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Introduction: Peripheral nerve injury (PNI) is increasingly prevalent and challenging to treat despite advances in microsurgical techniques. In this context, adipose tissue derivatives, such as adipose-derived stem cells, nanofat, and stromal vascular fraction have been gaining attention as potential allies in peripheral nerve regeneration. Objectives: This study aims to explore the use of adipose tissue derivatives in nerve regeneration following peripheral nerve transection in murine models. Thus, we assess and synthesize the key techniques and methods used for evaluating the obtained nerve regeneration to guide future experimental research and clinical interventions. Methodology: A systematic review was conducted in February 2024, adhering to the Cochrane and PRISMA 2020 guidelines, using the PubMed, SciELO, and LILACS databases. The focus was on experimental studies involving adipose tissue derivatives in nerve regeneration in animal models post-transection. Only experimental trials reporting nerve regeneration outcomes were included; studies lacking a comparator group or evaluation methods were excluded. Results: Out of 273 studies initially identified from MEDLINE, 19 were selected for detailed analysis. The average study included 32.5 subjects, with about 10.2 subjects per intervention subgroup. The predominant model was the sciatic nerve injury with a 10 mm gap. The most common intervention involved unprocessed adipose-derived stem cells, utilized in 14 articles. Conclusions: This review underscores the significant potential of current methodologies in peripheral nerve regeneration, particularly highlighting the use of murine models and thorough evaluation techniques. [ABSTRACT FROM AUTHOR]

Gap injuries to the peripheral nervous system result in pain and loss of function, without any particularly effective therapeutic options. Within this context, mesenchymal stem cell (MSC)-derived exosomes have emerged as a potential therapeutic option. Thus, the focus of this study was to review currently available data on MSC-derived exosome-mounted scaffolds in peripheral nerve regeneration in order to identify the most promising scaffolds and exosome sources currently in the field of peripheral nerve regeneration. We conducted a systematic review following PRISMA 2020 guidelines. Exosome origins varied (adipose-derived MSCs, bone marrow MSCs, gingival MSC, induced pluripotent stem cells and a purified exosome product) similarly to the materials (Matrigel, alginate and silicone, acellular nerve graft [ANG], chitosan, chitin, hydrogel and fibrin glue). The compound muscle action potential (CMAP), sciatic functional index (SFI), gastrocnemius wet weight and histological analyses were used as main outcome measures. Overall, exosome-mounted scaffolds showed better regeneration than scaffolds alone. Functionally, both exosome-enriched chitin and ANG showed a significant improvement over time in the sciatica functional index, CMAP and wet weight. The best histological outcomes were found in the exosome-enriched ANG scaffold with a high increase in the axonal diameter and muscle cross-section area. Further studies are needed to confirm the efficacy of exosome-mounted scaffolds in peripheral nerve regeneration. [ABSTRACT FROM AUTHOR]

The field of peripheral nerve regeneration is a dynamic and rapidly evolving area of research that continues to captivate the attention of neuroscientists worldwide. The quest for effective treatments and therapies to enhance the healing of peripheral nerves has gained significant momentum in recent years, as evidenced by the substantial increase in publications dedicated to this field. This surge in interest reflects the growing recognition of the importance of peripheral nerve recovery and the urgent need to develop innovative strategies to address nerve injuries. In this context, this article aims to contribute to the existing knowledge by providing a comprehensive review that encompasses both biomaterial and clinical perspectives. By exploring the utilization of nerve guidance conduits and pharmacotherapy, this article seeks to shed light on the remarkable advancements made in the field of peripheral nerve regeneration. Nerve guidance conduits, which act as artificial channels to guide regenerating nerves, have shown promising results in facilitating nerve regrowth and functional recovery. Additionally, pharmacotherapy approaches have emerged as potential avenues for promoting nerve regeneration, with various therapeutic agents being investigated for their neuroprotective and regenerative properties. The pursuit of advancing the field of peripheral nerve regeneration necessitates persistent investment in research and development. Continued exploration of innovative treatments, coupled with a deeper understanding of the intricate processes involved in nerve regeneration, holds the promise of unlocking the complete potential of these groundbreaking interventions. By fostering collaboration among scientists, clinicians, and industry partners, we can accelerate progress in this field, bringing us closer to the realization of transformative therapies that restore function and quality of life for individuals affected by peripheral nerve injuries. [ABSTRACT FROM AUTHOR]

