Modern end-to-side (ETS) nerve transfers have undergone several permutations since the early 1990\'s. Preclinical data have revealed important mechanisms and patterns of donor axon outgrowth into the recipient nerves and target reinnervation. The versatility of ETS nerve transfers can also potentially address several processes that limit functional recovery after nerve injury by babysitting motor end-plates and/or supporting the regenerative environment within the denervated nerve. Further clinical and basic science work is required to clarify the ideal clinical indications, contraindications, and mechanisms of action for these techniques in order to maximize their potential as reconstructive options.

Nerve autograft is the gold standard for reconstruction of peripheral nerve loss. The alternative is the interposition of a synthetic regeneration conduit. The purpose of the study was to evaluate the in vivo feasibility and interest of Adipose-Derived Stem Cells (ADSCs) using the Nanofat technique and chitosan conduit for peripheral nerve defect repair.
In vivo, after the creation of a 10 mm defect of the sciatic nerve, 2 groups were defined according to the nerve repair in rats: \"chitosan\" group (n = 10) and \"chitosan and ADSCs\" group (n = 10) with a clinical and paraclinical evaluation at 7 weeks.
The in vivo results seem to show that the adjunction of ADSCs was favorable clinically, histologically and functionally compare to a chitosan reconstruction alone.
Peripheral nerve repair with defect using a chitosan conduit associated with ADSCs would constitute a surgical alternative in a single surgical step.

Background  The rabbit sciatic nerve injury model may represent a valuable alternative for critical gap distance seen in humans but often leads to automutilation. In this study, we modified the complete sciatic nerve injury model for avoiding autophagy. Materials and Methods  In 20 adult female New Zealand White rabbits, instead of transecting the complete sciatic nerve, we unilaterally transected the tibial portion and preserved the peroneal portion. Thereby loss of sensation in the dorsal aspect of the paw was avoided. The tibial portion was repaired in a reversed autograft approach in a length of 2.6 cm. In an alternative repair approach, a gap of 2.6 cm in length was repaired with a chitosan-based nerve guide. Results  During the 6-month follow-up period, there were no incidents of autotomy. Nerve regeneration of the tibial portion of the sciatic nerve was evaluated histologically and morphometrically. A clear difference between the distal segments of the healthy contralateral and the repaired tibial portion of the sciatic nerve was detectable, validating the model. Conclusion  By transecting the isolated tibial portion of the rabbit sciatic nerve and leaving the peroneal portion intact, it was possible to eliminate automutilation behavior.

Peripheral nerve injury is a great challenge in clinical work due to the restricted repair gap and weak regrowth ability. Herein, we selected induced pluripotent stem cells (iPSCs) derived exosomes to supplement acellular nerve grafts (ANGs) with the aim of restoring long-distance peripheral nerve defects. Human fibroblasts were reprogrammed into iPSCs through non-integrating transduction of Oct3/4, Sox2, Klf4, and c-Myc. The obtained iPSCs had highly active alkaline phosphatase expression and expressed Oct4, SSEA4, Nanog, Sox2, which also differentiated into all three germ layers in vivo and differentiated into mature peripheral neurons and Schwann cells (SCs) in vitro. After isolation and biological characteristics of iPSCs-derived exosomes, we found that numerous PKH26-labeled exosomes were internalized inside SCs through endocytotic pathway and exhibited a proliferative effect on SCs that were involved in the process of axonal regeneration and remyelination. After that, we prepared ANGs via optimized chemical extracted process to bridge 15 mm long-distance peripheral nerve gaps in rats. Owing to the promotion of iPSCs-derived exosomes, satisfactory regenerative outcomes were achieved including gait behavior analysis, electrophysiological assessment, and morphological analysis of regenerated nerves. Especially, motor function was restored with comparable to those achieved with nerve autografts and there were no significant differences in the fiber diameter and area of reinnervated muscle fibers. Taken together, our combined use of iPSCs-derived exosomes with ANGs demonstrates good promise to restore long-distance peripheral nerve defects, and thus represents a cell-free strategy for future clinical applications.

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.

BACKGROUND: Even though several studies reported donor autologous nerve grafts for digital nerve defects, there is no report in the literature regarding acceptable graft for thumb nerves. The purpose of this study is to provide guidelines for autologous nerve graft selection by detecting similarities between thumb nerve zones and donor nerve with regard to the number of fascicles and cross-sectional area.
METHODS: Five cadavers were used in this study. An anatomical zoning system was defined for thumb nerves (zones 1, 2, 3). Sural nerve (SN), medial antebrachial cutaneous nerve (MABCN), lateral antebrachial cutaneous nerve (LABCN), posterior interosseous nerve (PIN), and anterior interosseous nerve (AIN) were selected as donor nerve grafts. The number of fascicles and surface area (mm2) was defined.
RESULTS: The mean of the fascicle number in zone 1, zone 2, zone 3, AIN, PIN, LABCN, MABCN, and SN were 3.8, 4.7, 6.1, 2.2, 1.8, 4.5, 3.1, and 6.4, respectively. The mean of the surface area in zone 1, zone 2, zone 3, AIN, PIN, LABCN, MABCN, and SN were 2.19, 6.26, 4.04, 1.58, 0.71, 5.00, 3.01, and 8.06, respectively.
CONCLUSIONS: LABCN is the best choice for all zones that has fascicular matching with all three zones of thumb nerves and caliber matching with zones 2 and 3. In zone 1, the best nerve graft is MABCN which has both suitable caliber and fascicle count.

