Table 1.

Microenvironment-targeted strategy.

Types	Pathway	Materials	Function	Ref.
Physiological Microenvironment	Immunomodulation	Titanium implant	Micro-rough and hydrophilic surfaces promote the release of anti-inflammatory factors from macrophages	[81]
		Polyethylene terephthalate	Macrophages adhering to hydrophilic and anionic surfaces selectively produce anti-inflammatory cytokines	[82]
		Magnesium containing microspheres	Mg2+ release upregulates anti-inflammatory genes and triggers immune regulation	[83]
		miR-181b exosomes	Exo-181b activates the PRKCD/AKT signaling pathway to promote M2 polarization	[84]
	Angiogenesis	Sulfated chitosan scaffold	Dual-module scaffold continuously releases rhBMP-2 and VEGF, synergistically promoting osteogenesis and angiogenesis	[85]
		Nanofibrous gelatin-silica hybrid scaffold	Vascular-mimicking microchannel scaffold promotes rapid vascularization and bone regeneration	[86]
	Energy metabolism	Bioenergetic-active material scaffold	Scaffold degradation fragments can increase mitochondrial membrane potential to accelerate bone regeneration	[87]
		GelMA hydrogel	Mg2+ increases cellular bioenergy levels to promote osteogenesis induction	[88]
		Citrate composite support	Citrate-mediated elevation of cellular energy levels supports metabolic osteogenesis	[89]
Chemical Microenvironment	Oxygen	Liposomal/hydrogel complexes	ROS-responsive hydrogel releases oxygen to promote bone regeneration	[90]
		PCL/nHA/CaO2 scaffold	The bionic scaffold releases oxygen continuously to promote bone defect repair	[91]
		Bioactive glass/collagen–glycosaminoglycan scaffold	Co2+ mimics hypoxic signaling to activate the HIF pathway to support osteogenesis	[92]
	pH	MOF@CaP nanoplatform	Nanoplatform mimics low pH environment to enhance bone regeneration and capacity	[93]
		Custom Titanium implant	The alkaline microenvironment mediates the osteogenic differentiation of stem cells and promotes new bone formation	[94]
	Enzymes and Cytokines	Chondroitin Sulfate/Polyethylene Glycol hydrogel	Matrix metalloproteinase-mediated degradation of hydrogels regulates stem cell differentiation	[95]
		GelMA hydrogel	Mineralized alkaline phosphatase enhances the osteogenic differentiation potential of BMSCs	[96]
		Hyaluronic acid hydrogel	Nanozymes mediate O2 production from endogenous H2O2 and provide a microenvironment for osteogenesis	[97]
Physical Microenvironment	Mechanical forces	Polydimethylsiloxane substrates	Stiff materials have a higher osteogenic potential than soft materials	[98]
		The flow loop apparatus	Sustained low-velocity shear stress stimulates the expression of osteogenic markers in stem cells	[99]
		Gelatin hydrogel	Reversibly connected, highly elastic hydrogel adapts to dynamic stresses and supports bone regeneration processes	[100]
	Temperature	light-responsive poly (N-isopropylacrylamide- co -nitrobenzyl methacrylate)	Ultraviolet light stimulates the release of dexamethasone from photosensitive materials to promote bone regeneration	[101]
		Poly (vinyl alcohol) fibers	Thermoresponsive fibers improve the toughness of calcium phosphate cement and enhance bone repair	[102]
		Biphasic calcium phosphate scaffold	Regulates drug release by changing the light source wavelength to promote bone repair	[103]
	Electric field	Whitlockite scaffold	Scaffolds provide an endogenous electric field to the defect site and inhibit the activity of osteoclasts.	[104]
		Triboelectric nanogenerator	Mediated proliferation and differentiation of osteoblasts by electrical stimulation	[105]
	Magnetic field	Poly(lactide-co-glycolide) scaffold	Magneto-thermal accelerated degradation behavior of magnetic scaffolds under alternating magnetic fields	[106]
		Static magnetic field	Magnetic fields can regulate the direction of osteoblast growth	[107]
	Acoustic	Collagen sponge	In situ recruitment of osteogenic factors by ultrasonically shocked microbubbles	[108]
		Acoustically responsive scaffold/hydrogel	Pulsed ultrasound recruits BMSCs for bone repair	[109]
	Programming design	Poly(aryl-ether-ether-ketone) (PEEK) implant	Programmed surface coating to release osteogenic drugs over time	[110]
		GelMA hydrogel	Programming a two-factor delivery system to match the bone repair healing process	[111]