A mechanically resilient soft hydrogel improves drug delivery for treating post-traumatic osteoarthritis in physically active joints

• 成果类型: Article
• 署名作者: Joshi, Nitin; Yan, Jing; Dang, Mickael; Slaughter, Kai; Wang, Yufeng; Wu, Dana; Ung, Trevor; Bhingaradiya, Nutan; Pandya, Virja; Chen, Mu Xian; Kaur, Shahdeep; Bhagchandani, Sachin; Alfassam, Haya A.; Joseph, John; Gao, Jingjing; Dewani, Mahima; Chu, Rachel Wai Chun; Yip, Ryan Chak Sang; Weldon, Eli; Shah, Purna; Pisal, Nishkal Dhiraj; Shukla, Chetan; Sherman, Nicholas E.; Luo, James N.; Conway, Thomas; Eickhoff Jr, James P.; Botelho, Luis; Alhasan, Ali H.; Karp, Jeffrey M.; Ermann, Joerg
• 署名单位: Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Massachusetts Institute of Technology (MIT); Harvard University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9659
• DOI: 10.1073/pnas.2409729122
• 发表日期: 2025-04-08
• 关键词: total knee arthroplasty; cathepsin-k; hyaluronic-acid; surgical destabilization; articular-cartilage; medial meniscus; in-vitro; arthritis; release; models

摘要

Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in the early stages of post-traumatic osteoarthritis (PTOA), when symptoms are minimal, and patients remain physically active. To ensure effective therapy, DMOAD delivery systems therefore must withstand repeated mechanical loading without altering the kinetics of drug release. While soft materials are typically preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt controlled drug release. In this study, we present a mechanically resilient soft hydrogel that rapidly self-heals under conditions simulating human running while maintaining sustained release of the cathepsin-K inhibitor L-006235, used as a proof-of-concept DMOAD. This hydrogel demonstrated superior performance compared to a previously reported hydrogel designed for intra-articular drug delivery, which, in our study, neither recovered its structure nor maintained drug release under mechanical loading. When injected into mouse knee joints, the hydrogel provided consistent release kinetics of the encapsulated drug in both treadmill-running and nonrunning mice. In a mouse model of severe PTOA exacerbated by treadmill-running, the L-006235 hydrogel significantly reduced cartilage degeneration, whereas the free drug did not. Overall, our data underscore the hydrogel's potential for treating PTOA in physically active patients.