pH-responsive physical gels from poly(meth)acrylic acid-containing crosslinked particles: the relationship between structure and mechanical properties

Abstract

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-comethacrylic 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 0-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.

Injectable Biocompatible and Biodegradable pH-Responsive Hollow Particle Gels Containing Poly(acrylic acid): The Effect of Copolymer Composition on Gel Properties

“…Compared to the corresponding MAA-containing crosslinked particles, 31,32,34 Q max values for the PMMA-AA/CYS and PMMA-AA/DTP particles are lower. This is unexpected in terms of the higher hydrophilicity of AA relative to MAA.…”

“…At pH 6.0, large particles with D h from 2725 to 4789 nm were observed which increased from 5337 to 5560 nm as the pH was increased to 7.0 (Table S1, Figure S6, Supporting Information). pH-Triggered particle swelling has also been reported in PMMA-MAA and PEA-MAA particles cross-linked with either CYS or DTP, 31,32,34 where the swelling process was attributed to electrostatic repulsion between negatively charged carboxylate groups in the polymers which are effectively held together by their cross-links. 56,57 As the pH increases, the disulfide groups, which are present in CYS and DTP, undergo hydroxide ion-mediated cleavage.…”

“…32 The pK a of poly(acrylic acid) is approximately one unit lower than that of poly(methacrylic acid). 47,48 Therefore, it is reasonable to assume that the hydrophobic MMA, which is also the dominant monomer in terms of the copolymer compositions, has the major effect on the pK a values.…”

“…32 All D h(collapse) values were measured at the lowest pH values tested. For the PMMA-AA particles the D h(collapse) values do not correspond to the fully collapsed state of the particles.…”

Smart polymers in drug delivery systems on crossroads: Which way deserves following?

“…Among them, poly(acrylic acid) (PAA) [104][105][106] and its derivative poly(methacrylate acid) (PMAA) [108][109][110], which have pK a values of about 4-5, are the most representative. Because PAA and PMAA are hydrophilic at pH 7.4 and hydrophobic at low pH (pH about 1-2), they can be used as building blocks for oral drug delivery [111].…”