Table 3.

The biological functions of biometals and their proposed role in bone regeneration [94,95].

Biometal	Body content	Blood content	Biological functions	Signaling molecules and their proposed role in bone regeneration
Ca	1.0–1.5 ​Kg [96]	8.8–10.4 ​mg/dL [96]	Enzyme co-factor, maintaining skeletal framework, signaling molecule [64]	Enhances the effects of BMP-2 on ​Osteocalcin, ​Runx2 ​and ​Osteria ​expression via SMAD signaling (7.5 ​mM Ca2+) [97]
Mg	24–25 ​g [98,99]	1.5–2.5 ​mg/dL [99]	Enzyme co-factor, composition of chlorophylls [94]	Stimulates CGRP-mediated osteogenic differentiation of stem cells (Mg rod) [100]; Promotes angiogenesis and prevents vessel leakage (10 ​mM ​Mg2+) [101]; Inhibits osteoclast differentiation (10 ​mM ​Mg2+) through regulating Ca2+ signal [101];
Zn	2–3 ​g [81]	6.3 ​mg/L [102]	Enzyme co-factor (nucleic-acids polymerases), involved in cell division [94]	Stimulates osteoblast bone formation (15 uM Zn2+) [83]; Inhibits osteoclast differentiation [84]; Increases alkaline phosphatase activity (1.0 ​mg Zn2+/100 ​g body weight) [85];
Cu	80–120 ​mg [81]	0.8–1.6 ​mg/L [102]	Transportation of oxygen, redox reactions [94]	Promotes angiogenesis, osteostimulation and antibacterial activity of bioactive glass (5%) [88];
Mn	12 ​mg [103]	4-15 ug/L [104]	Enzyme co-factor (superoxide dismutase, pyruvate kinase), metabolism of fats [94]	Accelerates fracture healing in a rat model (0.125 ​mg/kg) [90]; Enhances osteogenesis (0.55%) [105];
Co	3 ​mg [103]	0.39 ug/L [102]	Hematopoiesis (vitamin B12) [94]	Upregulates anti-inflammatory, osteogenic, and proangiogenic factors (1 ​ppm) [91]