Metal ions are essential for human health. The applications of ions cover a range of disciplines in basic science research, industrial applications, and clinical applications. Several ions have been shown to be capable of inducing osteoblast precursor differentiation through growth factor signaling pathways or to stimulate other processes in support of bone tissue growth. These ions include boron (B3+), calcium (Ca2+), cobalt (Co2+), copper (II) (Cu2+), fluoride (F–), lithium (Li+), magnesium (Mg2+), niobium (Nb5+), phosphate (PO4 3–), silicate (Si4––), silver (Ag+), strontium (Sr2+), vanadium (V5+), and zinc (Zn2+). Compared with protein growth factors, the advantages of using such ions to induce bone tissue repair are manifold, including lower cost, greater simplicity, higher stability, and more efficacy at low concentrations

Phosphorus

Phosphorus is the second most abundant mineral in the human body and is found in various organic materials like proteins, nucleic acids, ATP, and phospholipids. It plays a key role in energy metabolism, cellular signalling, maintaining cell membrane integrity, and regulating acid-base balance. About 85% of phosphorus is stored in bones as part of hydroxyapatite with calcium, while the rest is found in extracellular fluids and soft tissues. Inorganic phosphate (Pi) is the primary form of phosphorus in the body and is crucial for processes like skeletal growth and remodelling. Pi is produced by the enzyme alkaline phosphatase (ALP) and is also an important signalling molecule that can influence gene expression and cell function.

Silicon

Silicon, a common in vivo form, is essential for bone formation and metabolism. It increases bone density and reduces bone resorption due to calcium deficiency. Silicon promotes osteoblast differentiation, collagen I synthesis, and homeostasis in bone matrix. It also aids in vascularization and angiogenesis. Silicon-based biomaterials for bone tissue scaffolds can trigger pathways involved in angiogenesis and osteogenesis, potentially aiding in the replication of native tissue.

Strontium

Strontium, similar to calcium, is a strong bone-seeking trace element found in human bone tissue. It has been studied extensively for bone regeneration and is now recognized as a treatment for osteoporosis in the form of strontium ranelate. This drug decreases bone resorption and increases bone formation, leading to increased osteoblast surfaces, mineral apposition rate, and bone mineral density, reducing fracture risk.

Zinc

Zinc is a crucial trace element for cellular processes, growth, immunology, and neurological health. It’s also an antioxidant and anti-inflammatory agent with potential therapeutic benefits against chronic diseases like cancer, neurodegeneration, atherosclerosis, and immunological disorders. Zinc is essential for bone growth and development, and deficiency can lead to skeletal abnormalities.

Fluoride

Fluoride helps to prevent dental caries by substituting hydroxyl (OH) ions in dental apatite, making teeth more resistant to decay. This is the primary reason for its use in toothpaste and drinking water. Fluoride plays a role in bone mineralization and formation. Moderate doses of fluoride (25–500 ng/ml) can stimulate osteoblast activity, promoting bone formation, while higher doses may be toxic to these cells, potentially disrupting bone health. Fluoride ions, particularly when combined with cobalt ions, may enhance osteoblast proliferation, mineralization and further supporting its role in bone healing.

Copper

Copper have a unique and important role in vascular biology. Endothelial cells, which line the blood vessels, play a key role in angiogenesis. Studies suggest that copper ions can stimulate the proliferation, migration, and tube formation of endothelial cells, which are important steps in the development of new blood vessels. This can be particularly beneficial in situations where blood supply needs to be restored or enhanced, such as in wound healing, tissue regeneration, or ischemic conditions (where blood supply is compromised).

Titanium

As a transition metal, titanium is naturally reactive and forms a stable oxide layer (titanium oxide, TiO₂) when exposed to air. This oxide layer is crucial for titanium’s performance as a biomaterial because it offers Corrosion resistance, Ion-leaching resistance, Biological inertness,Bone healing. Titanium and its alloys are known to be supportive of osseointegration; thus, they can form direct chemical and physical bonds with bone cells without stimulating the undesirable formation of fibrous tissue.

