Sustained Inhibition of CC-chemokine Receptor-2 via intra-articular deposition of polymeric microPlates in Post-Traumatic Osteoarthritis

Abstract Post traumatic osteoarthritis (PTOA) is mostly treated via corticosteroids administration and total joint arthroplasty continues to be the sole effective intervention in severe conditions. To assess the therapeutic potential of CCR2 targeting in PTOA, we used biodegradable microPlates (µPL) to achieve a slow and sustained intra-articular release of the CCR2 inhibitor RS504393 into injured knees and followed joint damage during disease progression. RS504393-loaded µPL (RS-µPL) were fabricated via a template-replica molding technique. A mixture of poly(lactic-co-glycolic acid) (PLGA) and RS504393 was deposited into 20´10 μm (length´height) wells realized in a polyvinyl alcohol (PVA) square-patterned template. After physicochemical and toxicological characterizations, the RS504393 release profile from µPL was assessed in PBS buffer. C57BL/6J male mice were subjected to destabilization of the medial meniscus (DMM)/sham surgery and RS-µPL (1 mg/kg) were administered intra-articularly 1-week post-surgery. Administrations were repeated at 4- and 7-weeks post-DMM. Drug free-µPL (DF-µPL) and saline injections were performed as controls. Mice were euthanized at 4- and 10-weeks post-DMM (early and severe PTOA, respectively. Knees were evaluated for cartilage structure score (ACS, H&E), matrix loss (Safranin-O score), osteophyte formation and maturation from cartilage to bone, (cartilage quantification) and subchondral plate thickness. The RS-µPL architecture ensured the sustained release of CCR2 inhibitors over several weeks, with ~20% of RS504393 being still available at 21-days. This prolonged release improved cartilage structure, reduced bone damage and synovial hyperplasia at both PTOA stages. Extracellular matrix loss was also attenuated, although with less efficacy. Results indicate that local delivery is needed to optimize CCR2-targeting therapies.