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.

The Role of Exosomes in Upper-Extremity Tissue Regeneration.

Exosomes are cell-free membrane vesicles secreted by a wide variety of cells as secretomes into the extracellular matrix. Alongside facilitating intercellular communication, exosomes carry various bioactive molecules consisting of nucleic acids, proteins, and lipids. Exosome applications have increased in popularity by overcoming the disadvantages of mesenchymal stem cell therapies. Despite this, a better understanding of the underlying mechanisms of action of exosomes is necessary prior to clinical application in upper-extremity tissue regeneration. The purpose of this review is to introduce the concept of exosomes and their possible applications in upper-extremity tissue regeneration, detail the shortcomings of current exosome research, and explore their potential clinical application in the upper extremity.

Dose-response analysis after administration of a human platelet-derived exosome product on neurite outgrowth in vitro.

Modulating the nerve's local microenvironment using exosomes is proposed to enhance nerve regeneration. This study aimed to determine the optimal dose of purified exosome product (PEP) required to exert maximal neurite extension. An in vitro dorsal root ganglion (DRG) neurite outgrowth assay was used to evaluate the effect of treatment with (i) 5% PEP, (ii) 10% PEP, (iii) 15% PEP, or (iv) 20% PEP on neurite extension (N = 9/group), compared to untreated controls. After 72 h, neurite extension was measured to quantify nerve regeneration. Live cell imaging was used to visualize neurite outgrowth during incubation. Treatment with 5% PEP resulted in the longest neurite extension and was superior to the untreated DRG (p = 0.003). Treatment with 10% PEP, 15% PEP, and 20% PEP was found to be comparable to controls (p = 0.12, p = 0.06, and p = 0.41, respectively) and each other. Live cell imaging suggested that PEP migrated towards the DRG neural regeneration site, compared to the persistent homogenous distribution of PEP in culture media alone. 5% PEP was found to be the optimal concentration for nerve regeneration based on this in vitro dose-response analysis.

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.

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.