Mechanistic Insights into Bone-Like Apatite-Mediated Biomineralization for Osteoinductive Biomaterials

Jiayi Chen; Haokai Li; Rui Zhao; Yongjia Li; Hui Qian; Xiao Yang

doi:10.7536/PC20250810

Progress in Chemistry ›› 2026, Vol. 38 ›› Issue (4) : 773-788 DOI: 10.7536/PC20250810

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Mechanistic Insights into Bone-Like Apatite-Mediated Biomineralization for Osteoinductive Biomaterials

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Abstract

Bioactive materials， with their superior osteoinductive and tissue-integration capabilities， are progressively overcoming the limitations of traditional bioinert materials in tissue repair， emerging as a key development direction in bone tissue engineering. This article reviews recent progress in the application of metals， bioceramics， polymers， and their composites in inducing bone-like apatite formation and bone regeneration， with a focus on elucidating the mechanisms by which these materials regulate bone regeneration through dynamic interactions with the host microenvironment. Studies demonstrate that the surface chemical composition， micro-nano topological features， and interfacial energy state of materials synergistically induce biomimetic mineralization， oriented deposition， and structural evolution of bone-like apatite， thereby activating osteogenic signaling pathways and enhancing stem cell adhesion， proliferation， differentiation， and angiogenesis. Moreover， the diversity in crystal morphology and biological functionality of bone-like apatite induced by different material systems significantly impacts the efficiency and quality of bone regeneration. However， current research faces several challenges， including insufficient control over the mineralization process， difficulties in optimizing the coupling of bioactivity and mechanical properties， and the impact of individual variability on therapeutic consistency in clinical translation. Future research should focus on the integrated development of multiscale biomimetic bone materials， leveraging in situ dynamic characterization， molecular simulations， and artificial intelligence algorithms to deeply elucidate the temporal regulation mechanisms of material-induced biomineralization， thereby advancing the clinical translation and application of smart responsive scaffolds and persona. Therefore， systematic breakthroughs are urgently needed in material design， manufacturing technologies， and in vivo response mechanisms. By focusing on the development of multiscale biomimetic bone materials， leveraging in situ dynamic characterization， molecular simulation dynamics to deeply elucidate the temporal regulation mechanisms of material-induced biomineralization， thereby advancing the clinical translation of smart responsive scaffolds and personalized bone repair strategies in regenerative medicine.

Contents

1 Introduction

2 Mechanisms of bone-like apatite formation on material surfaces

2.1 Bone-like apatite formation induced by metallic materials

2.2 Bone-like apatite formation induced by polymeric materials

2.3 Bone-like apatite formation induced by bioceramics

3 Bone-like apatite coating characteristics in bone regeneration

3.1 Metallic materials and surface-engineered implants

3.2 Bioactive polymers and polymer-based composite scaffolds

3.3 Bioceramics including calcium phosphates and bioactive glasses

4 Conclusion and outlook

Graphical abstract

Keywords

bone-like apatite / osteoinductivity / bioactivity / biomineralization / biomaterials

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Jiayi Chen, Haokai Li, Rui Zhao, Yongjia Li, Hui Qian, Xiao Yang. Mechanistic Insights into Bone-Like Apatite-Mediated Biomineralization for Osteoinductive Biomaterials. Progress in Chemistry, 2026, 38(4): 773-788 DOI:10.7536/PC20250810

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1 Introduction

The excellent mechanical properties of natural bone tissue are closely related to its highly ordered structure ranging from the nanoscale to the macroscale. At the nanoscale, hydroxyapatite nanocrystals periodically deposit within the gap regions of collagen fibers during bone biomineralization, forming a composite structure with multi-scale ordered assembly, thereby endowing bone tissue with superior mechanical strength and fracture resistance.^[1]Clinically, the repair of critical-sized bone defects remains a major challenge in orthopedics, often caused by congenital malformations, tumor resection, or severe trauma. The repair requirements frequently exceed the self-regenerative capacity of bone tissue, urgently necessitating the implantation of functional biomaterials to achieve efficient bone reconstruction.^[2-3]Traditional bioinert materials (such as polyetheretherketone) possess excellent mechanical load-bearing capabilities; however, their bioinert interfaces tend to induce fibrous capsules, which may ultimately lead to implant loosening or failure.^[4]In recent years, bioactive materials, through precise regulation of surface chemical composition and multi-scale micro-nano structures, have been able to induce the in situ formation of bone-like apatite within the body, mimicking natural bone mineralization characteristics, thereby significantly enhancing the regenerative potential of bone tissue.^[5-6]Bone-like apatite is a low-crystallinity, nanoscale, carbonate-rich hydroxyapatite whose chemical composition and structural features are highly similar to those of natural bone minerals. In physiological environments, bioactive materials influence the local distribution of Ca²⁺ and PO₄^3- concentrations by regulating their surface and interface properties, inducing the generation of biomimetic mineral phases, thereby promoting the osteogenic differentiation of mesenchymal stem cells (MSCs), angiogenesis, and tissue integration, constructing an active interface with bidirectional regulation between the material and the host.^[7]However, existing in vitro evaluation systems (such as static simulated body fluid models) struggle to replicate the complex physiological microenvironment in vivo, including key factors like dynamic blood flow shear stress and immune microenvironment regulation, leading to significant deviations in predicting the osteogenic performance and bioactivity of materials.^[8]Against this backdrop, it is essential to systematically elucidate the differential mechanisms by which different material systems induce bone-like apatite formation through surface and interface engineering, as well as their dynamic coupling relationships with osteogenic cascade reactions, to advance the development of bone repair materials.

Typically, a correlation exists between the physicochemical characteristics of bioactive materials and the morphology of bone-like apatite crystals they induce (Figure 1). Metal-based materials (such as magnesium alloys and surface-modified titanium) primarily rely on the topology of oxide layers and controlled ion release behavior. By establishing a locally supersaturated microenvironment at the interface to guide heterogeneous nucleation, they often form granular, needle-like, or plate-like bone-like apatite^[9-10]. In contrast, bioactive ceramics (such as hydroxyapatite, biphasic calcium phosphate, and calcium silicate), due to their crystallographic homology with natural bone minerals, tend to induce epitaxial growth of bone-like apatite, often presenting various morphologies including plate-like, needle-like, rod-like, and layered structures^[11-12]. Polymer materials offer greater space for interfacial functionalization; through biomimetic modifications such as phosphorylation and carboxylation, or by constructing ordered mineralization templates via composite nanoparticles, they typically induce spherical or granular apatite deposition^[13-15]. Building on this, composite material systems achieve synergistic optimization of mechanical properties and bioactivity by integrating multiphase structures and functional advantages. For instance, inorganic components provide mineralization induction sites, while organic components regulate cell adhesion, osteogenic factor delivery, and degradability, thereby better adapting to the dynamic requirements during tissue repair^[16]. Furthermore, structure also plays a significant role in this process. Carbonated hydroxyapatite with micro/nano composite structures, due to its high consistency in chemical composition and microstructure with natural bone minerals, has been proven to effectively enhance integrin-mediated cell adhesion, activate osteogenesis-related signaling pathways, and promote the osteogenic differentiation of MSCs^[17]. Moreover, material surface parameters (such as hydrophilicity/hydrophobicity, zeta potential, roughness, and nano-morphology) play a key role in regulating cell-matrix interactions. They indirectly regulate cell adhesion, spreading morphology, and fate determination by influencing the conformation and adsorption patterns of fibronectin^[18-20]. Current research still faces two main challenges: First, most in vitro mineralization models are static systems that fail to consider complex in vivo factors such as vascularization and immune regulation, leading to limitations in interpreting material-induced mineralization behavior. Second, there is a lack of systematic studies revealing the explicit correlation between the polymorphism of material-induced bone-like apatite crystals (e.g., spherical clusters, needle-like, plate-like) and their osteogenic efficacy. Therefore, this review will focus on the following three aspects: (1) the physicochemical mechanisms by which different material systems induce bone-like apatite formation; (2) the structure-function regulatory patterns of bone-like apatite morphology on the bone regeneration process; and (3) material optimization strategies based on host microenvironment responses. Through a comprehensive analysis of the mineralization behavior and regenerative effects of multi-material systems, this work aims to provide theoretical support and design insights for constructing a new generation of tissue-inductive bone repair materials.

