A diagnostic imaging technique and therapeutic strategy for early osteoarthritis
Stewart, Rachel Christine
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Osteoarthritis (OA) is a chronic, progressive disease of diarthrodial joints arising from the breakdown of articular cartilage. As one of the leading causes of disability and lifestyle limitations in the United States, osteoarthritis is estimated to affect 27 million people in the U.S. and cost the economy $128 billion annually. Current diagnostic techniques detect OA only in its later stages, when irreversible cartilage damage has already occurred. A reliable, non-invasive method for diagnosing OA in its early stages would provide an opportunity to intervene and potentially to stay disease progression. Likewise, the field of OA research would benefit from a technique that allows tissue engineering and small molecule therapies to be evaluated longitudinally. Contrast-enhanced computed tomography (CECT) of cartilage is a developing medical imaging technique for evaluating cartilage biochemical and biomechanical properties. CECT has been shown to accurately quantify measures of cartilage integrity such as glycosaminoglycan (GAG) content, equilibrium compressive modulus, and coefficients of friction. In the studies presented herein, cationic iodinated contrast agents are developed for quantitative cartilage CECT, a technique predicated on the diffusion and partitioning of a charged contrast agent into the cartilage. The experiments show that cationic contrast agents lack specific interactions with anionic GAGs and are highly taken up in cartilage due, instead, to their electrostatic attraction. At diffusion equilibrium, both anionic and cationic agents indicate GAG content and biomechanical properties as measured by microcomputed tomography, though cationic contrast agents were found to diffuse through cartilage more slowly than anionic ones. Translating CECT to intact joints with clinically available helical CT scanners bears promising results, but concerns remain regarding in vivo applicability. Anionic contrast agents enable GAG content quantification following brief contrast agent exposure, whereas cationic agents require full equilibration within the tissue. To explore treatment modalities for early OA, a novel interpenetrating hydrogel method was developed to reconstitute the mechanical properties of cartilage models for early OA. Preliminary results show that the interpenetrating network strengthened cartilage with respect to compressive loading suggesting that the treatment could potentially serve as a functional replacement for GAG lost in the early stages of OA.
Thesis (Ph.D.)--Boston University