Multiscale Bionic Construction of Artificial Bone: Strategies and Clinical Application Prospects

Abstract

The development of effective biomaterials for bone defect repair remains challenging due to limitations in mechanical properties, bioactivity, and degradation characteristics. We summarize recent progress in synthetic bone materials, including metals, ceramics, and polymer composites, critically analyzing their clinical strengths and weaknesses. This review presents the fabrication of a new generation of mineralized collagen materials through biomimetic mineralization, demonstrating that their composites exhibit promising clinical application potential. Inspired by the hierarchical architecture of natural bone, a multiscale cascade regulation strategy is further proposed to achieve multidimensional mimicry in composition, structure, mechanical properties, and biological functionality. Special attention is given to multidimensional biomimetic strategies integrating nano-scale molecular self-assembly, electrospinning, and macroscale pressure-driven fusion to construct artificial lamellar bone and artificial cortical bone. In summary, this article provides valuable insights into understanding artificial bone repair materials and their development trends, offering significant guidance for the development of new degradable biomimetic artificial compact bone materials.

Impact Statement

This paper reviews the clinical needs for bone repair materials and the limitations of current options, emphasizing the potential of biomimetic approaches inspired by natural cortical bone’s hierarchical structure. It introduces the mineralization process and mechanical properties of compact bone, evaluates biomimetic mineralized collagen fibers, and summarizes preparation methods. A multidimensional strategy is proposed for constructing high-strength, biodegradable, and biocompatible artificial compact bone, offering insights into future development and clinical application.

Keywords

artificial bone mineralized collagen multidimensional biomimetics multiscale cascade regulation

Introduction

Bone defects caused by trauma, infection, congenital deformity, and other factors are a common occurrence and often require the implantation of bone repair grafts.^1–6 Autologous bone has long been considered the gold standard for clinical bone repair, yet due to its limited availability, inability to match defect shapes, and high risk of secondary surgeries, it fails to meet the needs for various types of bone defect repairs.^7–11 The development of artificial bone repair materials and orthopedic implants is currently receiving significant attention and has substantial market demand. In recent years, the market size in fields such as orthopedics, neurosurgery, and oral surgery has shown a significant growth trend.^12–14 According to incomplete statistics, the domestic market size for bone repair materials and medical devices has exceeded 30 billion yuan.¹⁵

Due to the wide range of sources of materials, ease of processing, and ability to load a variety of bioactive molecules, artificial bone materials are used more than autogenous bone and allogeneic bone in clinical applications and have occupied more than 60% of the market share so far.^16–18 There are many types of artificial bone repair materials commonly available. These include bioceramics, polyetheretherketone (PEEK),¹⁹ polymethylmethacrylate (PMMA),²⁰ porous polyethylene,²¹ titanium (Ti) and its alloys,²² and bioactive glass.²³ Although these materials exhibit good biocompatibility, they typically function merely as simple fillings or provide mechanical support, yet they lack osteoinductivity, osteogenic activity, and adequate biomechanical properties.^24–26 Hence, creating artificial bone materials that are biodegradable, possess osteogenic inducibility, and have superior mechanical characteristics is essential to addressing this difficulty. Ideal bone repair materials should gradually degrade during the osteoinduction process, meeting the dynamic requirements for “regenerative repair” and “growth and development” at the site of the bone defect.^27–29

Biomimetic bone materials have become the trend in bone implant materials due to their natural bone-like components, structures, mechanism, functionality, and their superior degradability.^30–32 Among them, biomimetic mineralized collagen (MC) artificial bone repair materials feature a composition and micronano hierarchical structure of collagen/nano-hydroxyapatite that closely resembles natural bone.^33–35 Clinical applications have demonstrated that these materials can induce new bone formation and accelerate bone healing when implanted at bone defect sites, making them a promising biomaterial. However, MC fibers are typically in the form of micronano scale powder, which makes it challenging to meet the rigid requirements for macroscopic mechanical support; therefore, they are commonly combined with synthetic polyester materials for application, which diminishes the advantages of mineralized collagen materials.^36–38 Consequently, the biomimetic fabrication of multidimensional high-performance bone structural materials and the three-dimensional manufacturing of a new generation of functional biomimetic MC-based bone defect regeneration repair materials have significant scientific and clinical value.

Synthetic Bone Repair Materials for Clinical Applications

Currently, with an aging population, the problem of bone damage is particularly serious. Although autogenous bone grafting is the gold standard of bone repair, the prolonged hospitalization caused by donor bone procuring is still a problem.^39–41 Therefore, artificial bone graft materials have gradually become the best choice for bone defect repair. Currently, according to the material composition, synthetic bone repair materials are mainly divided into metal-based, bioceramic-based (calcium phosphate/calcium sulfate bone cement), and composite structural materials (bioglass, synthetic polymers).^42–45

Metal-based bone repair materials

Due to properties of strong corrosion resistance, high mechanical strength, and fatigue resistance, metals are usually selected for internal fixation or large bone defect repair materials.⁴⁶ Currently, metal-based bone repair materials are mainly divided into two categories: nondegradable materials (Ti and tantalum [Ta]) and degradable materials (magnesium [Mg] alloy, zinc [Zn]-Mg alloy, etc.). These materials are usually precisely machined into mesh plates with periodic patterns or fabricated into controllable mesh-cage structures using 3D printing technology.⁴⁷ Ti has advantages in biocompatibility, osteointegration, low density, high mechanical strength, and a series of excellent biological properties.^47–49 It is generally used in permanent bone implants to repair critical bone defects and has been seen to achieve good repair results.^50–52 Ta metal implants have been used in clinical practice as early as the mid-20th century. Its excellent inertness and mechanical properties are considered to be a potential biomaterial for bone defects.^53–56 Although Ti and Ta alloys are widely used in bone repair due to their excellent mechanical strength and favorable biocompatibility, their inherent bioinertness limits effective osseointegration. Moreover, their elastic modulus, which is significantly higher than that of native bone, can induce stress shielding, leading to localized bone resorption at the implantation site.^57–59 In addition, their nondegradable nature poses potential risks for long-term implantation. The high density of Ta alloys may also result in postoperative discomfort, particularly in load-bearing regions.⁶⁰ Notably, the use of Ti mesh for cranioplasty is not recommended in children under the age of 11.^61–63

