Understanding intra-articular biodistribution is imperative as candidate osteoarthritis (OA) drugs become increasingly site-specific. Cartilage has been identified as opportunistic for therapeutic intervention, but poses numerous barriers to drug delivery. To facilitate drug delivery to cartilage, nanoscale vehicles have been designed with different features that target the tissue's matrix. However, it is unclear if these targeting strategies are influenced by OA and the associated structural changes that occur in cartilage. The goal of this work was to study the effectiveness of different cartilage-targeting nanomaterials with respect to cartilage localization and retention, and to determine how these outcomes change in OA. To address these questions, a nanoparticle (NP) system was developed, and the formulation was tuned to possess three distinct cartilage-targeting strategies: (1) passive targeting cationic NPs for electrostatic attraction to cartilage, (2) active targeting NPs with binding peptides for collagen type II, and (3) untargeted neutrally-charged NPs. Ex vivo analyses with bovine cartilage explants demonstrated that targeting strategies significantly improved NP associations with both healthy and OA-like cartilage. In vivo studies with collagenase-induced OA in rats revealed that disease state influenced joint biodistribution for all three NP formulations. Importantly, the extent of cartilage accumulation for each NP system was affected by disease differently; with active NPs, but not passive NPs, cartilage accumulation was increased in OA relative to healthy knees. Together, this work suggests that NPs can be strategically designed for site-specific OA drug delivery, but the biodistribution of the NPs are influenced by the disease conditions into which they are delivered.

Small animal models are essential for studying anterior cruciate ligament (ACL) injury, one of the leading risk factors for post-traumatic osteoarthritis (PTOA). Non-surgical models of ACL rupture have recently surged as a new tool to study PTOA, as they circumvent the confounding effects of surgical disruption of the joint. These models primarily have been explored in mice and rabbits, but are relatively understudied in rats. The purpose of this work was to establish a non-invasive, mechanical overload model of ACL rupture in the rat and to study the disease pathogenesis following the injury. ACL rupture was induced via non-invasive tibial compression in Lewis rats. Disease state was characterized for 4 months after ACL rupture via histology, computed tomography, and biomarker capture from the synovial fluid. The non-invasive knee injury (NIKI) model created consistent ACL ruptures without direct damage to other tissues and resulted in conventional OA pathology. NIKI knees exhibited structural changes as early as 4 weeks post-injury, including regional structural changes to cartilage, chondrocyte and cartilage disorganization, changes to the bone architecture, synovial hyperplasia, and the increased presence of biomarkers of cartilage fragmentation and pro-inflammatory cytokines. These results suggest that this model can be a valuable tool to study PTOA. By establishing the fundamental pathogenesis of this injury, additional opportunities are created to evaluate unique contributing factors and potential therapeutic interventions for this disease. METHODS NIKI Device Design and Injury Loading SchemeThe NIKI device induces an ACL tear in the supine rat with the foot and knee secured in custom fixtures, as 356 JOURNAL OF ORTHOPAEDIC RESEARCH ® FEBRUARY 2020