Calcium

Calcium has a variety of roles in cells and living systems, from intracellular molecular signalling to macroscale structural properties. This ion is especially important in bone tissue, because it is one of the two most essential components of mineralized bone matrix, along with phosphate. The hydroxyapatite that forms the inorganic phase of bone tissue contains approximately 99% of the calcium in the body, acting as a storage reservoir for the mineral. Calcium can be leached from, or deposited into, existing bone matrix to maintain calcium homeostasis in the body.

Magnesium

Magnesium is the tenth most abundant element in the body and the second most abundant intracellular cation after potassium. It is crucial for hundreds of enzymatic reactions, including energy metabolism and protein and nucleic acid synthesis. Magnesium is essential for maintaining proper tissue and organ function. About half of the body’s magnesium is found in bones, with two main locations: one as part of the hydroxyapatite lattice in the bone matrix and the other as an exchangeable cell surface-bound form, possibly linked to homeostasis. The process of bone mineralization, including ECM formation and crystal growth, is complex and tightly regulated.

Boron

Boron is a non-metallic element that forms compounds with other elements like vitamin D, calcium, and magnesium, which are important for bone health. It is considered an essential trace dietary element and is found in higher concentrations in bone and keratinous tissues. In vitro studies suggest that boron may stimulate bone formation by upregulating bone formation markers and producing BMPs, especially at concentrations between 1 and 100 ng/ml.

However, there is no clear link between dietary boron intake and bone mineral density in humans. Additionally, high concentrations of boron can be toxic to osteoblastic cells. While boron shows potential as a therapeutic agent for bone growth in vitro, more in vivo studies are needed to fully understand its effects, particularly regarding its use in bone-grafting materials.

Delivery strategies of ions in bone regeneration:

Different encapsulation techniques can control the release of therapeutic ions to damaged bone tissue based on the properties of the ions. Two main approaches are chemical immobilization, where ions are adsorbed or bonded to the surface, and physical encapsulation, where ions are embedded within the biomaterial matrix. These ions are stable and robust, allowing them to be used in various fabrication processes like self-assembly, freeze-drying, and phase separation without decomposing, unlike growth factor treatments. Common biomaterials for delivering ions in bone regeneration include bioactive glass, bio-ceramics, and biodegradable polymers.

Multipurpose, amorphous scaffolding materials known as “bioactive glasses” have been demonstrated to promote bone regeneration by effectively bonding to surrounding bone tissue in vivo and being able to be transformed into HA. During the manufacturing process, inorganic ions embedded in bioactive glasses can dissolve and release them at pharmacologically relevant doses to promote the angiogenic and osteogenic activity of nearby cell types. Many investigations have been carried out to demonstrate the in vitro and in vivo therapeutic potential of ionic dissolution products released from bio glass-based materials. Bio-ceramics, including calcium silicate, HA, and tricalcium phosphate, have also been employed as ion delivery systems in bone regeneration.

In the domains of tissue engineering and regenerative medicine, biodegradable polymers have been extensively employed as scaffold materials to customize the delivery of osteoinductive and angioinductive bio factors. The FDA-approved synthetic biomaterial poly(lactic-coglycolicacid) (PLGA) has been widely used in bone tissue engineering due to its mechanical qualities, biocompatibility, and adjustable rate of degradation, which can be adjusted to deliver ions within a specific pharmacological window.

Conclusion

The health of humans depends on metal ions. There are many different fields in which ions are used in basic science research, industry, and medicine. Because of their extraordinary qualities and highly adjustable nature, metal ions are now crucial components in the domains of biotechnology, medicine, and electrochemistry. Ions’ potential for bone-regenerative medications has received little attention. The development of ion-based bone regenerative therapies is, nevertheless, limited by a few factors. This occurs as a result of ions’ easy diffusion to nontarget cells or tissues, which can trigger undesirable reactions. An effective method for the local delivery of therapeutic ions to diseased bone tissue is a biomaterial-based approach, which reduces the nonspecific target effects of ions. Given their possible uses, there is a compelling case for more use in dentistry, and more investigation is required to look into potential uses. Applications for soft tissue and organ regeneration are also showing promise as a treatment paradigm, in addition to their use in bone.