Effects of topically administered FK506 on sciatic nerve regeneration and reinnervation after vein graft repair of short nerve gaps (original) (raw)
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Journal of the Peripheral Nervous System, 2003
We evaluated the effects of FK506, at doses of 0.2, 2, and 5 mg/kg/day, on the response to nerve grafts implanted in outbred mice. A 6 mm long segment of the sciatic nerve was transected and repaired by autograft (the same segment resected), allograft (from another mouse), or xenograft (from a rat nerve). The regenerating nerves were harvested after 3 weeks and studied under light and electron microscope. Allografts of animals treated with the 5 mg/kg/day dose of FK506 appeared similar to those from autografts, demonstrating an equivalent number of myelinated fibers. In mice treated with the 2 mg/kg/day dose, regeneration was slightly hindered, as indicated by the reduced number of myelinated fibers. In contrast, in mice given a 0.2 mg/kg/day dose of FK506, allografts were not different from untreated allografts; both groups showed a marked rejection response with only few unmyelinated axons and no myelinated fibers. Xenografts showed a more severe rejection than allografts, with a marked inflammatory cell reaction throughout the graft. In contrast, in mice treated with the 5 mg/kg/day dose, xenografts exhibited a mild cell reaction and a greater number of regenerated myelinated fibers. In conclusion, effective axonal regeneration is achieved with FK506 administration at doses of 5 mg/kg/day through allografts and, partially, through xenografts.
Journal of Reconstructive Microsurgery Open, 2019
Background The purpose of this study was to use artery grafts filled with CACIPLIQ20 and see if they promote nerve regeneration. Methods Sixty male Wistar rats were used. The rats were randomly divided into four experimental groups (n = 15): transected control group (negative control group [NCG]), sham-operated group (positive control group [SO]) artery graft group filled with saline (AG/NS), and CACIPLIQ20-treated group (AG/CACIPLIQ20). Fifteen rats were used as artery graft donors. In the SO group, the sciatic nerve was dissected from the surrounding tissues and left intact. In the NCG, AG/NS and AG/CACIPLIQ20) groups, a 10-mm gap was created in the left sciatic nerve. In the NCG group, the gap was not bridged with a graft. In the AG/NS group, the gap was bridged with a graft filled with saline. In the AG/CACIPLIQ20 group, the graft was filled with CACIPLIQ20. Walking track analysis was performed at 4, 8, 12, and 16 weeks after surgery. At 16 weeks postoperatively, the rats were s...
Journal of Oral and Maxillofacial Surgery, 2013
The objective of the study was to assess the effect of topically administered betamethasone on peripheral nerve regeneration and functional recovery after sciatic nerve transection in the rat. Materials and Methods: Forty-five healthy male white Wistar rats were divided into 3 experimental groups (n ϭ 15), randomly. In the treatment group, a 10-mm sciatic nerve defect was bridged by use of an inside-out vein graft filled with 10 L betamethasone (0.1 mg/kg) (IOVG/BETA group). In the control group, the vein was filled with phosphate-buffered saline solution alone (IOVG group). In the sham surgery group, the sciatic nerve was exposed with no further deleterious manipulations (SHAM group). Each group was subdivided into 3 subgroups of 5 animals each, and the regenerated nerve fibers were studied 4, 8, and 12 weeks after surgery. Results: Functional study confirmed faster recovery of regenerated axons in the IOVG/BETA group than in the IOVG group (P Ͻ .05). Gastrocnemius muscle mass in the IOVG/BETA group was found to be significantly greater than that in the IOVG group (P Ͻ .05). Morphometric indices of the regenerated fibers showed that the number and diameter of the myelinated fibers were significantly higher in the IOVG/BETA group than in the control group (P Ͻ .05). By use of immunohistochemistry, the location of reactions to S-100 in IOVG/BETA was clearly more positive than that in the IOVG group. Conclusions: When loaded in a vein graft, betamethasone resulted in improvement of functional recovery and quantitative morphometric indices of sciatic nerve. Topical application of this readily available agent offers the benefit of cost savings, as well as avoiding the complications associated with systemic administration.
