Major Peripheral Nerve Injuries Research Articles

Limited recovery following acellular nerve allograft reconstruction in major peripheral nerve injuries

Recent studies suggest that acellular nerve allografts (ANA) have similar efficacy as nerve autografts in certain applications of nerve surgery. However, multiple studies also demonstrate the limitations of nerve allografts, resulting in poor patient outcomes. This submission discusses a recent case series of patients who failed allograft use with subsequent histologic analyses of these allografts. Recommendations on the treatment of nerve gaps are presented, drawing from our current understanding of allograft and autograft utility in reconstruction. Factors taken into account include recipient critical nerve function, existent nerve gap, and nerve diameter.

Tissue-engineered grafts exploit axon-facilitated axon regeneration and pathway protection to enable recovery after 5-cm nerve defects in pigs.

Functional restoration following major peripheral nerve injury (PNI) is challenging, given slow axon growth rates and eventual regenerative pathway degradation in the absence of axons. We are developing tissue-engineered nerve grafts (TENGs) to simultaneously "bridge" missing nerve segments and "babysit" regenerative capacity by providing living axons to guide host axons and maintain the distal pathway. TENGs were biofabricated using porcine neurons and "stretch-grown" axon tracts. TENG neurons survived and elicited axon-facilitated axon regeneration to accelerate regrowth across both short (1 cm) and long (5 cm) segmental nerve defects in pigs. TENG axons also closely interacted with host Schwann cells to maintain proregenerative capacity. TENGs drove regeneration across 5-cm defects in both motor and mixed motor-sensory nerves, resulting in dense axon regeneration and electrophysiological recovery at levels similar to autograft repairs. This approach of accelerating axon regeneration while maintaining the pathway for long-distance regeneration may achieve recovery after currently unrepairable PNIs.

Advancing Our Understanding of the Chronically Denervated Schwann Cell: A Potential Therapeutic Target?

Outcomes for patients following major peripheral nerve injury are extremely poor. Despite advanced microsurgical techniques, the recovery of function is limited by an inherently slow rate of axonal regeneration. In particular, a time-dependent deterioration in the ability of the distal stump to support axonal growth is a major determinant to the failure of reinnervation. Schwann cells (SC) are crucial in the orchestration of nerve regeneration; their plasticity permits the adoption of a repair phenotype following nerve injury. The repair SC modulates the initial immune response, directs myelin clearance, provides neurotrophic support and remodels the distal nerve. These functions are critical for regeneration; yet the repair phenotype is unstable in the setting of chronic denervation. This phenotypic instability accounts for the deteriorating regenerative support offered by the distal nerve stump. Over the past 10 years, our understanding of the cellular machinery behind this repair phenotype, in particular the role of c-Jun, has increased exponentially, creating opportunities for therapeutic intervention. This review will cover the activation of the repair phenotype in SC, the effects of chronic denervation on SC and current strategies to ‘hack’ these cellular pathways toward supporting more prolonged periods of neural regeneration.

Biomanufacturing of Axon-Based Tissue Engineered Nerve Grafts Using Porcine GalSafe Neurons.

