Anionic and Zwitterionic Residues Modulate Stiffness of Photo-Cross-Linked Hydrogels and Cellular Behavior of Encapsulated Chondrocytes.

Photo-cross-linked poly(ethylene glycol) dimethacrylate (PEGDMA) hydrogels have been widely utilized for cartilage tissue engineering. However, strategies for improving their stiffness have been predominantly limited to increasing the degree of photo-cross-linking or weight fraction of the polymer. In this study, we tested the hypothesis that covalent incorporation of anionic sulfonate or zwitterionic sulfobetaine residues into photo-cross-linked PEGDMA hydrogels could enhance their mechanical properties without altering overall polymer content or swelling behavior. In addition, we investigated whether and how covalent incorporation of these chemical residues would affect cartilage extracellular matrix secretion by encapsulated chondrocytes. With the incorporation of 5-10% anionic or zwitterionic residues, the compressive moduli of PEGDMA hydrogels increased and the stress relaxation expedited while the swelling behavior and overall polymer fraction were kept the same. The incorporation of anionic residues exerted a more profound incorporation content-dependent impact on compressive moduli than zwitterionic residues. Higher-content incorporation of the anionic residue (10% vs 5%) also reduced the metabolic activity and type II collagen secretion by encapsulated murine chondrocytes and limited the pericellular diffusion of secreted proteoglycans within the 3D hydrogel. Although encapsulated human chondrocytes exhibited different sensitivity to serum level in culture than murine chondrocytes, the general trend of the impact of covalent incorporation of the chemical residues on their ECM secretion was the same. Overall, covalent incorporation of anionic and zwitterionic residues at an appropriate content presents a viable alternative to increasing the degree of photo-cross-linking for modulating the stiffness of PEGDMA hydrogels and the metabolism and phenotypical matrix secretion by encapsulated chondrocytes. It underscores the significance of noncovalent interactions imposed by charged residues in modulating biomechanical and cellular properties in tissue engineering scaffold designs.