The successful reconstruction of supercritical peripheral nerve injuries remains a major challenge in modern medicine. Progress in tissue engineering has enabled the development of nerve guidance conduits as an alternative to autologous nerve transplantation and the enrichment of conduits with fibrous materials or hydrogels has shown great potential in bridging nerve defects. The application of the dragline silk of spider genus Nephila as a filament for nerve guidance conduits has led to promising results. However, the use of spider silk has been phenomenological so far and the reasons for its success are still not identified. This renders a targeted tuning of synthetic fibrous luminal fillings such as recombinant silk out of reach. In this work the existing research was extended and in addition to dragline, the cocoon silk of Nephila edulis, as well as the connecting and attaching silk of Avicularia avicularia were investigated. Scanning electron microscopy revealed a difference in size and morphology of the spider silks. However, in vitro experiments indicated that Schwann cells adhere to the four fibers, independent of these two attributes. Raman spectroscopy in native state and aqueous environment demonstrated similar secondary protein structures for dragline, cocoon, and connecting silk. In contrast, the attaching silk showed a significant lower conformation of β-sheets, crucial for the stiffness of the silk. This was in line with the in vitro experiments, where the flexible attaching silk fibers adhered to each other when placed in liquid. This resulted in their inability to guide Schwann cells, leading to the generation of cell agglomerations. This direct comparison demonstrated the crucial role of β-sheets conformation for the guidance properties of natural spider silk, providing essential insights into the necessary material properties for the integration of fibrous luminal fillings in nerve guidance conduits.

Homuncular organization, i.e., the neuronal representation of the human body within the primary motor cortex, is one of the most fundamental principles of the human brain. Despite this, in rare peripheral nerve surgery patients, the transformation of a monofunctional (diaphragm activation) into a bifunctional motor area (diaphragm and arm activation is controlled by the same cortical area) has previously been demonstrated. The mechanisms behind this transformation are not fully known. To investigate this transformation of a monofunctional area we investigate functional connectivity changes in a unique and highly instructive pathophysiological patient model. These patients suffer from complete brachial plexus avulsion with arm paralysis and had been treated with reconnection of the end of the musculocutaneous nerve to the side of a fully functional phrenic nerve to regain function. Task-based functional connectivity between the arm representations and the diaphragm (phrenic nerve) representations were examined in six patients and 12 aged matched healthy controls at ultra-high field MRI while they either performed or tried isolated elbow flexion or conducted forced abdominal inspiration. Functional connectivity values are considerably increased between the diseased arm and the bilateral diaphragm areas while trying strong muscle tension in the diseased arm as compared to the healthy arm. This effect was not found as compared to the healthy arm in the patient group. This connectivity was stronger between ipsilateral than between corresponding contralateral brain regions. No corresponding differences were found in healthy subjects. Our data suggests that the increased functional connectivity between the deprived arm area and the diaphragm area drives biceps muscle function. From this findings we infer that this new rehabilitative mechanism in the primary motor cortex may establish new intrahemispheric connections within the brain and the motor cortex in particular to reroute the output of a completely denervated motor area. This study extend current knowledge about neuroplasticity within the motor cortex.

While systematic reviews are regarded as the strongest level of medical evidence, inconsistency in the quality and rigor of systematic reviews raises concerns about their use as a tool in guiding quality delivery in evidence-based clinical practice. The objective of this present study was to assess methodological soundness of systematic reviews with a particular focus on peripheral nerve repair and reconstruction. We performed a comprehensive search using PubMed and Scopus to identify all systematic reviews published on peripheral nerve reconstruction in 9 high-impact surgical journals. Two authors independently performed literature searches, screened abstracts, and extracted data. Discrepancies were resolved by discussion and consensus. The quality of systematic reviews was assessed using AMSTAR criteria. Initial search retrieved 184 articles. After screening duplicates, titles, abstracts, and conducting full text reviews, 26 studies met inclusion criteria. Of those, 18 (65%) were published by Plastic Surgery, 7 (27%) by Orthopedic Surgery, and 1 (4%) by Occupational Therapy. The total number of systematic reviews published on peripheral nerves each year has shown an increasing trend from 2004 through 2015. The overall median AMSTAR score was 5, reflecting a \"fair\" quality. There was no evidence of AMSTAR score improvement over time. Although the number of systematic reviews published on peripheral nerve repair has risen over the last decade, their quality has not exhibited the same increase. This highlights the necessity to increase familiarity with and conform to methodological quality criteria in order to improve the integrity of evidence-based medicine in peripheral nerve repair and reconstruction.

Cortical reorganization in response to peripheral nervous system damage is only poorly understood. In patients with complete brachial plexus avulsion and subsequent reconnection of the end of the musculocutaneous nerve to the side of a phrenic nerve, reorganization leads to a doubled arm representation in the primary motor cortex. Despite, homuncular organization being one of the most fundamental principles of the human brain, movements of the affected arm now activate 2 loci: the completely denervated arm representation and the diaphragm representation. Here, we investigate the details behind this peripherally triggered reorganization, which happens in healthy brains. fMRI effective connectivity changes within the motor network were compared between a group of patients and age matched healthy controls at 7 Tesla (6 patients and 12 healthy controls). Results show the establishment of a driving input of the denervated arm area to the diaphragm area which is now responsible for arm movements. The findings extend current knowledge about neuroplasticity in primary motor cortex: a denervated motor area may drive an auxilliary area to reroute its motor output.