Existing strategies for repair of major peripheral nerve injury (PNI) are inefficient at promoting axon regeneration and functional recovery and are generally ineffective for nerve lesions >5 cm. To address this need, we have previously developed tissue engineered nerve grafts (TENGs) through the process of axon stretch growth. TENGs consist of living, centimeter-scale, aligned axon tracts that accelerate axon regeneration at rates equivalent to the gold standard autograft in small and large animal models of PNI, by providing a newfound mechanism-of-action referred to as axon-facilitated axon regeneration (AFAR). To enable clinical-grade biomanufacturing of TENGs, a suitable cell source that is hypoimmunogenic, exhibits low batch-to-batch variability, and able to tolerate axon stretch growth must be utilized. To fulfill these requirements, a genetically engineered, FDA-approved, xenogeneic cell source, GalSafe® neurons, produced by Revivicor, Inc., have been selected to advance TENG biofabrication for eventual clinical use. To this end, sensory and motor neurons were harvested from genetically engineered GalSafe day 40 swine embryos, cultured in custom mechanobioreactors, and axon tracts were successfully stretch-grown to 5 cm within 25 days. Importantly, both sensory and motor GalSafe neurons were observed to tolerate established axon stretch growth regimes of ≥1 mm/day to produce continuous, healthy axon tracts spanning 1, 3, or 5 cm. Once stretch-grown, 1 cm GalSafe TENGs were transplanted into a 1 cm lesion in the sciatic nerve of athymic rats. Regeneration was assessed through histological measures at the terminal time point of 2 and 8 weeks. Neurons from GalSafe TENGs survived and elicited AFAR as observed when using wild-type TENGs. At 8 weeks postrepair, myelinated regenerated axons were observed in the nerve section distal to the injury site, confirming axon regeneration across the lesion. These experiments are the first to demonstrate successful harvest and axon stretch growth of GalSafe neurons for use as starting biomass for bioengineered nerve grafts as well as initial safety and efficacy in an established preclinical model-important steps for the advancement of clinical-grade TENGs for future regulatory testing and eventual clinical trials. Impact statement Biofabrication of tissue engineered medical products requires several steps, one of which is choosing a suitable starting biomass. To this end, we have shown that the clinical-grade, genetically engineered biomass-GalSafe® neurons-is a viable option for biomanufacturing of our tissue engineered nerve grafts (TENGs) to promote regeneration following major peripheral nerve injury. Importantly, this is a first step in clinical-grade TENG biofabrication, proving that GalSafe TENGs recapitulate the mechanism of axon-facilitated axon regeneration seen previously with research-grade TENGs.

Recovery of Motor Function after Mixed and Motor Nerve Repair with Processed Nerve Allograft.

Severe trauma often results in the transection of major peripheral nerves. The RANGER Registry is an ongoing observational study on the use and outcomes of processed nerve allografts (PNAs; Avance Nerve Graft, AxoGen, Inc., Alachua, Fla.). Here, we report on motor recovery outcomes for nerve injuries repaired acutely or in a delayed fashion with PNA and comparisons to historical controls in the literature. The RANGER database was queried for mixed and motor nerve injuries in the upper extremities, head, and neck area having completed greater than 1 year of follow-up. All subjects with sufficient assessments to evaluate functional outcomes were included. Meaningful recovery was defined as ≥M3 on the Medical Research Council scale. Demographics, outcomes, and covariate analysis were performed to further characterize this subgroup. The subgroup included 20 subjects with 22 nerve repairs. The mean ± SD (minimum-maximum) age was 38 ± 19 (16-77) years. The median repair time was 9 (0-133) days. The mean graft length was 33 ± 17 (10-70) mm with a mean follow-up of 779 ± 480 (371-2,423) days. Meaningful motor recovery was observed in 73%. Subgroup analysis showed no differences between gap lengths or mechanism of injury. There were no related adverse events. PNAs were safe and provided functional motor recovery in mixed and motor nerve repairs. Outcomes compare favorably to historical controls for nerve autograft and exceed those for hollow tube conduit. PNA may be considered as an option when reconstructing major peripheral nerve injuries.

Peripheral Nerve Injury After Elbow Arthroscopy: An Analysis of Risk Factors

To identify risk factors associated with peripheral nerve injury after elbow arthroscopy and provide an updated incidence of those complications. The elbow arthroscopies that were performed at our institution between 2006 and 2016 were identified. Over a 10-year period, 253 elbow arthroscopies were performed at our institution. Two hundred twenty-seven cases had a minimum follow-up of 4weeks, and were included in our analysis. Minor and major nerve-related complications were recorded. The surgeon's experience and training, body max index of the patients, surgical tourniquet time, type of anesthesia or surgery, radiographic appearance of the elbow, diagnosis at the time of surgery, and presence of diabetes were analyzed. There were 12 reported peripheral nerve injuries, 10 minor (4.4%) and 2 major complications (0.9%). The risk factors examined in this study were not correlated with a higher rate of complications. The minor nerve-related complication rate was 4.4%, with a 0.9% incidence of major peripheral nerve injury. Based on these findings, we conclude that elbow arthroscopy is a relatively safe procedure. The risk factors examined in this study had no association with the rate of complications. This finding could be potentially related to type II or beta error in the analysis of risk factors for nerve injury. The exact reasons for nerve injury are not known from this study. Level IV, retrospective case series.

