A simple method was developed for increasing the modulus of methacrylated chondroitin sulfate (MCS) hydrogels. Photopolymerized MCS gels are relatively soft with low cross-link density, but copolymerization of MCS with 0.5 to 2.0 wt % oligo(ethylene glycol) diacrylates (OEGDA) increased the moduli over an order of magnitude. The shear modulus of gels was amplified 2−25 times by increasing the methacrylation extent and copolymerizing with higher molar mass OEGDAs (up to 700 Da). In contrast, copolymerizing MCS with oligomers of ethylene glycol dimethacrylate (OEGDMA) reduced the moduli from that of MCS alone. The cross-linking appears to occur primarily by incorporation of methacrylate groups of different MCS molecules into common kinetic chains rather than by linking different kinetic chains together by EG linking chains since monoacrylate monomers enhanced cross-linking nearly as much as the diacrylates. The difference between the copolymerization behaviors of OEGDAs vs analogous OEGDMAs was hypothesized to be the result of differences in their reactivity ratios, as the latter suppressed copolymerization. The fracture strains of gels were ∼20% regardless of the extent of cross-linking, likely the consequence of the limited chain extensibility of chondroitin sulfate in water. The addition of modest amounts of low molecular weight monomers of appropriate reactivity is hypothesized to be a generally useful method to adjust the modulus of methacrylated polysaccharide gels to desired levels over a broad range.

This study develops a simple copolymerization/crosslinking technique to control the swelling and mechanical properties of hyaluronic acid‐based hydrogels. Because of the widespread acceptance of poly(ethylene glycol) in biomedical applications, functionalized oligomers of ethylene glycol (EG) were used as comonomers to crosslink methacrylated hyaluronic acid (MHA). The swelling degree, shear and elastic moduli, and fracture properties (stress and strain) of the gels were investigated as a function of the crosslinking oligomer length and reactive group(s). It was hypothesized that acrylated oligomers would increase the crosslink density of the gels through formation of kinetic chains by reducing the steric hindrances that otherwise may limit efficient crosslinking of hyaluronic acid into gels. Specifically, after crosslinking 13 wt % MHA (47% degree of methacrylation) with 0.06 mol % of (EG)n‐diacrylate, the swelling ratio of the MHA gel decreased from 27 to 15 g/g and the shear modulus increased from 140 to 270 kPa as n increased from 1 to 13 units. The length and functionality (i.e., acrylate vs. methacrylate) of the oligomer controlled the crosslink density of the gels. The significant changes in the gel properties obtained with the addition of low levels of the PEG comonomer show that this method allows precise tuning of the physical properties of hyaluronic acid (HA) gels to achieve desired target values for biomedical applications. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 42009.

Our group has previously reported on successful biofunctionalization of poly(ethylene glycol diacrylate) (PEGDA) gels using chondroitin sulfate (CS) and improving moduli of methacrylated-CS (MCS) gels using short PEGDA comonomers. Here, we focused on understanding the composition-property relationship of MCS-PEGDA copolymers. By changing concentration, composition, and medium's ionic strength the gels were modified to show a diverse range of properties. Photopolymerized copolymers with >4:1 ratio of one component had compressive moduli of up to 24 times higher and up to 17 times lower swelling degree (q) than those of MCS alone. The increased moduli and lowered q were consistent with the hypothesis that PEGDA improves kinetic chain growth by overcoming the steric hindrances of the macromer. The swelling and moduli of the gels were tuned by changing the ratio of the comonomers. The swelling and moduli of the gels were lowered with presence of salt in solution while the fracture strain increased. These changes were hypothesized to be the result of transition of CS chain conformation from highly extended and non-Gaussian to less extended and Gaussian distribution. The complete understanding of MCS-PEGDA compositionproperty relationship provides a general strategy to tune the moduli or q of polysaccharide-based hydrogels while avoiding undesirable phase separation. V C 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015, 53, 1070-1079 KEYWORDS: biomaterials; copolymers; hydrogels; mechanical properties; photopolymerization INTRODUCTION The mammalian extracellular matrix (ECM) is a multicomponent, hierarchically ordered structure. Chondroitin sulfate (CS) and hyaluronic acid (HA) are two of the main glycosaminoglycans (GAGs) present in the mammalian ECM. Collagen type II, keratan sulfate, and proteins are other major ECM components. Regeneration of the damaged ECM has been the focus of multiple tissue engineering studies. A common strategy is to replace the damaged matrix with naturally available biomimetic materials. An optimal scaffold to mimic the ECM would be made of multiple components to provide the appropriate balance of mechanical properties, water content, solute permeability, and cell interactions.