Background: Simulating the post-traumatic continuity defect of small human peripheral nerves, we compared the effectiveness of fibrin glue with neurorrhaphy for nerve gap restoration. Methods: In twenty-four male Wistar rats, a fifteen mm defect in one sciatic nerve only was made and immediately repaired with an inverted polarity autograft. According to the used technique, rats were divided into Group A (Control), using traditional neurorrhaphy, and Group B (Study), using fibrine glue sealing; in total, 50% of rats were sacrificed at 16 weeks and 50% at 21 weeks. Before sacrifice, an assessment of motor function was done through Walking Track Analysis and an electroneurophysiological evaluation. After sacrifice, selected muscle mass indexes and the histology of the regenerated nerves were assessed. All data were evaluated by Student's t test for unpaired data. Results: No significant differences were found between the two groups, with only the exception of a relative improvement in the tibialis anterior muscle's number of motor units in the study group. Conclusion: Despite the fact that the use of fibrin glue as a nerve sealant is not superior in terms of functional recovery, its effectiveness is comparable to that of microsurgical repair. Hence, the faster and technically easier glueing technique could deserve broader clinical application. [ABSTRACT FROM AUTHOR]

Simple Summary: Peripheral nerve injuries are common in the clinical setting and may affect functionality by permanent monoplegia that could end in amputation. Electrical stimulation is an option to help recovery, in addition to exercises and locomotor training with a positive synergetic effect on nerve regeneration. These approaches could benefit from other rehabilitation techniques, such as laser and ultrasounds, as well as cell-based therapies, considering a One Health perspective. Traumatic nerve injuries are common lesions that affect several hundred thousand humans, as well as dogs and cats. The assessment of nerve regeneration through animal models may provide information for translational research and future therapeutic options that can be applied mutually in veterinary and human medicine, from a One Health perspective. This review offers a hands-on vision of the non-invasive and conservative approaches to peripheral nerve injury, focusing on the role of neurorehabilitation in nerve repair and regeneration. The peripheral nerve injury may lead to hypersensitivity, allodynia and hyperalgesia, with the possibility of joint contractures, decreasing functionality and impairing the quality of life. The question remains regarding how to improve nerve repair with surgical possibilities, but also considering electrical stimulation modalities by modulating sensory feedback, upregulation of BDNF, GFNF, TrKB and adenosine monophosphate, maintaining muscle mass and modulating fatigue. This could be improved by the positive synergetic effect of exercises and physical activity with locomotor training, and other physical modalities (low-level laser therapy, ultrasounds, pulsed electromagnetic fields, electroacupuncture and others). In addition, the use of cell-based therapies is an innovative treatment tool in this field. These strategies may help avoid situations of permanent monoplegic limbs that could lead to amputation. [ABSTRACT FROM AUTHOR]

Oxygen is compulsory for mitochondrial function and energy supply, but it has numerous more nuanced roles. The different roles of oxygen in peripheral nerve regeneration range from energy supply, inflammation, phagocytosis, and oxidative cell destruction in the context of reperfusion injury to crucial redox signaling cascades that are necessary for effective axonal outgrowth. A fine balance between reactive oxygen species production and antioxidant activity draws the line between physiological and pathological nerve regeneration. There is compelling evidence that redox signaling mediated by the Nox family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases plays an important role in peripheral nerve regeneration. Further research is needed to better characterize the role of Nox in physiological and pathological circumstances, but the available data suggest that the modulation of Nox activity fosters great therapeutic potential. One of the promising approaches to enhance nerve regeneration by modulating the redox environment is hyperbaric oxygen therapy. In this review, we highlight the influence of various oxygenation states, i.e., hypoxia, physoxia, and hyperoxia, on peripheral nerve repair and regeneration. We summarize the currently available data and knowledge on the effectiveness of using hyperbaric oxygen therapy to treat nerve injuries and discuss future directions. [ABSTRACT FROM AUTHOR]

