title: Combination of injectable multiple growth factor-releasing scaffolds and cell therapy as an advanced modality to enhance tissue neovascularization.
abstract: OBJECTIVE
  Vasculogenic progenitor cell therapy for ischemic diseases bears great potential but still requires further optimization for justifying its clinical application. Here, we investigated the effects of in vivo tissue engineering by combining vasculogenic progenitors with injectable scaffolds releasing controlled amounts of proangiogenic growth factors.
  
  
  RESULTS
  We produced biodegradable, injectable polylactic coglycolic acid-based scaffolds releasing single factors or combinations of vascular endothelial growth factor, hepatocyte growth factor, and angiopoietin-1. Dual and triple combinations of scaffold-released growth factors were superior to single release. In murine hindlimb ischemia models, scaffolds releasing dual (vascular endothelial growth factor and hepatocyte growth factor) or triple combinations improved effects of cord blood-derived vasculogenic progenitors. Increased migration, homing, and incorporation of vasculogenic progenitors into the vasculature augmented capillary density, translating into improved blood perfusion. Most importantly, scaffold-released triple combinations including the vessel stabilizer angiopoietin-1 enhanced the number of perivascular smooth muscle actin(+) vascular smooth muscle cells, indicating more efficient vessel stabilization.
  
  
  CONCLUSIONS
  Vasculogenic progenitor cell therapy is significantly enhanced by in vivo tissue engineering providing a proangiogenic and provasculogenic growth factor-enriched microenvironment. Therefore, combined use of scaffold-released growth factors and cell therapy improves neovascularization in ischemic diseases and may translate into more pronounced clinical effects.
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, United Kingdom.
authors.forename: Jaimy
authors.initials: J
authors.lastname: Saif
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Schwarz
authors.forename: David Y S
authors.initials: DY
authors.lastname: Chau
authors.forename: James
authors.initials: J
authors.lastname: Henstock
authors.forename: Paramjit
authors.initials: P
authors.lastname: Sami
authors.forename: Simon F
authors.initials: SF
authors.lastname: Leicht
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Hermann
authors.forename: Sonia
authors.initials: S
authors.lastname: Alcala
authors.forename: Francisca
authors.initials: F
authors.lastname: Mulero
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Shakesheff
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
authors.forename: Alexandra
authors.initials: A
authors.lastname: Aicher
mesh_terms: D042683:Angiopoietin-1 / Q000008:administration & dosage; D000818:Animals; D002642:Chick Embryo; D004337:Drug Carriers; D016503:Drug Delivery Systems; D006133:Growth Substances / Q000008:administration & dosage*; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D019344:Lactic Acid; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D033581:Stem Cell Transplantation; D023822:Tissue Engineering; D054457:Tissue Scaffolds; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage
chemical_list: D042683:Angiopoietin-1; D004337:Drug Carriers; D006133:Growth Substances; D042461:Vascular Endothelial Growth Factor A; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D017228:Hepatocyte Growth Factor