Assessing the Relationship between Obesity and Trigger Point-specific Outcomes after Headache Surgery.

Background: Trigger point deactivation surgery is a safe and effective treatment for properly selected patients experiencing migraine, with 68.3%-100% experiencing symptom improvement postoperatively. However, it is still unknown why certain patients do not respond. Obesity has been shown to be associated with worsened migraine symptoms and a decreased response to select pharmacotherapies. This study aimed to determine whether obesity may also be associated with an attenuated response to surgery. Methods: A retrospective chart review was conducted to identify patients who had undergone trigger point deactivation surgery for migraine. Patients were split into obese and nonobese cohorts. Obesity was classified as a body mass index of 30 or higher per Centers for Disease Control and Prevention guidelines. Outcomes and follow-up periods were determined with respect to individual operations. Outcomes included migraine attack frequency, intensity, duration, and the migraine headache index. Differences in demographics, operative characteristics, and operative outcomes were compared. Results: A total of 62 patients were included in the study. The obese cohort comprised 31 patients who underwent 45 total operations, and the nonobese cohort comprised 31 patients who underwent 34 operations. Results from multivariable analysis showed no impact of obesity on the odds of achieving a more than 90% reduction in any individual outcome. The overall rates of improvement (≥50% reduction in any outcome) and elimination (100% reduction in all symptoms) across both cohorts were 89.9% and 65.8%, respectively. Conclusion: Obese patients have outcomes comparable to a nonobese cohort after trigger point deactivation surgery for migraine.

Secondary Trigger Point Deactivation Surgery for Nerve Compression Headaches: A Scoping Review.

Background: Primary trigger point deactivation surgery has been successful in reducing or eliminating nerve compression headaches between 79% and 90% of the time. The aim of this review article was to discuss the factors that contribute to index trigger point deactivation surgery failure, the importance of reevaluating trigger points following failure, and the options for secondary surgery. Methods: A literature search was performed using a combination of keywords involving "chronic headache" and "nerve deactivation surgery," in databases until February 2023. Results: Data of 1071 patients were evaluated and included (11 articles). The failure rate after index trigger point deactivation surgery occurs is approximately 12%, primarily due to incomplete primary trigger point deactivation. Secondary trigger points may not appear until the primary trigger is eliminated, which occurs in 17.8% of patients. Reevaluation of previously diagnosed trigger points as well as uncovered trigger points and additional preoperative testing is indicated to help determine candidacy for further surgical deactivation. To address scarring that could contribute to failure, corticosteroid injection, acellular dermal matrix, adipofascial fat, or expanded polytetrafluoroethylene sleeves have been described with beneficial effects. For neuroma management, regenerative peripheral nerve interface, targeted muscle reinnervation, a combination of both, relocation nerve grafting, or nerve capping have also been described. Neurectomy can be performed when patients prefer anesthesia and/or paresthesia over current pain symptoms. Conclusion: Secondary trigger point deactivation surgery is indicated when there is suspicion of incomplete deactivation, internal scarring, neuroma, or newly-diagnosed trigger points.

The Effect of Local Purified Exosome Product, Stem Cells, and Tacrolimus on Neurite Extension.

PURPOSE: The combination of cellular and noncellular treatments has been postulated to improve nerve regeneration through a processed nerve allograft. This study aimed to evaluate the isolated effect of treatment with purified exosome product (PEP), mesenchymal stem cells (MSCs), and tacrolimus (FK506) alone and in combination when applied in decellularized allografts. METHODS: A three-dimensional in vitro-compartmented cell culture system was used to evaluate the length of regenerating neurites from the neonatal dorsal root ganglion into the adjacent peripheral nerve graft. Decellularized nerve allografts were treated with undifferentiated MSCs, 5% PEP, 100 ng/mL FK506, PEP and FK506 combined, or MSCs and FK506 combined (N = 9/group) and compared with untreated nerve autografts (positive control) and nerve allografts (negative control). Neurite extension was measured to quantify nerve regeneration after 48 hours, and stem cell viability was evaluated. RESULTS: Stem cell viability was confirmed in all MSC-treated nerve grafts. Treatments with PEP, PEP + FK506, and MSCs + FK506 combined were found to be superior to untreated allografts and not significantly different from autografts. Combined PEP and FK506 treatment resulted in the greatest neurite extension. Treatment with FK506 and MSCs was significantly superior to MSC alone. The combined treatment groups were not found to be statistically different. CONCLUSIONS: Although all treatments improved neurite outgrowth, treatments with PEP, PEP + FK506, and MSCs + FK506 combined had superior neurite growth compared with untreated allografts and were not found to be significantly different from autografts, the current gold standard. CLINICAL RELEVANCE: Purified exosome product, a cell-free exosome product, is a promising adjunct to enhance nerve allograft regeneration, with possible future avenues for clinical translation.