Many research focus on finding a metal structural material that has good supporting function, biocompatibility, and biodegradable properties. Therefore, the research and development of Mg and Zn alloys as bone repair scaffolds has gradually deepened.^64–66 With the development of technology, additive manufacturing has enabled the expanded application of porous metal bone repair materials, achieving complex bone defect structures while ensuring mechanical strength.^67–69 It has been reported in the literature that the preparation of porous metal structures has a relatively low elastic modulus, so it can alleviate the stress shielding and bone resorption caused by modulus mismatch.⁷⁰ Yu et al.⁷¹ prepared MgO-doped Zn scaffolds by 3D printing technology, which took advantage of the fact that Cl⁻ in the body fluids is more likely to react with the MgO nanoparticles to release the Mg²⁺ and form in-situ pores, thus improving the bioactivity and osteogenic capacity of the composite and accelerating the degradation etching rate. In addition, the design of porous Zn scaffolds faces similar challenges to those of Mg scaffolds mentioned above, with equilibrium mechanics, degradation, and surface activity still not clearly standardized.⁶⁴ Mg alloys degrade at an excessively rapid rate, often resulting in substantial hydrogen gas evolution, which can lead to the formation of gas cavities and local pH fluctuations, thereby eliciting inflammatory responses. Although Zn alloys exhibit a more moderate degradation behavior, pure zinc possesses inherently low mechanical strength. Even after alloying, further improvements are required to enhance both mechanical performance and biosafety. Additionally, elevated concentrations of zinc ions have demonstrated cytotoxic effects, and thus Zn-based alloys remain primarily in the stages of large-animal studies and early clinical investigation.⁷²

Ceramics bone repair materials

There are many types of ceramic-based bone repair materials, which usually simulate the inorganic components in the natural bone matrix, including calcium phosphate and silicate.⁷³ The types of bioceramics formed are roughly divided into hydroxyapatite (HA), Ca₃PO₄, CaSO₄, and bioglass.^74–77 The advantage of ceramic bone repair materials lies in the wide range of material sources, and the porous structure formed by sintering, allowing for suitable support strength and bone conductivity. However, these materials also have disadvantages, being their brittleness and difficulty in degradation.^78–80 Other forms of ceramic repair material include cement bone repair products prepared from powdered ceramic materials, which are injectable. The clinical application scenarios of inorganic bone cements prepared from ceramic powder and hydrogel are also gradually increasing. Due to their advantages, such as injectability, curability, and plasticity, they are used in neurosurgery, maxillofacial surgery, orthopedics, and other fields. Many studies have focused on the problem that ceramic structures intrinsically have, which is their difficulty in degrading.⁸¹ Thus, a series of low-crystalline ceramic structures such as ACP and β-TCP have been developed to adapt to applications in more scenarios; however, the difficulty in applying to load-bearing bone defects remains a problem.⁸²

Composite bone repair materials

Composite structural materials are broadly defined, usually referring to the combination of two or more materials to form a composite structure that combines the excellent physical and chemical properties of both materials.^83–85 In the field of tissue engineering, composite materials are commonly created through a combination of inorganic materials and polymer materials to form structural materials with excellent biological properties.⁸⁶ Bio-friendly polymer materials mainly include processed natural polymers such as collagen, hyaluronic acid, and chitosan, as well as synthetic polymers such as polycaprolactone (PCL), l-polylactide (PLLA), porous polyethylene, PEEK, and PMMA, with their main functions being structural support.^87–89 Some of these materials can be prepared via scalable methods such as polymerization, molding, and spinning.⁹⁰ The advantages of these types of material are their good biocompatibility; tunable physical, chemical, and mechanical properties; and good osteogenic induction ability. The main downside of composites is their relatively complex preparation process. Also, due to their material complexity, composite materials tend to degrade too fast compared with the growth rate of new bone. Furthermore, some ester polymers form an acidic environment after degradation, which is not conducive to new bone formation.^91–93

Biomimetic Mineralized Collagen Materials for Bone Defect Repair

Biomimetic preparation has emerged as a significant approach for addressing the myriad challenges confronting materials utilized in bone defect repair.⁹⁴ Initially, a biomimetic MC fiber structure was successfully devised, employing the fundamental principles of mimicking natural bone at the micronano scale, and garnered favorable clinical evaluations. A comprehensive comprehension of the interplay between collagen and ion nucleation and growth during the mineralization process is imperative. Zhang et al.⁹⁵ investigated the nucleation sites of calcium phosphate crystals during the initial phases of collagen mineralization in vitro. They discovered that, in addition to carboxyl groups, carbonyl sites on the surface of collagen fiber molecules also undergo chemical interactions during the calcium phosphate nucleation process. Notably, chelation of calcium ions with carbonyl groups at nucleation sites induces a red shift in the amide I peak, reflecting weakened C=O bond strength during early-stage mineralization.⁹⁶ The aforementioned research plays a pivotal role in comprehending the organized crystal growth within MC fibers and the biomimetic synthesis procedure. In subsequent investigations, Cui et al.⁹⁷ capitalized on collagen templates’ capacity to absorb calcium ions in an acidic milieu, introduced phosphate groups to modulate pH, and ultimately achieved “self-assembly” to obtain biomimetic MC. TEM observations revealed periodic contrast lines of approximately 67 nm within the collagen interior, while selected area electron diffraction (SAED) exhibited an oriented crystal structure, indicating a (002) preferred orientation. Consequently, the synthesized MC exhibits a composition and crystal structure akin to authentic bone structure at the micronano scale.⁹⁸

