Several nerve guidance conduits (NGCs) and nerve protectant wraps are approved by the US Food and Drug Administration (FDA) for clinical use in peripheral nerve repair. These devices cover a wide range of natural and synthetic materials, which may or may not be resorbable. This review consolidates the data pertaining to all FDA approved materials into a single reference, which emphasizes material composition alongside pre-clinical and clinical safety and efficacy (where possible). This article also summarizes the key advantages and limitations for each material as noted in the literature (with respect to the indication considered). In this context, this review provides a comprehensive reference for clinicians which may facilitate optimal material/device selection for peripheral nerve repair. For materials scientists, this review highlights predicate devices and evaluation methodologies, offering an insight into current deficiencies associated with state-of-the-art materials and may help direct new technology developments and evaluation methodologies thereof.

FDA approved guidance conduits and wraps for peripheral nerve injury: A review of materials and efficacy

Schwann cells develop from the neural crest in a well-defined sequence of events. This involves the formation of the Schwann cell precursor and immature Schwann cells, followed by the generation of the myelin and nonmyelin (Remak) cells of mature nerves. This review describes the signals that control the embryonic phase of this process and the organogenesis of peripheral nerves. We also discuss the phenotypic plasticity retained by mature Schwann cells, and explain why this unusual feature is central to the striking regenerative potential of the peripheral nervous system (PNS).

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Schwann Cells: Development and Role in Nerve Repair

Construction of tissue engineered nerve grafts and their application in peripheral nerve regeneration

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Neural tissue engineering options for peripheral nerve regeneration

Repairing injured peripheral nerves: Bridging the gap

Nerve repair is usually accomplished by direct suture when the two stumps can be approximated without tension. In the presence of a nerve defect, the placement of an autologous nerve graft is the current gold standard for nerve restoration. However, over the last 20 years, an increasing number of research articles reported on the use of non-nervous tubes (tubulization) for repairing nerve defects. The clinical employment of tubes (both biological and synthetic) as an alternative to autogenous nerve grafts is mainly justified by the limited availability of donor tissue for nerve autografts and the related morbidity. In addition, tubulization was proposed as an alternative to direct nerve sutures in order to create optimal conditions for nerve regeneration over the short empty space intentionally left between two nerve stumps. This paper outlines recent important advances in this field. Different tubulization techniques proposed so far are described, focusing in particular on studies that reported on the employment of tubes with patients. Our personal clinical experience on tubulization repair of sensory nerve lesions (digital nerves), using both biological and synthetic tubes, is presented, and the clinical results are compared. In our case series, both types of tubes led to good clinical results. Finally, we speculate about the prospects in the clinical application of tubulization for peripheral nerve repair.

Nerve repair by means of tubulization: literature review and personal clinical experience comparing biological and synthetic conduits for sensory nerve repair.

The morphological features of regeneration in long-distance (3 cm) muscle-vein-combined grafts were experimentally investigated in the rat sciatic nerve by means of light and electron microscopy. In the early phases of regeneration (14 days after surgery), many regenerating nerve fibers were detected along the muscle-vein-combined graft. Six months after surgery, quantitative morphometrical analysis of myelinated nerve fibers showed that both the total number and density of myelinated nerve fibers were significantly greater in regenerated nerves than in control nerves. The contrary appeared true for the mean fiber size, with fiber size significantly smaller in regenerated nerves. Ultrastructural observations allowed the description of some peculiar aspects of the relationship between muscle fibers, nerve fibers, and Schwann cells in both early and late phases of regeneration.

Nerve repair by means of vein filled with muscle grafts. II. Morphological analysis of regeneration.