Management of Acute Surgical Pain in Plastic and Reconstructive Surgery.

SUMMARY: Fewer than half of all patients undergoing surgery report adequate postoperative pain relief. Poorly managed postoperative pain can lead to complications, increased hospital stays, prolonged rehabilitation, and a decreased quality of life. Pain rating scales are commonly used to identify, manage, and track the perceived intensity of pain. Changes in perceived pain severity and intensity are a key indicator for course of treatment. Postoperative pain is best treated with multimodal management with a variety of analgesic medications and techniques that target different receptors and mechanisms of action in the peripheral and central nervous systems. This includes systemic analgesia, regional analgesia, local analgesia (eg, topical and tumescent analgesia), and nonpharmacologic modalities. It is recommended that this approach is individually tailored and discussed through a shared decision-making approach. This review provides an overview of multimodal management for acute postoperative pain related to plastic surgery procedures. To increase patient satisfaction and provide effective pain control, it is recommended to educate patients on expectations of pain, multimodal options for pain control (including peripheral nerve blocks), complications of unrelieved pain, tracking and monitoring of pain by self-reporting, and how to reduce the use of opioid-based pain medication.

Functional outcomes of nerve allografts augmented with mesenchymal stem cells and surgical angiogenesis in a rat sciatic nerve defect model.

BACKGROUND: Motor function recovery following acellular nerve allograft (ANA) repair remains inferior to autologous nerve reconstruction. We investigated the functional recovery of ANAs after combined mesenchymal stem cell (MSC) delivery and surgical angiogenesis in a rat sciatic nerve defect model. METHODS: In 100 Lewis rats, unilateral sciatic nerve defects were reconstructed with (I) autografts, (II) ANAs, (III) ANAs wrapped with a superficial inferior epigastric artery fascial (SIEF) flap, combined with either (IV) undifferentiated MSCs or (V) Schwann cell-like differentiated MSCs. The tibialis anterior muscle area was evaluated during the survival period using ultrasonography. Functional recovery, histomorphometry, and immunofluorescence were assessed at 12 and 16 weeks. RESULTS: At 12 weeks, the addition of surgical angiogenesis and MSCs improved ankle contractures. The SIEF flap also significantly improved compound muscle action potential (CMAP) outcomes compared with ANAs. Autografts outperformed all groups in muscle force and weight. At 16 weeks, ankle contractures of ANAs remained inferior to autografts and SIEF, whereas the CMAP amplitude was comparable between groups. The muscle force of autografts remained superior to all other groups, and the muscle weight of ANAs remained inferior to autografts. No differences were found in histomorphometry outcomes between SIEF groups and ANAs. Vascularity, determined by CD34 staining, was significantly higher in SIEF groups compared with ANAs. CONCLUSIONS: The combination of surgical angiogenesis and MSCs did not result in a synergistic improvement in functional outcomes. In a short nerve gap model, the adipofascial flap may provide sufficient MSCs to ANAs without additional ex vivo MSC seeding.

Compression Neuropathies: Revisions and Managing Expectations.

Most compression neuropathies can be reliably treated with surgical decompression; however, in approximately 25% of the cases, this release fails, requiring revision surgery. Defining the correct diagnosis after a failed nerve decompression (ie, persistent, recurrent, or new symptoms) is of the utmost importance and guides toward the optimal treatment. This article describes the clinical categorization of secondary carpal tunnel syndrome and cubital tunnel syndrome, intraoperative principles of revision surgery and treatment options that are currently available.

Severe obesity is associated with increased migraine severity and frequency: A retrospective cohort study.