Biomimetic MC formulations typically exist in powder form and are commonly amalgamated with synthetic polymer materials to address substantial bone defects.^99–102 Drawing from the anatomical and physiological attributes of bone and inspired by the extracellular matrix, composite materials are engineered to possess strength akin to natural bone. Wang et al.³⁷ pioneered the fabrication of cortical MC scaffolds (compact mineralized collagen, cMC) and porous MC scaffolds (porous mineralized collagen, pMC). The pMC was prepared by mixing MC powder with PCL/1,4-dioxane solution and followed by freeze-drying. And cMC was prepared by mixing MC powder with melted PCL. MC powder and PCL are at a weight ratio of 1:1. Of course, an increase in MC content will also lead to an improvement in the strength of the scaffolds.³⁶ Mechanical evaluations in this investigation demonstrated that both cMC and pMC scaffolds exhibited compressive strength and elastic modulus levels comparable with those of natural cortical and cancellous bone, respectively. In vitro experiments revealed favorable biocompatibility, along with heightened osteogenic and osteoinductive activities, and a degree of biodegradability for both scaffold variants. In vivo assessments demonstrated the potential of biomimetic bone materials in regenerating and repairing large-sized skull defects in developing sheep. A sheep skull defect model, established at one month of age, served as a platform for evaluating the biological attributes, osteogenic inducibility, and biodegradation kinetics of the two scaffolds. Over a 6-month period of in vivo observation, both materials exhibited promising capabilities for bone repair. Although the acidic environment resulting from polymer degradation may potentially affect bone defect repair, the incorporation of MC fibrils may help buffer local acidity. As a result, preliminary in vivo evaluations revealed no significant cytotoxicity or pro-inflammatory responses. Notably, clinical follow-up of 105 patients who underwent cranioplasty using pMC, cMC, and biphasic MC (bMC) demonstrated relatively favorable outcomes, with evident new bone regeneration at the defect sites.¹⁰³ The results indicated that pMC is more suitable for the repair of small-scale defects, cMC is appropriate for large-area defect reconstruction, and bMC is particularly well-suited for repairing cranial defects in younger pediatric patients.

Hierarchical Structure of Natural Bone Inspires the Biomimetic Construction of Next-Generation Artificial Bone

The cortical bone is mainly composed of three main components: mineral component (∼65 wt%), organic component (∼25 wt%), and water (∼10 wt%).¹⁰⁴ The mineral component in bones is mainly composed of ion-substituted carbonated apatite (ic-HA) with slight impurities, such as carbonate (4–6%), sodium (0.9%), and Mg (0.5%) ions.³³ Type I collagen (97%) is the most abundant collagen and serves as a substrate for the formation of structures during bone mineralization.¹⁰⁵ Weiner et al.¹⁰⁶ defined bone structure into seven levels through a multilevel structural characteristic from nanoscale to micron scale to macroscale. Simply described as: Level 1, collagen fibers (50–70 nm in diameter) and ic-HA nanocrystals (2–3 nm thick); Level 2, MC fibrils structures; Level 3, the fibril bundles (micron-scale); Level 4, bundles were organized as different array patterns (3- to 7-µm thick); Level 5, Haverson system (200–300 µm diameter); Level 6, cancellous or cortical bone structural units; and Level 7, whole bone tissues.³⁵ Most intriguingly, beyond the multilayered structural order characteristic of the architectural hierarchy, HA crystals exhibit a specific crystallographic orientation in relation to collagen. SAED patterns revealed a pronounced (002) preferential orientation, growth along their crystallographic c-axis.¹⁰⁷ Despite its relatively simple components, achieving a truly bionic bone structure remains a challenge, with limited reports in the literature documenting successful attempts thus far. In this context, we propose multidimensional criteria for bionic bone repair materials, encompassing component structure bionics, performance bionics, and multifunctional bionics.¹⁰⁸ MC microfibril, which mimics the micronano structure and composition of natural bone, particularly collagen/HA, has garnered attention as a potential biomaterial for bone repair.¹⁰⁹ Nonetheless, pure micronanoscale structures struggle to effectively convey the macrostructural mechanical characteristics of materials. Thus, there is a proposal for higher-dimensional bionic bone structural strategies. Currently, research on select natural materials such as bones, nacre, and lobster cuticle offers boundless inspiration for the development of novel bionic structural materials.^110–112 However, the integration of mechanical properties with functional attributes through the precise control of hierarchical biomimetic nanocomposite design remains a formidable challenge. Hence, the primary focus lies in advancing the development of multilayered bionic bone structural materials. Concurrently, the creation of “natural bone structures” possessing multidimensional bionic significance holds promise in addressing the intricate challenges encountered in the realm of bone repair materials.