Glia, 2004
We assessed the effects of FK506 administration on regeneration after a 6-mm gap repair with a collagen guide seeded with allogeneic Schwann cells (SCs) in the mouse sciatic nerve. SCs were isolated from predegenerated adult sciatic nerves and expanded in culture using a defined medium, before being seeded in the collagen guide embedded in Matrigel. Functional reinnervation was evaluated by noninvasive methods to determine recovery of motor, sensory, and autonomic functions in the hindpaw over 4 months postoperation. Histological analysis of the regenerated nerves was performed at the end of the study. Using simple collagen guides for tubulization repair, treatment with an immunosuppressant dose of FK506 (5 mg/kg/day) resulted in significant improvement of the onset and the degree of reinnervation. While the introduction of allogeneic SCs did not improve regeneration versus a collagen guide filled only with Matrigel, treatment with FK506 allowed for successful regeneration in all the mice and for significant improvement in the levels of functional recovery. Compared with the untreated group, there was greater survival of transplanted pre-labeled SCs in the FK506-treated animals. Morphologically, the best nerve regeneration (in terms of nerve caliber and numbers of myelinated axons) was obtained with SC-seeded guides from FK506-treated animals. Thus, FK506 should be considered as adjunct therapy for various types of tubulization repair.
Drug‐delivering nerve conduit improves regeneration in a critical‐sized gap
Biotechnology and Bioengineering, 2018
Autologous nerve grafts are the current "gold standard" for repairing large nerve gaps. However, they cause morbidity at the donor nerve site and only a limited amount of nerve can be harvested. Nerve conduits are a promising alternative to autografts and can act as guidance cues for the regenerating axons, without the need to harvest donor nerve. Separately, it has been shown that localized delivery of GDNF can enhance axon growth and motor recovery. FK506, an FDA approved small molecule, has also been shown to enhance peripheral nerve regeneration. This This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as
Anatomy, 2016
Objectives: FK506 is an effective immunosuppressive drug for treating graft rejection in transplants patients. However, the neuroregenerative effect of FK506 has been well described in the literature. The aim of this study was to investigate the effects of FK506 in alpha motor neurons after primary and delayed repair of sciatic nerve. Methods: Rats (n=72) were divided into 6 groups. Control, sham-operated, primary repair FK506 (-), primary repair FK506 (+), delayed repair FK506 (-), and delayed repair FK506 (+) groups. Results: After injury, the normal structure of the motor neuron perikarya was maintained by primary repair in the FK506 (+) group. In the delayed repair group, beneficial effect of FK506 was found to be less effective. The SFI value reached-50 recovery level in the FK506-treated group earlier than those of not FK506-treated groups. Conclusion: Beneficial effect of FK506 has been approved by functional and ultrastructural data in both of primary and delayed repair groups.
Fundamentals and Current Strategies for Peripheral Nerve Repair and Regeneration
Advances in Experimental Medicine and Biology
A body of evidence indicates that peripheral nerves have an extraordinary yet limited capacity to regenerate after an injury. Peripheral nerve injuries have confounded professionals in this field, from neuroscientists to neurologists, plastic surgeons, and the scientific community. Despite all the efforts, full functional recovery is still seldom. The inadequate results attained with the "gold standard" autograft procedure still encourage a dynamic and energetic research around the world for establishing good performing tissue engineered alternative grafts. Resourcing to nerve guidance conduits, a variety of methods have been experimentally used to bridge peripheral nerve gaps of limited size, up to 30-40 mm in length, in humans. Herein, we aim to summarize the fundamentals related to peripheral nerve anatomy and overview the challenges and scientific evidences related to peripheral nerve injury and repair mechanisms. The most relevant reports dealing with the use of both synthetic and naturalbased biomaterials used in tissue engineering strategies when treatment of nerve injuries is envisioned are also discussed in depth, along with the state-of-the-art approaches in this field.