maximum-isometric-tetanic-force-measurement-tibialis-anterior-muscle

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 ...

Mayo Clinic

Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Plastic Surgery, Nijmegen, The Netherlands

A single-institution case series is reported and a review of the literature on the outcomes of digital nerve gap reconstruction with the NeuraGen type 1 collagen nerve conduit (Integra Life Sciences, Plainsboro New Jersey, USA) and the Avance Nerve Graft (Axogen Inc., Alachua, Florida, USA) is presented.

Collagen Nerve Conduits and Processed Nerve Allografts for the Reconstruction of Digital Nerve Gaps: A Single-Institution Case Series and Review of the Literature.

Nerve regeneration involves multiple processes, which enhance blood supply that can be promoted by growth factors. Currently, tools are lacking to visualize the vascularization patterns in transplanted nerves in vivo. The purpose of this study was to describe three-dimensional visualization of the vascular system in the rat sciatic nerve and to quantify angiogenesis of nerve reconstruction.

New methods for objective angiogenesis evaluation of rat nerves using microcomputed tomography scanning and conventional photography.

The specific patterns of revascularization of allograft nerves after the addition of vascularization remain unknown. The aim of this study was to determine the revascularization patterns of optimized processed allografts (OPA) after surgically induced angiogenesis to the wound bed in a rat sciatic nerve model.

Revascularization patterns of nerve allografts in a rat sciatic nerve defect model.

Vascularization is an important factor in nerve graft survival and function. The specific molecular regulations and patterns of angiogenesis following peripheral nerve injury are in a broad complex of pathways. This review aims to summarize current knowledge on the role of vascularization in nerve regeneration, including the key regulation molecules, and mechanisms and patterns of revascularization after nerve injury. Angiogenesis, the maturation of pre-existing vessels into new areas, is stimulated through angiogenic factors such as vascular endothelial growth factor and precedes the repair of damaged nerves. Vascular endothelial growth factor administration to nerves has demonstrated to increase revascularization after injury in basic science research. In the clinical setting, vascularized nerve grafts could be used in the reconstruction of large segmental peripheral nerve injuries. Vascularized nerve grafts are postulated to accelerate revascularization and enhance nerve regeneration by providing an optimal nutritional environment, especially in scarred beds, and decrease fibroblast infiltration. This could improve functional recovery after nerve grafting, however, conclusive evidence of the superiority of vascularized nerve grafts is lacking in human studies. A well-designed randomized controlled trial comparing vascularized nerve grafts to non-vascularized nerve grafts involving patients with similar injuries, nerve graft repair and follow-up times is necessary to demonstrate the efficacy of vascularized nerve grafts. Due to technical challenges, composite transfer of a nerve graft along with its adipose tissue has been proposed to provide a healthy tissue bed. Basic science research has shown that a vascularized fascial flap containing adipose tissue and a vascular bundle improves revascularization through excreted angiogenic factors, provided by the stem cells in the adipose tissue as well as by the blood supply and environmental support. While it was previously believed that revascularization occurred from both nerve ends, recent studies propose that revascularization occurs primarily from the proximal nerve coaptation. Fascial flaps or vascularized nerve grafts have limited applicability and future directions could lead towards off-the-shelf alternatives to autografting, such as biodegradable nerve scaffolds which include capillary-like networks to enable vascularization and avoid graft necrosis and ischemia.

The role of vascularization in nerve regeneration of nerve graft.

Surgical angiogenesis modifies the cellular environment of nerve allografts in a rat sciatic nerve defect model.

Peripheral nerve injuries (PNI) are common and frequently afflict otherwise healthy individuals after traumatic or iatrogenic events. Adjuvant therapies to improve functional outcomes after surgical repair of PNI have been investigated extensively in preclinical studies; however, to date, none have been clinically proven to have a notable therapeutic effect. FK506 (tacrolimus), a US Food and Drug Administration-approved systemic immunosuppressant, has demonstrated promising neuro-regenerative properties in both animal studies and clinical reports, but its adverse effects when systemically administered have precluded its broader applicability for patients with PNI. Recent advances in bioengineered drug delivery systems have made local FK506 delivery to a site of PNI an intriguing method of promoting peripheral nerve regeneration, with promising results in preclinical translational investigations. This review summarizes the preclinical and clinical evidence for FK506's beneficial effect in promoting peripheral nerve regeneration when administered systemically and locally.

Systemic and Local FK506 (Tacrolimus) and its Application in Peripheral Nerve Surgery.

We report a patient who has been on tacrolimus for bilateral lung transplantation and presented with a brachial plexus injury (BPI), with unusual improvement of lower trunk innervated hand function. The lower trunk injury with resultant left hand paralysis had developed after his sternotomy 18 months ago. He has been treated with tacrolimus as part of his immunosuppression protocol since the surgery, without severe side effects. Physical examination at 18 months demonstrated unusual excellent grip pattern and full opposition of his thumb with slight claw deformity of his ulnar two digits. While the neurotoxic effects of tacrolimus are more emphasised, the neuroregenerative properties have been recently explored. The recovery in this patient is unique and unusual after BPI and is most likely as a result of the low dose tacrolimus treatment.

Role of tacrolimus in return of hand function after brachial plexus injury in a lung transplantation patient.

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.

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

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.

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

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.

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

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.

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

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.

Article	Year
Collagen Nerve Conduits and Processed Nerve Allografts for the Reconstruction of Digital Nerve Gaps: A Single-Institution Case Series and Review of the Literature. World neurosurgery\| PubMed ID: 31003028	2019
New methods for objective angiogenesis evaluation of rat nerves using microcomputed tomography scanning and conventional photography. Microsurgery\| PubMed ID: 31758730	2020
Revascularization patterns of nerve allografts in a rat sciatic nerve defect model. Journal of plastic, reconstructive & aesthetic surgery : JPRAS\| PubMed ID: 31928962	2020
The role of vascularization in nerve regeneration of nerve graft. Neural regeneration research\| PubMed ID: 32209756	2020
Surgical angiogenesis modifies the cellular environment of nerve allografts in a rat sciatic nerve defect model. Gene\| PubMed ID: 32353583	2020
Systemic and Local FK506 (Tacrolimus) and its Application in Peripheral Nerve Surgery. The Journal of hand surgery\| PubMed ID: 32359866	2020
Role of tacrolimus in return of hand function after brachial plexus injury in a lung transplantation patient. BMJ case reports\| PubMed ID: 32381527	2020
The interaction of stem cells and vascularity in peripheral nerve regeneration. Neural regeneration research\| PubMed ID: 33433464	2021
Peripheral Nerve Basic Science Research-What Is Important for Hand Surgeons to Know? The Journal of hand surgery\| PubMed ID: 33867203	2021
Combined local delivery of tacrolimus and stem cells in hydrogel for enhancing peripheral nerve regeneration. Biotechnology and bioengineering\| PubMed ID: 33913523	2021
Functional Outcomes of Nerve Allografts Seeded with Undifferentiated and Differentiated Mesenchymal Stem Cells in a Rat Sciatic Nerve Defect Model. Plastic and reconstructive surgery\| PubMed ID: 34153019	2021
Administration of Purified Exosome Product in a Rat Sciatic Serve Reverse Autograft Model. Plastic and reconstructive surgery\| PubMed ID: 34153020	2021

Tiam M. Saffari

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