The Tenocyte from Atom to Cell: A Critical Multiscale Synthesis Linking Collagen Chemistry, Tissue Mechanics, Cell Mechanobiology and Mathematical Modelling

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Abstract
The tenocyte builds, maintains, senses and degrades one of the most mechanically demanding extracellular matrices in vertebrates, yet the chemical, physical, biological and mathematical descriptions of this system have developed in largely separate literatures. This review examines the tenocyte–matrix unit as a single causal system spanning eight orders of magnitude in length, organised around five transitions: from collagen chemistry to molecular mechanics; from molecule to fibril and fascicle; from tissue loading to the cellular mechanical stimulus; from stimulus to transcription; and from cellular output back to matrix composition. At each transition, we weigh competing hypotheses, identify where evidence is decisive and where it remains correlative, and state the governing equations. We integrate advances from 2021–2026, including single-cell and spatial transcriptomic atlases of human tendons, the establishment of PIEZO1 as a causal regulator of tendon stiffness, and microstructurally derived constitutive models. We argue that tendon homeostasis is a closed-loop control problem, formalised as a mechanostat with an inverted-U dose–response, and that the recurrent pathologies of tendon-tendinopathy, ageing, diabetic stiffening and fibrotic healing are failures of this loop rather than of any single component. An open-source computational companion (tenocyte-virtual-cell) is introduced, and a prioritised research agenda closes the review.

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