2 Mechanism of bone-like apatite formation induced on material surfaces

Bone-like apatite, as a key mineralized phase in bone tissue engineering, exhibits characteristics highly similar to natural bone minerals, including low crystallinity, nanoscale dimensions, and carbonate doping.^[21]. Studies indicate that the chemical properties (such as surface charge and functional group distribution) and physical properties (such as roughness and porosity) of material surfaces and interfaces jointly regulate the adsorption-nucleation-growth process of Ca²⁺ and PO₄^3- in simulated body fluid (SBF) environments, thereby influencing the morphological evolution and biological functions of bone-like apatite.^[22]. Different material systems induce diverse bone-like apatite microstructures through unique surface and interface engineering strategies, thereby affecting their osteogenic activity (Table 1)^[23-33]. Metallic materials (such as titanium alloys) construct nanoscale oxide layers through techniques like anodization and alkali heat treatment; their surface hydroxyl density and Zeta potential significantly affect the nucleation kinetics of bone-like apatite.^[34]. Bioceramics (such as hydroxyapatite and bioactive glass), due to their chemical composition similarity to bone minerals, can induce the formation of continuous and dense bone-like apatite layers, the crystallinity of which is regulated by the material's calcium-phosphorus ratio and specific surface area.^[35]. Polymer materials simulate the mineralization microenvironment of the extracellular matrix (ECM) by introducing functional groups such as carboxyl and amino groups, often forming nano-needle-like or cluster-like bone-like apatite aggregates.^[36]. Composite materials leverage synergistic effects, such as the collaboration between the high specific surface area of metal-organic frameworks and bioactive ions, to significantly enhance the deposition rate and uniformity of bone-like apatite.^[37]. Additionally, it is noteworthy that trace element doping (such as Sr²⁺, Zn²⁺) also significantly alters the crystal growth habits of bone-like apatite: strontium-doped hydrogels induce cluster-like bone-like apatite, while zinc-doped surfaces generate needle-like structures; these morphological differences directly affect cellular responses and osseointegration efficiency.^[38]. Although significant progress has been made in material surface and interface engineering, the dynamic mechanisms by which different materials induce bone-like apatite and their coupling relationship with the osteogenic process still require in-depth study. In particular, achieving controllable bone-like apatite morphology and biological functions in complex in vivo environments remains a core challenge in the design of bone regeneration materials.

2.1 Metal material-induced bone-like apatite formation

Titanium (Ti) and its alloys are widely used in orthopedic implants due to their excellent mechanical strength, corrosion resistance, and biocompatibility; however, their inherent biological properties limit the in situ formation of bone-like apatite, reducing osseointegration efficiency.^[39]. Through surface modification technologies, metallic materials can significantly enhance bone-like apatite deposition capacity, promote cell adhesion, osteogenic differentiation, and tissue integration, and exhibit diverse bone-like apatite morphologies in SBF, such as dune-shaped and spherical forms of apatite layers, confirming the biomimetic mineralization capability of metal surfaces.^[40-41]. Metal surface modification technologies mainly include physical methods (such as sandblasting and laser texturing), chemical methods (such as acid-base treatment and sol-gel coating), and electrochemical methods (such as anodizing and micro-arc oxidation).^[42]. These technologies enrich Ca²⁺ and PO₄^3- ions by regulating surface morphology, hydrophilicity, and chemical groups, thereby inducing bone-like apatite deposition. For example, anodizing generates a nano-oxide layer on the titanium alloy surface, significantly improving hydrophilicity and promoting the formation of spherical bone-like apatite particles.^[43]. Ehlert et al.^[23] verified the advantage of accelerating bone-like apatite formation in SBF by modifying titanium alloys (Ti6Al4V) through sodium hydroxide treatment and anodizing. Zhao et al.^[24] utilized Selective Laser Melting (SLM) 3D printing technology to fabricate titanium-tantalum (Ti-Ta Gyroid) scaffolds, achieving 90% porosity and forming a self-passivating Ta₂O₅ layer. This self-passivating layer induced the formation of spherical bone-like apatite, enhancing biomineralization and osseointegration. Furthermore, femtosecond laser micromachining technology achieved precise fabrication of bioactive nanopatterns on titanium surfaces. It was found that after laser etching at 0.3 and 0.5 W, the surface rapidly induced a continuous and dense bone-like apatite layer with a Ca/P ratio of approximately 1.67, exhibiting a typical nanosheet morphology. The layer thickness increased significantly with prolonged immersion time. This method is markedly superior to traditional acid-base treatment and further accelerates bone-like apatite deposition and cell proliferation (Figure 2)^[44]. In addition, Xu et al.^[25] utilized laser texturing technology to create structures mimicking fish scales and shrimp surfaces on Ti-6Al-4V titanium alloys. This textured surface exhibited good frictional stability in SBF and promoted the deposition of spherical particulate apatite during the friction process, which plays a significant role in reducing material wear and corrosion.

