Bedar, Meiwand

Background: Functional recovery after acellular nerve allograft (ANA) reconstruction remains inferior to that after autologous nerve grafting, but improved outcomes have been demonstrated with the addition of adipose-derived mesenchymal stem cells (MSCs). Controversy exists regarding the optimal cell-delivery method to enhance ANA reconstructions. The authors investigated the functional recovery of ANAs after dynamic seeding versus microinjection of MSCs. Methods: Forty Lewis rats underwent reconstruction of a 10-mm sciatic nerve defect. Animals were divided into 4 groups: reversed autograft, ANA alone, dynamically seeded ANA, or ANA injected with MSCs. During the survival period, ultrasound measurements of the tibialis anterior muscle cross-sectional area were performed. At 12 weeks, functional recovery was evaluated using measurements of ankle contracture, compound muscle action potential, maximum isometric tetanic force, muscle mass, histomorphometry, and immunofluorescence. Results: The dynamic seeding and microinjection groups demonstrated higher cross-sectional tibialis anterior muscle area recovery than autografts and ANAs alone at week 8 and weeks 4 and 8, respectively. The ankle contracture and compound muscle action potential amplitude recovery were superior in autografts and both seeding methods compared with ANAs alone. The microinjection group demonstrated significantly higher isometric tetanic force, muscle mass, and number of axons compared with ANAs alone. Both seeding methods showed higher CD34 densities compared with ANAs alone. No significant differences between dynamic seeding and microinjection were observed in functional or histologic outcomes. Conclusions: The addition of MSCs to ANAs demonstrated earlier motor regeneration compared with autografts and ANAs alone. Both seeding methods improved functional outcomes in the 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.