Concentration dependence of interstitial flow buffering by hyaluronan in synovial joints

Hyaluronan concentration in synovial fluid spans a 20-fold range, from as low as 0.2 mg ml(-1) in synovitis to as high as 4 mg ml(-1) in healthy joints. The aim was to determine the effect of this on fluid drainage from the joint cavity. The study extends the finding of P. J. Coleman, D. Scott, R. M. Mason, and J. R. Levick (1999, J. Physiol. 514, 265-282) that dissolved hyaluronan at 3.6-4.0 mg ml(-1) (the concentration in young human and rabbit joints) causes the opposition to interstitial fluid drainage to increase with pressure. Hyaluronan was infused into rabbit knees at 0, 0.2, 2.0, and 4.0 mg ml(-1) over a range of intraarticular pressures. Hyaluronan at 2 mg ml(-1) (as in healthy elderly joints and some osteoarthritis) greatly reduced drainage rates and generated a flattening (convex) pressure-flow relation, as observed previously with 4 mg ml(-1). Drainage rates were greater at 2 mg ml(-1) than at 4 mg ml(-1) hyaluronan (P < 0.0001, ANOVA, n = 7). The opposition to outflow (pressure required to drive unit outflow) increased with pressure, but less markedly than with 4 mg ml(-1) hyaluronan. Hyaluronan at 0.2 mg ml(-1) reduced outflow by approximately 50% relative to Ringer solution (P < 0.0001, ANOVA, n = 7) but the pressure-flow relation no longer flattened out with increasing pressure, because there was no significant increase in opposition to outflow with pressure. At 0 mg ml(-1) hyaluronan, outflow opposition decreased with pressure. Viscometry showed a marked transition in the hyaluronan state at >/=1.35 mg ml(-1), indicating that this is the critical concentration for molecular domain overlap and intermolecular coupling. The results broadly supported the concentration-polarization hypothesis, which predicts significant osmotic buffering of drainage at >/=1 mg ml(-1) hyaluronan; at 0.2 mg ml(-1) other factors may predominate. It is inferred that hyaluronan at physiological concentrations can conserve synovial fluid when pressures are raised (e.g., flexion): whereas dilution of hyaluronan, as in severe effusions, can effectively abolish buffering and thus facilitate fluid drainage.