Appropriate animal models, mimicking conditions of both health and disease, are needed to understand not only the biology and the physiology of neurons and other cells under normal conditions but also under stress conditions, like nerve injuries and neuropathy. In such conditions, understanding how genes and different factors are activated through the well-orchestrated programs in neurons and other related cells is crucial. Knowledge about key players associated with nerve regeneration intended for axonal outgrowth, migration of Schwann cells with respect to suitable substrates, invasion of macrophages, appropriate conditioning of extracellular matrix, activation of fibroblasts, formation of endothelial cells and blood vessels, and activation of other players in healthy and diabetic conditions is relevant. Appropriate physical and chemical attractions and repulsions are needed for an optimal and directed regeneration and are investigated in various nerve injury and repair/reconstruction models using healthy and diabetic rat models with relevant blood glucose levels. Understanding dynamic processes constantly occurring in neuropathies, like diabetic neuropathy, with concomitant degeneration and regeneration, requires advanced technology and bioinformatics for an integrated view of the behavior of different cell types based on genomics, transcriptomics, proteomics, and imaging at different visualization levels. Single-cell-transcriptional profile analysis of different cells may reveal any heterogeneity among key players in peripheral nerves in health and disease. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries are quite common and often require a surgical intervention. However, even after surgery, patients do not often regain satisfactory sensory and motor functions. This, in turn, results in a heavy socioeconomic burden. To some extent, neurons can regenerate from the proximal nerve stump and try to reconnect to the distal stump. However, this regenerating capacity is limited, and depending on the type and size of peripheral nerve injury, this process may not lead to a positive outcome. To date, no pharmacological approach has been used to improve nerve regeneration following repair surgery. We elected to investigate the effects of local delivery of minocycline on nerve regeneration. This molecule has been studied in the central nervous system and was shown to improve the outcome in many disease models. In this study, we first tested the effects of minocycline on SCL 4.1/F7 Schwann cells in vitro and on sciatic nerve explants. We specifically focused on the Schwann cell repair phenotype, as these cells play a central role in orchestrating nerve regeneration. Finally, we delivered minocycline locally in two different rat models of nerve injury, a sciatic nerve transection and a sciatic nerve autograft, demonstrating the capacity of local minocycline treatment to improve nerve regeneration. [ABSTRACT FROM AUTHOR]

Regenerative therapies for the treatment of peripheral nerve and spinal cord injuries can require hundreds of millions of autologous cells. Current treatments involve the harvest of Schwann cells (SCs) from nerves; however, this is an invasive procedure. Therefore, a promising alternative is using skin-derived Schwann cells (Sk-SCs), in which between 3–5 million cells can be harvested from a standard skin biopsy. However, traditional static planar culture is still inefficient at expanding cells to clinically relevant numbers. As a result, bioreactors can be used to develop reproducible bioprocesses for the large-scale expansion of therapeutic cells. Here, we present a proof-of-concept SC manufacturing bioprocess using rat Sk-SCs. With this integrated process, we were able to simulate a feasible bioprocess, taking into consideration the harvest and shipment of cells to a production facility, the generation of the final cell product, and the cryopreservation and shipment of cells back to the clinic and patient. This process started with 3 million cells and inoculated and expanded them to over 200 million cells in 6 days. Following the harvest and post-harvest cryopreservation and thaw, we were able to maintain 150 million viable cells that exhibited a characteristic Schwann cell phenotype throughout each step of the process. This process led to a 50-fold expansion, producing a clinically relevant number of cells in a 500 mL bioreactor in just 1 week, which is a dramatic improvement over current methods of expansion. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries (PNI) are common and often result in lifelong disability. The peripheral nervous system has an inherent ability to regenerate following injury, yet complete functional recovery is rare. Despite advances in the diagnosis and repair of PNIs, many patients suffer from chronic pain, and sensory and motor dysfunction. One promising surgical adjunct is the application of intraoperative electrical stimulation (ES) to peripheral nerves. ES acts through second messenger cyclic AMP to augment the intrinsic molecular pathways of regeneration. Decades of animal studies have demonstrated that 20 Hz ES delivered post-surgically accelerates axonal outgrowth and end organ reinnervation. This work has been translated clinically in a series of randomized clinical trials, which suggest that ES can be used as an efficacious therapy to improve patient outcomes following PNIs. The aim of this review is to discuss the cellular physiology and the limitations of regeneration after peripheral nerve injuries. The proposed mechanisms of ES protocols and how they facilitate nerve regeneration depending on timing of administration are outlined. Finally, future directions of research that may provide new perspectives on the optimal delivery of ES following PNI are discussed. [ABSTRACT FROM AUTHOR]

