The Role of Proteoglycan 4 in the Rheology of Synovial Fluid
Date
2021-09-14
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Abstract
The free motion of joints in the body is rendered safe by the biomechanical properties of articular cartilage and synovial fluid (SF). Cartilage is an elastic tissue capable of withstanding large compressive forces, whereas SF is a lubricating fluid with remarkable viscoelastic properties. The high molecular weight polysaccharide hyaluronan (HA) and the mucin-like glycoprotein proteoglycan 4 (PRG4 or lubricin) are crucial macromolecules in SF that lubricate cartilage synergistically; however, there is an ongoing debate on how their interactions in influence SF rheology. This thesis examined the relationship between the microstructure and the rheological properties of physiologically relevant formulations of HA and recombinant human PRG4 (rhPRG4) to elucidate on the interactions between them in SF. A succinct fractional framework was adapted to effectively describe the linear and nonlinear viscoelastic behaviour of HA+rhPRG4 solutions at both macroscopic and microscopic length scales. It was found that the bulk rheology of HA solutions increased with the addition of rhPRG4 in a dose-dependent manner, but the extent of these enhancements depended on the degree of rhPRG4 glycosylation. Afterwards, an optical tweezers-based methodology was modified using our fractional framework to characterize the rheology of the microstructure in our solutions. Contrary to previous studies, no evidence was found of a favourable physical interaction between HA and rhPRG4 which could functionally alter the macroscopic rheology of the solutions. At the microscopic level, rhPRG4 was shown to cluster into stiff gel-like aggregates that did not interact with the surrounding continuous phase of HA polymers. Furthermore, the interfacial adsorption of rhPRG4 molecules at the air-water interface of the rotational rheometer was shown to play a considerable effect in the interpretation of macrorheological data. Finally, clinically relevant non-ionic surfactants used in the stabilization of rhPRG4 formulations were shown to both suppress the interfacial adsorption of rhPRG4 in rotational rheometers and disrupt the aggregation behaviour of rhPRG4 in the bulk. Taken together, these results suggest that, in SF and potential HA+PRG4 biotherapeutic supplements designed for osteoarthritic joints, HA governs the bulk rheology of the fluid whereas the impact of PRG4 is restricted to its tribological performance.
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Keywords
Lubricin, Proteoglycan-4, Hyaluronan, Hyaluronic Acid, Synovial Fluid, Rheology, Microrheology, Optical Tweezers, Cartilage Lubrication
Citation
Martin-Alarcon, L. (2021). The Role of Proteoglycan 4 in the Rheology of Synovial Fluid (Doctoral thesis). University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca .