UC San Diego

Synovial fluid (SF) in native joints functions as a biomechanical lubricant, lowering the friction and wear of articulating cartilage in synovial joints. SF lubricant macromolecules, including hyaluronan (HA) and proteoglycan 4 (PRG4), are secreted by synoviocytes lining the joint and chondrocytes in cartilage, and concentrated in SF due to the retaining property of the semi-permeable synovium. A bioengineered SF recapitulating the properties of native SF may be beneficial in tissue engineering articular cartilage and synovial joints for the treatment of arthritis, as an appropriate lubricating environment may be critical to maintain the low-friction, low-wear properties of articulating cartilage surfaces undergoing joint-like motion in bioreactors. The ability to generate such a fluid may have additional applications in developing arthritis therapies targeted at restoration of failed joint lubrication, such as viscosupplements and molecules that regulate lubricant secretion, and may also further our understanding of in vivo SF lubricant regulation. Thus, the overall motivation for this dissertation was to develop and integrate theoretical and experimental models of the synovial joint. More specifically, the goals were to (1) incorporate biophysical features of the joint into a theoretical model of the SF compartment, and (2) recapitulate these features in a biomimetic bioreactor system to produce a bioengineered SF with lubricant composition and function similar to that of native SF. Theoretical modeling of the dynamics of SF lubricant composition in native joints predicted steady-state lubricant concentrations within physiological ranges, marked alteration in these concentrations with chemical regulation, and distinct kinetics for HA and PRG4 in SF. Cytokine regulation of lubricant secretion by synoviocytes showed distinct regulation of HA and PRG4 secretion rates, with certain cytokines synergistically interacting to markedly increase HA secretion rates and regulate the molecular weight (MW) of secreted HA to resemble that present in native SF. Assessment of the ability of semi-permeable membranes to retain lubricant molecules demonstrated a selective retention of HA and PRG4 as a function of membrane pore size, lubricant MW, and the presence of a cell layer adherent on the membrane. Finally, it was shown that a bioengineered SF with lubricant composition and function similar to that of native SF could be generated in a novel bioreactor system at the tissue explant scale by incorporating biomimetic features of the synovial joint, including lubricant secreting cell types, a lubricant retaining membrane, and cytokine regulatory factors. Application of the theoretical model to this system predicted lubricant concentrations in bioengineered SF that were similar to those observed experimentally, and kinetics that varied with lubricant structure and membrane pore size. This work has contributed to a greater understanding of the dynamics of in vivo SF lubricant composition that may occur in health, injury, and disease, and it may also aid in the development of novel arthritis therapies targeted at restoration of failed joint lubrication. Specifically, the ability to bioengineer a functional SF may have applications in developing viscosupplements, evaluating the effects of potential therapeutic agents on SF lubricant composition, and in providing an appropriate lubricating environment to whole joints being tissue engineered and mechanically stimulated in bioreactors for biological joint replacement