Sustained intra-articular delivery of disease modifying osteoarthritis drugs (DMOADs) holds promise for preventing the progression of osteoarthritis (OA). However, since (DMOADs) are intended for early OA, when patients are active, repeated mechanical loading of joints can be detrimental to the delivery system, causing rapid drug release. To our knowledge, none of the previously reported intra-articular platforms for DMOAD delivery have been evaluated in physically active animals or have considered the impact of activity induced mechanical stress on the delivery platform and the drug release. We have developed a hydrogel platform that can rapidly recover following mechanical stress relevant to running human knee joints, with no impact on sustained release of the encapsulated agents. Hydrogel loaded with cathepsin-K inhibitor (L-006235) – a small molecule DMOAD prevented OA progression in mice undergoing treadmill running. The overall objective of this application are to (i) develop variants of our hydrogel platform with different release kinetics of L-006235 to understand how local release kinetics/pharmacokinetics impacts therapeutic efficacy and (ii) further engineer the hydrogel platform for delivery of biologic DMOADs. Our long-term goal is to develop a versatile and mechanically stable drug delivery platform with tunable release kinetics for intra-articular delivery of DMOADs in active joints to prevent OA progression. Our central hypothesis is that a mechanically stable hydrogel platform can minimize the impact of joint-related mechanical stress on sustained release of DMOADs and therapeutic efficacy of this system can be maximized by tuning the local release kinetics of DMOADs. To achieve our objectives, we propose two specific aims: 1) Investigate the impact of release kinetics of L-006235 on therapeutic efficacy; and 2) Investigate the delivery of biologic DMOADs in active joints using hydrogel. Under the first aim, we will develop hydrogel variants with different release kinetics of L-006235 and will study the impact of mechanical stress relevant to human joints on hydrogel variants and L-006235 release. Next, we will validate the differences in release kinetics in treadmill running mice and evaluate the therapeutic efficacy and off-target effects in treadmill running mice with OA. For the second aim, we will identify formulation parameters, including TG-18 concentration and choice of solvent to maximize loading and stability of three different biologic DMOADs (IL-1Ra, FGF-18 and sTNFRII). Formulations will be evaluated for mechanical stability in vitro, release kinetics in treadmill running mice and efficacy and off-target effects in treadmill running mice with OA. The research proposed in this application is innovative, in our opinion, because it focuses on a novel hydrogel platform that is mechanically stable in joints, allows tunability of release kinetics and is versatile. We will be the first to (i) demonstrate therapeutic efficac...