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 PEG-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 3D 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 that did not support cell spreading; suggesting an underlying mechanism of polymerization-induced phase separation resulting 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 (~10 kPa 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 3D cell survival, spreading, and migration for a variety of cell therapy applications.

Cell-Mediated Dexamethasone Release from Semi-IPNs Stimulates Osteogenic Differentiation of Encapsulated Mesenchymal Stem Cells

“…As a potential improvement, we have recently shown that PEG-bis-AP can be combined with two other PEG-diacrylate derivatives possessing faster and slower degradation rates to produce semi-IPNs with more finely controlled degradation over 5 weeks. 38 A second potential limitation is that cell spreading within the networks via HA degradation accelerates between about 4–12 days post-encapsulation, leading to a rapid rise in DX release. In this study, we conjugated DX to HA at a relatively low degree of substitution.…”

“…35–38 We hypothesized that dexamethasone covalently conjugated to HA through a double ester linkage (HA-DXM) and PEG-bis-AP could form semi- IPN structures that release free dexamethasone in response to cell-mediated remodeling and stimulate osteogenic differentiation of encapsulated MSCs (Figure 1). In this study, we synthesized HA-DXM and characterized DX release in response to chemical and enzymatic hydrolysis.…”

Development of 3D Microvascular Networks Within Gelatin Hydrogels Using Thermoresponsive Sacrificial Microfibers

“…Fibroblasts cultured for 7 d in the thin gelatin hydrogels under static conditions also exhibited similar elongation (Figure S5, Supporting Information). Anchorage‐dependent fibroblasts can only survive when attached to ECM and a stretched cell morphology is both an indication of health and necessary for migration, proliferation, and differentiation . It is known that gelatin, the denatured form of collagen, retains MMP‐sensitive degradation sites .…”

All-polymer fiber-optic pH sensor

“…simply curried under UV lamp). Furthermore, it is good choice to be used in biomedical application due to its bio-compatibility [23,24]. This novel polymer fiber-optic sensor exhibits a sensitivity of up to −0.41 nm/pH and an average response time of 30 s. As the sensor was developed toward bio-medical application, only acidic range was considered [24].…”