Corneal defects can seriously affect human vision, and keratoplasty is the most widely accepted therapy method for visual rehabilitation. Currently, effective treatment for clinical patients has been restricted due to a serious shortage of donated cornea tissue and high-quality artificial repair materials. As the predominant component of cornea tissue, collagen-based materials have promising applications for corneal repair. However, the corneal nerve repair and epithelization process after corneal transplantation must be improved. This research proposes a new collagen-based scaffold with good biocompatibility and biological functionality enhanced by surface chemical grafting of natural taurine molecular. The chemical composition of collagen-taurine (Col-Tau) material is evaluated by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy, and its hydrophilic properties, light transmittance, swelling performance and mechanical tensile properties have been measured. The research results indicate that the Col-Tau sample has high transmittance and good mechanical properties, and exhibits excellent capacity to promote corneal nerve cell growth and the epithelization process of corneal epithelial cells. This novel Col-Tau material, which can be easily prepared at a low cost, should have significant application potential for the treating corneal disease in the future. [ABSTRACT FROM AUTHOR]

The rat median nerve model is a well-established and frequently used model for peripheral nerve injury and repair. The grasping test is the gold-standard to evaluate functional recovery in this model. However, no comprehensive review exists to summarize the course of functional recovery in regard to the lesion type. According to PRISMA-guidelines, research was performed, including the databases PubMed and Web of Science. Groups were: (1) crush injury, (2) transection with end-to-end or with (3) end-to-side coaptation and (4) isogenic or acellular allogenic grafting. Total and respective number, as well as rat strain, type of nerve defect, length of isogenic or acellular allogenic allografts, time at first signs of motor recovery (FSR) and maximal recovery grasping strength (MRGS), were evaluated. In total, 47 articles met the inclusion criteria. Group I showed earliest signs of motor recovery. Slow recovery was observable in group III and in graft length above 25 mm. Isografts recovered faster compared to other grafts. The onset and course of recovery is heavily dependent from the type of nerve injury. The grasping test should be used complementary in addition to other volitional and non-volitional tests. Repetitive examinations should be planned carefully to optimize assessment of valid and reliable data. [ABSTRACT FROM AUTHOR]

Investigations reporting positive effects of extracorporeal shockwave therapy (ESWT) on nerve regeneration are limited to the rat sciatic nerve model. The effects of ESWT on muscle-in-vein conduits (MVCs) have also not been investigated yet. This study aimed to evaluate the effects of ESWT after repair of the rat median nerve with either autografts (ANGs) or MVCs. In male Lewis rats, a 7 mm segment of the right median nerve was reconstructed either with an ANG or an MVC. For each reconstructive technique, one group of animals received one application of ESWT while the other rats served as controls. The animals were observed for 12 weeks, and nerve regeneration was assessed using computerized gait analysis, the grasping test, electrophysiological evaluations and histological quantification of axons, blood vessels and lymphatic vasculature. Here, we provide for the first time a comprehensive analysis of ESWT effects on nerve regeneration in a rat model of median nerve injury. Furthermore, this study is among the first reporting the quantification of lymphatic vessels following peripheral nerve injury and reconstruction in vivo. While we found no significant direct positive effects of ESWT on peripheral nerve regeneration, results following nerve repair with MVCs were significantly inferior to those after ANG repair. [ABSTRACT FROM AUTHOR]

Nerve regeneration and repair still remain a huge challenge for both central nervous and peripheral nervous system. Although some therapeutic substances, including neuroprotective agents, clinical drugs and stem cells, as well as various growth factors, are found to be effective to promote nerve repair, a carrier system that possesses a sustainable release behavior, in order to ensure high on-site concentration during the whole repair and regeneration process, and high bioavailability is still highly desirable. Hydrogel, as an ideal delivery system, has an excellent loading capacity and sustainable release behavior, as well as tunable physical and chemical properties to adapt to various biomedical scenarios; thus, it is thought to be a suitable carrier system for nerve repair. This paper reviews the structure and classification of hydrogels and summarizes the fabrication and processing methods that can prepare a suitable hydrogel carrier with specific physical and chemical properties. Furthermore, the modulation of the physical and chemical properties of hydrogels is also discussed in detail in order to obtain a better therapeutic effect to promote nerve repair. Finally, the future perspectives of hydrogel microsphere carriers for stroke rehabilitation are highlighted. [ABSTRACT FROM AUTHOR]