The lamellar structure stands out as the predominant fiber arrangement in bone, prevalent in both cortical and cancellous bone. It comprises approximately five consecutive and parallel layers of MC Microfibrils, each layer rotating by approximately 30°, creating a plywood-like configuration. This anisotropic and densely packed layered arrangement is crucial for the outstanding mechanical properties observed in natural bone. To replicate the intricate plywood-like structure of natural bone, a meticulously controlled approach termed the “multiscale cascade regulation strategy” has been devised.¹¹³ This strategy integrates nanoscale molecular self-assembly, micronanoscale electrospinning techniques, and macroscale pressure fusion methods to precisely guide the assembly process of collagen molecules and nano-hydroxyapatite crystals at room temperature (Fig. 1). Specifically, MC fibrils were synthesized via cotitration of a collagen/phosphate solution and a saturated Ca(OH)₂ solution at a molar ratio of Ca:P = 5:3. For the synthesis of element-doped MC microfibrils, designated cations and anions were introduced into the respective solutions, and mineralization was carried out under mildly alkaline buffered conditions. The electrospinning precursor solution was prepared by homogenously dispersing a defined amount of wet-state MC microfibrils into a 7 wt% collagen/hexafluoroisopropanol (HFIP) solution. Electrospinning was conducted under an applied voltage of 19 kV to achieve aligned fibrous sublayers, which were subsequently stacked with a 30° rotational offset.¹¹⁵ And the MC microfibrils align in a parallel orientation within the electrospun fiber bundles due to shear-induced forces at the nozzle tip. The multilayered structure was then consolidated under ambient pressure at room temperature to form a bulk material exhibiting a characteristic Bouligand structure.¹¹⁶

FIG. 1.

Fabrication process of ALB and ACB. (A) Self-assembly of MC microfibers; (B) Preparation of prespinning solution and frozen slurry; (C and D) The cascade regulation strategy is used to prepare ALB and ACB.¹¹⁴

Figure 2 illustrates the chemical composition and hierarchical assembly structure of the resulting centimeter-scale large artificial lamellar bone (ALB).¹¹³ The synthetic ALB closely mirrors the organizational pattern of natural lamellar bone, faithfully reproducing the hierarchical arrangement of MC microfibrils from the nano- to the macroscale. At the nanoscale, evidence from HRTEM morphology and fast Fourier transform (FFT) patterns verifies the in situ coassembly process of nano-hydroxyapatite and collagen microfibrils. The SAED pattern displays characteristic diffraction rings of nano-HA (nHA). Moreover, the electrospun collagen microfibrils exhibit a uniform diameter distribution of around 100 nm, resembling natural self-assembled mineralized fiber bundles. These microfibrils are aligned parallelly during the electrospinning process, resulting in a preferred orientation of the crystallographic plane (002) of HA approximately parallel to the longitudinal axis of the collagen fiber. At the micrometer scale, the electrospun collagen microfibrils are assembled into layers with ordered orientation, akin to the fiber array layer structure found in natural bone tissue. These oriented microfibril layers are then stacked incrementally at 30° orientations to simulate lamellar bone sublayer units, ultimately forming compact biomimetic bone structures at the centimeter scale after pressure-driven fusion. Importantly, the resulting sublayers maintain their original fiber orientation and structural arrangement. In subsequent work,¹¹⁴ the research team dispersed MC microfibrils in a 5 wt% PVA solution and subjected the slurry to gradient freezing. Following freeze-drying, a bulk material with parallel lamellar porosity was obtained, wherein the intralamellar MC fibrils exhibited aligned orientation. Upon compression at room temperature, an artificial cortical bone (ACB) structure with a mineral content of 60–70% was achieved. Compared with the ALB, ACB demonstrated a significantly higher mineral content; however, this enhancement came at the expense of interlamellar misalignment. The increased mineral content also resulted in reduced swelling capacity and degradation rate of the ACB structure. From a mechanical perspective, both ACB and ALB exhibited hierarchical architectures that conferred bone-matching strength and toughness, with bending strength exceeding 90 MPa and fracture toughness surpassing 2 MPa·m^1/2.

FIG. 2.

Hierarchical morphologies and mechanical properties of ALB at multiple scales. (A) Hierarchical organization of natural bone and synthetic ALB from nanoscale to macroscale; (B) TEM and SEM morphologies of MC microfibers, fibers, fiber bundles, and plywood-like structure. SAED patterns and FFT patterns shows (002) preferred orientation. (C) The mechanical properties corresponding to biomimetic materials.¹¹³

Discussion

Although these bone repair materials encompass various categories, including metals, ceramics, and composites, they all exhibit essential biological properties such as soft tissue protection and osseointegration.¹¹⁷ Table 1 compares the overall performance of several clinically used bone repair materials. Among them, the incorporation of MC fibers has significantly enhanced the clinical performance and application potential of polymer-based systems.^121–123 Although ALB and ACB have not yet been applied clinically, their favorable composition, architecture, mechanical properties, and degradability collectively demonstrate strong potential for clinical translation. The comprehensive performance is shown in Figure 3. Of particular interest, MC fibers substituted with bioactive elements can exhibit additional functional properties, bringing them closer to the biomimetic characteristics of ic-HA and native bone.

FIG. 3.

Multidimensional bionic bone structure synthesis strategy. The multidimensional biomimetic construction of bone structures achieves the preparation of biomimetic bone structures in terms of component structure biomimetic, mechanical biomimetic, and biological function biomimetic by integrating biomimetic mineralization and assembly processes.

Table 1.