Migraine headaches and obesity are both prevalent disorders, resulting in a high socioeconomic burden. To better understand the relationship between obesity and migraine, the aim of this study was to investigate the association between migraine severity, metabolic syndrome and estrogen-associated variables. A retrospective analysis of adult patients with refractory migraine seen by our senior author (J.E.J.) was performed. Patient demographics and migraine characteristics, including migraine intensity, duration, and number of headaches per month were collected from medical records. Migraine headache index (MHI) was calculated by multiplying frequency, intensity and duration of headaches. Weight and height were used to calculate body mass index (BMI) and these were divided per Center for Disease Control (CDC) classifications. Univariate linear regression models were used to evaluate associations. Patients (n = 223) were predominantly female (78%) with a mean age of 44 years at presentation. Patients with a BMI higher than 40 (class 3 obesity) had a higher MHI (p = 0.01) and experienced a higher number of migraines per month (p = 0.007), compared to patients with a healthy BMI, respectively. Migraine frequency was found to be significantly higher in post-menopausal women compared to pre-menopausal women (p = 0.02). No other significant associations were found. This study found that severe obesity (BMI > 40) is associated with increased migraine severity and frequency. Post-menopausal patients are also found to have increased migraine frequency, which could be explained by the estrogen-withdrawal hypothesis. Future studies are needed to evaluate the outcomes of individuals with obesity after nerve deactivation surgery.

Diverse Leadership in Hand Surgery: Foundation on the Shoulder of Giants.

Surgical leaders exhibit unique characteristics that allow them to impact and innovate their respective fields. In Hand Surgery, we recognize areas of leadership success, including leadership of position, leadership of innovation, and academic leadership. This article aims to define the term "success" and provide examples of how a diverse climate can lead to leadership success by highlighting a few stories of diverse giants in the field of Hand Surgery.

Promoting Nerve Regeneration: Electrical Stimulation, Gene Therapy, and Beyond.

Peripheral nerve injuries often result in life-altering functional deficits even with optimal management. Unlike the central nervous system, peripheral nerves have the ability to regenerate lost axons after injury; however, axonal regeneration does not equate to full restoration of function. To overcome this physiological shortcoming, advances in nerve regeneration and repair are paramount, including electrical stimulation, gene therapy, and surgical technique advancements.

The effect of mesenchymal stem cells and surgical angiogenesis on immune response and revascularization of acellular nerve allografts in a rat sciatic defect model.

BACKGROUND: Increasing evidence demonstrates an interplay between neoangiogenesis and immune cells. We investigated the immune response and revascularization of acellular nerve allografts (ANA) after combined stem cell delivery and surgical angiogenesis in a rat model. METHODS: Unilateral sciatic nerve defects in 60 Lewis rats were repaired with (I) autografts, (II) ANAs, and (III) ANAs wrapped within a pedicled superficial inferior epigastric artery fascial flap to induce surgical angiogenesis, combined with seeding of either (IV) undifferentiated mesenchymal stem cells (uMSCs) or (V) MSCs differentiated into Schwann cell-like cells. Immune cell phenotyping was performed on days 7 and 14. The vascular volume of nerves was measured by microcomputed tomography at 12 and 16 weeks. RESULTS: On day 7, helper T cells (CD4+) were significantly increased in groups IV and V compared to group I. Regulatory T cells (CD4+CD25+) were significantly higher in groups III-IV, and cytotoxic T cells (CD8+) were significantly reduced in groups IV and V compared to group II, respectively. Group II demonstrated the highest levels of natural killer cells (CD161+) compared to groups III-V. On day 14, group IV demonstrated the highest CD4/CD8 ratio. Vascular volume was significantly higher in groups III-V compared to group II at 12 weeks and groups IV and V compared to group II at 16 weeks. The CD4/CD8 ratio demonstrated a positive correlation to vascular volumes at 12 weeks. CONCLUSION: Early favorable immune responses were observed in ANAs treated with surgical angiogenesis with or without stem cell delivery and demonstrated improved vascularity at longer follow-up.

Role of adipose tissue grafting and adipose-derived stem cells in peripheral nerve surgery.

