Biologic-free mechanically induced muscle regeneration successful in animal studies.


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.  Clinically, no therapeutic intervention exists that allows for a full functional restoration.  Now, a study from researchers at the Wyss Institute and the Harvard School shows 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 team state that their findings demonstrate how direct physical and mechanical intervention can impact biological processes and can potentially be exploited to improve clinical outcomes.  The findings are published in the journal Proceedings of the National Academy of Sciences.

Previous studies show that muscle injury induces strong changes in muscle cells and extracellular matrix. Muscle regeneration after injury has similarities to muscle development during embryogenesis and seems to follow the same procedure.  Skeletal muscles have a robust capacity to regenerate, but under compromised conditions, such as severe trauma, the loss of muscle functionality is inevitable.  However, clinical devices are often plagued by the formation of thickened tissue capsules that form at the device/human intersection, and 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.  The current study shows that mechanical stimulation alone is enough to enhance muscle repair and 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 current study utilised murine models of muscle injury and hind limb ischemia to investigate two potential mechanotherapies, namely, an implanted magnetic biocompatible gel and an external, soft robotic pressurized cuff.  To alleviate severe muscle injuries, the group 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 and instead were fitted with a soft robotic, non-invasive pressurized cuff over the injured leg. 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.

Results show that cyclic mechanical stimulation provided by either magnetized gel or robotic cuff both 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 an improvement in regained muscle function and an exciting new finding that mechanical stimulation of muscle alone can foster regeneration. Data findings show that the ferrogel implant and pressurized cuff also resulted in high-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.

The lab explain that the direct stimulation of muscle tissue increases the transport of oxygen, nutrients, fluids and waste removal from the site of the injury, which are all vital components of muscle health and repair. They go on to note that one of the most exciting aspects of their research is that its translation to the clinic in the form of a stimulatory device could be relatively rapid as compared to drug or cell therapies.

The team surmise that their work clearly demonstrates that mechanical forces are as important biological regulators as chemicals and genes, and shows the immense potential of developing mechanotherapies to treat injury and disease.  For the future, the researchers state that 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.

Source: The Wyss Institute for Biologically Inspired Engineering at Harvard University

 

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.

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.

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