The need for reconstruction of lower limb amputations is increasing, due to high-energy trauma in road accidents and work-related injuries. The indication for lower limb replantation is still controversial. Compared with upper limb replantations, indications are more select due to the frequent complications in lower limb salvage procedures, such as severe general complications or local complications such as necrosis, infections, nonunions, the need for secondary lengthening, or other reconstructive procedures. The satisfactory results given by artificial prosthesis, such as quicker recovery time and fewer secondary procedures, also contribute to the higher degree of selection for lower limb replantation candidates. Since 1993, we have replanted 14 amputations of the lower limb in 12 patients, including 2 bilateral cases. Although survival of the replanted segment was obtained in all patients, 5 cases were subsequently amputated for severe secondary complications. Of the remaining 9 cases, evaluated by means of Chen criteria, 7 had good results (3 Chen I and 4 Chen II), 1 sufficient (Chen III), and 1 poor (Chen IV). The best results were obtained in young patients. Our experience led us to examine the necessity for careful, objective patient selection. We developed a score evaluation system by modifying the international classifying method for severe limb traumas (mangled extremity severity score, or MESS system). This relatively simple system, based on the retrospective study of our cases, considers several parameters (patient's age, general conditions, level and type of lesion, time of injury, and associated lesions), giving each one a score. The total score gives the indication for replantation, predicts the functional outcome, and facilitates decision-making.

Lower limb replantations: indications and a new scoring system.

Diffusible factors from the distal stumps of transected peripheral nerves exert a neurotropic effect on regenerating nerves in vivo (specificity). This morphological study was designed to investigate the existence of tissue specificity in peripheral nerve fiber regeneration through a graft of vein filled with fresh skeletal muscle. This tubulization technique demonstrated experimental and clinical results similar to those obtained with traditional autologous nerve grafts. Specifically, we used Y-shaped grafts to assess the orientation pattern of regenerating axons in the distal stump tissue. Animal models were divided into four experimental groups. The proximal part of the Y-shaped conduit was sutured to a severed tibial nerve in all experiments. The two distal stumps were sutured to different targets: group A to two intact nerves (tibial and peroneal), group B to an intact nerve and an unvascularized tendon, group C to an intact nerve and a vascularized tendon, and group D to a nerve graft and an unvascularized tendon. Morphological evaluation by light and electron microscopy was conducted in the distal forks of the Y-shaped tube. Data showed that almost all regenerating nerve fibers spontaneously oriented towards the nerve tissue (attached or not to the peripheral innervation field), showing a good morphological pattern of regeneration in both the early and late phases of regeneration. When the distal choice was represented by a tendon (vascularized or not), very few nerve fibers were detected in the corresponding distal fork of the Y-shaped graft. These results show that, using the muscle-vein-combined grafting technique, regenerating axons are able to correctly grow and orientate within the basement membranes of the graft guided by the neurotropic lure of the distal nerve stump. © 2000 Wiley-Liss, Inc. MICROSURGERY 20:65–71 2000

Tissue specificity in rat peripheral nerve regeneration through combined skeletal muscle and vein conduit grafts.

Despite extensive research and surgical innovation, the treatment of peripheral nerve injuries remains a complex issue, particularly in nonsharp lesions. The aim of this study was to assess the clinical outcome in a group of 16 patients who underwent, in emergency, a primary repair for crush injury of sensory and mixed nerves of the upper limb with biological tubulization, namely, the muscle-vein-combined graft. The segments involved were sensory digital nerves in eight cases and mixed nerves in another eight cases (four median nerves and four ulnar nerves). The length of nerve defect ranged from 0.5 to 4 cm (mean 1.9 cm). Fifteen of 16 patients showed some degree of functional recovery. Six patients showed diminished light touch (3.61), six had protective sensation (4.31), and three showed loss of protective sensation (4.56) using Semmes-Weinstein monofilament test. All the patients who underwent digital nerve repair had favorable results graded as S4 in one case, S3+ in six cases, and S3 in one case. With respect to mixed nerve repair, we observed two S4, two S3+, two S3, one S2, and one S0 sensory recovery. Less favorable results were observed for motor function with three M4, one M3, two M2, and two M0 recoveries. Altogether, the results of this retrospective study demonstrates that tubulization nerve repair in emergency, in case of short nerve gaps, may restore the continuity of the nerve avoiding secondary nerve grafting. This technique preserves donor nerve and, in case of failure, does not preclude a delayed repair with a nerve graft.

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Pierluigi Tos

Papers

Nerve repair by means of tubulization: literature review and personal clinical experience comparing biological and synthetic conduits for sensory nerve repair.

Nerve repair by means of vein filled with muscle grafts. II. Morphological analysis of regeneration.

Lower limb replantations: indications and a new scoring system.

Tissue specificity in rat peripheral nerve regeneration through combined skeletal muscle and vein conduit grafts.

Primary repair of crush nerve injuries by means of biological tubulization with muscle-vein-combined grafts.