Major Peripheral Nerve Injuries After Elbow Arthroscopy

To survey the American Society for Surgery of the Hand membership to determine the nature and distribution of nerve injuries treated after elbow arthroscopy. An online survey was sent to all members of the American Society for Surgery of the Hand under an institutional review board-approved protocol. Collected data included the number of nerve injuries observed over a 5-year period, the nature of treatment required for the injuries, and the outcomes observed after any intervention. Responses were anonymous, and results were securely compiled. We obtained 372 responses. A total of 222 nerve injuries were reported. The most injured nerves reported were ulnar, radial, and posterior interosseous (38%, 22%, and 19%, respectively). Nearly half of all patients with injuries required operative intervention, including nerve graft, tendon transfer, nerve repair, or nerve transfer. Of the patients who sustained major injuries, those requiring intervention, 77% had partial or no motor recovery. All minor injuries resolved completely. Our results suggest that major nerve injuries after elbow arthroscopy are not rare occurrences and the risk of these injuries is likely under-reported in the literature. Furthermore, patients should be counseled on this risk because most nerve injuries show only partial or no functional recovery. With the more widespread practice of elbow arthroscopy, understanding the nature and sequelae of significant complications is critically important in ensuring patient safety and improving outcomes.

Complex Regional Pain Syndrome and Spontaneous Pain Following Simple Incision With Immobilization: A Case Report

Complex regional pain syndrome (CRPS) is characterized by vasomotor and sudomotor changes. Its etiology generally includes trauma, fracture, stroke, and coronary disease. It is evaluated in two subtypes: CRPS type I (reflex sympathetic dystrophy), presenting with complex regional pain syndromes accompanied by spontaneous pain, hyperalgesia, allodynia, edema, autonomic anomalies, and trophic changes; regional pain occurring after minor injuries and fractures in the extremities; and coexisting vasomotor, sudomotor changes, and sensorial changes, and CRPS type II (coxalgia), including major peripheral nerve injuries, in addition to all of these symptoms (1, 2). Although the pathogenesis of CRPS is not exactly known, peripheral and central sensitization, which causes neurogenic inflammation, is held responsible. The most possible mechanism is considered to be increased sensitivity against catecholamine, depending on sympathetic denervation, in addition to increased numbers or sensitivity of peripheral axonal adrenoreceptors. Moreover, some mechanisms, such as the release of neuropeptides from primary nociceptive afferents and sympathetic efferents [substance P, calcitonin gene-related peptide (CGRP) and neuropeptide Y] and the development of neurogenic inflammation, are suggested. This results clinically in hyper algesia and central sensitization, in which allodynia develops (3, 4). CASE REPORT

Repairing peripheral nerve injury using tissue engineering techniques.

Each year approximately 360,000 people in the United States suffer a peripheral nerve injury (PNI), which is a leading source of lifelong disability (Kelsey et al., 1997; Noble et al., 1998). The most frequent cause of PNIs is motor vehicle accidents, while gunshot wounds, stabbings, and birth trauma are also common factors. Patients suffering from disabilities as a result of their PNIs are also burdensome to the healthcare system, with average hospital stays of 28 days each year (Kelsey et al., 1997; Noble et al., 1998).

Cortical plasticity induced by different degrees of peripheral nerve injuries: a rat functional magnetic resonance imaging study under 9.4 Tesla.

