Controlled release of vascular endothelial growth factor (VEGF) in alginate and hyaluronic acid (ALG–HA) bead system to promote wound healing in punch-induced wound rat model

Abstract

For wound healing, angiogenesis is one of the main therapeutic factors for recovering the injured tissue. To address this issue, a combination of two different polymers, alginate (ALG) and hyaluronic acid (HA) in an 80:20 ratio composition is used to optimize the bead system along with the 5 IU heparin (Hep) by crosslinking into calcium chloride (CaCl₂). Encapsulation of Vascular endothelial growth factor (VEGF) in the bead system shows delayed cumulative release in phosphate buffer saline (PBS). For in vitro studies, calf pulmonary artery endothelial (CPAE) cells showed biocompatibility. ALG–HA/VEGF150 improves endothelial Vascular cell adhesion protein 1 (VCAM1) and endothelial nitric oxide synthase (eNOS) expression markers in CPAE cells. In vivo evaluation of the bead system shows around 68% of wound closure 2 weeks post-implantation in 8 mm punch wound models. The treatment group shows decreased epithelial gap between the ends of the wound and neo-epidermal regeneration. ALG–HA/VEGF150 induced significant vascularization, collagen type-1 (Col-1) and fibronectin (FN) development in the in vivo models after 2 weeks of the implantation. Hence, ALG–HA/VEGF150 beads can be used to promote wound healing.

Graphical Abstract

Schematic workflow diagram including in vitro and in vivo results. ALG-HA/VEGF150 implanted in the punch-induced wound rat model for 1 and 2 weeks (figure created with Biorender).

Keywords:

• Alginate
• hyaluronic acid
• beads
• wound healing
• vascular endothelial growth factor (VEGF)

Authors’ contributions

Maqsood Ali: Conceptualization, formulation, in vitro and in vivo analysis, data curation, methodology, investigation, writing of the original manuscript, editing, and revisions. Si Hyun Kwak: In vivo implantation and sacrifice. Byong-Taek Lee: Resources, supervision, research funding, review and manuscript revision, editing and validation. Hwan Jun Choi: Supervision, research funding, animal model surgeries, editing and validation, and manuscript revision.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (2020R1A2C1100891) and by Ministry of Education (2015R1A03032522). This research was also partially supported by the Soonchunhyang University.