Coating-based surface engineering is another key strategy to enhance the bioactivity of metallic materials. By applying functional coatings on substrates such as titanium alloys, nickel-titanium alloys (NiTi), magnesium alloys, and zirconium, the formation of bone-like apatite in SBF can be significantly enhanced, promoting osseointegration and biological performance.^[45-46]. Among these, hydroxyapatite (HA), due to its chemical similarity to natural bone minerals, is often applied to titanium alloy surfaces via chemical or electrodeposition, accelerating the induction of bone-like apatite layers and significantly enhancing osseointegration. For example, Wang et al.^[47]developed HA-coated titanium metals that induce the formation of dense spherical or granular bone-like apatite, significantly improving osteogenesis and angiogenesis efficiency. Similarly, Lin et al.^[48]developed HA-coated titanium metals capable of inducing needle-shaped bone-like apatite formation, significantly enhancing osteogenesis efficiency. Therefore, composite coating and biofunctionalization strategies have been further extended to other metallic substrates (such as NiTi, magnesium alloys, and zirconium). For instance, treating NiTi metal surfaces by adding Nb₂O₅particles in an aqueous electrolyte to form an HAp-Nb₂O₅composite layer; this treatment significantly improved the bioactivity and antibacterial properties of NiTi, while also enhancing its corrosion resistance and bone-like apatite formation ability.^[49]. Meanwhile, Witkowska et al.^[26]successfully formed a continuous nanocrystalline titanium oxide TiO₂(rutile) layer on the surface of NiTi alloys using glow discharge oxidation technology in a low-temperature plasma environment. This oxide layer significantly improved the alloy's bioactivity, promoted apatite deposition in SBF, and enhanced osteoblast proliferation and platelet adhesion activity. Subsequently, Li et al.^[27]prepared a polyethylene oxide-zinc oxide metal-organic framework composite coating (PEO-ZnO@MOF) on magnesium alloy surfaces through a combination of plasma electrolytic oxidation (PEO), hydrothermal methods, and solvothermal methods, which significantly improved the material's corrosion resistance, biocompatibility, and wear resistance. This coating uses a PEO layer as the base, followed by the deposition of a zinc oxide (ZnO) transition layer via the hydrothermal method, and its in-situ conversion into a metal-organic framework (MOF, ZIF-8) outer layer using the solvothermal method. This structured PEO-ZnO@MOF coating not only effectively seals the micropores and microcracks on the PEO coating surface but also significantly improves the coating's comprehensive performance through the self-lubricating effect of ZIF-8 and the flake-like apatite induced in SBF. Furthermore, HA coatings doped with silver nanoparticles were prepared on zirconium surfaces via micro-arc oxidation and electrochemical deposition techniques, significantly enhancing the material's bioactivity and antibacterial properties. The addition of silver nanoparticles not only improved the material's hydrophilicity but also facilitated the formation of spherical bone-like apatite, enhancing its bioactivity and making it a strong candidate for preventing implant infections.^[50]. In addition, biofunctionalized coatings (such as collagen and RGD peptides) bring multifunctionality to metal implants. For example, Yuan et al.^[51]introduced black phosphorus nanosheets via layer-by-layer assembly to form a bisphosphonate-hydroxyapatite-titanium alloy composite coating (BPs@HA@Ti). Utilizing the photothermal effect of black phosphorus to eliminate bacterial biofilms, while driving dynamic phosphorus/calcium mineralization, it induces bone-like apatite deposition in SBF, promotes osteogenic differentiation of stem cells, and achieves synergistic regulation of "anti-infection-mineralization-osteogenesis" in infected bone defect models. Although coating strategies have significantly enhanced bone-like apatite induction capabilities, rapid coating degradation, excessive ion release, and the unpredictability of complex in vivo microenvironments still limit long-term osseointegration efficiency.

2.2 Polymer material-induced bone-like apatite formation

Polymeric materials occupy an important position in the field of bone tissue engineering due to their unique physicochemical properties and biological performance^[52]. Compared with metal and ceramic materials, polymeric materials possess excellent processing flexibility, good biocompatibility, and allow precise regulation of mechanical properties and degradation behavior through molecular design. Some polymeric materials (such as polycaprolactone) are biodegradable, capable of gradually degrading in vivo and being replaced by tissue; non-degradable polymers (such as polyaryletherketone, polymethyl methacrylate, etc.) are suitable for long-term orthopedic implants due to their long-term stability^[53-54]. Furthermore, the chemical modification potential of polymeric materials makes their surfaces easy to functionalize, providing a pathway for regulating biological activity. Polymeric materials are widely used in fields such as bone repair scaffolds, bone cements, and implant coatings. However, their inherent bioinertness limits the in situ formation of bone-like apatite, hindering direct integration with bone tissue. Through surface functionalization techniques and composite additive strategies, polymeric materials can significantly enhance bone-like apatite deposition in SBF, thereby promoting cell adhesion, proliferation, and osteogenic differentiation, offering new solutions for bone regeneration^[55]. For example, Masamoto et al.^[28] treated the PEEK surface using plasma technology, which could induce the formation of uniform fine granular bone-like apatite nanocrystals in SBF, significantly improving osseointegration ability while maintaining the mechanical properties of PEEK. Furthermore, Luo et al.^[29] employed femtosecond laser micromachining technology to treat the PEEK surface, introducing hydroxyl and amorphous carbon groups to increase surface energy and promote cauliflower-like bone-like apatite deposition in SBF, enhancing cell proliferation and osteogenic differentiation (Figure 3). Meanwhile, Cheng et al.^[56] introduced phosphonic acid groups onto the surface of poly(phthalazinone ether ketone) (PPEK) via wet chemical modification, inducing the formation of nanorod-like bone-like apatite, thereby improving in vitro osteogenic capability and cell viability. Yamane et al.^[30] developed a carbon fiber-reinforced PEEK composite and modified its surface using sulfuric acid treatment and oxygen plasma treatment, which rapidly formed calcium phosphate "apatite nucleation sites" within one day in modified SBF, demonstrating extremely high bioactivity.

The composite strategy of polymer materials and inorganic additives further optimizes the formation efficiency and biological performance of bone-like apatite. For example, Khallaf et al.^[31]incorporated 50 nm BG particles into PEEK via vacuum pressing combined with MWCNTs, inducing cauliflower-like bone-like apatite deposition in SBF while simultaneously enhancing flexural strength and elastic modulus. Adding nano-magnesium silicate (n-MS) to the PEEK matrix followed by particle impact and sulfuric acid treatment can form a rough, hydrophilic surface, further inducing spherical bone-like apatite deposition and enhancing antibacterial properties as well as stem cell adhesion and differentiation.^[57]. By compounding BG, HA, or tricalcium phosphate (TCP) with poly(methyl methacrylate) (PMMA), the prepared composite scaffolds form a spherical bone-like apatite layer in SBF, where their porous structure promotes cell ingrowth and osseointegration.^[58]. Furthermore, biodegradable polymers such as chitosan (CS), polycaprolactone (PCL), and polylactic acid (PLA), when compounded with inorganic minerals via electrospinning or 3D printing, can significantly promote bone-like apatite formation. For instance, Yahia et al.^[59]constructed PCL/CS/PEO electrospun nanofiber scaffolds that formed dense bone-like apatite crystals after 8 weeks of immersion in SBF. Guo et al.^[60]utilized 3D printing technology to fabricate PLA/pearl powder composite scaffolds, leveraging Ca²⁺released from the pearl powder to induce typical granular morphological bone-like apatite deposition in SBF, significantly improving mineralization efficiency. Pant et al.^[33]compounded MBG with PLA, rapidly inducing bone-like apatite deposition in SBF and activating osteogenic gene expression, which was significantly superior to pure PLA scaffolds (Figure 4). Moreover, the Ca²⁺and Si⁴⁺released from MBG can promote the biomineralization of bone-like apatite and activate the expression of osteogenesis-related genes, thereby enhancing the osteoinductive capacity of the scaffolds. Therefore, composite additives can provide sustained ionic signals and nucleation sites, while surface functionalization can precisely activate apatite nucleation; the combination of both enables rapid and stable formation of bone-like apatite on polymer implants, providing a pathway to enhance their bioactivity.