Properties of Commonly Clinical Used Materials for Bone Repair

Material type	Mechanical property				Clinical performance						Ref.
Material type	Molding	Flexural strength (MPa)	Fracture toughness (MPa·m^1/2)	Modulus (GPa)	Radiography	Osseointegration	Toxicity	Degradation	Stress shielding	Infection risk	Ref.
Autologous
Nature bone	Split calvarium/Particulate corticocancellous/Exchange cranioplasty and difficult to shape	100.0–130.8	2.0–8.0	24.0–77.4	None	Potential to resorb	None	Moderation	Low	Low, but donor-site morbidity is high	^118–120
Alloplastic
Injectable bone cement	UV curable	<1.0	0.5	10⁻³–10⁻¹	None	Limited	None	Fast	Low	Low	^80–82
Porous HA ceramic	Cement form is moldable, but unworkable	2.0–50.0	0.5–1.2	1.0–10.0	Clear	Good	None	None	None	High	^74–76
PMMA	Easy to shape and process	0.8–2.0	45.7–50.1	3.2	Clear	Limited	Exothermic and potential toxicity	None	Weak	High	²⁰
PEEK	Easy to shape and process	80.1–100.8	1.5–2.4	3.7	Clear	Limited	None	None	Weak	Low	¹⁹
Ti/Ta alloy	Laser beam	800.0–1100.0	55.0–75.0	100.0–120.0	Artifact	Poor	Corrosion and potential toxicity	None	Strong	Low	^47–60
Mg alloy	3D print	100.0–255.0	5.0–15.0	40.0–45.0	Artifact	Limited	Corrosion and ion toxicity	Slow	Weak	Low	^64–69
Mineralized collagen/Polymer	Easy to shape and process	15.0–38.0	∼0.4	∼0.2	Clear	Excellent	None	Moderation of degradability depends on the structure	None	Low	^{36,37,95–97}
Artificial lamellae bone (ALB)	Multilevel structure	70.0–110.0	1.0–3.0	6.7–9.6	Clear	Excellent	None	Moderation	None	Low	¹¹³
Artificial compact bone (ACB)	Multilevel structure	96.0–97.5	0.78–1.1	5.8–7.3	Clear	Excellent	None	Moderation	None	Low	¹¹⁴

Hard materials found in nature have excellent damage resistance and achieve an optimal combination of hardness, strength, and toughness to cope with changes in the natural environment, such as seashells, teeth, and lobster claws.^118–120 One factor behind this ability is the multilevel structure of most biological and natural materials, which have unique structural features at multiple scales from molecules to near-macroscopic dimensions.¹²⁴ The biomimetic bone structure within the realm of bone tissue engineering diverges from material systems such as shells and teeth, given the more intricate multilevel composition of natural bone. The specificity of structure originates from the organized assembly of inorganic minerals by organic tissues acting as templates during the biological evolution process. These structures are closely related to the mechanical properties of multiscale reinforced materials. The difficulty in understanding the fracture mechanisms of these materials lies in determining the relative importance of these microstructural levels on crack initiation, crack propagation, and unstable fracture, as well as the impact of different levels of structure on critical fracture behavior.^125–127 Many studies have shown that these materials rely on both intrinsic and extrinsic toughening effects.^128–130 Human cortical bone provides a good example and can provide a feasible solution for the development of bionic materials.¹³¹ The origin of the intrinsic toughening mechanism is often at the smaller submicron length scale, while the extrinsic toughening and fracture processes occur at larger scales, usually up to micron level. Robert et al.¹³² conducted a systematic study on the anisotropic mechanical properties and fracture mechanism of bone structure. The process of fracturing in bone mainly originates from the external toughening mechanism, shown in crack bridging and crack deflection. This is caused by the deflection of the growing crack that encounters the mineralized interface of the bone structure. Since the size and spacing of bone structural units range from tens to hundreds of microns, the characteristic scale of this toughening method can approach millimeter dimensions.^133–135 The intrinsic toughening method of bone originates from the fiber sliding mechanism on the scale of tens to hundreds of nanometers, being the scale range related to MC fibers.¹³⁶

Building upon the understanding of the superior strengthening and toughening design advantage in natural bone fractures, it is essential in the design of biomimetic artificial bone materials to possess a certain level of strength and toughness to meet the service requirements during implantation in the body. By emulating the layered structure inherent in natural bone, the ALB and ACB present an opportunity for synergistic effects from both intrinsic and extrinsic toughening mechanisms.^137–139 Fracture analysis reveals that cracks initiate from notches ahead of the tip and progress along irregular paths. Various toughening mechanisms, such as crack deflection, twisting, microcracking, MC microfiber bridging, and crack branching, are evident, contributing significantly to extrinsic toughening. Intrinsic toughening primarily manifests in the behavior of MC microfibrils, involving sliding, bending, and pull-out during the yielding phase. This fundamental mechanism stems from sliding occurrences at the interface of HA and collagen, effectively dissipating energy and enhancing fracture resistance. Thus, the combined action of intrinsic and extrinsic toughening mechanisms can effectively redistribute and mitigate high stresses across multiple scales. The simultaneous presence of multiscale, multiphase, and microfiber conditions ultimately enhances the toughness of artificial bulk bone structures.^41,140,141

Although the assembly strategy is not difficult to understand, the advantages of natural materials remain challenging to surpass, especially in functions such as self-repair, recycling, and external adaptation. Moreover, the advancement of biomimetic materials is impeded by the absence of scalable manufacturing techniques and dependable design methodologies capable of mimicking diverse levels of ordered structures. Despite recent research endeavors in this domain, there exists an urgent imperative to innovate scalable manufacturing processes to propel the development of high-performance synthetic materials. 3D printing technology exhibits significant advantages in controlling the macroscopic structural precision and porosity of complex bone scaffolds.^76,142–144 However, it still faces substantial challenges in achieving nanoscale mineralization and precise regulation of the organic–inorganic interface. In contrast, biomimetic mineralization strategies offer effective simulation of the micro and nanoscale features of native bone tissue, particularly excelling in the orientation control of MC microfibrils and interfacial optimization. Nevertheless, biomimetic strategies alone are limited in their ability to precisely tailor the macroscopic architecture required for patient-specific bone scaffolds. Recent studies have demonstrated that integrating 3D printing with multiscale biomimetic mineralization enables the synergistic advantages of both technologies, combining the macroscopic precision of additive manufacturing with the micro/nanoscale structural and functional mimicry afforded by biomineralization. This integrated approach allows for coordinated biomimicry and performance enhancement across composition, structure, mechanical properties, and biological functionality and thus represents a promising direction for the development of next-generation high-performance biomimetic bone repair materials.

