Role of in vivo mechanical loading in the pathology, treatment, and prevention of osteoarthritis
Osteoarthritis (OA) is a degenerative joint disease that affects millions of people worldwide and is the leading cause of disability in the elderly population. To date, no cure exists for OA, and the exact cause is not clearly understood. Mechanical loading at high magnitudes, however, is a primary risk factor for the disease. To better understand the role of mechanical loading in OA, we used an in vivo model that applies cyclic axial compression to the knee joints of mice. First, we used the model to study the role of abnormal cartilage matrix properties in load-induced OA. Next, we characterized a novel hydrogel-based drug delivery system and tested the hydrogel’s therapeutic efficacy for intra-articular treatment of load-induced OA. Finally, we applied low-level mechanical forces to attenuate OA-like changes after joint injury. We first sought to understand the effects of an abnormal cartilage matrix on the onset and progression of load-induced OA. The cho/+ mouse has abnormal collagen fibrils in its cartilage matrix due to a Col11a1 haploinsufficiency. We hypothesized that cho/+ mice would develop more severe load-induced OA pathology compared to wildtype (WT) littermates with normal cartilage. Contrary to our hypothesis, cho/+ mice had less severe load-induced cartilage damage. Cho/+ mice also had thinner, less dense cortical bone and thicker cartilage. Both characteristics may have played a role in attenuating load-induced OA pathology in cho/+ mice. The next goal was to characterize an on-demand hydrogel-based drug delivery system for intra-articular OA treatment. Synthetic hydrogels were made of cross-linked 4-arm maleimide functionalized polyethylene glycol, and we analyzed their mechanical integrity and on-demand release in vitro. The hydrogels maintained their mechanical properties after 10,000 cycles of cyclic compression at 80% strain. In addition, they released particles in response to collagenase exposure, highlighting their on-demand release characteristics in the OA joint environment. In vivo, hydrogel injections reduced load-induced cartilage damage and osteophyte size. Further work is needed to determine the most effective drugs to combine with the hydrogel system. Finally, we sought to determine whether low-level loads could attenuate post-traumatic OA. Mice underwent the destabilization of the medial meniscus (DMM) surgery to mimic an injury in the knee joint. These DMM joints were then loaded with low-level cyclic axial compression. The loading regimen attenuated DMM-induced cartilage degradation, osteophyte formation, and subchondral bone sclerosis. Thus, low-level axial loading may be used to slow post-traumatic OA progression. In summary, in vivo cyclic tibial compression allowed us to better understand the role of mechanical loading in the pathology, treatment, and prevention of OA. Our results show that both cartilage and bone are involved in OA progression, and both tissues must be considered when predicting disease severity. Furthermore, synthetic hydrogel systems combined with therapeutics may be an effective approach to improve intra-articular drug retention time. Finally, low-level axial loading has the potential to aid as a preventive intervention for OA, particularly after a joint injury.
Mechanical engineering; bone; mechanobiology; Biomedical engineering; Biomechanics; Animal models; Cartilage; Osteoarthritis
van der Meulen, Marjolein
Hernandez, Christopher J.; Goldring, Mary
Ph. D., Biomedical Engineering
Doctor of Philosophy
dissertation or thesis