Sustained zinc release in cooperation with CaP scaffold promoted bone regeneration via directing stem cell fate and triggering a pro-healing immune stimuli

Abstract

Metal ions have been identified as important bone metabolism regulators and widely used in the field of bone tissue engineering, however their exact role during bone regeneration remains unclear. Herein, the aim of study was to comprehensively explore the interactions between osteoinductive and osteo-immunomodulatory properties of these metal ions. In particular, the osteoinductive role of zinc ions (Zn2+), as well as its interactions with local immune microenvironment during bone healing process, was investigated in this study using a sustained Zn2+ delivery system incorporating Zn2+ into β-tricalcium phosphate/poly(L-lactic acid) (TCP/PLLA) scaffolds. The presence of Zn2+ largely enhanced osteogenic differentiation of periosteum-derived progenitor cells (PDPCs), which was coincident with increased transition from M1 to M2 macrophages (M$$\varphi $$ φ s). We further confirmed that induction of M2 polarization by Zn2+ was realized via PI3K/Akt/mTOR pathway, whereas marker molecules on this pathway were strictly regulated by the addition of Zn2+. Synergically, this favorable immunomodulatory effect of Zn2+ further improved the osteogenic differentiation of PDPCs induced by Zn2+ in vitro. Consistently, the spontaneous osteogenesis and pro-healing osteoimmunomodulation of the scaffolds were thoroughly identified in vivo using a rat air pouch model and a calvarial critical-size defect model. Taken together, Zn2+-releasing bioactive ceramics could be ideal scaffolds in bone tissue engineering due to their reciprocal interactions between osteoinductive and immunomodulatory characteristics. Clarification of this synergic role of Zn2+ during osteogenesis could pave the way to develop more sophisticated metal-ion based orthopedic therapeutic strategies.

Zinc Coordination Compounds with Benzimidazole Derivatives: Synthesis, Structure, Antimicrobial Activity and Potential Anticancer Application

“…Low and high concentrations can cause many diseases. Zinc deficiency can inhibit the growth of children as it is involved in bone metabolism [ 7 , 9 ]. It has an effect on the immune system and inhibits inflammation, and its deficiency has been found in children with pneumonia and bronchitis [ 10 , 11 ].…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles for Bone Defect Repair

“…The PI3K/AKT signaling pathway plays a key role during the process of osteogenic and adipogenic differentiation of BMSCs [ 163 ]. As a lipid kinase located in the cytoplasm, PI3K is activated through the stimulation of upstream growth factors, and then PI3K transduces upstream signals from receptors to generate PIP3 [ 164 ].…”

Mg-, Zn-, and Fe-Based Alloys With Antibacterial Properties as Orthopedic Implant Materials

“…Huang et al demonstrated that Zn 2+ could promote the polarization of macrophages from M1 to M2 through PI3K/Akt/mTOR pathway. The M2 phenotype polarization of macrophages and the subsequent biological events will create a favorable osteogenic microenvironment ( Huang et al, 2021 ). The immunomodulatory action of Mg 2+ is related to its concentration.…”