Background/Purpose: Joint injuries, including sports- or combat-related ligamentous tears and fractures, can lead to post-traumatic osteoarthritis (PTOA), a chronic condition that causes pain, disability and limited quality of life. Current treatment options only provide symptomatic relief without modifying the progressive course of the disease, and are plagued by dose- or duration-limiting toxicity. Pharmacologic inhibition of catabolic factors, including cartilage degrading enzymes, pro-inflammatory cytokines and catabolic cell signaling pathways appears to reduce progressive joint damage in preclinical and clinical studies. However, the clinical translation of such disease modifying osteoarthritis drugs (DMOADs) has been hampered by short half-lives following intra-articular administration. Although platforms have been developed for local delivery of therapeutics, most suffer from major drawbacks, including a lack of control points to tune release kinetics and complex design that limits scalability and adaptability to a wide range of DMOADs. A localized drug delivery depot that provides long-term release of DMOADs in response to OA associated local factors like matrix metalloproteinase-2 (MMP-2) would represent an attractive paradigm shift in OA therapy.

Methods: We designed a self-assembled hydrogel depot using small molecules that are Generally Recognized As Safe (GRAS) by the FDA without chemical modifications, and evaluated the hydrogel’s ability to encapsulate an MMP-13 inhibitor (Sigma-Aldrich) and a Cathepsin-K inhibitor (TOCRIS Bioscience). Release studies were performed in vitro to explore the responsiveness of the system to MMP-2 and synovial fluid (SF) collected from healthy and arthritic human joints. Hydrogels were evaluated in vitro for biocompatibility using chondrocytes and synoviocytes. Therapeutic efficacy of Cathepsin-K inhibitor loaded gels was determined in vivo using the medial meniscal tear model of PTOA in Lewis rats.

Results: Hydrogels encapsulated both MMP-13 and cathepsin-K inhibitors with high loading efficiencies and showed excellent hydrolytic stability in PBS and synovial fluid from healthy human joints, with cumulative drug release <30% over a 30-day period. The encapsulated DMOADs were released from the hydrogel in response to MMP-2 and synovial fluid collected from arthritic human joints. The release of DMOADs was directly proportional to the dose of enzyme or amount of arthritic synovial fluid added. Drug-loaded gels showed biocompatibility with both chondrocytes and synoviocytes, suggesting their safety for intra-articular administration. In the medial meniscal tear model of PTOA, intra-articular treatment with Cathepsin-K inhibitor-loaded hydrogels resulted in a significant reduction in cartilage damage compared to controls (rats injected with blank hydrogel).

Conclusion: Our results suggest that self-assembled hydrogels are a promising strategy for efficient, localized delivery of DMOADs and can offer improved therapeutic benefit in the treatment of PTOA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-simple-self-assembled-hydrogel-depot-for-localized-treatment-of-post-traumatic-osteoarthritis/