Injectable VEGF-loaded gelatin–hyaluronic acid hydrogel to synergistically promote flap survival via rapid angiogenesis

Abstract

Random-pattern skin flaps are commonly used in plastic surgery to close skin defects, but necrosis often occurs in the distal portions of flaps due to insufficient blood supply, which severely limits their clinical utility. Thus, we developed a vascular endothelial growth factor (VEGF)-loaded injectable hydrogel to promote local angiogenesis to improve skin flap survival. The hydrogel, composed of gelatin and low-molecular-weight hyaluronic acid, is obtained via microbial transglutaminase (mTG)-catalyzed crosslinking and hydrogen bonding. By adjusting the concentrations of gelatin and hyaluronic acid, the properties of the injectable hydrogel, including gelation time, internal pore size, swelling rate and degradation rate, were tuned and slow and sustained release of VEGF from the hydrogel was achieved. Benefiting from the ability of the gelatin–hyaluronic acid (Gel-HA) hydrogel to induce HUVEC proliferation and migration, and the enhanced bioactivity of VEGF when loaded in the Gel-HA hydrogel, the combination of Gel-HA hydrogel and VEGF synergistically promotes angiogenesis. Moreover, in a rat dorsal random skin flap model, the VEGF-loaded Gel-HA hydrogel was easily injected into the skin flap, significantly reducing necrosis and enhancing blood perfusion in skin flap areas. Therefore, this VEGF-loaded Gel-HA hydrogel could be an effective, easily prepared platform for rapid vascularization and ischemic flap repair, and it also has potential for clinical applications for other ischemic tissues.