Mechanotherapy: Modulating immune cell function in tissue regeneration and fibrosis.

Mechanotherapy - therapy which uses mechanical forces to produce a remedial or prophylactic effect - has great potential to improve therapeutic outcomes in the fields of regenerative medicine and drug delivery due to its adaptable and tunable nature. In particular, numerous in vivo studies have demonstrated the ability of mechanotherapies to improve functional muscle regeneration and modulate fibrosis. However, the cellular interactions that underlie these tissue level responses are poorly understood. To further harness the potential of mechanotherapies and inform their design and development, a more comprehensive understanding of immune cell responses to mechanical loading is required. Here, we review findings from preclinical investigations of mechanotherapies as both a treatment for muscular injury and as an immunomodulating component of medical implants. We then discuss the mechanosensitive nature of immune cells, emphasizing how mechanical loading and microenvironmental stresses can influence immune signalling pathways in the context of tissue regeneration and fibrosis. Finally, we offer our perspective on the future of the field, including the challenges facing mechanotherapeutic device development and the potential to further broaden the therapeutic targets of mechanotherapies. STATEMENT OF SIGNIFICANCE: Tissue regeneration following injury requires precise regulation of the innate and adaptive immune responses to restore tissue function and prevent fibrosis. Fibrotic tissue alters mechanical properties and impairs physiological function, making fibrosis a critical barrier to effective healing. Mechanotherapy, which uses mechanical forces for therapeutic effect, offers a promising approach to modulate immune responses and improve regenerative outcomes. Emerging evidence suggests that mechanical stimulation can attenuate fibrosis, yet the immune response to mechanical loading is highly dependent on loading parameters such as magnitude, frequency, and duration. Understanding how these parameters influence healing remains a key challenge. This review explores the relationship between mechanotherapy, immune modulation, and fibrosis, highlighting the potential for mechanotherapy to guide wound healing and improve clinical outcomes.