title: Poly(ethylene glycol) diacrylate/hyaluronic acid semi-interpenetrating network compositions for 3-D cell spreading and migration.
abstract: To serve as artificial matrices for therapeutic cell transplantation, synthetic hydrogels must incorporate mechanisms enabling localized, cell-mediated degradation that allows cell spreading and migration. Previously, we have shown that hybrid semi-interpenetrating polymer networks (semi-IPNs) composed of hydrolytically degradable poly(ethylene glycol) diacrylates (PEGdA), acrylate-PEG-GRGDS and native hyaluronic acid (HA) support increased cell spreading relative to fully synthetic networks that is dependent on cellular hyaluronidase activity. This study systematically investigated the effects of PEGdA/HA semi-IPN network composition on 3-D spreading of encapsulated fibroblasts, the underlying changes in gel structure responsible for this activity, and the ability of optimized gel formulations to support long-term cell survival and migration. Fibroblast spreading exhibited a biphasic response to HA concentration, required a minimum HA molecular weight, decreased with increasing PEGdA concentration and was independent of hydrolytic degradation at early time points. Increased gel turbidity was observed in semi-IPNs, but not in copolymerized hydrogels containing methacrylated HA, which did not support cell spreading. This suggests that there is an underlying mechanism of polymerization-induced phase separation that results in HA-enriched defects within the network structure. PEGdA/HA semi-IPNs were also able to support cell spreading at relatively high levels of mechanical properties (∼10kPa elastic modulus) compared to alternative hybrid hydrogels. In order to support long-term cellular remodeling, the degradation rate of the PEGdA component was optimized by preparing blends of three different PEGdA macromers with varying susceptibility to hydrolytic degradation. Optimized semi-IPN formulations supported long-term survival of encapsulated fibroblasts and sustained migration in a gel-within-gel encapsulation model. These results demonstrate that PEGdA/HA semi-IPNs provide dynamic microenvironments that can support 3-D cell survival, spreading and migration for a variety of cell therapy applications.
authors.affiliation: Microenvironmental Engineering Laboratory, Department of Bioengineering, Clemson University, 301 Rhodes Research Center, Clemson, SC 29634, USA.
authors.forename: Ho-Joon
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Microenvironmental Engineering Laboratory, Department of Bioengineering, Clemson University, 301 Rhodes Research Center, Clemson, SC 29634, USA.
authors.forename: Atanu
authors.initials: A
authors.lastname: Sen
authors.affiliation: Microenvironmental Engineering Laboratory, Department of Bioengineering, Clemson University, 301 Rhodes Research Center, Clemson, SC 29634, USA.
authors.forename: Sooneon
authors.initials: S
authors.lastname: Bae
authors.affiliation: Microenvironmental Engineering Laboratory, Department of Bioengineering, Clemson University, 301 Rhodes Research Center, Clemson, SC 29634, USA.
authors.forename: Jeoung Soo
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Microenvironmental Engineering Laboratory, Department of Bioengineering, Clemson University, 301 Rhodes Research Center, Clemson, SC 29634, USA. Electronic address: kwebb@clemson.edu.
authors.forename: Ken
authors.initials: K
authors.lastname: Webb
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D018929:Cell Culture Techniques / Q000379:methods*; D002465:Cell Movement / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects; D020405:Dermis / Q000166:cytology; D055119:Elastic Modulus / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology*; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000494:pharmacology; D007700:Kinetics; D018613:Microscopy, Confocal; D008970:Molecular Weight; D009391:Nephelometry and Turbidimetry; D011092:Polyethylene Glycols / Q000494:pharmacology*
chemical_list: D000199:Actins; C437167:poly(ethylene glycol)diacrylate; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011092:Polyethylene Glycols; D006820:Hyaluronic Acid
keywords: Cell spreading; Hyaluronic acid; Hybrid hydrogel; PEG diacrylate; Semi-interpenetrating polymer network