Therapeutic strategies aimed at overcoming the loss of myelin sheath in central nervous system demyelinating diseases are often unsuccessful due to nescience underlying the mechanisms of remyelination failure. The environment surrounding a demyelination lesion is seen as a hostile terrain, characterized by factors that can inhibit myelin production by oligodendrocytes (OLs). The formation of a glial scar containing reactive astrocytes producing high amounts of altered matrix proteins can compromise OL remyelination. Allied to glial scar, mechanical properties of the tissue are altered. The paradigms in the remyelination failure are changing. We point mechanobiology as a missing key towards unravelling the nature of (de)myelination. Mechanical cues as stiffness, axonal tension or physical constraints are emerging as dictators of tissue homeostasis and pathology. Here we delve into an in-depth characterization of the preeminent models to study mechanobiology events of (de)myelination and remyelination. Alternatives to in vivo systems are provided, either through the exploration of simpler animal models, creation of in vitro models using tissue engineered approaches or through in silico tools. We discuss how bioengineering is being explored to generate relevant models to dissect new mechanobiology mechanisms and identify novel therapeutic targets, being expected to profoundly impact the treatment of demyelinating diseases.
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