Multimodal mechanoregulation strategies towards tissue regeneration

Mechanical microenvironment of each tissue plays an important role in regulating its special cellular behaviors, such as morphology, proliferation, differentiation, and migration. Mechanical signals can direct lineage specification or promote cell migration towards injury sites and facilitate tissue repair. During tissue regeneration, mechanoregulation is also important due to the ability of providing an extracellular microenvironment that closely resembles the physiological state for cells. Currently, mechanoregulation strategies have been usually applied to promote tissue regeneration. However, the <i>in vivo</i> mechanical environment is highly complex, these single mechanical conditioning strategies cannot comprehensively replicate the mechanical microenvironment experienced by cells or tissues in the body, thereby hindering the achievement of efficient tissue regeneration. The proposal of multimodal mechanoregulation strategies offers promising avenues to address this limitation. Herein, we summarize the critical role of mechanical factors in promoting tissue regeneration and the current development of different multimodal mechanoregulation approaches. Furthermore, the complex mechanical microenvironment of various tissues such as bone, intervertebral disc and cardiac. Afterwards, the recent successful applications of multimodal mechanical strategies in regenerative therapies were reviewed. And we delineate the persisting challenges, potential resolutions, and emerging translational prospects for multimodal mechanoregulation strategies in regenerative medicine, providing a reference for further development of multimodal mechanoregulation approaches.