title: 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.
authors.affiliation: School of Pharmaceutical Sciences Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ye
authors.affiliation: School of Pharmaceutical Sciences Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhu
authors.affiliation: School of Pharmaceutical Sciences Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Zecong
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: School of Pharmaceutical Sciences Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Chaochao
authors.initials: C
authors.lastname: He
authors.affiliation: School of Pharmaceutical Sciences Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Hongxue
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Bioengineering and the McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania 15219, United States.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The First Affiliate Hospital Wenzhou Medical University , Wenzhou, 325035, China.
authors.forename: Cai
authors.initials: C
authors.lastname: Lin
authors.affiliation: School of Pharmaceutical Sciences Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Yingzheng
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Wound Healing and Cell Biology Laboratory Institute of Basic Medical Science, Chinese PLA General Hospital , Beijing 1008553, China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Fu
authors.affiliation: Department of Chemical and Biomolecular Engineering, The University of Akron , Akron, Ohio 44325, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.|Department of Chemical and Biomolecular Engineering, The University of Akron , Akron, Ohio 44325, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: School of Pharmaceutical Sciences Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
mesh_terms: D000279:Administration, Cutaneous; D000287:Administration, Topical; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology* / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage* / Q000737:chemistry; D006493:Heparin / Q000737:chemistry*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D006493:Heparin