The application of autologous fat grafting in reconstructive surgery is commonly used to improve functional form. This review aims to provide an overview of the scientific evidence on the biology of adipose tissue, the role of adipose-derived stem cells, and the indications of adipose tissue grafting in peripheral nerve surgery. Adipose tissue is easily accessible through the lower abdomen and inner thighs. Non-vascularized adipose tissue grafting does not support oxidative and ischemic stress, resulting in variable survival of adipocytes within the first 24 hours. Enrichment of adipose tissue with a stromal vascular fraction is purported to increase the number of adipose-derived stem cells and is postulated to augment the long-term stability of adipose tissue grafts. Basic science nerve research suggests an increase in nerve regeneration and nerve revascularization, and a decrease in nerve fibrosis after the addition of adipose-derived stem cells or adipose tissue. In clinical studies, the use of autologous lipofilling is mostly applied to secondary carpal tunnel release revisions with promising results. Since the use of adipose-derived stem cells in peripheral nerve reconstruction is relatively new, more studies are needed to explore safety and long-term effects on peripheral nerve regeneration. The Food and Drug Administration stipulates that adipose-derived stem cell transplantation should be minimally manipulated, enzyme-free, and used in the same surgical procedure, e.g. adipose tissue grafts that contain native adipose-derived stem cells or stromal vascular fraction. Future research may be shifted towards the use of tissue-engineered adipose tissue to create a supportive microenvironment for autologous graft survival. Shelf-ready alternatives could be enhanced with adipose-derived stem cells or growth factors and eliminate the need for adipose tissue harvest.

Mesenchymal stem cells and local tacrolimus delivery synergistically enhance neurite extension.

BACKGROUND: The aim of this study was to investigate the combined effect of mesenchymal stem cells (MSC) and local delivery of tacrolimus (FK506) on nerve regeneration when applied to nerve autografts and decellularized allografts. METHODS: A three-dimensional in vitro compartmented cell culture system consisting of a neonatal dorsal root ganglion adjacent to a nerve graft was used to evaluate the regenerating neurites into the peripheral nerve scaffold. Nerve autografts and allografts were treated with (i) undifferentiated MSCs, (ii) FK506 (100 ng/mL) or (iii) both (N = 9/group). After 48 hours, neurite extension was measured to quantify nerve regeneration and stem cell viability was evaluated. RESULTS: Stem cell viability was confirmed in all MSC-treated grafts. Neurite extension was superior in autografts treated with FK506, and MSCs and FK506 combined (p < 0.001 and p = 0.0001, respectively), and autografts treated with MSCs (p = 0.12) were comparable to untreated autografts. In allografts, FK506 treatment and combined treatment were superior to controls (p < 0.001 and p = 0.0001, respectively), and treatment with MSCs (p = 0.09) was comparable to controls. All autograft groups were superior compared to their respective allograft treatment group (p < 0.05) in neurite extension. CONCLUSIONS: Alone, either MSC or FK506 treatment improved neurite outgrowth, and combined they further enhanced neurite extension in both autografts and allografts.

Surgical Angiogenesis of Decellularized Nerve Allografts Improves Early Functional Recovery in a Rat Sciatic Nerve Defect Model.

BACKGROUND: Surgical angiogenesis applied to nerve grafts has been suggested to enhance nerve regeneration after nerve injury. The authors hypothesized that surgical angiogenesis to decellularized nerve allografts would improve functional recovery in a rat sciatic nerve defect model. METHODS: Sixty Lewis rats were divided in three groups of 20 animals each. Unilateral sciatic nerve defects were repaired with (1) autografts, (2) decellularized allografts, and (3) decellularized allografts wrapped with a superficial inferior epigastric artery fascial flap to add surgical angiogenesis. Twelve and 16 weeks after surgery, nerve regeneration was assessed using functional, electrophysiologic, histologic, and immunofluorescence analyses. Ultrasonography was used during the survival period to noninvasively evaluate muscle atrophy and reinnervation by measuring cross-sectional muscle area. RESULTS: Surgical angiogenesis of allografts demonstrated significantly improved isometric tetanic force recovery at 12 weeks, compared to allograft alone, which normalized between groups at 16 weeks. Cross-sectional muscle areas showed no differences between groups. Electrophysiology showed superiority of autografts at both time points. No differences were found in histologic analysis, besides a significantly inferior N ratio in allografts at 12 weeks. Immunofluorescent expression of CD34, indicating vascularity, was significantly enhanced in the superficial inferior epigastric artery fascial group compared to allografts at 12 weeks, with highest expression at 16 weeks compared to all groups. CONCLUSION: Surgical angiogenesis with an adipofascial flap to the nerve allograft increases vascularity in the nerve graft, with subsequent improvement of early muscle force recovery, comparable to autografts.

