Dual growth factor-induced angiogenesis in vivo using hyaluronan hydrogel implants.
Crosslinked hyaluronan (HA) hydrogels preloaded with two cytokine growth factors, vascular endothelial growth factor (VEGF) and keratinocyte growth factor (KGF), were employed to elicit new microvessel growth in vivo. As a major glycosaminoglycan (GAG) component of extracellular matrix (ECM), HA is an excellent biopolymeric building block for new biomimetic, biocompatible therapeutic materials. HA hydrogel film samples were surgically implanted in the ear pinnae of mice, and the ears were harvested at 7 or 14 days post-implantation. Histologic analysis showed that each of the groups receiving an implant demonstrated significantly more microvessel density than control ears undergoing surgery but receiving no implant (p<0.001). Treatment groups receiving either co-delivery of both KGF and VEGF, an HA hydrogel lacking a growth factor or HA hydrogels containing a single cytokine were statistically unchanged with time, whereas treatment with KGF alone produced continuing increases in vascularization from day 7 to day 14. Strikingly, presentation of both VEGF and KGF in crosslinked HA generated intact microvessel beds with well-defined borders. In addition, an additive response to co-delivery of both cytokines in the HA hydrogel was observed. The HA hydrogels containing KGF+VEGF produced the greatest angiogenic response of any treatment group tested (NI=5.4 at day 14, where NI is a neovascularization index). This was 33% greater vessel density than in the next largest treatment group, that received HA+KGF (NI=4.0, p<0.002). New therapeutic approaches for numerous pathologies could be notably enhanced by the localized, sustained angiogenic response produced by release of both VEGF and KGF from crosslinked HA films.
Peattie
Robert A
RA
Department of Chemical Engineering, Oregon State University, 103 Gleeson Hall, Corvallis, OR 97331, USA. peattie@engr.orst.edu
Rieke
Erin R
ER
Hewett
Erin M
EM
Fisher
Robert J
RJ
Shu
Xiao Zheng
XZ
Prestwich
Glenn D
GD
D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D001672:Biocompatible Materials / Q000008:administration & dosage / Q000737:chemistry; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development; D004423:Ear / Q000033:anatomy & histology / Q000098:blood supply / Q000601:surgery; D051523:Fibroblast Growth Factor 7 / Q000008:administration & dosage* / Q000737:chemistry; D006820:Hyaluronic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D020100:Hydrogels / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000737:chemistry
D043925:Angiogenesis Inducing Agents; D001672:Biocompatible Materials; C509315:HA-DTPH-PEGDA; D020100:Hydrogels; D042461:Vascular Endothelial Growth Factor A; D051523:Fibroblast Growth Factor 7; D011092:Polyethylene Glycols; D006820:Hyaluronic Acid