The potential of various pH-responsive alkyl (meth)acrylate ester- and (meth)acrylic acid-based copolymers, including poly(methyl methacrylate-co-acrylic acid) (PMMA-AA) and poly(n-butyl acrylate-co-methacrylic acid) (PBA-MAA), to form pH-sensitive biocompatible and biodegradable hollow particle gel scaffolds for use in non-load-bearing soft tissue regeneration have been explored. The optimal copolymer design criteria for preparation of these materials have been established. Physical gels which are both pH- and redox-sensitive were formed only from PMMA-AA copolymers. MMA is the optimal hydrophobic monomer, whereas the use of various COOH-containing monomers, e.g., MAA and AA, will always induce a pH-triggered physical gelation. The PMMA-AA gels were prepared at physiological pH range from concentrated dispersions of swollen, hollow, polymer-based particles cross-linked with either cystamine (CYS) or 3,3′-dithiodipropionic acid dihydrazide (DTP). A linear relationship between particle swelling ratios, gel elasticity, and ductility was observed. The PMMA-AA gels with lower AA contents feature lower swelling ratios, mechanical strengths, and ductilities. Increasing the swelling ratio (e.g., through increasing AA content) decreased the intraparticle elasticity; however, intershell contact and gel elasticity were found to increase. The mechanical properties and performance of the gels were tuneable upon varying the copolymers’ compositions and the structure of the cross-linker. Compared to PMMA-AA/CYS, the PMMA-AA/DTP gels were more elastic and ductile. The biodegradability and cytotoxicity of the new hollow particle gels were tested for the first time and related to their composition, mechanical properties, and morphology. The new PMMA-AA/CYS and PMMA-AA/DTP gels have shown good biocompatibility, biodegradability, strength, and interconnected porosity and therefore have good potential as a tissue repair agent.

Gels that feature high internal porosity and have both high elasticity and ductility have potential to provide immediate load support and enable subsequent tissue regeneration of damaged soft tissue if combined with cells. Herein, we report results from a recent investigation of novel poly(methyl methacrylate-co-methacrylic acid), (PMMA-MAA) and poly(ethyl acrylate-co-methacrylic acid), (PEA-MAA) biodegradable, pH-sensitive particle gels which are with high porosity, elasticity and ductility. These gels formed at physiological pH range and are potentially injectable. The particles were prepared using solvent evaporation. They were functionalized by crosslinking the MAA groups of the particles via bis-amide formation with either cystamine (CYS) or 3,3′-dithiodipropionic acid dihydrazide (DTP) which simultaneously incorporated reversibility due to the presence of disulphide bonds within the crosslinker. The crosslinked particles were observed by dynamic light scattering to swell appreciably in size upon increasing the pH. Concentrated dispersions formed elastic and ductile physical gels within the physiological pH range. A key finding of this study was that for crosslinked particles of similar composition the formation of considerably more elastic and ductile gels was observed from the most lightly crosslinked particles. Furthermore, compared to the PMMA-MAA/CYS and PEA-MAA/CYS gels, those formed from DTP-crosslinked particles had higher elasticity, thicker pore walls and improved interconnectivity. For the PMMA-MAA/DTP gels an elastic modulus value as high as 100 kPa and a yield strain greater than 100% were observed for a gel containing only 5 wt% of particles. The improved mechanical properties of these new gel-forming dispersions imply that they now have good potential for future application as injectable gels for regenerative medicine.