2.3 Bio-ceramic-induced bone-like apatite formation

Bioactive ceramics such as HA, β-tricalcium phosphate (β-TCP), and biphasic calcium phosphate (BCP) are widely used in bone tissue engineering due to their chemical composition similar to natural bone minerals, excellent osteoconductivity, and tunable degradation properties^[61]. Calcium phosphate-based bioceramics can directly induce the formation of bone-like apatite, constructing a bioactive interface that integrates with host bone tissue, making them classic materials for inducing bone-like apatite formation. Compared to metals and polymers, bioceramics exhibit unique advantages in osteoinduction and bone regeneration, but their mechanical properties and early mineralization efficiency urgently need further optimization. Through doping modification, surface morphology control, and composite material design, the bone-like apatite induction capability of bioceramics can be enhanced^[5,62]. For example, HA containing 10 mol% Sr induces spherical bone-like apatite deposition in SBF while enhancing bone-implant bonding strength^[63]. Silicon-doped HA (SiHA) exhibits a faster rate of spherical bone-like apatite formation compared to magnesium-doped HA (MgHA)^[64]. BCP combines the stability of HA with the degradability of β-TCP; by optimizing the HA/β-TCP ratio, it forms crystalline structures in SBF. The crystal size increases over time, eventually forming uniform and mature bone-like apatite, significantly enhancing the expression of osteogenic-related genes^[65]. Due to its higher degradation rate, β-TCP forms needle-like bone-like apatite in SBF, promoting early bone integration^[66]. Other studies have prepared calcium silicate (CaSiO₃)-based ceramic scaffolds using digital light processing (DLP) technology, adding 10% HA, 10% strontium phosphate, and varying amounts of calcium sulfate dihydrate (CaSO₄·2H₂O). The addition of 5 wt% CaSO₄·2H₂O not only enhanced the compressibility and compressive strength of the scaffolds but also promoted sporadic HA deposition resembling coral in SBF^[67]. Calcium silicate ceramics with high β-CaSiO₃ content form a thick spherical bone-like apatite layer in SBF, and their degradation capacity increases with higher calcium silicate content^[68]. Notably, surface morphology control further improves mineralization efficiency; sub-micron grains and microporous structures promote cell differentiation through mechanotransduction, outperforming traditional ion release mechanisms. For instance, plasma-treated β-TCP surfaces, due to increased roughness and crystal distortion, form larger and more oriented bone-like apatite crystals in SBF^[69].

BG and other ceramic systems demonstrate multifunctionality through compositional design and surface modification. For instance, surface activation modification of glass-ceramics (BGC) via low-temperature plasma technology, using high-energy particle bombardment, significantly increases the roughness and active sites on the BGC surface. These changes not only enhance the material's surface solubility but also promote local supersaturation of calcium and phosphate ions, facilitating the nucleation and growth of bone-like apatite.^[70]. Researchers successfully synthesized Hench bioactive glass containing varying concentrations of boron (B) (BaG-Bx) using the sol-gel method, achieving up to 20 wt% B addition in BaG. They found that increasing B content enhances the glass dissolution rate and the crystallinity of the calcium phosphate layer, significantly improving biomineralization capability, resulting in the formation of flake-like and needle-like bone-like apatite after one month of immersion in SBF.^[71]. Mesoporous bioactive glasses (MBG) co-doped with Mg and Cu prepared by the sol-gel method form a flake-like bone-like apatite layer in SBF, exhibiting excellent mineralization ability and antibacterial properties.^[32]. Furthermore, bioinert ceramics such as silicon nitride ceramics (Si₃N₄), after adding varying proportions of SiO₂, CaO, and MgO, show significant improvements in pressureless sintering performance and bioactivity.^[72]. High SiO₂ content can improve the densification and mechanical properties of the material, while low MgO content performs better in enhancing biomineralization capability, especially in forming spherical calcium-phosphate-rich layers similar to HA in SBF. Piezoelectric ceramics (Bi_0.5Na_0.5)TiO₃, under polarized conditions through surface polarity regulation, induce the formation of bone-like apatite with different morphologies in SBF, significantly affecting osteoblast behavior.^[73]. Hammami et al.^[74]developed a 45S5 BG coating material doped with 2 mol% zirconia. When placed in SBF, it forms spherical bone-like apatite particles with a diameter of approximately 1–2 μm in cauliflower-like aggregates within one day. Over time, these gradually fuse into a dense, continuous layer. This dense apatite layer significantly promotes osseointegration, reduces the risk of implant micromotion and bacterial infection, thereby enhancing bone regeneration and implant stability.

3 Effect of bone-like apatite layer characteristics on bone regeneration

In bone tissue engineering, the induction of bone-like apatite formation on material surfaces is a key indicator for evaluating their bioactivity, closely related to reflecting material surface properties (such as chemical composition, nano-morphology, and doped elements)^[75], which can directly affect the interaction between materials and cells as well as the potential for bone regeneration^[76]. Surface chemical functional groups of materials (such as hydroxyl and carboxyl groups) promote heterogeneous nucleation by enriching Ca²⁺and PO₄^3-. Doped elements such as Sr²⁺, Zn²⁺, and Mg²⁺can significantly regulate crystal growth kinetics. For example, Mg²⁺-doped HA typically forms typical nanoneedle (or nanorod)-like bone-like apatite deposits in SBF, whereas Sr²⁺-doped HA usually forms fine granular or aggregated bone-like apatite deposits in SBF^[77-78]. Nano-porous or sub-micron surface morphologies increase nucleation sites and promote rapid mineralization; microporous structures can enhance cellular responses through mechanical signals^[79-80]. For instance, TiO₂ nano-micro porous oxide films formed by anodic oxidation possess high surface energy, hydrophilicity, and enhanced ion exchange capacity; these characteristics act synergistically to significantly promote the formation of uniform, dense spherical or granular bone-like apatite deposit layers in SBF. Moreover, there are significant differences in mineralization rates and osteoblast attachment and differentiation between two different surface morphologies: nano/micro pores versus smooth surfaces, with nano/micro pores being superior^[81]. The morphology of bone-like apatite shows a significant correlation with biological effects in in vitro experiments. For example, needle-like bone-like apatite enhances protein adsorption due to its higher specific surface area, significantly upregulating the expression of osteogenesis-related genes; amorphous bone-like apatite promotes M2 macrophage polarization by rapidly releasing Ca²⁺and PO₄^3-, creating a microenvironment conducive to bone repair; crystalline bone-like apatite, due to its high structural stability, is more suitable for long-term cell-material integration^[82-84]. In addition, plate-like bone-like apatite formed on ceramic surfaces enhances cell traction forces through mechanotransduction, promoting osseointegration^[85]. These studies indicate that bone-like apatite morphology can drive bone regeneration-related processes by regulating protein adsorption and cell signal transduction, with specific effects depending on the material type and surface design.

