3D scaffolds-specific cellular mechanoresponse as a pivotal regulating factor in tissue engineering

In tissue engineering, the mechanical properties of the extracellular matrix (ECM) or scaffolds have increasingly been considered to impact therapeutic efficacy by regulating cell behaviors, including differentiation, proliferation, migration, and adhesion. However, the understanding of how cells sense, integrate, and convert the mechanical cues from the ECM cues into biochemical signals to control certain cell behaviors is still elusive, especially in 3D, which more closely mimics the natural microenvironment than 2D systems. This review highlights the key differences between 2 and 3D in the contexts of mechanoregulative cell behaviors such as cell adhesion, spreading, migration, and force transmission. Furthermore, critical designing factors that needs to be considered for the fabrication of 3D tissue engineering scaffolds is discussed: stiffness, viscoelasticity, degradability, and the immobilization of biomolecules. Although mechanotransduction in 3D is actively being studied, understanding cellular mechanotransduction in 3D and designing of mechanoregulative 3D scaffolds still presents several challenges, including varying mechanical properties depending on different tissues, dynamic mechanical environments, and integration of multimodal cues. Interdisciplinary methodologies encompassing material engineering, cell biology, and mechanical engineering would serve to mitigate these challenges and augment our understanding of mechanoregulation governing cellular behaviors, thus fostering advancements in biomedical applications in the future.