title: Incorporation of a prolyl hydroxylase inhibitor into scaffolds: a strategy for stimulating vascularization.
abstract: Clinical applications of tissue engineering are constrained by the ability of the implanted construct to invoke vascularization in adequate extent and velocity. To overcome the current limitations presented by local delivery of single angiogenic factors, we explored the incorporation of prolyl hydroxylase inhibitors (PHIs) into scaffolds as an alternative vascularization strategy. PHIs are small molecule drugs that can stabilize the alpha subunit of hypoxia-inducible factor-1 (HIF-1), a key transcription factor that regulates a variety of angiogenic mechanisms. In this study, we conjugated the PHI pyridine-2,4-dicarboxylic acid (PDCA) through amide bonds to a gelatin sponge (Gelfoam(®)). Fibroblasts cultured on PDCA-Gelfoam were able to infiltrate and proliferate in these scaffolds while secreting significantly more vascular endothelial growth factor than cells grown on Gelfoam without PDCA. Reporter cells expressing green fluorescent protein-tagged HIF-1α exhibited dose-dependent stabilization of this angiogenic transcription factor when growing within PDCA-Gelfoam constructs. Subsequently, we implanted PDCA-Gelfoam scaffolds into the perirenal fat tissue of Sprague Dawley rats for 8 days. Immunostaining of explants revealed that the PDCA-Gelfoam scaffolds were amply infiltrated by cells and promoted vascular ingrowth in a dose-dependent manner. Thus, the incorporation of PHIs into scaffolds appears to be a feasible strategy for improving vascularization in regenerative medicine applications.
authors.affiliation: 1 Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore , Singapore, Singapore .
authors.forename: Adeline
authors.initials: A
authors.lastname: Sham
authors.forename: Eliana C
authors.initials: EC
authors.lastname: Martinez
authors.forename: Sebastian
authors.initials: S
authors.lastname: Beyer
authors.forename: Dieter W
authors.initials: DW
authors.lastname: Trau
authors.forename: Michael
authors.initials: M
authors.lastname: Raghunath
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016616:Cryoultramicrotomy; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005781:Gelatin Sponge, Absorbable / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D016062:Porosity; D064800:Prolyl-Hydroxylase Inhibitors / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet; D054457:Tissue Scaffolds / Q000737:chemistry*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064800:Prolyl-Hydroxylase Inhibitors; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; C055293:2,4-pyridinedicarboxylic acid