BackgroundMajor peripheral nerve injuries not only result in local deficits but may also cause distal atrophy of target muscles or permanent loss of sensation. Likewise, these injuries have been shown to instigate long-lasting central cortical reorganization.MethodsCortical plasticity changes induced after various types of major peripheral nerve injury using an electrical stimulation technique to the rat upper extremity and functional magnetic resonance imaging (fMRI) were examined. Studies were completed out immediately after injury (acute stage) and at two weeks (subacute stage) to evaluate time affect on plasticity.ResultsAfter right-side median nerve transection, cortical representation of activation of the right-side ulnar nerve expanded intra-hemispherically into the cortical region that had been occupied by the median nerve representation After unilateral transection of both median and ulnar nerves, cortical representation of activation of the radial nerve on the same side of the body also demonstrated intra-hemispheric expansion. However, simultaneous electrical stimulation of the contralateral uninjured median and ulnar nerves resulted in a representation that had expanded both intra- and inter-hemispherically into the cortical region previously occupied by the two transected nerve representations.ConclusionsAfter major peripheral nerve injury, an adjacent nerve, with similar function to the injured nerve, may become significantly over-activated in the cortex when stimulated. This results in intra-hemispheric cortical expansion as the only component of cortical plasticity. When all nerves responsible for a certain function are injured, the same nerves on the contralateral side of the body are affected and become significantly over-activated during a task. Both intra- and inter-hemispheric cortical expansion exist, while the latter dominates cortical plasticity.

A rodent model of partial muscle re-innervation

BackgroundThere is limited appreciation of the risks and benefits of the few salvage treatment options available for inadequate motor function following incomplete spontaneous recovery or surgical repair of major peripheral nerve injuries. The lack of a reliable and economical animal model has hindered laboratory investigation into this difficult clinical problem. We propose a straightforward and reproducible rodent model of partial re-innervation of a hind limb muscle. New methodTwelve Sprague-Dawley rats underwent identical surgical manipulations: the left tibial nerve was isolated, partially transected (2/3rds), and the remaining intact portion crushed. Eight weeks later, bilateral (1) gastrocnemius (2) soleus and (3) flexor digitorum longus muscles underwent maximal isometric contraction force testing before being excised and weighed. ResultsOnly the gastrocnemius muscles were statistically weaker (p<0.05) in the experimental limb compared with the contralateral (control) limb. There was no difference in muscle weights between experimental and control sides. Comparison with existing methodsOur model differs from other published models by: allowing time for compensatory axonal sprouting as would be seen in clinical scenarios, precisely identifying the portion of the tibial nerve to be transected to ensure reproducibility, and achieving temporary but complete denervation by crushing the intact portion of the nerve. ConclusionsControlled partial transection and crushing of the rodent tibial nerve results in a consistently partially re-innervated and clinically weakened gastrocnemius muscle that can serve as a model in studying incomplete recovery following nerve injury.

Limb Salvage With Major Nerve Injury: Current Management and Future Directions

Major peripheral nerve injuries are often associated with devastating functional deficits. Current management techniques fail to achieve adequate functional neural regeneration, and the development of adjunct therapies is necessary to improve outcomes. Recent efforts at enhancing the regeneration rate of peripheral nerves and developing axonal guidance channels or conduits have had limited success. The neuromuscular junction serves as the interface between the peripheral nerves and muscle. This critical area undergoes significant changes following peripheral nerve injury and induces end-organ atrophy after denervation, which limits the chance of true functional regeneration. Stabilization of the neuromuscular junction may be an important adjunct in peripheral nerve repair and should be explored as a method of managing major nerve injuries.

