Mechanobiology of Collagen Synthesis, Assembly, and Mineralization

Mineralized collagen fibrils constitute the fundamental structural units within collagenous mineralized tissues (CMTs), particularly in bone and dentin, where they play a critical role in maintaining mechanical resilience and structural integrity. The mechanical microenvironment of CMTs is dynamically shaped by diverse physiologic loads from muscle contraction, body support, vascular system pressure, orthodontic movement, and mastication. While many reviews have covered cellular responses to mechanical stimuli, they often focus on cell differentiation at the generalized cellular level and lack a microscopic and dynamic perspective on mineralized collagen formation. There is an urgent need to review the behavior of collagen fibrils as primary effectors in response to mechanical stimuli. On the basis of compartmental changes and structural evolution, herein we analyze the effects of mechanical stimuli on mineralized collagen formation through 3 distinct stages: 1) intracellular collagen synthesis, where mechanical stimuli can regulate intracellular collagen synthesis at the gene level; 2) extracellular collagen assembly, where appropriate mechanical stimuli can induce orderly collagen fibril arrangement; and 3) intrafibrillar collagen mineralization, where mechanical stimuli can facilitate effective intrafibrillar mineralization. In this review, we trace the mechanobiological journey of mineralized collagen, showcase the latest research advancements in this field, and propose future perspectives. This review may aid in developing novel therapeutic strategies to improve CMT homeostasis and draw attention to the application of biomimetic mechanical microenvironments in tissue engineering.