3.1 Metal materials and their surface-engineered implants

Titanium and its alloys are strong candidate materials for load-bearing bone implant applications due to their excellent mechanical properties and biocompatibility; however, they may face issues such as corrosion, wear, and insufficient integration with host bone in vivo.^[86]To address this, researchers have developed bioactive coatings that mimic the chemical composition and microstructure of natural bone tissue to promote the deposition of bone-like apatite and enhance osseointegration. Researchers employed laser texturing technology to construct multiple microstructures on the surface of Ti-6Al-4V bone screws, which not only promoted early adhesion of MSCs and spherical bone-like apatite deposition but also reduced friction and wear by forming a micro-lubricating layer, providing a new direction for extending implant lifespan and reducing postoperative complications, suitable for patients with mild osteoporosis.^[25]Additionally, BioCer implants prepared via 3D printing can form a carbonated bone-like apatite coating on the titanium framework surface, effectively inducing new bone formation in large-area skull defect regions.^[87]Moreover, this coating not only promotes bone regeneration at the defect edges but also achieves bone tissue regeneration in non-bone areas, demonstrating excellent osteoinductive performance and bone-like mineralization capabilities. Lu et al.^[88]prepared nanoplate-, nanorod-, and nanoneedle-shaped HA coatings on titanium implants via electrochemical deposition. These coatings rapidly formed a complete apatite layer in SBF, exhibiting high bioactivity, promoting stem cell proliferation and differentiation, and enhancing osseointegration. Among them, the nanoplate HA coating was more conducive to enhancing MSC proliferation and alkaline phosphatase (ALP) activity, as well as upregulating the expression of the osteogenic gene osteopontin (OPN). Other studies have also indicated that nanoplate HA coatings formed on titanium substrates via electrochemical deposition exhibit superior bioactivity.^[89]Compared with traditional acid/alkali treatment and plasma-sprayed HA coatings, coatings prepared by this method possess higher surface roughness and better wettability, thereby significantly improving cell adhesion, proliferation, and osteogenic differentiation. This coating has demonstrated excellent osseointegration capability in animal models, with biological performance in certain aspects even surpassing that of traditional HA coatings.

Tantalum (Ta), as an emerging metallic biomaterial, is increasingly used in bone repair research due to its excellent bioactivity and corrosion resistance. For example, Wang et al.^[90]designed a three-dimensional, multiscale, and interconnected trabecular bone-mimicking porous tantalum scaffold (PTaS). It possesses high porosity (60%~80%), pore size (200~500 μm), and an elastic modulus (0.5~4.0 GPa) close to that of cancellous bone. In vitro cell experiments demonstrated that PTaS supports the adhesion and proliferation of MSCs; in vivo experiments using a canine femoral shaft defect model showed that PTaS integrates tightly with host bone. New bone formation was observed at the scaffold-host bone interface after 3 and 6 months, and good intra-osseous growth was observed in the center of the Ta rod, with bone integration strength comparable to normal bone. Pan et al.^[91]designed hierarchical porous tantalum granules (PTaG) for repairing irregular bone defects. PTaG can efficiently chelate Ca²⁺ and PO₄^3- from body fluids to form a mineralized layer. Micro-CT and histological analyses indicated that its bone regeneration effect is superior to commercial porous titanium granules (PTiG) and Bio-Oss. Another study developed cobalt-chromium-tungsten-tantalum (Co₆₃Cr₂₈W_9-_xTa_x) alloys with varying tantalum content to optimize their bioactivity and mechanical properties^[92]. As the tantalum content increases, the alloy hardness improves. After chemical treatment, a Ta₂O₅ layer forms on the surface, promoting HA nucleation and enhancing bone-implant interface integration. The Ta surface enhances anchoring protein adsorption by optimizing surface characteristics, thereby improving cell behavior and accelerating the cascade mechanism of osteogenic differentiation. This achieves a comprehensive and significant improvement in osteoblast adhesion, proliferation, maturation, and mineralization, demonstrating excellent bone integration capability^[93]. Zhang et al.^[94]fabricated porous tantalum scaffolds via 3D printing and formed a Na₃TaO₄phase on their surface through alkali-heat and hydrothermal treatments, making the scaffolds more hydrophilic. This nanostructure enhanced fibronectin adsorption, activated the integrin Rho-ROCK pathway, and upregulated the expression of osteogenic genes such as ALP, collagen type I (COL-1), bone sialoprotein (BSP), and bone morphogenetic protein-2 (BMP-2) in MSCs. In a rabbit mandibular critical defect model, the modified scaffolds promoted early bone integration, with significantly higher new bone volume compared to the unmodified group. Another study employed polydopamine (PDA) to coat tantalum pentoxide (Ta₂O₅) nanoparticles onto a polyimide (PI) surface to construct orthopedic implant materials. This coating significantly increased surface roughness (Raincreased from 2.263 μm to 6.512 μm) and hydrophilicity (water contact angle decreased from 81° to 36.5°), increasing protein adsorption to 23 mg/g, thereby enhancing stem cell adhesion, proliferation, and osteogenic differentiation^[95].

Biodegradable metals offer significant advantages in bone repair due to their ability to gradually degrade within the body, thereby reducing complications and patient burden. An in vivo study using a clinically applicable magnesium alloy showed that the alloy releases Mg²⁺ as well as Ca²⁺, Zn²⁺, thereby significantly enhancing angiogenesis and coupling to promote osteogenesis, ultimately improving bone repair outcomes^[96]. Shao et al.^[97] investigated a novel zinc-magnesium-iron (Zn-Mg-Fe) alloy by implanting it into the frontal bone, mandible, and femur of beagle dogs for a one-year in vivo study on biocompatibility and degradability. The study found that the alloy exhibited good biocompatibility, with Zn accumulating in adjacent bone tissue but not in the liver, kidneys, or spleen. The alloy degraded at a uniform rate in vivo, with no significant differences in degradation among the frontal bone, mandible, and femur. Degradation products included ZnO, Zn(OH)₂, Zn₅(OH)₆(CO₃)₂, and Zn₃(PO₄)₂⋅4H₂O; these products resemble the morphology of bone-like apatite in bone tissue and can promote new bone formation. Klíma et al.^[98] studied a Zn-0.8Mg-0.2Sr absorbable alloy screw implanted into rabbit tibiae for 12 months, finding that the alloy had good biocompatibility, caused no toxic reactions, and degraded slowly in vivo, forming a phosphate-based corrosion layer rich in zinc, calcium, phosphorus, and oxygen on its surface. This layer resembles bone-like apatite morphology and aids osseointegration. A novel magnesium-tin-zinc-sodium (Mg-Sn-Zn-Na) alloy achieves trace sodium alloying via Sn-Na intermetallic phases, exhibiting excellent mechanical strength, corrosion resistance, and osteogenic potential. It functions by promoting angiogenesis, inducing osteogenesis, and regulating apatite deposition, significantly inducing new bone generation after 12 weeks of implantation in a calvarial defect model^[99]. To reduce the cytotoxicity caused by the rapid release of Zn²⁺, Zhuang et al.^[100] modified degradable porous zinc scaffolds with a biomimetic Ca-P coating. This coating not only significantly enhanced the scaffold's biomineralization capacity and improved the osteogenic differentiation and calcium deposition of MSCs but also promoted new bone formation in vivo. However, degradable metals also face challenges. Taking magnesium as an example, it corrodes rapidly in physiological environments; during degradation, it releases hydrogen gas and may form bubbles, which can interfere with tissue integration and even cause tissue problems^[101].

