title: Dual delivery of growth factors with coacervate-coated poly(lactic-co-glycolic acid) nanofiber improves neovascularization in a mouse skin flap model.
abstract: Random skin flaps are commonly used in plastic and reconstructive surgery for patients suffering from severe or large scale wounds or in facial reconstruction. However, skin flaps are sometimes susceptible to partial or complete necrosis at the distal parts of the flaps due to insufficient blood perfusion in the defected area. In order to improve neovascularization in skin flaps, we developed an exogenous growth factor (GF) delivery platform comprised of coacervate-coated poly(lactic-co-glycolic acid) (PLGA) nanofibers. We used a coacervate that is a self-assembled complex of poly(ethylene argininyl aspartate diglyceride) (PEAD) polycation, heparin, and cargo GFs (i.e., vascular endothelial growth factor (VEGF) and/or transforming growth factor beta 3 (TGF-β3)). The coacervate was coated onto a nanofibrous PLGA membrane for co-administration of dual GFs. In vitro proliferation of human dermal fibroblasts and endothelial tube formation using human umbilical vein endothelial cells indicated an enhanced bioactivity of released GFs when both VEGF and TGF-β3 were incorporated into coacervate-coated PLGA nanofibers (Coa-Dual NFs). Moreover, an in vivo study using a mouse skin flap model demonstrated that implantation of Coa-Dual NF reduced necrosis and enhanced blood perfusion in skin flap areas after 10 days, as compared to any single GF-loaded coacervate/PLGA fiber (Coa-Single NF) along with direct administration of the other GF onto the defect site. Moreover, Coa-Dual NFs exhibited a well-composed skin appendage and a significantly higher number of blood vessels. Based upon these results, we conclude that Coa-Dual NFs may stimulate cellular activity by enhancing the bioactivity of the released GF, leading to a synergetic effect of dual GFs for reducing necrosis in the random skin flaps. Therefore, Coa-Dual NFs could be a valuable drug delivery platform for a variety of potential clinical applications for skin tissue regeneration applications.
authors.affiliation: Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 330-714, Republic of Korea.
authors.forename: Min Suk
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Bioengineering & BK21 PLUS Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 133-791, Republic of Korea.
authors.forename: Taufiq
authors.initials: T
authors.lastname: Ahmad
authors.affiliation: Department of Bioengineering & BK21 PLUS Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 133-791, Republic of Korea.
authors.forename: Jinkyu
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Hassan K
authors.initials: HK
authors.lastname: Awada
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Bioengineering, College of Life Sciences and Bioengineering, Incheon National University, Incheon, 406-772, Republic of Korea. Electronic address: kyobum.kim@inu.ac.kr.
authors.forename: Kyobum
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Bioengineering & BK21 PLUS Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 133-791, Republic of Korea. Electronic address: hshin@hanyang.ac.kr.
authors.forename: Heungsoo
authors.initials: H
authors.lastname: Shin
authors.affiliation: Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 330-714, Republic of Korea. Electronic address: hsyang@dankook.ac.kr.
authors.forename: Hee Seok
authors.initials: HS
authors.lastname: Yang
mesh_terms: D000818:Animals; D003102:Colloids / Q000737:chemistry; D004338:Drug Combinations; D005260:Female; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry*; D051379:Mice; D008813:Mice, Inbred ICR; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D058726:Nanoconjugates / Q000008:administration & dosage / Q000737:chemistry / Q000648:ultrastructure; D057139:Nanofibers / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D044367:Phase Transition; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012867:Skin / Q000098:blood supply* / Q000187:drug effects; D016038:Skin Transplantation / Q000379:methods; D053782:Transforming Growth Factor beta3 / Q000008:administration & dosage*; D014783:Viscosity
chemical_list: D003102:Colloids; D004338:Drug Combinations; D036341:Intercellular Signaling Peptides and Proteins; D053769:Nanocapsules; D058726:Nanoconjugates; D053782:Transforming Growth Factor beta3; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: Coacervate; Dual growth factor delivery; Mouse skin flap; Neovascularization; Reconstructive surgery