Conclusion

With the growing clinical demand for bone repair, current artificial bone scaffold materials still face limitations in terms of mechanical properties, bioactivity, and degradability. This review systematically evaluates the advantages and disadvantages of various classes of bone repair materials, including metals, ceramics, polymers, and their composites. Particular emphasis is placed on biomimetic MC materials, which exhibit promising clinical potential due to their excellent biocompatibility, osteoinductive capacity, and controllable degradability. However, conventional single-scale biomineralization strategies remain insufficient to fully replicate the complex hierarchical architecture of native bone tissue. To address this challenge, we propose a multiscale cascade regulation strategy that integrates nanoscale molecular self-assembly, electrospinning-based alignment, gradient freezing, and macroscale compression. This approach enables the fabrication of next-generation ACB materials with hierarchical structures closely resembling those of natural bone, achieving significant improvements in the balance between mechanical strength and toughness. Furthermore, the combination of this multiscale biomimetic strategy with advanced manufacturing techniques such as 3D printing is expected to overcome the limitations of individual approaches, offering synergistic enhancement in both macroscopic structural precision and microscale functional mimicry. This integrated technological framework provides a promising direction for the clinical translation of high-performance bone repair materials.

Authors’ Contributions

Y.Z.: Data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, software, writing—original draft, and writing—review & editing (The funding acquisition by Y.Z.). L.K.: Data curation, investigation, methodology, project administration, resources, software, and writing—original draft. T.N.: Investigation, methodology, project administration, resources, and writing—original draft. X.W.: Conceptualization, formal analysis, methodology, writing—original draft, and writing—review & editing.

Footnotes

Acknowledgments

The authors acknowledge the Basic Research and Strategic Reserve Technology Research Fund project of CNPC (No. 2023DQ03-10), and the National Natural Science Foundation of China (52502352).

Funding Information

No funding was received for this article.

Disclosure Statement

No competing financial interests exist.

References

Aydin

, Kucukyuruk

, Abuzayed

, et al. Cranioplasty: Review of materials and techniques. J Neurosci Rural Pract, 2011; 2(2):162–167; doi: 10.4103/0976-3147.83584

Szpalski

, Barr

, Wetterau

, et al. Cranial bone defects: Current and future strategies. Neurosurg Focus, 2010; 29(6):E8–E19; doi: 10.3171/2010.9.FOCUS10201

Chen

, Liu

, Manuchehrabadi

, et al. Umbilical cord and bone marrow mesenchymal stem cell seeding on macroporous calcium phosphate for bone regeneration in rat cranial defects. Biomaterials, 2013; 34(38):9917–9925; doi: 10.1016/j.biomaterials.2013.09.002

Fouda

, Seltzer

, Zappi

, et al. Posterior cranial vault distraction in children with syndromic craniosynostosis: The era of biodegradable materials-a comprehensive review of the literature and proposed novel global application. Childs Nerv Syst, 2024; 40(3):759–768; doi: 10.1007/s00381-023-06221-7

Perozzo

FAG

, Ku

, Kshettry

, et al. High-density porous polyethylene implant cranioplasty: A systematic review of outcomes. J Craniofac Surg, 2024; 35(4):1074–1079; doi: 10.1097/SCS.0000000000010135

Shields

, Vessell

, Mutchnick

. Epidural effusion as allergic reaction following polyetheretherketone cranioplasty: An illustrative case and review of the literature. Cureus Journal of Medical Science, 2022; 14(1):e21390; doi: 10.7759/cureus.21390

Aprianto

, Parenrengi

, Utomo

, et al. Autograft and implant cranioplasty in pediatric patients. IJHMS, 2022; 5(1):129–136; doi: 10.21744/ijhms.v5n1.1852

Hersh

, Anderson

, Woodworth

, et al. Bone flap resorption in pediatric patients following autologous cranioplasty. Oper Neurosurg, 2021; 20(5):436–443; doi: 10.1093/ons/opaa452

Aprianto

, Parenrengi

, Utomo

, et al. Comparison of autograft and implant cranioplasty in pediatrics: A meta-analysis. Surg Neurol Int, 2022; 13:406; doi: 10.25259/SNI_1204_2021

10.

Dang

, Echevarría

, Martin

, et al. Repeat exchange autologous cranioplasty for recurrent benign osteoma: Meta-analysis and literature review. J Craniofac Surg, 2024; 35(8); doi: 10.1097/SCS.0000000000010530

11.

Perry

, Lee

, Kilcommons

, et al. Immediate and long-term outcomes of autologous and alloplastic cranioplasty in pediatric population. J Craniofac Surg, 2025; 10; doi: 10.1097/SCS.0000000000011463

12.

Minmin

, Shihai

, Mingzi

, et al. Current status and prospects of metal–organic frameworks for bone therapy and bone repair. J Materials Chemistry, B, 2022; 10(27):5105–5128; doi: 10.1039/D2TB00742H

13.

Rong

, Yen

, Adnan

, et al. Cementoplasty to cryoablation: Review and current status. Br J Radiol, 2024; 6(1):tzae007; doi: 10.1093/bjro/tzae007

14.

Shi

, Chen

, et al. Application of additively manufactured bone scaffold: A systematic review. Biofabrication, 2024; 16(2); doi: 10.1088/1758-5090/ad35e8

15.