3.2 Bioactive polymers and polymer-based composite scaffolds

Polymeric materials are widely used in bone tissue engineering and can significantly promote the formation of bone-like apatite, thereby accelerating bone regeneration, through chemical modification or compositing with bioactive substances such as bioceramics. PEEK has become a preferred choice for orthopedic implant materials due to its excellent mechanical properties and biocompatibility. Liu et al.^[102]utilized 3D printing technology to fabricate five porous PEKK scaffolds with different pore sizes. Among them, the P600 scaffold with a pore size of approximately 596±23.4 μm exhibited the best performance in terms of mechanical properties and osteogenic effects. The apatite crystals formed via in situ mineralization endowed the scaffolds with a micro-nano structured surface, significantly enhancing biocompatibility and bioactivity. Both in vivo and in vitro experiments confirmed that PEKK-HA scaffolds can effectively promote bone tissue regeneration. Luo et al.^[103]modified the PEEK surface by combining femtosecond laser processing with hydroxylation technology, which significantly improved the material's hydrophilicity and surface energy, promoting bone-like apatite deposition and osteogenic activity. Yuan et al.^[104]developed a novel hierarchical porous PEKK scaffold (PEKK-B) combining sulfonation treatment with nano-hydroxyapatite deposition technology. After implantation in beagle dogs for 12 weeks, it successfully induced ectopic bone formation, with performance significantly superior to unmodified PEKK materials. The surface of the PEKK-B scaffold formed a multi-level microporous network similar to natural cancellous bone. The osteogenic differentiation effect of this scaffold on bone marrow mesenchymal stem cells (BMSCs) was closely related to the activation of the adenylyl cyclase 9 (ADCY9) and cyclic AMP/protein kinase A (cAMP/PKA) signaling pathways (Figure 5). Another study prepared HA/PEEK biocomposites via composite injection molding, selecting 30 wt% HA to optimize mechanical properties^[105]. This composite demonstrated significant bone-like apatite formation capability in SBF, forming square apatite islands in SBF, which enhanced bioactivity and promoted cell attachment, proliferation, and ALP activity. In vivo experiments indicated a significant increase in bone contact area and new bone formation volume, exhibiting excellent osteoinductive capacity. Researchers developed a PEEK composite containing nano-magnesium silicate (n-MS) and subjected its surface to particle impact and sulfuric acid treatment. This material exhibited significantly increased surface roughness and hydrophilicity, thereby improving its spherical apatite mineralization capability in SBF. Meanwhile, this surface treatment also endowed the material with antibacterial properties and significantly enhanced the adhesion, proliferation, and differentiation of MSCs^[57].

Biodegradable polymers can significantly enhance biomineralization capacity and thereby improve osteogenic activity by incorporating bioactive components or employing surface mineralization techniques. For example, Sun et al.^[106]investigated a porous polylactic acid-gelatin-hydroxyapatite composite (PLA-gH). In vitro experiments showed that PLA-gH formed spherical to blocky bone-like apatite deposits in SBF, whereas spherical and rod-shaped deposits formed in SBF containing bovine serum albumin (BSA), demonstrating the regulatory role of BSA in the mineralization process. A SD rat calvarial defect model revealed that the PLA-gH group exhibited significantly superior bone regeneration and vascularization effects compared to the PLA group at 12 weeks post-surgery. Zhang et al.^[107]developed poly(L-lactic acid) (PLLA)/nHA composite bone repair scaffolds using FDM technology. During degradation in PBS, these scaffolds formed nano-needle-like bone-like apatite, possessing suitable compressive strength and excellent osteogenic properties. Four weeks after implantation into rabbit femoral defects, they achieved complete integration with surrounding bone tissue, with pores filled by new bone. Wang et al.^[108]studied a polylactic acid/nano-hydroxyapatite composite (PLA/nHA), preparing and optimizing its performance via low-cost fused deposition modeling (FDM) technology. In vitro experiments indicated that PLA/nHA scaffolds exhibited good cytocompatibility, significantly promoting MSC proliferation and growth. As nHA content increased, the scaffold surface gradually became rougher, forming a microenvironment similar to natural bone tissue, which favored cell attachment and growth. In vivo implantation into New Zealand white rabbit femoral defects demonstrated that PLA scaffolds containing 30% nHA (Pn30 group) significantly promoted new bone formation within 12 weeks post-surgery, with superior bone regeneration effects compared to the pure PLA group. However, while high-crystallinity nHA favors bone integration, it does not directly participate in bone matrix mineralization. To address this, Liu et al.^[109]synthesized CaP oligomers and co-incorporated them with α-ketoglutarate (α-KG) into PLGA/FC scaffolds to enhance the scaffolds' mineralization capacity and osteogenic activity, achieving synergistic regulation of bone immunity and vascular/bone regeneration. Zheng et al.^[110]combined layer-by-layer (LbL) nano-coating with mineralization techniques to construct a biomimetic apatite interface on electrospun PCL fibers, fabricating artificial scaffolds with osteoinductive functions. PCL-HA composite scaffolds performed excellently in mimicking the composition and structure of bone tissue; their surfaces formed plate-like HA crystals approximately 200 nm in length with a Ca/P ratio of about 1.67, close to that of natural bone tissue. Similarly, gelatin/sodium alginate interpenetrating network hydrogels loaded with Li⁺also demonstrated osteogenic activity by regulating signaling pathways through ion release. Li⁺promoted bone regeneration by inhibiting glycogen synthase kinase-3β (GSK-3β) and stabilizing β-catenin to activate the Wnt pathway: the 5 mM group significantly enhanced cell proliferation and rat calvarial repair, whereas the 10 mM group was ineffective due to excessive Li⁺release. This indicates that the release kinetics of bioactive ions greatly influence osteogenic outcomes.^[111]. Furthermore, Leite et al.^[112]developed bioactive hydrogel marbles (BHM) with a core of gelatin methacrylate and a shell of fluorosilane-modified hydrophobic bioactive glass nanoparticles (H-BGNPs). Within 7 days in SBF, a dense bone-like apatite layer composed of nano-needle-like crystals with a typical cauliflower morphology formed on the surface. This layer, by releasing Ca²⁺, Si⁴⁺, PO₄^3-, and other ions, significantly upregulated ALP activity in mouse calvarial preosteoblasts, driving the differentiation of osteoprogenitor cells toward the osteogenic lineage without exogenous inducers, thereby demonstrating excellent bone regeneration potential.

