The rheological properties of synovial fluid (SF) are largely attributed to the presence of high molecular weight hyaluronan (HA). However, rheological differences between SF and pure HA solutions suggest that SF proteins actively contribute towards the bulk viscoelasticity of this biological fluid. Due to various experimental challenges involved with the rheometry of low-viscosity biological fluids, the macromolecular interactions in SF and their relative rheological importance are still a matter of active discussion. Interestingly however, recent evidence suggests that the concentration and structure of proteoglycan 4 (PRG4, also known as lubricin) can directly modulate the viscoelastic properties of HA-PRG4 solutions. The objective of this review is to highlight recent rheological studies that examine the macromolecular interactions between HA and proteins in SF. First, a general overview of the chemical composition of SF and the molecular structure of its key constituents HA and PRG4 is provided. Subsequently, diverse rheological experimental techniques that have been developed to characterize HA solutions are discussed. Finally, rheological investigations of macromolecular interactions between HA, serum proteins, and PRG4 are examined. This review illustrates how diverse rheological techniques can expand our understanding of the composition-structure-function relationships in SF.

The fields of regenerative medicine and tissue engineering require large-scale manufacturing of stem cells for both therapy and recombinant protein production, which is often achieved by culturing cells in stirred suspension bioreactors. The rheology of cell suspensions cultured in stirred suspension bioreactors is critical to cell growth and protein production, as elevated exposure to shear stress has been linked to changes in growth kinetics and genetic expression for many common cell types. Currently, little is understood on the rheology of cell suspensions cultured in stirred suspension bioreactors. In this study, we present the impact of three common cell culture parameters, serum content, cell presence, and culture age, on the rheology of a model cell line cultured in stirred suspension bioreactors. The results reveal that cultures containing cells, serum, or combinations thereof are highly shear thinning, whereas conditioned and unconditioned culture medium without serum are both Newtonian. Non-Newtonian viscosity was modeled using a Sisko model, which provided insight on structural mechanisms driving the rheological behavior of these cell suspensions. A comparison of shear stress estimated by using Newtonian and Sisko relationships demonstrated that assuming Newtonian viscosity underpredicts both mean and maximum shear stress in stirred suspension bioreactors. Non-Newtonian viscosity models reported maximum shear stresses exceeding those required to induce changes in genetic expression in common cell types, whereas Newtonian models did not. These findings indicate that traditional shear stress quantification of cell or serum suspensions is inadequate and that shear stress quantification methods based on non-Newtonian viscosity must be developed to accurately quantify shear stress.

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