Fatima

, Negi

, Jarial

, et al. Various materials used for the repair of bone defects: A review. JDP, 2023; 5(1):13–16; doi: 10.18231/j.jdp.2023.003

16.

Luo

, Xiao

, Yang

, et al. Biomaterials for surgical repair of osteoporotic bone defects. Chinese Chemical Letters, 2025; 36(1):109684; doi: 10.1016/j.cclet.2024.109684

17.

Czyżewski

, Jachimczyk

, Hoffman

, et al. Low-cost cranioplasty-a systematic review of 3D printing in medicine. Materials (Basel), 2022; 15(14):4731; doi: 10.3390/ma15144731

18.

Salam

, Ibbett

, Thani

. Material of choice in pediatric cranioplasty. Indian Journal of Neurosurgery, 2021; 10(02):103–107; doi: 10.1055/s-0040-1716933

19.

Kurapati

, Mahendar Reddy

, Sujithra

, et al. Nanomaterials and nanostructures in additive manufacturing: Properties, applications, and technological challenges. Nanotechnol‐Based Additive Manufac: Product Design, Properties Applications, 2023; 1:53–102; doi: 10.1002/9783527835478.ch3

20.

Boschetto

, Honma

, Adachi

, et al. Development and evaluation of osteogenic pmma bone cement composite incorporating curcumin for bone repairing. Mater Today Chem, 2023; 27:101307; doi: 10.1016/j.mtchem.2022.101307

21.

Aghayan

, Alizadeh

, Keshavarz

. Multifunctional polyethylene imine hybrids decorated by silica bioactive glass with enhanced mechanical properties, antibacterial, and osteogenesis for bone repair. Mater Sci Eng C Mater Biol Appl, 2021; 131:112534; doi: 10.1016/j.msec.2021.112534

22.

Guo

, Huang

, Sun

, et al. Ti-Mo-Zr alloys for bone repair: Mechanical properties, corrosion resistance, and biological performance. J Mater Res Technol, 2023; 24:7624–7637; doi: 10.1016/j.jmrt.2023.05.006

23.

, Wang

, Ying

, et al. Mild photothermal therapy assist in promoting bone repair: Related mechanism and materials. Mater Today Bio, 2023; 23:100834; doi: 10.1016/j.mtbio.2023.100834

24.

Zhang

, Xie

, Zhang

. Mesenchymal stem cells plus bone repair materials as a therapeutic strategy for abnormal bone metabolism: Evidence of clinical efficacy and mechanisms of action implied. Pharmacol Res, 2021; 172:105851; doi: 10.1016/j.phrs.2021.105851

25.

Khalid

, Thomson

, Maasarani

, et al. Materials used in cranial reconstruction: A systematic review and meta-analysis. World Neurosurg, 2022; 164:e945–e963; doi: 10.1016/j.wneu.2022.05.073

26.

Zhu

, Jiang

, Zhang

, et al. Biofunctionalized composite scaffold to potentiate osteoconduction, angiogenesis, and favorable metabolic microenvironment for osteonecrosis therapy. Bioact Mater, 2022; 9:446–460; doi: 10.1016/j.bioactmat.2021.08.005

27.

Niu

, Wang

, Shi

, et al. Modulating macrophage activities to promote endogenous bone regeneration: Biological mechanisms and engineering approaches. Bioact Mater, 2021; 6(1):244–261; doi: 10.1016/j.bioactmat.2020.08.012

28.

Zhang

, Tong

, Song

, et al. Osteoimmunity-regulating biomimetically hierarchical scaffold for augmented bone regeneration. Adv Mater, 2022; 34(36):e2202044; doi: 10.1002/adma.202202044

29.

Zhu

, Jiang

, Zhang

, et al. Construction and validation of steroid-induced rabbit osteonecrosis model. MethodsX, 2022; 9:101713; doi: 10.1016/j.mex.2022.101713

30.

Bai

, Chen

, Delattre

, et al. Bioinspired large-scale aligned porous materials assembled with dual temperature gradients. Sci Adv, 2015; 1(11):e1500849; doi: 10.1126/sciadv.1500849

31.

Cao

, Liu

, Zhu

, et al. Nature-inspired hierarchical steels. Sci Rep, 2018; 8(1):5088; doi: 10.1038/s41598-018-23358-7

32.

Liu

, Zhu

, Jiao

, et al. Enhanced protective role in materials with gradient structural orientations: Lessons from nature. Acta Biomater, 2016; 44:31–40; doi: 10.1016/j.actbio.2016.08.005

33.

Liu

, Luo

, Wang

. Hierarchical structures of bone and bioinspired bone tissue engineering. Small, 2016; 12(34):4611–4632; doi: 10.1002/smll.201600626

34.

Peng

, Cheng

. High-performance nanocomposites inspired by nature. Adv Mater, 2017; 29(45); doi: 10.1002/adma.201702959

35.

Olszta

, Cheng

, Jee

, et al. Bone structure and formation: A new perspective. Materials Sci Eng: R: Reports, 2007; 58(3–5):77–116; doi: 10.1016/j.mser.2007.05.001

36.

Wang

, Yang

, Zhao

, et al. Mineralized collagen-based composite bone materials for cranial bone regeneration in developing sheep. ACS Biomater Sci Eng, 2017; 3(6):1092–1099; doi: 10.1021/acsbiomaterials.7b00159

37.

Wang

, Zhao

, Yang

, et al. A high-strength mineralized collagen bone scaffold for large-sized cranial bone defect repair in sheep. Regen Biomater, 2018; 5(5):283–292; doi: 10.1093/rb/rby020

38.