In recent decades, microfluidics have significantly advanced nerve regeneration research. Microfluidic devices can provide an accurate simulation of in vivo microenvironment for different research purposes such as analyzing myelin growth inhibitory factors, screening drugs, assessing nerve growth factors, and exploring mechanisms of neural injury and regeneration. The microfluidic platform offers technical supports for nerve regeneration that enable precise spatio-temporal control of cells, such as neuron isolation, single-cell manipulation, neural patterning, and axon guidance. In this paper, we review the development and recent advances of microfluidic platforms for nerve regeneration research. [ABSTRACT FROM AUTHOR]

Photochemical sealing of a nerve wrap over the repair site isolates and optimizes the regenerating nerve microenvironment. To facilitate clinical adoption of the technology, we investigated photosealed autologous tissue in a rodent sciatic nerve transection and repair model. Rats underwent transection of the sciatic nerve with repair performed in three groups: standard microsurgical neurorrhaphy (SN) and photochemical sealing with a crosslinked human amnion (xHAM) or autologous vein. Functional recovery was assessed at four-week intervals using footprint analysis. Gastrocnemius muscle mass preservation, histology, and nerve histomorphometry were evaluated at 120 days. Nerves treated with a PTB-sealed autologous vein improved functional recovery at 120 days although the comparison between groups was not significantly different (SN: -58.4 +/- 10.9; XHAM: -57.9 +/- 8.7; Vein: -52.4 +/- 17.1). Good muscle mass preservation was observed in all groups, with no statistical differences between groups (SN: 69 +/- 7%; XHAM: 70 +/- 7%; Vein: 70 +/- 7%). Histomorphometry showed good axonal regeneration in all repair techniques. These results demonstrate that peripheral nerve repair using photosealed autologous veins produced regeneration at least equivalent to current gold-standard microsurgery. The use of autologous veins removes costs and foreign body concerns and would be readily available during surgery. This study illustrates a new repair method that could restore normal endoneurial homeostasis with minimal trauma following severe nerve injury.

In this review we summarize the events known to occur after an injury in the peripheral nervous system. We have focused on the Schwann cells, as they are the most important cells for the repair process and facilitate axonal outgrowth. The environment created by this cell type is essential for the outcome of the repair process. The review starts with a description of the current state of knowledge about the initial events after injury, followed by Wallerian degeneration, and subsequent regeneration. The importance of surgical repair, carried out as soon as possible to increase the chances of a good outcome, is emphasized throughout the review. The review concludes by describing the target re-innervation, which today is one of the most serious problems for nerve regeneration. It is clear, compiling this data, that even though regeneration of the peripheral nervous system is possible, more research in this area is needed in order to perfect the outcome. [ABSTRACT FROM AUTHOR]

Bridging nerve gaps with suitable grafts is a major clinical problem. The autologous nerve graft is considered to be the gold standard, providing the best functional results; however, donor site morbidity is still a major disadvantage. Various attempts have been made to overcome the problems of autologous nerve grafts with artificial nerve tubes, which are "ready-to-use" in almost every situation. A wide range of materials have been used in animal models but only few have been applied to date clinically, where biocompatibility is an inevitable prerequisite. This review gives an idea about artificial nerve tubes with special focus on their biocompatibility in animals and humans. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries are a common clinical problem. They not only affect the physical capabilities of the injured person due to loss of motor or sensory function but also have a significant impact on psychosocial aspects of life. The aim of this work is to review the interplay of psychosocial factors and peripheral nerve lesions. By reviewing the published literature, we identified several factors to be heavily influenced by peripheral nerve lesions. In addition to psychological factors like pain, depression, catastrophizing and stress, social factors like employment status and worker's compensation status could be identified to be influenced by peripheral nerve lesions as well as serving as predictors of functional outcome themselves, respectively. This work sheds a light not only on the impact of peripheral nerve lesions on psychosocial aspects of life, but also on the prognostic values of these factors of functional outcome. Interdisciplinary, individualized treatment of patients is required to identify patient at risk for adverse outcomes and provide them with emotional support when adapting to their new life situation. [ABSTRACT FROM AUTHOR]

