Convergence of Calcium Channel Regulation and Mechanotransduction in Skeletal Regenerative Biomaterial Design

Cells are known to perceive their microenvironment through extracellular and intracellular mechanical signals. Upon sensing mechanical stimuli, cells can initiate various downstream signaling pathways that are vital to regulating proliferation, growth, and homeostasis. One such physiologic activity modulated by mechanical stimuli is osteogenic differentiation. The process of osteogenic mechanotransduction is regulated by numerous calcium ion channels—including channels coupled to cilia, mechanosensitive and voltage‐sensitive channels, and channels associated with the endoplasmic reticulum. Evidence suggests these channels are implicated in osteogenic pathways such as the YAP/TAZ and canonical Wnt pathways. This review aims to describe the involvement of calcium channels in regulating osteogenic differentiation in response to mechanical loading and characterize the fashion in which those channels directly or indirectly mediate this process. The mechanotransduction pathway is a promising target for the development of regenerative materials for clinical applications due to its independence from exogenous growth factor supplementation. As such, also described are examples of osteogenic biomaterial strategies that involve the discussed calcium ion channels, calcium‐dependent cellular structures, or calcium ion‐regulating cellular features. Understanding the distinct ways calcium channels and signaling regulate these processes may uncover potential targets for advancing biomaterials with regenerative osteogenic capabilities. This work summarizes notable calcium channels that regulate mechanotransduction signaling pathways and their relevance in skeletal biomaterial design. The various calcium channels, structures, and associated pathways that are relevant to osteogenic differentiation and regeneration are thus discussed in this review. Ultimately, the purpose of this work is to inform the next generation of biomaterial development through calcium centered strategies.