Table 5.

Microenvironment modulation mechanisms by different biomaterials to enhance bone regeneration in different phases

Strategy	Cement	Modification method	Model	Simulated diseases	Mechanism	Refs.
Reduction of inflammation	CPC	Magnesium	In vitro	Bone substitute implantation	MCPC reduces macrophage M1 polarization to attenuate inflammation	[93]
	MPC	rhBMP2 + cement scaffold	SD rats	Bone substitute implantation	Mg ions reduce inflammation through macrophage regulation to enhance osteogenesis	[182]
	CS/CC/DCPA	Mg-MOF	In vitro	Non-load-bearing bone defects	Mg-MOF modulates macrophage M1/M2 polarization	[183]
	CPC	Zinc-doped calcium silicate	New Zealand white rabbits	Distal femoral bone defect	Zn-CS/CPC promoted the recruitment of macrophages and enhanced M2 polarization while inhibiting M1 polarization	[184]
	CaSO4 bone cement	Sr/Cu-BSG	SD rats/New Zealand white rabbits	Femoral condylar defects	BSG cement reduces M1 macrophage polarization and inflammatory cytokines while promoting M2 phenotype	[188]
Promotion of anti-oxidation	CPC	Se	SD rats	Osteoporotic bone defects	Se-CPC upregulates SOD2/GPX1 antioxidant enzymes	[194]
	CPC	Se	SD rats	Osteoporotic bone defects	Se-CPC rescued mitochondrial functions through activation of the GPx1-mediated antioxidant pathway	[195]
	PMMA	Amino graphene	Rabbits	Failure of the prosthesis	AG exerts antioxidant effects through free radical scavenging	[163]
	CPC	Fullerenol	In vitro	Bone reconstruction	The antioxidant activity of Ful not only protected cellular viability but also promoted osteogenic differentiation	[197]
Bone homeostasis maintenance	PMMA	TBB initiator	In vitro	Local osteolysis at the cement–bone interface	PMMA-TBB enhances polymerization efficiency and reduces monomer toxicity	[203]
	CPC	Solid lipid microparticles + ALN	In vitro	Severe bone turnover inhibition	Solid lipid microparticles deliver alendronate to promote osteogenesis while inhibiting osteoclastogenesis	[204]
	PMMA	Borosilicate Glass	SD rats/Goats	Tibia defects/Vertebral defect	BSG provides an alkaline microenvironment that spontaneously balanced the activities between osteoclasts and osteoblasts	[206]
	CPC	PEGs + ALN	SD rats	Osteoporotic bone defects	CPC buffers pH while ALN inhibits osteoclasts and Ca2 + promotes osteoblast differentiation	[43]
Prevascularization	CPC	Chitosan + Arg-Gly-Asp (RGD)	In vitro	Large skeletal defects	RGD-modified CPCs promote rapid vascular integration	[212]
	CPC	hPDLSCs + hUVECs	In vitro	Large skeletal defects	hPDLSCs support vessel formation through angiogenic factors while hUVECs enhance osteogenesis via paracrine signaling	[213]
	β-TCP scaffolds	In vivo bioreactors for prevascularization	SD rats	Tibia bone defect	In-vivo prevascularization in muscle pouch promotes vessel network formation within β-TCP scaffolds	[214]
Material-cell interactions	CPC	Calcium silicate + rhBMP-2	New Zealand rabbits	Femoral defects	Synergistic effects between calcium silicate and rhBMP-2 in promoting osteogenesis	[219]
	CPC	rhBMP2 + BMSC	Nude mice	Oral and maxillofacial defects	rhBMP2 enhances BMSCs proliferation and osteogenic differentiation through sustained release from CPC scaffolds	[220]
	CPC	chondroitin sulfate + PDA + rhBMP-2	SD rats	Bone tissue repair	CS enhances rhBMP-2 bioactivity by promoting BMPR expression and binding	[221]