Ionic medicine: exploiting metallic ions to stimulate skeletal muscle tissue regeneration

The regeneration of healthy and functional skeletal muscle at sites of injuries and defects remains a challenge. Mimicking the natural environment surrounding skeletal muscle cells and the application of electrical and mechanical stimuli are approaches being investigated to promote muscle tissue regeneration. Likewise, chemical stimulation with therapeutic (biologically active) ions is an emerging attractive alternative in the tissue engineering and regenerative medicine fields, specifically to trigger myoblast proliferation, myogenic differentiation, myofiber formation, and ultimately to promote new muscle tissue growth. The present review covers the specialized literature focusing on the biochemical stimulation of muscle tissue repair by applying inorganic ions (bioinorganics). Extracting information from the literature, different ions and their potential influence as chemical cues on skeletal muscle regeneration are discussed. It is revealed that different ions and their varied doses have an individual effect at different stages of muscle cellular development. The dose-dependent effects of ions, as well as applications of ions alone and in combination with biomaterials, are also summarized. Some ions, such as boron, silicon, magnesium, and zinc, are reported to exhibit a beneficial effect on skeletal muscle cells in carefully controlled doses, while the effects of other ions such as iron and copper appear to be contradictory. In addition, calcium is an essential regulatory ion for the differentiation of myoblasts. On the other hand, some ions such as phosphate have been shown to inhibit muscle cell behaviour. It is expected that this review will provide a complete overview of the application of ionic stimulation for skeletal muscle tissue engineering applications, and will highlight the importance of inorganic ions as an attractive alternative to the application of small molecules and growth factors to stimulate muscle tissue repair. STATEMENT OF SIGNIFICANCE: Ionic medicine (IM) is emerging as a promising and attractive approach in the field of tissue engineering, including muscle tissue regeneration. IM is based on the delivery of biologically active ions to injury sites, acting as stimulants for the repair process. This method offers a potentially simpler and more affordable alternative to conventional biomolecule-based regulators such as growth factors. Different biologically active ions, depending on their specific doping concentrations, can have varying effects on cellular development, which could be either beneficial or inhibitory. This literature review covers the field of IM in muscle regeneration with focus on the impact of various ions on skeletal muscle regeneration. The paper is thus a critical summary for guiding future research in ionic-related regenerative medicine, highlighting the potential and challenges of this approach for muscle regeneration.