A mechanically resilient soft hydrogel improves drug delivery for treating post-traumatic osteoarthritis in physically active joints
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (30)
Nitin Joshi
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Jing Yan
Mickael Dang
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Kai Slaughter
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Yufeng Wang
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, SAR 999077, P. R. China
Dana Wu
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Trevor Ung
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Nutan Bhingaradiya
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Virja Pandya
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Mu Xian Chen
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Shahdeep Kaur
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Sachin Bhagchandani
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Haya A. Alfassam
National Center for Biotechnology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology
John Joseph
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Jingjing Gao
Mahima Dewani
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Rachel Wai Chun Chu
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Ryan Chak Sang Yip
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Eli Weldon
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Purna Shah
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Nishkal Dhiraj Pisal
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Chetan Shukla
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Nicholas E. Sherman
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
James N. Luo
Harvard Medical School
Thomas Conway
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
James P. Eickhoff
Anton Paar USA, Inc.
Luis Botelho
Anton Paar USA, Inc.
Ali H. Alhasan
National Center for Biotechnology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology
Jeffrey M. Karp
Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Joerg Ermann
Harvard Medical School