Despite the progressive advances, current standards of treatments for peripheral nerve injury do not guarantee complete recovery. Thus, alternative therapeutic interventions should be considered. Complementary and alternative medicines (CAMs) are widely explored for their therapeutic value, but their potential use in peripheral nerve regeneration is underappreciated. The present systematic review, designed according to guidelines of Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols, aims to present and discuss the current literature on the neuroregenerative potential of CAMs, focusing on plants or herbs, mushrooms, decoctions, and their respective natural products. The available literature on CAMs associated with peripheral nerve regeneration published up to 2020 were retrieved from PubMed, Scopus, and Web of Science. According to current literature, the neuroregenerative potential of Achyranthes bidentata, Astragalus membranaceus, Curcuma longa, Panax ginseng, and Hericium erinaceus are the most widely studied. Various CAMs enhanced proliferation and migration of Schwann cells in vitro, primarily through activation of MAPK pathway and FGF-2 signaling, respectively. Animal studies demonstrated the ability of CAMs to promote peripheral nerve regeneration and functional recovery, which are partially associated with modulations of neurotrophic factors, pro-inflammatory cytokines, and anti-apoptotic signaling. This systematic review provides evidence for the potential use of CAMs in the management of peripheral nerve injury. [ABSTRACT FROM AUTHOR]

We investigated injury-induced heat shock protein 27 (HSP27) expression and its association to axonal outgrowth after injury and different nerve repair models in healthy Wistar and diabetic Goto-Kakizaki rats. By immunohistochemistry, expression of HSP27 in sciatic nerves and DRG and axonal outgrowth (neurofilaments) in sciatic nerves were analyzed after no, immediate, and delayed (7-day delay) nerve repairs (7- or 14-day follow-up). An increased HSP27 expression in nerves and in DRG at the uninjured side was associated with diabetes. HSP27 expression in nerves and in DRG increased substantially after the nerve injuries, being higher at the site where axons and Schwann cells interacted. Regression analysis indicated a positive influence of immediate nerve repair compared to an unrepaired injury, but a shortly delayed nerve repair had no impact on axonal outgrowth. Diabetes was associated with a decreased axonal outgrowth. The increased expression of HSP27 in sciatic nerve and DRG did not influence axonal outgrowth. Injured sciatic nerves should appropriately be repaired in healthy and diabetic rats, but a short delay does not influence axonal outgrowth. HSP27 expression in sciatic nerve or DRG, despite an increase after nerve injury with or without a repair, is not associated with any alteration in axonal outgrowth. [ABSTRACT FROM AUTHOR]

Acellular nerve allografts (ANGs) represent a promising alternative in nerve repair. Our aim is to improve the structural and biomechanical properties of biocompatible Sondell (SD) and Roosens (RS) based ANGs using genipin (GP) as a crosslinker agent ex vivo. The impact of two concentrations of GP (0.10% and 0.25%) on Wistar rat sciatic nerve-derived ANGs was assessed at the histological, biomechanical, and biocompatibility levels. Histology confirmed the differences between SD and RS procedures, but not remarkable changes were induced by GP, which helped to preserve the nerve histological pattern. Tensile test revealed that GP enhanced the biomechanical properties of SD and RS ANGs, being the crosslinked RS ANGs more comparable to the native nerves used as control. The evaluation of the ANGs biocompatibility conducted with adipose-derived mesenchymal stem cells cultured within the ANGs confirmed a high degree of biocompatibility in all ANGs, especially in RS and RS-GP 0.10% ANGs. Finally, this study demonstrates that the use of GP could be an efficient alternative to improve the biomechanical properties of ANGs with a slight impact on the biocompatibility and histological pattern. For these reasons, we hypothesize that our novel crosslinked ANGs could be a suitable alternative for future in vivo preclinical studies. [ABSTRACT FROM AUTHOR]