Maximum Isometric Tetanic Force Measurement of the Tibialis Anterior Muscle in the Rat.

Traumatic nerve injuries result in substantial functional loss and segmental nerve defects often necessitate the use of autologous interposition nerve grafts. Due to their limited availability and associated donor side morbidity, many studies in the field of nerve regeneration focus on alternative techniques to bridge a segmental nerve gap. In order to investigate the outcomes of surgical or pharmacological experimental treatment options, the rat sciatic nerve model is often used as a bioassay. There are a variety of outcome measurements used in rat models to determine the extent of nerve regeneration. The maximum output force of the target muscle remains the most relevant outcome for clinical translation of experimental therapies. Isometric force measurement of tetanic muscle contraction has previously been described as a reproducible and valid technique for evaluating motor recovery after nerve injury or repair in both rat and rabbit models. In this video, we will provide a step-by-step instruction of this invaluable procedure for assessment of functional recovery of the tibialis anterior muscle in a rat sciatic nerve defect model using optimized parameters. We will describe the necessary pre-surgical preparations in addition to the surgical approach and dissection of the common peroneal nerve and tibialis anterior muscle tendon. The isometric tetanic force measurement technique will be detailed. Determining the optimal muscle length and stimulus pulse frequency is explained and measuring the maximum tetanic muscle contraction is demonstrated.

Functional Outcomes of Nerve Allografts Seeded with Undifferentiated and Differentiated Mesenchymal Stem Cells in a Rat Sciatic Nerve Defect Model.

BACKGROUND: Mesenchymal stem cells have the potential to produce neurotrophic growth factors and establish a supportive microenvironment for neural regeneration. The purpose of this study was to determine the effect of undifferentiated and differentiated mesenchymal stem cells dynamically seeded onto decellularized nerve allografts on functional outcomes when used in peripheral nerve repair. METHODS: In 80 Lewis rats, a 10-mm sciatic nerve defect was reconstructed with (1) autograft, (2) decellularized allograft, (3) decellularized allograft seeded with undifferentiated mesenchymal stem cells, or (4) decellularized allograft seeded with mesenchymal stem cells differentiated into Schwann cell-like cells. Nerve regeneration was evaluated over time by cross-sectional tibial muscle ultrasound measurements, and at 12 and 16 weeks by isometric tetanic force measurements, compound muscle action potentials, muscle mass, histology, and immunofluorescence analyses. RESULTS: At 12 weeks, undifferentiated mesenchymal stem cells significantly improved isometric tetanic force measurement and compound muscle action potential outcomes compared to decellularized allograft alone, whereas differentiated mesenchymal stem cells significantly improved compound muscle action potential outcomes. The autografts outperformed both stem cell groups histologically at 12 weeks. At 16 weeks, functional outcomes normalized between groups. At both time points, the effect of undifferentiated versus differentiated mesenchymal stem cells was not significantly different. CONCLUSIONS: Undifferentiated and differentiated mesenchymal stem cells significantly improved functional outcomes of decellularized allografts at 12 weeks and were similar to autograft results in the majority of measurements. At 16 weeks, outcomes normalized as expected. Although differences between both cell types were not statistically significant, undifferentiated mesenchymal stem cells improved functional outcomes of decellularized nerve allografts to a greater extent and had practical benefits for clinical translation by limiting preparation time and costs.

Administration of Purified Exosome Product in a Rat Sciatic Serve Reverse Autograft Model.

BACKGROUND: The nerve autograft remains the gold standard when reconstructing peripheral nerve defects. However, although autograft repair can result in useful functional recovery, poor outcomes are common, and better treatments are needed. The purpose of this study was to evaluate the effect of purified exosome product on functional motor recovery and nerve-related gene expression in a rat sciatic nerve reverse autograft model. METHODS: Ninety-six Sprague-Dawley rats were divided into three experimental groups. In each group, a unilateral 10-mm sciatic nerve defect was created. The excised nerve was reversed and used to reconstruct the defect. Group I animals received the reversed autograft alone, group II animals received the reversed autograft with fibrin glue, and group III animals received the reversed autograft with purified exosome product suspended in the fibrin glue. The animals were killed at 3 and 7 days and 12 and 16 weeks after surgery. Evaluation included compound muscle action potentials, isometric tetanic force, tibialis anterior muscle wet weight, nerve regeneration-related gene expression, and nerve histomorphometry. RESULTS: At 16 weeks, isometric tetanic force was significantly better in group III (p = 0.03). The average axon diameter of the peroneal nerve was significantly larger in group III at both 12 and 16 weeks (p = 0.015 at 12 weeks; p < 0.01 at 16 weeks). GAP43 and S100b gene expression was significantly up-regulated by purified exosome product. CONCLUSIONS: Local administration of purified exosome product demonstrated improved nerve regeneration profiles in the reverse sciatic nerve autograft rat model. Thus, purified exosome product may have beneficial effects on nerve regeneration, gene profiles, and motor outcomes.

