severely contaminated wounds or wounds with a large zone of injury, delayed repairs are beneficial to ensuring that the reconstruction is outside of the zone of injury.

For closed nerve injuries, such as with fractures and/or crush injuries, serial examinations are essential for monitoring recovery. Follow-up for patients with these injuries can begin with serial electromyography starting at approximately 10 weeks, which is the earliest time that motor unit action potentials would appear to indicate spontaneous recovery. If no recovery on electromyography or physical examination is detected by 3 to 6 months, surgical intervention is warranted.

Direct Nerve Repair

In 1972, Hanno Millesi introduced the technique of tension-free repair, which is now one of the basic tenets of nerve repair. Direct end-to-end tension-free nerve repair can be achieved in sharp transection injuries with minimal tissue loss. Loose epineurial repair is used most commonly as opposed to grouped fascicular repairs. Nerve ends are oriented visually by using visible fascicular matching and aligning any superficial vasa nervorum present in the epineurium for reference. If the topography of a mixed motor nerve is well known to the surgeon or able to be identified by distal nerve stump stimulation, then a fascicular repair can be performed. In situations where this is not possible, loose epineurial repair is preferable because of the principle of contact guidance whereby the nerves are guided by spatial cues and neurotrophic factors orient to their appropriate distal fascicles.

Nerve preparation is critical in achieving a successful nerve repair. Identifying and getting outside of the zone of injury is essential for success. Both nerve ends should be identified and débrided back to healthy bulging fascicles and evidence of intraneural blood flow. Nerve coaptation is achieved using 9-0 nylon sutures under microscopic or loupe magnification.²³ The extremity should be moved through full range of motion to ensure there is no tension on the repair and/or to assess the need for immobilization to protect the repair. Flexing joints to allow for primary repair is not recommended. If there is tension on the coaptation with range of motion, nerve grafting should be considered.

Management of Nerve Gap With Autologous Nerve Graft

When nerve gaps are encountered and nerves are not able to be coapted primarily, there are multiple options for bridging these gaps²⁴ (Table 2). Autologous nerve grafts are still currently considered the gold standard for nerve repair when gaps are present. Autologous nerves provide not only the essential scaffolding structure for nerve regeneration but also include endoneurial tubes, vascular bridges, and the critical cells that support regeneration, that is, Schwann cells. Small thin grafts and grafts that are shorter in length revascularize sooner and are often more reliable than long grafts and grafts with increasing diameter.

There are several factors that help determine the donor autograft, including donor nerve caliber and length, donor site morbidity, ease of harvest, and positioning. Two of the most commonly used donor nerves are sural nerve and medial antebrachial cutaneous nerve. Other expendable options include the lateral antebrachial cutaneous, the saphenous obturator branch to gracilis, and spare-part nerves from amputated digits or limbs. Potential drawbacks to nerve autograft include limited available nerve, donor site morbidity, loss of sensation in the donor distribution, scarring, and potential neuroma formation at the additional surgical site.²⁵

TABLE 2 Options for Nerve Gap Fillers

Material	Pros	Cons	Usage
Autograft	Gold standard Retained nerve architecture Presence of Schwann cells	Donor site morbidities Donor site scar/healing Limited availability	Preferred for motor nerve and mixed nerve gap
Processed nerve allograft (PNA—Axogen Avance)	Readily available Retained nerve architecture	Additional cost Lack of Schwann cells Length limitation (further data needed)	Sensory nerve gap <3 cm Alternative for motor and mixed nerve when autograft not available
Conduit	Readily available	Lack of Schwann cells Lack of nerve architecture	Sensory nerve gap <3 cm
Adapted from Moore AM, Wagner IJ, Fox IK: Principles of nerve repair in complex wounds of the upper extremity. Semin Plast Surg 2015;29(1):40-47.

ORTHOBIOLOGICS

Nerve Allograft

Cadaver nerve allografts can provide similar advantages as autologous nerve graft while minimizing the donor site morbidity of nerve autograft. However, the use of cadaver nerve allograft requires temporary systemic immunosuppression, which can increase the risk of infection after surgery and has limited the use of these grafts clinically. The efforts to eliminate immunosuppression led to the development of processed (or acellular) nerve allografts (PNAs), which have gained popularity as an alternative to nerve autograft in the recent years. PNAs are processed cadaver nerves that remove immunogenic cellular components but retain the highly organized extracellular matrix to provide ideal scaffolding structure for nerve regeneration, thereby eliminating the need for immunosuppression.

Since the introduction of the PNAs, there are a few multicenter studies that have been published in the literature evaluating their efficacy. Notably, in 2008, a multicenter observational registry study (RANGER) was started; the first publication from this registry was released in 2012 by Brooks et al.²⁶ In this study, the nerve gap length was 5 to 50 mm and stratified into three different groups (5 to 14 mm, 15 to 29 mm, and 30 to 50 mm). The meaningful recovery was defined as S3-S4 or M3-M5 on the MacKinnon modification of the Medical Research Council grading system. In the 5- to 14-mm group, 100% had meaningful recovery, whereas the 15- to 29-mm group had a 76% meaningful recovery rate and the 30- to 50-mm group had a 91% meaningful recovery rate. When stratified by type of nerve repair, meaningful recovery was observed in 89% of sensory, 86% of motor, and 77% of mixed nerve repairs. When analyzed based on mechanism of injury, meaningful recovery was seen in 89% of the laceration group, 88% of the neuroma group, and 82% of the complex group (blast injury, avulsion, crush, compression, and gunshot wound). In 2020, a follow-up study by Safa et al²⁷ reported meaningful recovery of 82% for nerve gap up to 70 mm. This study showed similar findings in the repair of different nerve types when compared with the study by Brooks et al²⁶ (meaningful recovery 84%, 83%, and 71% for sensory, motor, and mixed nerve repairs, respectively). In the nerve gap subanalysis, the new study added another category of nerve gap, 50 to 70 mm. Meaningful recovery rates for less than 15 mm, 15 to 29 mm, and 30 to 49 mm were 91%, 85%, and 78%, respectively, and they were not significantly different. The meaningful recovery was significantly better in the less than 15-mm group when compared with the 50- to 70-mm group (91% versus 60%, P = 0.011). However, the 50- to 70-mm group had more complex injury than the less than 15-mm group. Of note, the RECON study, which is a multicenter prospective randomized subject and evaluator blinded comparative study of manufactured conduits and PNAs, has completed its enrollment and has met its primary end point required to officially apply for a biologics license application with the FDA.

Nerve Conduits

Nerve conduits are tubular structures used predominantly in the setting of short, noncritical sensory-only nerve gaps to guide the regenerating axons to the distal nerve stump. Multiple options for both autologous and synthetic conduits exist and are discussed in the following paragraphs; however, for many surgeons, the use of conduits has been largely replaced by acellular nerve allografts²⁸ (Table 3).

Autologous Nerve Conduits

In 1891, Büngner demonstrated sciatic nerve regeneration through a brachial artery.²⁹,³⁰ However, this method of nerve conduit has become less popular because of high morbidity and lack of donor vessels. In 1980, Chiu introduced veins as an option for autologous nerve conduits.³¹ In this study, successful nerve regeneration was done via
autologous vein nerve conduit with nerve gap of 1 cm in rat sciatic nerve. Suematsu et al and Chiu and Strauch validated this method of nerve conduit in their studies in 1988 and 1990, respectively.³²,³³ Notably, Chiu and Strauch suggested that successful nerve repair can be achieved with vein conduits in nerve injury with nerve gap of 3 cm or less.

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