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

Abstract

<jats:title>Abstract</jats:title><jats:p>Approximately 20 million Americans currently experience residual deficits from traumatic peripheral nerve injury. Despite recent advancements in surgical technique, peripheral nerve repair typically results in poor functional outcomes due to prolonged periods of denervation resulting from long regenerative distances coupled with relatively slow rates of axonal regeneration. Development of novel surgical solutions requires valid preclinical models that adequately replicate the key challenges of clinical peripheral nerve injury. Our team has developed a porcine model using Yucatan minipigs that provides an opportunity to investigate peripheral nerve regeneration using different nerves tailored for a specific mechanism of interest, such as (1) nerve modality: motor, sensory, and mixed-modality; (2) injury length: short versus long gap; and (3) total regenerative distance: proximal versus distal injury. Here, we describe a comprehensive porcine model of two challenging clinically relevant procedures for repair of long segmental lesions (≥ 5 cm) – the deep peroneal nerve repaired using a sural nerve autograft and the common peroneal nerve repaired using a saphenous nerve autograft – each featuring ultra-long total regenerative distances (up to 20 cm and 27 cm, respectively) to reach distal targets. This paper includes a detailed characterization of the relevant anatomy, surgical approach/technique, functional/electrophysiological outcomes, and nerve morphometry for baseline and autograft repaired nerves. These porcine models of major peripheral nerve injury are suitable as preclinical, translatable models for evaluating the efficacy, safety, and tolerability of next-generation artificial nerve grafts prior to clinical deployment.</jats:p>

Neurorrhaphy in Presence of Polyethylene Glycol Enables Immediate Electrophysiological Conduction in Porcine Model of Facial Nerve Injury

“…Most preclinical research in peripheral nerve repair and regeneration has focused on rodent models ( 12 , 27 , 28 ). Nevertheless, rodent experiments of peripheral nerve injury do not effectively replicate the major impediments to recovery encountered in the clinical setting, such as large diameter nerve injury and long total regenerative distances to reach distal targets ( 13 , 29 ). In addition, it is unclear to what extent rodent nerve regeneration recapitulates human physiological processes.…”

“…Female Yorkshire pigs (3 months old, 25–35 kg; Animal Biotech Industries) were used to study the efficacy of nerve fusion immediately after repair [ n = 12 nerves (6 swine) with PEG application and n = 5 nerves (3 swine) without PEG application]. Anesthesia, preoperative, and postoperative management were completed as described previously ( 13 ). Each animal in the study received bilateral facial nerve repairs, therefore, unless otherwise specified, sample size represents the number of nerves per group.…”

Tyrosine-Derived Polycarbonate Nerve Guidance Tubes Elicit Pro-Regenerative Extracellular Matrix Deposition When Used to Bridge Segmental Nerve Defects in Swine

“…For example, if the coating was disrupted, then hole(s) in the coated layer spanning the pores would be observed. A 10 cm longitudinal incision was made on the lateral aspect of the right hind limb from 1.5 cm distal to the stifle joint, and extending to the lateral malleolus as previously described [14].…”

“…Axon regeneration and Schwann cell infiltration was measured by imaging 2-3 serial longitudinal sections at low magnification to find the sections with the most deeply penetrating axons and Schwann cells as measured from the proximal stump for axons, and from the proximal and distal stump for the Schwann cells. The mean rate of acute axon regeneration was then calculated by dividing the mean penetration by the number of days in vivo (14). The proportion of Schwann cell infiltration was calculated by adding the proximal and distal penetration and dividing by the total gap length (1 cm) [19].…”

“…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.…”