The double-network (DN) hydrogel concept developed by J.P. Gong and Y. Osada builds upon interpenetrating networks by combining brittle and ductile components to have significantly enhanced fracture properties. The generality of the DN effect was tested by creating biopolymer-based hydrogels of methacrylated chondroitin sulfate (MCS) and polyacrylamide (PAAm) and extended upon creating DNs of MCS and poly(N,N dimethyl acrylamide) (PDMAAm), verifying that DNs were not limited to the original combination of poly(2-acrylamido-2-methylpropanesulfonic acid) (PAMPS)/polyacrylamide (PAAm). Further, the mechanical properties were varied by changing the monomer concentrations, cross-linker concentrations and the addition of cross-linking groups through copolymerizations of MCS and poly(ethylene glycol) diacrylate (PEGDA). Overall, this work demonstrates that a broad range of mechanical properties achievable through DN effect under tension and compression, generally independent of the swelling degree, which is fundamentally different behavior than possible with single networks.

Summary: Despite widespread use of hydrogels in biomedical devices, low moduli and brittleness of hydrogels has hindered applications with load bearing requirements. In this study, different molecular network design strategies (homopolymer, copolymer, and double network) were used to control the arrangement of macromers to tune the mechanical properties of glycosaminoglycan (GAG)-based hydrogels. The resulting changes in swelling ratio, crosslink density, and fracture properties of the gels were then investigated. It was hypothesized that increasing the number of polymerizable groups on the macromers methacrylated chondroitin sulfate (MCS) or methacrylated hyaluronic acid (MHA) and using oligo(ethylene glycol diacrylate) s to copolymerize with can improve the crosslinking by increasing the effectiveness of polymerization through the kinetic chains. By increasing the degree of methacrylation of MCS from 24 to 34 mol%, the swelling ratio q and the crosslink density r x of 13 wt% MCS gel was changed from 210 to 44 g/g and from 230 to 740 mol/m 3 , respectively. Despite improved r x and tuned q, the fracture strain of the homo-and copolymer gels remained fairly low (<25%), likely due to the highly extended conformation of glycosaminoglycans, and the microheterogeneity induced by the kinetic chains. However, using a DN double network design (with PAAm), the fracture strain and toughness of the gels were greatly improved as the fracture strain of 15 wt% MCS-PAAm DN increased more than 3 times, from 15 to 55%. The versatile physical and favorable biological properties of GAG-based hydrogels make them promising materials for many biomedical applications.

Chondroitin sulfate (CS) is one of the major glycosaminoglycans (GAGs) present in the connective tissue extracellular matrix (ECM) and is responsible for the regulation of cellular activities as well as providing mechanical support for the surrounding tissue. Due to presence of CS in the natural tissues including cartilage, hydrogels of CS and other GAGs have been widely used in cartilage regeneration. Due to their polyelectrolyte nature, GAG-based hydrogels are brittle and require modifications to overcome the weak mechanical properties. In this work, we showed copolymerization of methacrylated chondroitin sulfate with oligo(ethylene glycol)s improved the crosslink density of the gels from 2 to 20 times depending on the methacrylation degree of CS and length of the crosslinking monomer. Copolymerization of CS with oligo(ethylene glycol) acrylates is a method to design hydrogels with tunable swelling and mechanical properties.