Matrix Viscoelasticity Tunes the Mechanobiological Behavior of Chondrocytes

ABSTRACT In articular cartilage, the pericellular matrix acting as a specialized mechanical microenvironment modulates environmental signals to chondrocytes through mechanotransduction. Matrix viscoelastic alterations during cartilage development and osteoarthritis (OA) degeneration play an important role in regulating chondrocyte fate and cartilage matrix homeostasis. In recent years, scientists are gradually realizing the importance of matrix viscoelasticity in regulating chondrocyte function and phenotype. Notably, this is an emerging field, and this review summarizes the existing literatures to the best of our knowledge. This review provides an overview of the viscoelastic properties of hydrogels and the role of matrix viscoelasticity in directing chondrocyte behavior. In this review, we elaborated the mechanotransuction mechanisms by which cells sense and respond to the viscoelastic environment and also discussed the underlying signaling pathways. Moreover, emerging insights into the role of matrix viscoelasticity in regulating chondrocyte function and cartilage formation shed light into designing cell‐instructive biomaterial. We also describe the potential use of viscoelastic biomaterials in cartilage tissue engineering and regenerative medicine. Future perspectives on mechanobiological comprehension of the viscoelastic behaviors involved in tissue homeostasis, cellular responses, and biomaterial design are highlighted. Finally, this review also highlights recent strategies utilizing viscoelastic hydrogels for designing cartilage‐on‐a‐chip. Summary It is well known that viscoelasticity has been found to be a universal characteristic of living tissues, cells, and molecules. Matrix viscoelasticity, as a critical physical cues of cartilage matrix microenvironment, regulates collective chondrocyte fate and cartilage formation. But, how matrix viscoelasticity affects the chondrocyte behavior and function remains unclear. Growing evidence has demonstrated that matrix viscoelasticity regulates chondrocytes in some ways not anticipated from previous mechanisms of mechanotransduction, which was based on purely substrate stiffness. In this review, we introduce recent work elucidating the effect of matrix viscoelasticity on chondrocytes morphology, phenotype, function, inflammatory response, and signaling pathways. These findings have provided insights into viscoelasticity as a design parameter for cartilage tissue engineering, regenerative medicine, and cartil