3.3 Bioceramics such as calcium phosphate and bioactive glass

Bioceramics possess significant advantages in bone tissue engineering due to their excellent biocompatibility, osteoconductivity, osteoinductivity, and low cost^[35]. Their ability to readily form bone-like apatite in vivo is crucial for promoting the integration of materials with surrounding bone tissue. Compared to larger-scale structures, nanostructured calcium phosphate-based bioceramics exhibit higher osteogenic activity, as their nanoscale morphology provides a high specific surface area that is more conducive to protein adsorption and the deposition of bone-like apatite nanocrystals^[113]. For instance, He et al.^[114]evaluated the osteoinductive effects of five CaP materials (20 nm HA, 60 nm HA, 12 μm HA, 100 nm TCP, and 12 μm HA/100 nm TCP) in mouse muscle, finding that the 20 nm HA, 60 nm HA, 100 nm TCP, and HA/TCP groups formed new bone 10 weeks post-surgery, whereas no obvious bone regeneration was observed in the 12 μm HA group. Lei et al.^[115]developed BCP ceramics with submicron surface topography and compared them with deproteinized bovine bone mineral (DBBM). Through experiments involving intramuscular implantation in FVB mice for 5 weeks and maxillary sinus floor elevation in rabbits for 12 weeks, they confirmed that BCP significantly promoted osteoclastogenesis, with a new bone formation rate (38.24%) higher than that of DBBM (29.23%). Zhu et al.^[116]prepared BCP bioceramics with a hybrid structure of composite HA whiskers and nanoparticles via hydrothermal reaction, which induced higher quality new bone formation in a beagle dog long bone defect model compared to traditional smooth-surface BCP. Other studies have indicated that the micro/nano HA layer formed on β-TCP/CaSiO₃porous scaffolds through biomimetic mineralization can regulate the fate of MSCs and human umbilical vein endothelial cells (HUVECs)^[117]. This study employed dual models of extra-periosteal calvarial grafting and dorsal subcutaneous ectopic implantation in SD rats. In the calvarial model without bone defects, continuous newly formed bone matrix appeared at the scaffold-bone interface at 4 weeks, and bone tissue grew into the scaffold interior by 8 weeks, achieving significant bone augmentation. Meanwhile, the subcutaneous model excluded interference from bone-derived stem cells; at 4 weeks, the micro/nano HA surface induced abundant capillary formation, yet by 8 weeks, these vessels regressed due to the lack of support from a bone microenvironment, suggesting that long-term vascular stability requires a coupled bone-vascular microenvironment. Although bioactive HA nanocrystals hold significant potential for enhancing bone integration, their nature as foreign bodies limits their ability to directly participate in bone mineralization^[118]. In our previous work, we synthesized tea polyphenol-functionalized micro-nano HA bioceramics (TP-nwHA) via a hydrothermal method. After implantation in vivo, these materials can induce the formation of flake-like apatite through a non-classical nucleation pathway, thereby promoting direct adhesion of tissue cells (Figure 6)^[119]. In contrast, after implantation in vivo, micron- and submicron-structured HA ceramic materials undergo coverage by collagen fibers and formation of bone-like apatite before tissue cell attachment occurs. In vitro experiments further confirmed that TP-nwHA enhances osteogenic differentiation of MSCs while inhibiting osteoclastic differentiation. Studies in a rat model of osteoporotic bone defects demonstrated that this material significantly accelerates osteoporotic bone regeneration by promoting angiogenesis. Therefore, the synergistic effect of nanoscale surface topography and bone-like apatite layers can significantly optimize the biological response at the cell-material interface, enhancing osteoinductivity and tissue integration capabilities.

Porous scaffolds provide an ideal three-dimensional microenvironment for angiogenesis and nutrient exchange, but the introduction of macroscopic macropores and microporous structures may also lead to stress concentration, reducing overall mechanical strength^[120]. To address this challenge, Zhang et al.^[121]by doping CaSO₄ into HA printing ink and using digital light projection (DLP) technology to prepare porous scaffold green bodies, during the sintering process, CaSO₄ guided the in-situ rearrangement and directional growth of HA crystals to form whisker-like or rod-like microstructures and densified growth, constructing a mechanically reinforced microstructure. Meanwhile, by regulating Ca²⁺ release, the mineralization induction and osteogenic capacity of the scaffolds were significantly enhanced. In vivo experiments showed that the scaffold could repair critical-sized bone defects within 3 months and restore mechanical strength to over 70% of autologous bone. Similarly, Wang et al.^[122]used DLP 3D printing to fabricate calcium phosphate ceramics with three different macroscopic pore structures, all of which successfully induced the formation of sheet-like bone-like apatite mineralization layers in vitro. In particular, foam-like and inverse face-centered cubic pore structures, owing to their unique geometric features, significantly improved ectopic bone formation and bone tissue remodeling, highlighting the key role of macropores in the osteoinduction process. He et al.^[123]constructed composite scaffolds by epitaxially growing CaSO₄·H₂O on the surface of β-TCP. During degradation, CaSO₄·H₂O formed synchronously with nanosheet-like bone-like apatite, providing not only sustained calcium ion release but also creating a microenvironment conducive to immune cell recruitment and MSC adhesion and proliferation, thereby accelerating bone defect repair. Bioactive ions or small molecules generated during the degradation and release of bioceramics and their mineralization layers can actively regulate bone regeneration through multiple pathways. Dynamic regulation of ion release can further enhance osteogenic differentiation and angiogenesis by activating key signaling pathways such as Wnt/β-catenin, providing a multifunctional integrated platform for complex bone defect repair. For example, Hu et al.^[124]prepared Zn-Sr co-doped porous scaffolds using an impregnation-calcination method, achieving controlled release of Zn²⁺ and Sr²⁺ to synergistically promote osteogenic differentiation and angiogenesis. The introduction of manganese into β-TCP can promote the sustained release of Mn²⁺, significantly enhancing the scavenging capacity of oxygen and nitrogen free radicals, inhibiting osteoclast activity, and improving the repair effect of osteoporotic defects^[125]. Wang et al.^[126]prepared MS/β-TCP scaffolds that synergistically activated the PI3K/Akt pathway by releasing Mg/Si ions, upregulating osteogenic genes such as Runt-related transcription factor 2 (RUNX2) to achieve osteogenesis-angiogenesis coupling. In vivo rat experiments showed that at 12 weeks, the bone volume/total volume reached 33.18% and bone density was 0.26 g/cm³ in the 10% doped group, with repair effects superior to the control group. In addition, hierarchically porous β-TCP scaffolds coated with BG possess both bone scaffold and antibiotic delivery functions; while degradation proceeds synchronously with plate-like apatite mineralization, they continuously release calcium, phosphorus, silicon, and loaded antibiotics, preventing bacterial recurrence in infected bone defects while accelerating endogenous bone regeneration^[127]. Zhang et al.^[128]constructed a 3D printed β-tricalcium phosphate (MBG-β-TCP) scaffold functionalized with an MBG nanolayer featuring a hierarchical porous structure to accelerate osteogenesis and angiogenesis in bone tissue engineering. Studies showed that the MBG-β-TCP scaffold could induce the formation of a uniform bone-like apatite layer in SBF, and its in vivo bone repair effect was significantly superior to traditional BG-modified β-TCP and pure β-TCP scaffolds. In addition, Katsaros et al.^[129]developed a silicon nitride (Si₃N₄) implant surface material with enhanced bioactivity through thermochemical treatment. Experiments showed that compared with untreated materials, the thermochemically treated materials formed a large amount of bone-like apatite with a denser plate-like structure on the surface after soaking in SBF for 21 days, capable of promoting osteogenesis. Shen et al.^[130]doped nano-silicon nitride (Si₃N₄) particles onto titanium surfaces via micro-arc oxidation technology to prepare coatings with osteogenic, angiogenic, and corrosion-resistant properties. In vitro experiments showed that the coating could significantly promote the adhesion, proliferation, osteogenic differentiation, and mineralized nodule formation of MC3T3-E1 osteoblasts, and could also effectively enhance the viability, migration, and tubular structure formation ability of HUVECs.

