title: In vitro and ex vivo hemocompatibility of off-the-shelf modified poly(vinyl alcohol) vascular grafts.
abstract: Synthetic small diameter vascular grafts with mechanical properties of native arteries, resistance to thrombosis and capacity to stimulate in situ endothelialization are an unmet clinical need. Poly(vinyl alcohol) hydrogel (PVA) is an excellent candidate as a vascular graft due to its tunable mechanical properties. However, the hydrophilicity and bio-inertness of PVA prevents endothelialization in vivo. We hypothesize that the modification of PVA with biomolecules and topographies creates a hemocompatible environment that also enhances bioactivity. PVA modified with fibronectin, RGDS peptide, cyclicRGD (cRGD) peptide, or heparin provided cell-adhesion motifs, which were confirmed by detection of nitrogen through X-ray photoelectron spectroscopy. Protein- and peptide-modified surfaces showed a slight increase in human vascular endothelial cell proliferation over unmodified PVA. With the exception of fibronectin modification, modified surfaces showed in vitro hemocompatibility comparable with unmodified PVA. To further improve bioactivity, cRGD-PVA was combined with gratings and microlens topographies. Combined modifications of 2 μm gratings or convex topography and cRGD significantly improved human vascular endothelial cell viability on PVA. In vitro hemocompatibility testing showed that topography on cRGD-PVA did not significantly trigger an increase of platelet adhesion or activation compared with unpatterned PVA. Using the more physiologically relevant ex vivo hemocompatibility testing, all PVA grafts tested showed similar platelet adhesion to ePTFE and significantly lower platelet accumulation compared to collagen-coated ePTFE grafts. The biochemical and topographical modification of PVA demonstrates excellent hemocompatibility with enhanced bioactivity of PVA, thus highlighting its potential as a vascular graft.
  
  
  CONCLUSIONS
  New synthetic small diameter vascular grafts with mechanical properties, blood-clot resistance and endothelial lining mimicking native arteries remains an unresolved critical clinical need. We aim to achieve this by modifying the mechanically-tunable poly(vinyl alcohol) hydrogel (PVA) vascular graft with both biochemical and biophysical cues in the lumenal surface. PVA modified with cyclic RGD peptide and ordered micrometer-sized topography showed low platelet adhesion in both a rabbit in vitro and baboon ex vivo blood compatibility assay. Modified PVA also exhibited significant enhancement of human vascular endothelial cell viability and proliferation in vitro. The readily available, modified PVA grafts are the first to show biophysical and biochemical modification in a three-dimensional scaffold with hemocompatibility, biofunctionality and excellent potential for clinical application.
authors.affiliation: Department of Biomedical Engineering, National University of Singapore, Singapore. Electronic address: biemfac@nus.edu.sg.
authors.forename: Marie F A
authors.initials: MF
authors.lastname: Cutiongco
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University, OR, United States. Electronic address: anderdei@ohsu.edu.
authors.forename: Deirdre E J
authors.initials: DE
authors.lastname: Anderson
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University, OR, United States. Electronic address: hindsm@ohsu.edu.
authors.forename: Monica T
authors.initials: MT
authors.lastname: Hinds
authors.affiliation: Department of Biomedical Engineering, National University of Singapore, Singapore; Mechanobiology Institute, Singapore, National University of Singapore, Singapore; Department of Surgery, National University of Singapore, Singapore. Electronic address: eyim@nus.edu.sg.
authors.forename: Evelyn K F
authors.initials: EK
authors.lastname: Yim
mesh_terms: D000818:Animals; D001807:Blood Vessel Prosthesis; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005337:Fibrin / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008297:Male; D008422:Materials Testing / Q000379:methods*; D010215:Papio; D010456:Peptides, Cyclic / Q000494:pharmacology; D010973:Platelet Adhesiveness; D011142:Polyvinyl Alcohol / Q000494:pharmacology*; D011817:Rabbits; D013499:Surface Properties; D014867:Water / Q000737:chemistry
chemical_list: D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide; D014867:Water; D005337:Fibrin; D011142:Polyvinyl Alcohol
keywords: Biomolecules; Endothelialization; Hemocompatibility; Lumenal patterning; Surface modification