These side by side microscopic images reveal the dramatic effect that a novel mechanotherapy has on muscle regeneration over a period of two weeks: no treatment is pictured (left) in contrast to direct mechanical stimulation of the muscle (right). Developed by a multi-disciplinary team of Wyss Institute and Harvard SEAS faculty and researchers, the application of cylic mechanical stimulation of the injured tissue resulted in two-and-a-half-fold improvement in muscle regeneration, reduced tissue scarring and fibrosis, and a visible increase in the density of muscle cells. Credit: Wyss Institute at Harvard University

(CAMBRIDGE, Mass.) – Researchers in the field of mechanobiology are revealing new insights into how the body’s physical forces and mechanics impact development, physiological health, and the prevention and treatment of disease. A new study from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and the Wyss Institute for Biologically Inspired Engineering at Harvard University suggests that mechanically-driven therapies that promote skeletal muscle regeneration through direct physical stimulation could one day replace or enhance drug and cell-based regenerative treatments. The finding was published today in the journal Proceedings of the National Academy of Sciences.

“Chemistry tends to dominate the way we think about medicine, but it has become clear that physical and mechanical factors play very critical roles in regulating biology,” said David Mooney, the Robert P. Pinkas Family Professor of Bioengineering at SEAS and Wyss Institute Core Faculty member, senior author on the new study. “The results of our new study demonstrate how direct physical and mechanical intervention can impact biological processes and can potentially be exploited to improve clinical outcomes. ”

The multi-disciplinary team was led by Mooney and also included soft roboticist Conor Walsh, who is a Associate Professor of Mechanical and Biomedical Engineering at SEAS, founder of the Harvard Biodesign Lab, and Wyss Core Faculty member; and biomechanical engineer Georg Duda, who is a Wyss Associate Core Faculty member, vice-director of the Berlin-Brandenburg Center for Regenerative Therapies, and director of the Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration at Charité-Universitätsmedizin Berlin.

In humans, up to half of body mass is made up of skeletal muscle, which plays a key role in locomotion, posture, and breathing. Although skeletal muscles can overcome minor tears and bruising without intervention, major injuries commonly caused by motor vehicle accidents, other traumas, or nerve damage can lead to extensive scarring, fibrous tissue, and loss of muscle function.

The team applied combined murine models of muscle injury and hind limb ischemia to investigate two potential mechanotherapies: an implanted magnetic biocompatible gel and an external, soft robotic pressurized cuff.  To alleviate severe muscle injuries, the team implanted a magnetized gel called a “biphasic ferrogel” so that it would be in direct contact with the damaged tissue. Another experimental group of mice did not receive the ferrogel implant, but instead were fitted with a soft robotic, non-invasive pressurized cuff over the injured leg. Then, the ferrogel was subjected to magnetic pulses to apply cyclic stimulation to the muscle, while pulses of air allowed the cuff to cyclically massage the hind leg. Both groups received two weeks of localized mechanical perturbation using the two distinct methods.

The researchers discovered that cyclic mechanical stimulation provided by both magnetized gel and robotic cuff resulted in a two-and-a-half-fold improvement in muscle regeneration and reduced tissue scarring over the course of two weeks, ultimately leading to regained muscle function, demonstrating that mechanical stimulation of muscle alone can foster regeneration. To their surprise, the ferrogel implant and pressurized cuff also resulted in very similar levels of regeneration, suggesting that the use of non-invasive pressurized cuffs or devices could one day help heal patients suffering from severe muscle injuries.

“Until now most approaches to muscle regeneration have been biologic, relying on the use of drugs or cells,” said Christine Cezar, lead author on the study. “Our finding that mechanical stimulation alone is enough to enhance muscle repair could open the door to new non-biologic therapies, or even combinatorial therapies that employ both mechanical and biological interventions to treat severely damaged skeletal muscles.”

The direct stimulation of muscle tissue increases the transport of oxygen, nutrients, fluids, and waste removal from the site of the injury, all vital components of muscle health and repair. And according to Mooney, translation of this research to the clinic in the form of a stimulatory device could be relatively rapid compared to drug or cell therapies.

The principle of using mechanical stimulation to enhance regeneration or reduce formation of scarring or fibrosis could also be applied to a wide range of medical devices that interface mechanical components with body tissues. Currently, clinical devices are often plagued by the formation of thickened tissue capsules that form at the intersection of machine and man.

In addition to Mooney, Walsh, Duda, and Cezar, the authors of the study included Ellen Roche, a former SEAS doctoral student who is now a Postdoctoral Research Fellow at the National University of Ireland, Galway; and Herman Vandenburgh, Associate Professor in the Department of Pathology and Lab Medicine at Brown University.

The work was supported by funding from the National Institutes of Health, the National Science Foundation’s Materials Research Science and Engineering Center at Harvard University, a Fulbright International Science and Technology Award and the Wyss Institute Director’s Cross-Platform Challenge Award.