Peripheral Nerve Basic Science Research-What Is Important for Hand Surgeons to Know?

Peripheral nerve injury and regeneration continue to be extensively studied through basic science research using animal models. A translational gap remains between basic science research and clinical application. The importance of peripheral nerve regeneration in basic science research depends on the design of the study, the outcome measures, and the time of regeneration selected. The purpose of this article is to provide an overview of the importance of the design and outcome measures of peripheral nerve basic science research, for hand surgeons to understand for potential clinical translation.

Combined local delivery of tacrolimus and stem cells in hydrogel for enhancing peripheral nerve regeneration.

The application of scaffold-based stem cell transplantation to enhance peripheral nerve regeneration has great potential. Recently, the neuroregenerative potential of tacrolimus (a U.S. Food and Drug Administration-approved immunosuppressant) has been explored. In this study, a fibrin gel-based drug delivery system for sustained and localized tacrolimus release was combined with rat adipose-derived mesenchymal stem cells (MSC) to investigate cell viability in vitro. Tacrolimus was encapsulated in poly(lactic-co-glycolic) acid (PLGA) microspheres and suspended in fibrin hydrogel, using concentrations of 0.01 and 100 ng/ml. Drug release over time was measured. MSCs were cultured in drug-released media collected at various days to mimic systemic exposure. MSCs were combined with (i) hydrogel only, (ii) empty PLGA microspheres in the hydrogel, (iii) 0.01, and (iv) 100 ng/ml of tacrolimus PLGA microspheres in the hydrogel. Stem cell presence and viability were evaluated. A sustained release of 100 ng/ml tacrolimus microspheres was observed for up to 35 days. Stem cell presence was confirmed and cell viability was observed up to 7 days, with no significant differences between groups. This study suggests that combined delivery of 100 ng/ml tacrolimus and MSCs in fibrin hydrogel does not result in cytotoxic effects and could be used to enhance peripheral nerve regeneration.

The interaction of stem cells and vascularity in peripheral nerve regeneration.

The degree of nerve regeneration after peripheral nerve injury can be altered by the microenvironment at the site of injury. Stem cells and vascularity are postulated to be a part of a complex pathway that enhances peripheral nerve regeneration; however, their interaction remains unexplored. This review aims to summarize current knowledge on this interaction, including various mechanisms through which trophic factors are promoted by stem cells and angiogenesis. Angiogenesis after nerve injury is stimulated by hypoxia, mediated by vascular endothelial growth factor, resulting in the growth of pre-existing vessels into new areas. Modulation of distinct signaling pathways in stem cells can promote angiogenesis by the secretion of various angiogenic factors. Simultaneously, the importance of stem cells in peripheral nerve regeneration relies on their ability to promote myelin formation and their capacity to be influenced by the microenvironment to differentiate into Schwann-like cells. Stem cells can be acquired through various sources that correlate to their differentiation potential, including embryonic stem cells, neural stem cells, and mesenchymal stem cells. Each source of stem cells serves its particular differentiation potential and properties associated with the promotion of revascularization and nerve regeneration. Exosomes are a subtype of extracellular vesicles released from cell types and play an important role in cell-to-cell communication. Exosomes hold promise for future transplantation applications, as these vesicles contain fewer membrane-bound proteins, resulting in lower immunogenicity. This review presents pre-clinical and clinical studies that focus on selecting the ideal type of stem cell and optimizing stem cell delivery methods for potential translation to clinical practice. Future studies integrating stem cell-based therapies with the promotion of angiogenesis may elucidate the synergistic pathways and ultimately enhance nerve regeneration.