Tissue damage occurs if cell death rates exceed those of proliferation, migration and repair. All these factors can be potentially influenced by mechanical stimuli, e.g. force application and localized extracellular stiffness changes. This talk reviews important mechanobiological factors that can potentially affect cell and tissue tolerance to sustained mechanical loads and repair capacities, towards developing the next generation of pressure ulcer prevention (PUP) technologies. Mechanobiology, the study of interactions between mechanical stimuli and biological responses of cells, including remodeling of the dynamic cell cytoskeleton (CSK), cell proliferation, en-mass migration, differentiation, synthesis of collagen and other proteins by cells is poorly addressed in the context of PUP. Cell damage initiates with loss of plasma membrane (PM) integrity, leading to loss of cell homeostasis; the PM is supported by the CSK which may adapt to external loading conditions (remodel) by polymerization of actin filaments. Cell culture models indicate that manipulation of cell mechanostructures and dynamics, particularly the process of CSK remodeling, combined with optimal extracellular deformation levels, can be used for next-level evolution of PUP technologies. In particular, medical devices or consumables that passively or actively deform cells and tissues, respectively, e.g. prophylactic dressings or negative pressure wound therapy systems, can be redesigned based on mechanobiological knowledge and know-how to enhance cell tolerance to loads and optimize reparative mechanotaxis-driven en-mass cell migration. Examples from our recent experimental work in cell culture models as well as from computational simulations of clinically relevant PUP scenarios will be provided.