Positioning in Anesthesia and Surgery. 3rd ed

Positioning in Anesthesia and Surgery. 3rd ed., John T. Martin and Mark A. Warner, eds. Saunders, Philadelphia: WB 1997, ISBN 0-7216-6674-4, 345 pp, $75.00. Positioning in Anesthesia and Surgery, is a multi-authored, hardcover book with minimum overlapping of information among chapters. It is divided into seven different sections, with each section having between one and five chapters. It is easy to read and well referenced, and the chapters are well illustrated with clear drawings by Roy E. Schneider. Section I discusses the general principles of surgical positioning of an anesthetized patient, followed by an overview of the basic operating Table withits various modifications. Subsequent chapters in Sections II-V describe the process of positioning an anesthetized patient in the desired surgical posture, i.e., supine, prone, lateral decubitus, sitting, and lithotomy, in a stepwise fashion. The physiological changes brought about by these positions in an anesthetized patient are well discussed. This book makes it quite clear that the process of getting an anesthetized patient to a desired position is a team-work approach requiring communication, coordination, meticulousness, and vigilance among operating room workers. Section VI describes positioning in special conditions because of unique surgical requirements, e.g., extracorporeal shockwave lithotripsy in waterbath or in nonwaterbath. Similarly, positioning in various patient populations, e.g., morbidly obese, pediatric, pregnant and geriatric, is well described. Their special needs, i.e., technical difficulty in handling the morbidly obese, guarding against hypothermia while positioning a pediatric patient, supine hypotensive syndrome in the obstetric patient, degenerative diseases of the geriatric population, and altered physiological state with its attendant implication in positioning are well discussed. In Section VII, possible predisposing factors and mechanism of nerve injury during the perioperative period and quick and reliable ways of diagnosing major peripheral nerve injury are described. Finally, Chapter 21 in Section VII discusses the medico-legal consideration and reminds the clinician to keep adequate documentation regarding surgical positioning for future reference. In summary, as Dr. Martin states in the introduction, "Outlining specific techniques for establishing a surgical postures can be 'cook-bookish.' Potentially, the practice implies that the reader will accept the presentation as the definitive standard for that maneuver, condemn all other alternatives, and attempt to enforce compliance thereto. Such an interpretation we neither intend nor support." To that end, this book provides the reader with ample information in achieving a particular surgical posture, its physiological implications on the anesthetized patient, and ways and means of avoiding potential complications arising from the position. This book is highly recommended for anesthesiology department libraries so that clinicians can use it as a quick reference guide to bring about desired patient outcome. Gaury S. Adhikary, MD Theodore J. Sanford, Jr. MD Department of Anesthesiology; University of Michigan; Ann Arbor, MI 48109-0048

Positioning in Anesthesia and Surgery. 3rd ed

Positioning in Anesthesia and Surgery. 3rd ed., John T. Martin and Mark A. Warner, eds. Saunders, Philadelphia: WB 1997, ISBN 0-7216-6674-4, 345 pp, $75.00. Positioning in Anesthesia and Surgery, is a multi-authored, hardcover book with minimum overlapping of information among chapters. It is divided into seven different sections, with each section having between one and five chapters. It is easy to read and well referenced, and the chapters are well illustrated with clear drawings by Roy E. Schneider. Section I discusses the general principles of surgical positioning of an anesthetized patient, followed by an overview of the basic operating Table withits various modifications. Subsequent chapters in Sections II-V describe the process of positioning an anesthetized patient in the desired surgical posture, i.e., supine, prone, lateral decubitus, sitting, and lithotomy, in a stepwise fashion. The physiological changes brought about by these positions in an anesthetized patient are well discussed. This book makes it quite clear that the process of getting an anesthetized patient to a desired position is a team-work approach requiring communication, coordination, meticulousness, and vigilance among operating room workers. Section VI describes positioning in special conditions because of unique surgical requirements, e.g., extracorporeal shockwave lithotripsy in waterbath or in nonwaterbath. Similarly, positioning in various patient populations, e.g., morbidly obese, pediatric, pregnant and geriatric, is well described. Their special needs, i.e., technical difficulty in handling the morbidly obese, guarding against hypothermia while positioning a pediatric patient, supine hypotensive syndrome in the obstetric patient, degenerative diseases of the geriatric population, and altered physiological state with its attendant implication in positioning are well discussed. In Section VII, possible predisposing factors and mechanism of nerve injury during the perioperative period and quick and reliable ways of diagnosing major peripheral nerve injury are described. Finally, Chapter 21 in Section VII discusses the medico-legal consideration and reminds the clinician to keep adequate documentation regarding surgical positioning for future reference. In summary, as Dr. Martin states in the introduction, "Outlining specific techniques for establishing a surgical postures can be 'cook-bookish.' Potentially, the practice implies that the reader will accept the presentation as the definitive standard for that maneuver, condemn all other alternatives, and attempt to enforce compliance thereto. Such an interpretation we neither intend nor support." To that end, this book provides the reader with ample information in achieving a particular surgical posture, its physiological implications on the anesthetized patient, and ways and means of avoiding potential complications arising from the position. This book is highly recommended for anesthesiology department libraries so that clinicians can use it as a quick reference guide to bring about desired patient outcome. Gaury S. Adhikary, MD Theodore J. Sanford, Jr. MD Department of Anesthesiology; University of Michigan; Ann Arbor, MI 48109-0048