Synovial fluid homeostasis : bulk flow, lubricant transport, and biophysical restoration

Synovial fluid (SF) is an ultrafiltrate of blood plasma found in diathrodial joints that contributes to low- friction and low-wear joint articulation. SF normally contains high molecular mass (M/r) hyaluronan (HA), secreted in response to mechanical and biological cues from local cell populations, and a major contributor to the fluid's biophysical properties. During joint pathology, the composition of SF, including HA M/r, is decreased, resulting in decreased viscosity and altered biophysics. The overall motivation of this dissertation work was to contribute to the understanding of synovial fluid physiology, including fluid movement during flexion, post- injury rheology, lubricant homeostasis, and biophysical properties. The objectives were to determine 1) SF movement and joint capsule strain due to flexion, 2) the rheological and biomechanical properties of mixtures of SF and blood, 3) the mechanisms of lubricant homeostasis in normal and injured joints, and 4) the molecular determinants of the biophysical properties of SF and to utilize them to control those properties in solutions of HA and in OA SF. 1) Ev vivo and in vivo imaging of rabbit joints were used to determine that flexion of the knee shifts SF from anterior to posterior, and the joint capsule undergoes proximal-distal tension and circumferential shortening relative to the femur axis. 2) Dilution with SF altered the coagulation torque profile of blood over time, resulting in a decreased maximum torque generation and clot mechanical stiffness. 3) In vivo in the adult rabbit, endogenous secretion of high-M/r HA after washout replenished in SF over time, secretion rates were diminished after ACLT, and HA loss from the SF occurred in a M/r-dependent manner leading to decreased residence times of HA at day 7 after ACLT, likely due to subsynovial cell infiltration. 4) The importance of HA binding proteins to OA SF viscosity was demonstrated, with protein removal resulting in significant viscosity decreases. Modification of HA with inter-[alpha]-inhibitor heavy chains increased the viscosity of HA solutions and OA SF. Major contributions of this work include to understanding the structural physiology of the joint, molecular homeostasis in SF, the effects of injury on joints, and clinical implications for joint diseas