Stimuli-responsive materials are very attractive candidates for on-demand drug delivery applications. Precise control over therapeutic agents in a local area is particularly enticing to regulate the biological repair process and promote tissue regeneration. Macromolecular therapeutics are difficult to embed for delivery, and achieving controlled release over long-term periods, which is required for tissue repair and regeneration, is challenging. Biohybrid composites incorporating natural biopolymers and electroconductive/active moieties are emerging as functional materials to be used as coatings, implants or scaffolds in regenerative medicine. Here, we report the development of electroresponsive biohybrid composites based on Bombyx mori silkworm fibroin and reduced graphene oxide that are electrostatically loaded with a high-molecular-weight therapeutic (i.e., 26 kDa nerve growth factor-β (NGF-β)). NGF-β-loaded composite films were shown to control the release of the drug over a 10-day period in a pulsatile fashion upon the on/off application of an electrical stimulus. The results shown here pave the way for personalized and biologically responsive scaffolds, coatings and implantable devices to be used in neural tissue engineering applications, and could be translated to other electrically sensitive tissues as well. [ABSTRACT FROM AUTHOR]

Conduits for the repair of peripheral nerve gaps are a good alternative to autografts as they provide a protected environment and a physical guide for axonal re-growth. Conduits require colonization by cells involved in nerve regeneration (Schwann cells, fibroblasts, endothelial cells, macrophages) while in the autograft many cells are resident and just need to be activated. Since it is known that soluble Neuregulin1 (sNRG1) is released after injury and plays an important role activating Schwann cell dedifferentiation, its expression level was investigated in early regeneration steps (7, 14, 28 days) inside a 10 mm chitosan conduit used to repair median nerve gaps in Wistar rats. In vivo data show that sNRG1, mainly the isoform α, is highly expressed in the conduit, together with a fibroblast marker, while Schwann cell markers, including NRG1 receptors, were not. Primary culture analysis shows that nerve fibroblasts, unlike Schwann cells, express high NRG1α levels, while both express NRG1β. These data suggest that sNRG1 might be mainly expressed by fibroblasts colonizing nerve conduit before Schwann cells. Immunohistochemistry analysis confirmed NRG1 and fibroblast marker co-localization. These results suggest that fibroblasts, releasing sNRG1, might promote Schwann cell dedifferentiation to a "repair" phenotype, contributing to peripheral nerve regeneration. [ABSTRACT FROM AUTHOR]

Over the recent years, several methods have been experienced to repair injured peripheral nerves. Among investigated strategies, the use of natural or synthetic conduits was validated for clinical application. In this study, we assessed the therapeutic potential of vein guides, transplanted immediately or two weeks after a peroneal nerve injury and filled with olfactory ecto-mesenchymal stem cells (OEMSC). Rats were randomly allocated to five groups. A3 mm peroneal nerve loss was bridged, acutely or chronically, with a 1 cm long femoral vein and with/without OEMSCs. These four groups were compared to unoperated rats (Control group). OEMSCs were purified from male olfactory mucosae and grafted into female hosts. Three months after surgery, nerve repair was analyzed by measuring locomotor function, mechanical muscle properties, muscle mass, axon number, and myelination. We observed that stem cells significantly (i) increased locomotor recovery, (ii) partially maintained the contractile phenotype of the target muscle, and (iii) augmented the number of growing axons. OEMSCs remained in the nerve and did not migrate in other organs. These results open the way for a phase I/IIa clinical trial based on the autologous engraftment of OEMSCs in patients with a nerve injury, especially those with neglected wounds. [ABSTRACT FROM AUTHOR]

Following peripheral nerve trauma that damages a length of the nerve, recovery of function is generally limited. This is because no material tested for bridging nerve gaps promotes good axon regeneration across the gap under conditions associated with common nerve traumas. While many materials have been tested, sensory nerve grafts remain the clinical "gold standard" technique. This is despite the significant limitations in the conditions under which they restore function. Thus, they induce reliable and good recovery only for patients < 25 years old, when gaps are <2 cm in length, and when repairs are performed <2–3 months post trauma. Repairs performed when these values are larger result in a precipitous decrease in neurological recovery. Further, when patients have more than one parameter larger than these values, there is normally no functional recovery. Clinically, there has been little progress in developing new techniques that increase the level of functional recovery following peripheral nerve injury. This paper examines the efficacies and limitations of sensory nerve grafts and various other techniques used to induce functional neurological recovery, and how these might be improved to induce more extensive functional recovery. It also discusses preliminary data from the clinical application of a novel technique that restores neurological function across long nerve gaps, when repairs are performed at long times post-trauma, and in older patients, even under all three of these conditions. Thus, it appears that function can be restored under conditions where sensory nerve grafts are not effective. [ABSTRACT FROM AUTHOR]