4 Conclusion and Outlook

The development of tissue-inductive biomaterials has significantly advanced innovative research in bone tissue regeneration. The core mechanism of osteoinduction lies in enhancing material bioactivity through the in situ formation of a bone-like apatite layer, achieving dynamic integration with host tissues.^[131]. However, the molecular and cellular mechanisms driving bone induction via biomineralization have not been fully elucidated, limiting its potential for clinical application.^[132]. In vivo studies reveal significant heterogeneity in the morphology of bone-like apatite; apatite with a nanosheet structure generated via non-classical nucleation pathways can directly promote cell adhesion and osteogenic differentiation, synergizing with layered collagen deposition to optimize the local regenerative microenvironment.^[119]. These processes are jointly regulated by biochemical signals such as bone morphogenetic proteins and MAPK, as well as integrin-mediated mechanotransduction, modulating MSC differentiation and immune responses.^[133]. Furthermore, the surface chemistry and nano-morphology of bone-like apatite can further influence MSC fate determination by regulating the Notch and YAP/TAZ signaling pathways.^[134]. Inflammatory cells such as macrophages play a crucial role in the osteoinduction process of biomaterials through their response to implanted biomaterials and the secretion of various signaling molecules regulated by material factors. M2 macrophages secrete anti-inflammatory cytokines that help create a favorable regenerative environment, whereas the aggregation of multinucleated giant cells may trigger foreign body reactions, affecting material absorption rates and bone formation efficiency.^[135].

Currently, achieving controlled biomineralization and predictable bone regeneration still faces numerous challenges, primarily stemming from the significant heterogeneity of bone-like apatite formation and the high complexity of the host microenvironment^[136]. In vivo studies have found that the same material can form diverse nanostructures under different physiological conditions; this non-classical nucleation pathway increases the diversity of apatite morphology, posing difficulties for standardized bioactivity assessment^[119,137]. Furthermore, although SBF immersion experiments provide an important tool for evaluating material-induced mineralization and biological effects, their static environment struggles to simulate the dynamic shear stress, immune regulation, and metabolic influences in vivo, limiting predictive accuracy^[8]. Regarding the impact of dynamic SBF immersion on apatite formation, it was found that compared to static environments, the apatite layers formed under dynamic conditions are thinner and more uniform rather than more diverse. However, neither the dynamic flow rate nor the apatite morphological characteristics have been confirmed in the text to have a clear correlation with in vivo osteogenic efficacy. The limitations of SBF testing (lack of proteins, buffer interference, etc.) prevent it from independently predicting bioactivity. Therefore, most current research still relies on in vitro evidence, lacking systematic in vivo validation to clarify the dynamic coupling relationship among material properties, bone-like apatite morphology, and bone regeneration effects. In addition, the mismatch between the material degradation rate and the kinetics of new bone formation often leads to decreased bone repair efficiency^[138]. To address these issues, constructing novel biomimetic materials that simulate the hierarchical tissue structure of natural bone is necessary to support collagen fiber stratification and the dynamic regulation of the regenerative microenvironment, thereby enhancing material bioactivity^[139]. Meanwhile, surface functionalization also provides an effective means for precisely regulating non-classical nucleation and MSC differentiation. The ion doping strategy optimizes the dissolution characteristics and biological performance of the apatite layer by regulating crystal growth kinetics^[140].

Future research should focus on revealing the spatiotemporal dynamic mechanisms of biomineralization to provide novel, precise, and personalized bone regeneration strategies. First, the high heterogeneity of bone-like apatite morphology highlights the necessity of applying advanced characterization techniques to capture in real time the evolution of nanostructures during mineralization and their impact on cellular behavior.^[141]. Elucidating the mechanisms of ion-mediated nucleation and crystal growth based on molecular dynamics simulations will reveal how apatite couples with MSC differentiation and collagen stratification, providing a theoretical basis for regulating the local microenvironment. Second, developing in vitro models capable of reproducing diverse bone-like apatite morphologies (such as systems dynamically simulating the in vivo environment) and standardized animal models (including bone defect and osteoinductive models) will facilitate the systematic evaluation of material performance under different physiological conditions. Finally, research should focus on constructing hierarchically structured hybrid scaffolds that integrate tunable bioactive components (such as bioceramics, ion doping, and growth factors) with smart responsive mechanisms (such as pH- or enzyme-triggered degradation) to achieve dynamic regulation of the regeneration process. By deeply uncovering the mechanisms underlying biomineralization, further bridging materials science, computational biology, and clinical research, and integrating multi-omics data, it will be possible to develop mineralized regenerative scaffolds with both high predictability and personalized adaptability, thereby significantly enhancing the clinical therapeutic efficacy of bone defect repair.

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Funding

National Natural Science Foundation of China(82202332)

National Natural Science Foundation of China(82204477)

Postgraduate Research & Practice Innovation Program of Jiangsu Province(KYCX24_4037)

Central University Basic Research Business Expense Special Fund(20826041G4189)

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Cite this article

1 Introduction

2 Mechanism of bone-like apatite formation induced on material surfaces

2.1 Metal material-induced bone-like apatite formation

2.2 Polymer material-induced bone-like apatite formation

2.3 Bio-ceramic-induced bone-like apatite formation

3 Effect of bone-like apatite layer characteristics on bone regeneration

3.1 Metal materials and their surface-engineered implants

3.2 Bioactive polymers and polymer-based composite scaffolds

3.3 Bioceramics such as calcium phosphate and bioactive glass

4 Conclusion and Outlook

References

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