A8.27 Intraarticular drug delivery of anti-HMGB1 in hyaluronan gels for osteoarthritis treatment

Abstract

Background and objectives Joint pain due to degeneration of cartilage tissue in osteoarthritis is a major problem affecting people of different ages and there are no long-term solutions available today. During recent years means suppression of inflammation that stops joint destruction have been developed and there is now a need for new approaches to stimulate repair. This should preferably be done without use of complicated cell therapies, and an opportunity to accomplish such development is provided by the application of new, injectable derivatives of hyaluronan. The cross linking chemistry applied here is a very rapid reaction between carbazate moieties on one component and aldehyde groups in the other, where a solid gel is formed within 30 s. HMGB1 is an endogenous molecule released from activated immune cells as well as dying cells with both proinflammatory and osteoclast-activating features. HMGB1 blockade is proven effective in experimental models of RA and the presence of extracellular HMGB1 is reported in OA specimens. The aim of this study was to evaluate the effect of HMGB1 blockade on cartilage repair and evaluate drug delivery into the joint using hyaluronan gels in an experimental osteoarthritis model in mice. Materials and methods OA was induced in mice by surgically destabilising the knee joint through anterior cruciate ligament transection. Anti-HMGB1 encapsulated in the gel was injected intraarticularly. After 8 weeks the animals were sacrificed and knees processed for histology. Sections were stained with Safranin-O and HMGB1 and scored blinded. Results We demonstrated that cartilage could be rescued by treatment with anti-HMGB1 in the OA model. HMGB1 staining in the cartilage specimens showed intra and pericellular expression in chondrocytes of proteoglycan depleted areas in articular cartilage. HMGB1 was also present in ligaments, synovia and osteophytes. A surprising observation was that also the gel alone showed improvement of cartilage. The negative impact of endogenous aldehydes on chondrogenesis have been demonstrated in a number of studies. The gel precursors carry aldehyde and hydrazide functional groups for the gel formation and we believe that interaction and neutralisation of endogenous aldehydes in the joint cavity may have affected cartilage healing. Conclusions The hyaluronan hydrogel has shown promising results for cell free regeneration therapies by local treatment in the joints. We showed that blocking of HMGB1 improved the cartilage regeneration in experimental OA and the hyaluronan gel in itself carried anti-inflammatory properties.