Heparin-Based Coacervate of FGF2 Improves Dermal Regeneration by Asserting a Synergistic Role with Cell Proliferation and Endogenous Facilitated VEGF for Cutaneous Wound Healing

Abstract

Effective wound healing requires complicated, coordinated interactions and responses at protein, cellular, and tissue levels involving growth factor expression, cell proliferation, wound closure, granulation tissue formation, and vascularization. In this study, we develop a heparin-based coacervate consisting of poly(ethylene argininylaspartate digylceride) (PEAD) as a storage matrix, heparin as a bridge, and fibroblast growth factor-2 (FGF2) as a cargo (namely heparin-FGF2@PEAD) for wound healing. First, in vitro characterization demonstrates the loading efficiency and control release of FGF2 from the heparin-FGF2@PEAD coacervate. The following in vivo studies examine the wound healing efficiency of the heparin-FGF2@PEAD coacervate upon delivering FGF2 to full-thickness excisional skin wounds in vivo, in comparison with the other three control groups with saline, heparin@PEAD as vehicle, and free FGF2. Collective in vivo data show that controlled release of FGF2 to the wounds by the coacervate significantly accelerates the wound healing by promoting cell proliferation, stimulating the secretion of vascular endothelial growth factor (VEGF) for re-epithelization, collagen deposition, and granulation tissue formation, and enhancing the expression of platelet endothelial cell adhesion molecule (CD31) and alpha-smooth muscle actin (α-SMA) for blood vessel maturation. In parallel, no obvious wound healing effect is found for the control, vehicle, and free FGF2 groups, indicating the important role of the coavervate in the wound healing process. This work designs a suitable delivery system that can protect and release FGF2 in a sustained and controlled manner, which provides a promising therapeutic potential for topical treatment of wounds.

Common Angiogenic Signaling Pathways Induced by Monomeric C - reactive protein and FGF-2 through MAPK and PI3K

“…Using ductus ateriosus smooth muscle cells, Wu and colleagues demonstrated that DAPT inhibits cell proliferation by not only inhibiting ERK1/2 and Akt phosphorylation but also by promoting cell cycle arrest in the G0/G1-phase [50]. Collectively, these effects of single stimulation of mCRP, FGF-2 and their combination mCRP with FGF-2 on EC proliferation confirm the theory that growth factors display additive and even synergistic characteristics during early stages of angiogenesis, with the combination of at least two growth factors displaying the highest proliferation rate [51].…”

Review: Multimodal bioactive material approaches for wound healing

“…16 Regranex gel has defined our understanding of growth factor mediated gels for wound healing, and the use of PDGF has been common for many years. [20][21][22][23][24] Other commonly used growth factors include the epidermal growth factor (EGF), [25][26][27][28][29][30][31] fibroblast growth factor (FGF), 21,26,27,32,33 and vascular endothelial growth factor (VEGF). [34][35][36] Table I has a summary of growth factor modified materials and their corresponding strategies for growth factor encapsulation and delivery.…”

“…The FGF2 coacervate had a prolonged release, with only 60% of the growth factor being released by 17 days, which can support long-term delivery of the growth factor to the wound environment. 33 Alternatively, the growth factor can be chemically conjugated to the delivery material hydrogel. Kim et al conjugated the amine terminal of EGF to an aldehyde modified hyaluronate.…”

Recent developments in drug-eluting dressings for the treatment of chronic wounds

“…The delivery of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) incorporated nanoparticles from a fibrin based scaffold has shown to promote wound healing in diabetic ulcer [11]. The controlled release of bFGF from a heparin-based coacervate accelerated the wound healing by promoting cell proliferation, re-epithelialization by stimulating secretion of VEGF, and collagen deposition in vivo, in a mouse cutaneous wound model, where the heparin stabilizes the bFGF and prolongs its half-life [12]. The sequential activity of proadrenomedullin N-terminal 20 peptide and bemiparin (a fractionated low-molecular-weight heparin) topically from a bilayered construct favored epithelialization in both ischemic and non-ischemic model [13].…”