Viscoelastic Cell Microenvironment: Hydrogel‐Based Strategy for Recapitulating Dynamic ECM Mechanics

Abstract

The native extracellular matrix (ECM) generally exhibits dynamic mechanical properties and displays time‐dependent responses to deformation or mechanical loading, in terms of viscoelastic behaviors (e.g., stress relaxation and creep). Viscoelasticity of the ECM plays a critical role in development, homeostasis, and tissue regeneration, and its implication in disease progression has also been recognized recently. Hydrogels with tunable viscoelastic properties hold a great promise to recapitulate such time‐dependent mechanics found in native ECM, which have been recently used to regulate cell behavior and guide cell fate. Here the importance of tissue viscoelasticity is first highlighted, the molecular mechanisms of hydrogel viscoelasticity are summarized, and characterization techniques used at the macroscale and microscale are reviewed. Then, recent advances in developing novel hydrogels with tunable viscoelasticity through varying crosslinking strategies, engineering of viscoelastic cell microenvironment and its substantial effects on cell behavior and fate are described, and the underlying mechanobiology mechanisms are subsequently discussed. Finally, the ongoing challenges and future perspectives on the design and modulation of viscoelastic hydrogels and the mechanobiology mechanisms on cellular responses to viscoelastic cell microenvironment are proposed.

Enhancing Stem Cell Therapy for Cartilage Repair in Osteoarthritis—A Hydrogel Focused Approach

“…Hydrogel, a crosslinked hydrophilic polymer that possess similar structural network and water content with ECM, can be designed with specific viscoelasticity that toward target tissues for controlling the cellular behaviors [ 42 ]. Different crosslinking mechanisms (e.g., physical interactions, supramolecular interaction and dynamic covalent interactions) for synthesizing viscoelastic hydrogels and the underlying mechanobiology mechanisms have been reviewed elsewhere [ 43 ]. Here we will highlight the influence of dynamically mechanical microenvironment created by various viscoelastic hydrogels, including supramolecular networks, interpenetrating network (IPN) and dynamic bonds formed networks, on the fate of MSCs in the osteochondral restore and regeneration.…”

“…They found that highly adaptive linking improved cellular structures (proliferation, ECM deposition, et al), but slowly relaxed cross-linking was also required to achieve high quality new cartilage tissue [ 51 , 52 ]. Besides the temporally evolving properties capable of directing cell behavior provided from dynamic materials, dynamic covalent hydrogels also enhance stem cell therapy for cartilage regeneration including as minimally invasive injectable cell delivery vehicles, bioinks for 3D printing [ 43 ]. To advance the field of dynamic covalent hydrogels and their application for cartilage tissue engineering, more research should focus on standardizing methods to characterize the viscoelastic properties, especially in presence of stem cells and in vivo condition.…”

Influence of Temperature and Polymer Concentration on the Nonlinear Response of Highly Acetylated Chitosan–Genipin Hydrogels

“…The time-dependent response of the native ECM to the action of stress is crucial for its interactions with cells. Indeed, the tensile forces of cells are used to remodel and reorganize the matrix to achieve spreading, proliferation and migration [ 26 ].…”

A Self-Healing, Viscoelastic Hydrogel Promotes Healing of Brain Lesions

“…Our efforts were motivated by observations that many cells spread more when cultured in three-dimensional (3D) hydrogels that are viscoelastic than in hydrogels that are elastic [7] , and that brain parenchyma is soft and viscoplastic [7-8] . We sought to develop a self-healing hydrogel with the low stiffness and fast stress relaxation of brain parenchyma, which could be injected into a brain lesion with in situ solidification (sol-gel transitions) with controllable material dispersion within the brain.…”