Biologic-free mechanically induced muscle regeneration

Significance Much progress has been made toward the development of drug and cell therapies for the treatment of severely injured skeletal muscle, although reliable clinical therapies still do not exist. In contrast, this work demonstrates that biphasic ferrogels with a capacity for large, fatigue-resistant deformations can be used to mechanically stimulate and regenerate injured muscle tissue without the use of growth factors or cells. These biologic-free scaffolds exhibit a potential immunomodulatory role when stimulated and could potentially translate rapidly to the clinic. The therapeutic use of direct mechanical stimulation of injured tissues via externally actuated biomaterials could establish a new paradigm for regenerative medicine broadly. Severe skeletal muscle injuries are common and can lead to extensive fibrosis, scarring, and loss of function. Clinically, no therapeutic intervention exists that allows for a full functional restoration. As a result, both drug and cellular therapies are being widely investigated for treatment of muscle injury. Because muscle is known to respond to mechanical loading, we investigated instead whether a material system capable of massage-like compressions could promote regeneration. Magnetic actuation of biphasic ferrogel scaffolds implanted at the site of muscle injury resulted in uniform cyclic compressions that led to reduced fibrous capsule formation around the implant, as well as reduced fibrosis and inflammation in the injured muscle. In contrast, no significant effect of ferrogel actuation on muscle vascularization or perfusion was found. Strikingly, ferrogel-driven mechanical compressions led to enhanced muscle regeneration and a ∼threefold increase in maximum contractile force of the treated muscle at 2 wk compared with no-treatment controls. Although this study focuses on the repair of severely injured skeletal muscle, magnetically stimulated bioagent-free ferrogels may find broad utility in the field of regenerative medicine.

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