The role of vascularization in nerve regeneration of nerve graft

Abstract

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.

Keywords: angiogenesis; fascial flap; nerve graft; nerve injury; nerve regeneration; peripheral nerve; vascular endothelial growth factor; vascularization; vascularized nerve graft.

Figure 1

Schematic illustration of a peripheral nerve. The peripheral nerve is depicted, demonstrating the axon protected by the endoneurium. The nerve fascicle is enveloped by the perineurium. Groups of fascicles are surrounded by the epineurium. Each fascicle of endoneurium contains up to several thousands of axons. Blood is supplied by a network of capillary-like microvessels derived from arterioles and venules, which are branches of major limb vessels. The zoomed image depicts the close relationship of vessels and axons. When the nerve is injured, vascular endothelial cells guide the regeneration of peripheral nerve axons by producing vascular endothelial growth factor (VEGF, green dots) to induce angiogenesis preceding the repair of damaged nerves. With permission of the Mayo Foundation, Copyright Mayo Foundation 2019. All rights reserved.

Figure 2

Schematic drawing of the superficial inferior epigastric fascia (SIEF) flap harvest. Depicted is the elevation of the flap from distal to proximal (A), providing a 4 × 3 cm adipofascial flap (B) with lateral branch of the superficial inferior (SIE) vessels. The SIEF flap was tunneled subcutaneously toward the nerve without vascular twisting of the epigastric trunk (C) and wrapped around the nerve graft reaching both anastomoses (D). The flap edges were trimmed if needed and two 10-0 nylon sutures were placed to secure the position of the SIEF flap (E). With permission of the Mayo Foundation, Copyright Mayo Foundation 2019. All rights reserved.

Figure 3

Vascularized ulnar nerve graft (VUNG) harvest. Depicted is the harvest of the ulnar nerve (small arrow), based on the superior ulnar collateral artery (SUCA, denoted with large arrow, (A) in a patient with a C8–T1 brachial plexus root avulsion. (B) Denoted a close-up view of the SUCA joining the ulnar nerve (ulnar nerve denoted with small arrow, SUCA denoted with large arrow). The completion of the harvest of the entire length of the ulnar nerve based on the SUCA measured approximately 30 cm (C, SUCA denoted with arrow). The VUNG was used to graft the C6 root to the lateral cord. In D the vascular anastomosis of the SUCA to the thoracoacromial trunk was depicted.