Regulation of extracellular bioactive cations in bone tissue microenvironment induces favorable osteoimmune conditions to accelerate in situ bone regeneration

Abstract

The design of orthopedic biomaterials has gradually shifted from “immune-friendly” to “immunomodulatory,” in which the biomaterials are able to modulate the inflammatory response via macrophage polarization in a local immune microenvironment that favors osteogenesis and implant-to-bone osseointegration. Despite the well-known effects of bioactive metallic ions on osteogenesis, how extracellular metallic ions manipulate immune cells in bone tissue microenvironments toward osteogenesis and subsequent bone formation has rarely been studied. Herein, we investigate the osteoimmunomodulatory effect of an extracellular bioactive cation (Mg 2+ ) in the bone tissue microenvironment using custom-made poly lactic-co-glycolic acid (PLGA)/MgO-alendronate microspheres that endow controllable release of magnesium ions. The results suggest that the Mg 2+ -controlled tissue microenvironment can effectively induce macrophage polarization from the M0 to M2 phenotype via the enhancement of anti-inflammatory (IL-10) and pro-osteogenic (BMP-2 and TGF-β1) cytokines production. It also generates a favorable osteoimmune microenvironment that facilitates the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells. The in vivo results further verify that a large amount of bony tissue, with comparable bone mineral density and mechanical properties, has been generated at an early post-surgical stage in rat intramedullary bone defect models. This study demonstrates that the concept of in situ immunomodulated osteogenesis can be realized in a controlled magnesium tissue microenvironment.

The spatial form periosteal-bone complex promotes bone regeneration by coordinating macrophage polarization and osteogenic-angiogenic events

“…Vascular infiltration might also be related to proteins that promote angiogenesis and regulate blood vessel diameter or structure. Finally, transplantation of the periosteal bone scaffold showed newly formed bone in vivo, and the underlying mechanism might be attributed to the bioactive components, complete structure, related functional proteins, and macrophage regulation of the periosteal bone scaffold [ [62] , [63] , [64] ].…”

New insights into the biomimetic design and biomedical applications of bioengineered bone microenvironments

“…Briefly, the secretion of cytokines by macrophages recruits other immune cells that initiate a foreign body reaction, inflammatory modulation, and subsequent bone regeneration and healing. 68 …”

Cross-Talks between the Cardiovascular Disease-Sarcopenia-Osteoporosis Triad and Magnesium in Humans

“…It is a physiological blocker of the NMDA receptor. At the bone level, regeneration and osteogenic differentiation are facilitated by the activation of Wnt-βcatenin [50], Integrins [51], Notch-1 [52], and the inhibition of TGF-β [53]. At the cardiovascular level, diminution of calcification, improved endothelial function, and fibrosis are facilitated by the activation of angiotensin II receptor [54], Wnt β catenin [55], and the inhibition of TGF-β [56].…”

“…Low serum Mg levels have been shown to be associated with increased cardiovascular disease (CVD) and all-cause mortality in the general population [64]. A recent meta-analysis of [50], Integrins [51], Notch-1 [52], and the inhibition of TGF-β [53]. At the cardiovascular level, diminution of calcification, improved endothelial function, and fibrosis are facilitated by the activation of angiotensin II receptor [54], Wnt/β-catenin [55], and the inhibition of TGF-β [56].…”

“…Mg ions promote osteogenic differentiation of mesenchymal stem cells [128], but high concentrations of extracellular Mg ions may inhibit mineralization [129]. Solute carriers across the membrane [129], parathyroid hormone, cytokines, TGFβ [53,56], Wnt/β-catenin [50], integrins, MAP kinases [51], and Akt-mTor [130] signalling pathways are all known to play a role in osteogenic differentiation. Mg probably uses these pathways to modulate bone ossification, but the fine tuning of this modulation with physiological Mg levels or supplemented Mg may suggest different mechanisms.…”