A Porcine Model of Peripheral Nerve Injury Enabling Ultra-Long Regenerative Distances: Surgical Approach, Recovery Kinetics, and Clinical Relevance

Abstract

BACKGROUND Millions of Americans experience residual deficits from traumatic peripheral nerve injury (PNI). Despite advancements in surgical technique, repair typically results in poor functional outcomes due to prolonged periods of denervation resulting from long regenerative distances coupled with slow rates of axonal regeneration. Novel surgical solutions require valid preclinical models that adequately replicate the key challenges of clinical PNI. OBJECTIVE To develop a preclinical model of PNI in swine that addresses 2 challenging, clinically relevant PNI scenarios: long segmental defects (≥5 cm) and ultra-long regenerative distances (20-27 cm). Thus, we aim to demonstrate that a porcine model of major PNI is suitable as a potential framework to evaluate novel regenerative strategies prior to clinical deployment. METHODS A 5-cm-long common peroneal nerve or deep peroneal nerve injury was repaired using a saphenous nerve or sural nerve autograft, respectively. Histological and electrophysiological assessments were performed at 9 to 12 mo post repair to evaluate nerve regeneration and functional recovery. Relevant anatomy, surgical approach, and functional/histological outcomes were characterized for both repair techniques. RESULTS Axons regenerated across the repair zone and were identified in the distal stump. Electrophysiological recordings confirmed these findings and suggested regenerating axons reinnervated target muscles. CONCLUSION The models presented herein provide opportunities to investigate peripheral nerve regeneration using different nerves tailored for specific mechanisms of interest, such as nerve modality (motor, sensory, and mixed fiber composition), injury length (short/long gap), and total regenerative distance (proximal/distal injury).

Establishment of a Sheep Model for Hind Limb Peripheral Nerve Injury: Common Peroneal Nerve

“…This factor negatively affects the ability of distal nerve structures to support regeneration and reinnervation of target organs [12]. The creation and development of new approaches to stimulate peripheral nerve regeneration, although necessary, require the use of reliable preclinical models that adequately mimic the challenges associated with clinical PNI [13].…”

“…Larger animal models are ideal for simulating the long-distance nerve defects and regenerative phenomena that are observed in human PNI. Since these models can more reliably replicate some characteristics of human nerves, such as their structural composition, dimensions, diameter and regenerative process, there are already several published studies based on the use of dogs [16,17], cats [18], rabbits [19], non-human primates [20], pigs [13,21], mini-pigs [22], guinea-pigs [23], and sheep models [24].…”

Tyrosine‐derived polycarbonate nerve guidance tubes elicit proregenerative extracellular matrix deposition when used to bridge segmental nerve defects in swine

“…Indeed, a major consideration for development of novel, clinically translatable NGTs is the inability of rodent models to fully replicate human segmental nerve defects due to critical differences in biological physiology and the short regenerative distances to distal end‐target relative to the longer distances implicated in poor functional recovery in humans 13 . Thus, to evaluate whether a novel biomaterial designed for nerve regeneration has potential for clinical translation, demonstration of regenerative efficacy and evaluation of host responses should be performed using in a suitable large animal pre‐clinical model 14 . The transition of a novel biomaterial from evaluation in a small animal model to a large animal model typically follows a two‐step process—the critical first step is to investigate acute regeneration in a short (e.g., 1 cm) nerve gap.…”

Establishment of a Sheep Model for Hind limb Peripheral Nerve Injury: Common Peroneal Nerve

“…The creation and development of new approaches to stimulate peripheral nerve regeneration, although necessary, require the use of reliable preclinical models that adequately mimic the challenges associated with clinical PNI (26). Traditionally, peripheral nerve regeneration studies have been conducted in small animal models such as rodents, but the differences between species are several and limit the clinical translation of the obtained results.…”

“…Larger animal models are ideal for simulating the long-distance nerve defects and regenerative phenomena that are observed in human PNI. Since these models can more reliably replicate some characteristics of human nerves, such as their structural composition, dimensions, diameter and regenerative process, there are already several published studies based on the use of dogs (29,30), cats (31), rabbits (32), non-human primates (33), pigs (26,34), mini-pigs (35), guinea-pigs (36), and sheep models (37).…”