Systematic Engineering of Intra-Articular Drug Release Profiles Reveals a Key Determinant of Disease-Modifying Efficacy in Post-Traumatic Osteoarthritis
Year: 2026
Type: preprint
Abstract: Post-traumatic osteoarthritis (PTOA) is a progressive joint disease for which no disease-modifying osteoarthritis drugs (DMOADs) have been approved. Although injectable drug delivery systems can prolong therapeutic retention within the joint, it remains unclear whether local drug release kinetics influence disease-modifying efficacy. Here, we developed a modular platform of injectable supramolecular hydrogels using biocompatible, generally recognized as safe (GRAS) amphiphilic molecules and systematically engineered a range of degradation and drug release profiles. Using the cathepsin-K inhibitor L-006235 as a model DMOAD, we generated hydrogels with distinct release kinetics and evaluated their therapeutic performance in PTOA. Hydrogels exhibiting slower degradation and more sustained drug release like Sucrose Stearate (SS hydrogel) showed prolonged intra-articular retention and improved therapeutic outcomes. In a destabilization of the medial meniscus (DMM) mouse model, sustained-release formulations significantly reduced cartilage degeneration, preserved aggrecan expression, improved joint histopathology, and enabled effective monthly dosing. In contrast, formulations with faster degradation and release kinetics required more frequent administration to achieve comparable benefits. To our knowledge, this is the first study to establish local drug release kinetics as a critical determinant of disease-modifying efficacy in PTOA. This work provides one of the clearest demonstrations to date that engineering intra-articular release kinetics, rather than merely prolonging residence time, can improve disease-modifying outcomes. Our findings establish local release kinetics as a key design parameter for osteoarthritis therapeutics and highlight the potential of tunable supramolecular hydrogels for long-acting drug delivery.
Authors: Jingjing Gao, Nutan Bhingaradiya, Ziting Judy Xia, Ryan Yip, Eli Weldon, Bou Chosson Leite Chilan, Nishkal Dhiraj Pisal, Swetharajan Gunasekar, Pranav Chandrasekar, Paula Oliva Ribas, Mahima Dewani, Christopher Jiang, Gopinathan Janarthanan, Alexandra Dolliver, Rachel Wai Chun Chu, Gunjan Malik, Sohyung Lee, Ranit Dutta, Sanjairaj Vijayavenkataraman, Jeffrey M. Karp, Joerg Ermann, Nitin Joshi
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7163383667