Enhanced Diffusion and Retention of Proteoglycan Replacements in Cartilage through Thermoresponsive Polyelectrolytes

During osteoarthritis (OA), negatively-charged proteoglycans are digested and lost from cartilage, which impairs tissue osmotic behavior and mechanical integrity, leading to further tissue degeneration. Existing strategies for introducing supplemental, soluble polyelectrolytes face barriers in compound performance in solid tissue: achieving sufficient tissue penetration by diffusion without losing the therapeutic in a short time by the same diffusive process. Here, we investigated thermo-responsive block copolymers, poly(styrene sulfonate)-block-poly(N-isopropylacrylamide) (PSS-b-PNIPAM) with a series of varying block ratios, as a strategy to improve polyelectrolyte delivery and improve retention due to thermal self-assembly into less-mobile aggregates within cartilage explants. Through histological staining, we found that block copolymers exhibited enhanced penetration into deeper zones of the tissue compared to PSS alone. Additionally, PSS-b-PNIPAM copolymers with a higher PNIPAM ratio improved solute retention compared to those with a lower PNIPAM ratio. Through diffusion modeling and polymer characterization by dynamic light scattering and small angle x-ray scattering, we showed that the design of thermo-responsive polyelectrolytes to penetrate and retain within solid porous tissue is an interplay between molecular weight, strength of the thermal response, and tissue microstructure.