Injectable biocompatible and biodegradable pH-responsive hollow particle gels containing poly(acrylic acid): the effect of copolymer composition on gel properties.

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.

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

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.

Hollow polymer particles that are pH-responsive and redox sensitive: two simple steps to triggered particle swelling, gelation and disassembly.

A new, simple, two-step method is introduced for preparing hollow particles that are both pH-responsive and redox sensitive. Hollow poly(methyl methacrylate-co-methacrylic acid) particles swell at moderate pH values, form gels in concentrated dispersions and can be disassembled by adding reducing agents.

pH-Responsive microgel dispersions for repairing damaged load-bearing soft tissue.

An important challenge for colloid scientists is to design injectable dispersions that provide structural support for damaged soft tissue and enable regeneration of tissue over the longer term. In this article we highlight a new area of research that aims to produce pH-responsive microgel dispersions that restore the mechanical properties of damaged, load-bearing, soft tissue. Chronic back pain due to degeneration of the intervertebral disc (IVD) is a major health problem and is the primary potential application for the work discussed. pH-Responsive microgel dispersions contain cross-linked polymer particles that swell when the pH approaches the pKa of the incorporated ionic co-monomer. The work considered here involves microgel particles containing MAA (methacrylic acid). The particles show pronounced pH-triggered swelling. The concentrated microgel dispersions change from a fluid to a gel at pH values greater than ca. 6.2, which is within the physiological pH range. The rheological properties are pH-dependent and can be adjusted using particle composition or concentration. Degenerated IVDs containing injected, gelled, microgel dispersions show improved mechanical properties. The disc height under biomechanically meaningful loads can be restored to values observed in non-degenerated IVDs. We also discuss the steps required to provide a minimally invasive injectable microgel system for restoring both the IVD mechanical properties and regenerating tissue in vivo. The approach discussed should also be suitable for other soft tissue types in the body.

Microgel particles containing methacrylic acid: pH-triggered swelling behaviour and potential for biomaterial application.

pH-responsive microgels are crosslinked polymer particles that swell when the pH approaches the pK(a) of the ionic monomer incorporated within the particles. In recent work from our group it was demonstrated that the mechanical properties of degenerated intervertebral discs (IVDs) could be restored to normal values by injection of poly(EA/MAA/BDDA) (ethylacrylate, methacrylic acid and butanediol diacrylate) microgel dispersions [J.M. Saunders, T. Tong, C.L. Le Maitre, T.J. Freemont, B.R. Saunders, Soft Matter 3 (2007) 486]. In this work we report the pH dependent swelling and rheological properties of poly(MMA/MAA/EGDMA) (methylmethacrylate and ethyleneglycol dimethacrylate) microgel dispersions. This system was investigated because it contains monomers that are already used as biomaterials. The poly(MMA/MAA/EGDMA) particles exhibit pH-triggered volume swelling ratios of up to ca. 250. The swelling onset for these particles occurs at pH values greater than ca. 6.0. A pK(a) for these particles of ca. 6.7 is consistent with titration and swelling data. Fluid-to-gel phase diagrams for concentrated poly(MMA/MAA/EGDMA) dispersions were determined as a function of polymer volume fraction and pH using tube-inversion measurements. The rheological properties for the gelled microgel dispersions were investigated using dynamic rheology measurements. The elastic modulus data for the poly(MMA/MAA/EGDMA) gelled dispersions were compared to data for poly(EA/MAA/BDDA) microgels. A similar pH-dependence for the elastic modulus was apparent. The maximum elastic modulus was achieved at a pH of about 7.0. The elastic modulus is an exponentially increasing function of polymer volume fraction at pH 7.0. Preliminary cell challenge experimental data are reported that indicate that gelled poly(MMA/MAA/EGDMA) microgel dispersions are biocompatible with cells from human intervertebral discs. However, the duration over which these experiments could be performed was limited by gradual redispersion of the gelled microgel dispersions. Based on the results presented it is suggested that poly(MMA/MAA/EGDMA) microgel would be a good candidate as a biomaterial for structural support of soft connective tissues.

A study of pH-responsive microgel dispersions: from fluid-to-gel transitions to mechanical property restoration for load-bearing tissue.

An interesting, and potentially important, challenge for colloid scientists is to design injectable dispersions that enable repair of damaged and degenerated tissue. This work presents a study of the ability of pH-responsive microgel particles to restore the mechanical properties of load-bearing soft tissue. Microgel particles are cross-linked polymer colloid particles that are swollen with solvent. The first part of the study consists of an investigation of the pH-triggered swelling of poly(EA/MAA/BDDA) (ethylacrylate, methacrylic acid and 1,4-butanediol diacrylate) microgel particles using photon correlation spectroscopy (PCS) measurements. The concentrated dispersions exhibit a strong fluid-to-gel transition when the pH is increased to above 6.0, i.e., above this pH they form gelled microgel dispersions. The swelling data are used to aid interpretation of the pH-triggered changes in the gel modulus, as probed using dynamic rheology. The second part of the study involves an investigation of the mechanical properties of artificially degenerated, model intervertebral discs (IVDs) containing gelled microgel dispersions. High concentration microgel dispersions were injected as fluids into the interior of degenerated IVDs and the pH increased by subsequent alkaline solution injection to cause particle swelling and dispersion gelation. Uniaxial compression data measured for the IVDs containing injected microgel dispersions indicate that the pH-induced particle swelling of the microgel restores the mechanical properties of degenerated IVDs to values similar to those measured for normal, non-degenerated, IVDs.

A multicenter study on the effects of lanthanum carbonate (Fosrenol) and calcium carbonate on renal bone disease in dialysis patients.

BACKGROUND: Lanthanum carbonate (LC) (Fosrenol) is a novel new treatment for hyperphosphatemia. In this phase III, open-label study, we compared the effects of LC and calcium carbonate (CC) on the evolution of renal osteodystrophy (ROD) in dialysis patients. METHODS: Ninety-eight patients were randomized to LC (N = 49) or CC (N = 49). Bone biopsies were taken at baseline and after one year of treatment. Acceptable paired biopsies were available for static and dynamic histomorphometry studies in 33 LC and 30 CC patients. Blood samples were taken at regular intervals for biochemical analysis and adverse events were monitored. RESULTS: LC was well tolerated and serum phosphate levels were well controlled in both treatment groups. The incidence of hypercalcemia was lower in the LC group (6% vs. 49% for CC). At baseline, subtypes of ROD were similarly distributed in both groups, with mixed ROD being most common. At one-year follow-up in the LC group, 5 of 7 patients with baseline low bone turnover (either adynamic bone or osteomalacia), and 4 of 5 patients with baseline hyperparathyroidism, had evolved toward a normalization of their bone turnover. Only one lanthanum-treated patient evolved toward adynamic bone compared with 6 patients in the CC group. In the LC group, the number of patients having either adynamic bone, osteomalacia, or hyperpara decreased overall from 12 (36%) at baseline to 6 (18%), while in the calcium group, the number of patients with these types of ROD increased from 13 (43%) to 16 (53%). CONCLUSION: LC is a poorly absorbed, well-tolerated, and efficient phosphate binder. LC-treated dialysis patients show almost no evolution toward low bone turnover over one year (unlike CC-treated patients), nor do they experience any aluminum-like effects on bone.