Feng

, Zhang

, Cui

, et al. Clinical evaluations of mineralized collagen in the extraction sites preservation. Regen Biomater, 2016; 3(1):41–48; doi: 10.1093/rb/rbv027

39.

Xia

, Hu

, Ma

, et al. Robust hierarchical porous polycaprolactone/nano-hydroxyapatite/polyethylene glycol scaffolds with boosted in vitro osteogenic ability. Colloids Surfaces A: Physicochem Engineering Aspects, 2024; 681:132740; doi: 10.1016/j.colsurfa.2023.132740

40.

Elshirbiny

, Ahmed

, Amen

. Autograft cranioplasty for skull defects in children. Interdisciplinary Neurosurgery, 2023; 33:101789; doi: 10.1016/j.inat.2023.101789

41.

Wang

, Fang

, Zhu

, et al. Bioinspired highly anisotropic, ultrastrong and stiff, and osteoconductive mineralized wood hydrogel composites for bone repair. Adv Funct Materials, 2021; 31(20); doi: 10.1002/adfm.202010068

42.

Chen

, Cheng

, Wu

. Recent trends in bone defect repair and bone tissue regeneration of the two-dimensional material mxene. Ceram Int, 2023; 49(12):19578–19594; doi: 10.1016/j.ceramint.2023.03.109

43.

Battistelli

, Calabria

, Giani

, et al. Perioperative management and outcomes of pediatric craniosynostosis patients undergoing cranioplasty: A retrospective analysis. J Craniofac Surg, 2025; 36(1):215–218; doi: 10.1097/SCS.0000000000010723

44.

Henry

, Amoo

, Taylor

, et al. Complications of cranioplasty in relation to material: Systematic review, network meta-analysis and meta-regression. Neurosurgery, 2021; 89(3):383–394; doi: 10.1093/neuros/nyab180

45.

Zaed

, Tinterri

. Comparison of complications in cranioplasty with various materials: A systematic review and meta-analysis. Br J Neurosurg, 2022; 36(5):661; doi: 10.1080/02688697.2020.1814995

46.

Zhao

, Shu

, Yu

, et al. Metal-organic frameworks functionalized biomaterials for promoting bone repair. Mater Today Bio, 2023; 21:100717; doi: 10.1016/j.mtbio.2023.100717

47.

Huang

, Pan

S-T

, Qiu

J-X

. The osteogenic effects of porous tantalum and titanium alloy scaffolds with different unit cell structure. Colloids Surf B Biointerfaces, 2022; 210:112229; doi: 10.1016/j.colsurfb.2021.112229

48.

Jing

, Ni

, Wang

, et al. Practical strategy to construct anti-osteosarcoma bone substitutes by loading cisplatin into 3D-printed titanium alloy implants using a thermosensitive hydrogel. Bioact Mater, 2021; 6(12):4542–4557; doi: 10.1016/j.bioactmat.2021.05.007

49.

Shao

, Zhang

, Sun

, et al. Effects of hydroxyapatite-coated porous titanium scaffolds functionalized by exosomes on the regeneration and repair of irregular bone. Front Bioeng Biotechnol, 2023; 11:1283811; doi: 10.3389/fbioe.2023.1283811

50.

Xie

, Sun

, Mu

, et al. Tribological behavior and in vitro biocompatibility of powder metallurgical ti–15mo/ha composite for bone repair. J Mech Behav Biomed Mater, 2024; 152:106466; doi: 10.1016/j.jmbbm.2024.106466

51.

, Zhu

, Jing

, et al. Effect of 3d-printed porous titanium alloy pore structure on bone regeneration: A review. Coatings, 2024; 14(3):253; doi: 10.3390/coatings14030253

52.

Sun

, Shi

, Niu

, et al. Mg-Sr-Ca containing bioactive glass nanoparticles hydrogel modified mineralized collagen scaffold for bone repair. J Biomater Appl, 2024; 39(2):117–128; doi: 10.1177/08853282241254741

53.

Wang

, Mao

, Jiao

, et al. Novel nano-thin amorphous ta-coating on 3d-printed porous tc4 implant: Microstructure and enhanced biological effects. Materials & Design, 2024; 242:112986; doi: 10.1016/j.matdes.2024.112986

54.

Liang

, Zhong

, Jiang

, et al. Fabrication of porous tantalum with low elastic modulus and tunable pore size for bone repair. ACS Biomater Sci Eng, 2023; 9(3):1720–1728; doi: 10.1021/acsbiomaterials.2c01239

55.

Liu

, Zhang

, Chen

, et al. Bioactive and fatigue-resistant ti–ta alloy by additive manufacturing for orthopedic applications. Smart Materials Manufacturing, 2025; 3:100086; doi: 10.1016/j.smmf.2025.100086

56.

Qian

, Lei

, et al. Additively manufactured tantalum implants for repairing bone defects: A systematic review. Tissue Eng Part B Rev, 2021; 27(2):166–180; doi: 10.1089/ten.TEB.2020.0134

57.

Fan

, Chen

, Yang

, et al. Metallic materials for bone repair. Adv Healthc Mater, 2024; 13(3):e2302132; doi: 10.1002/adhm.202302132

58.

Sun

, Tong

, Yang

, et al. The effects of graphene on the biocompatibility of a 3D-printed porous titanium alloy. Coatings, 2021; 11(12):1509; doi: 10.3390/coatings11121509

59.

Meyer

, Khalid

, Dorafshar

, et al. The materials utilized in cranial reconstruction: Past, current, and future. Plast Surg (Oakv), 2021; 29(3):184–196; doi: 10.1177/2292550320928560

60.

Qian

, Yao

, Pi

, et al. Current advances and applications of tantalum element in infected bone defects. ACS Biomater Sci Eng, 2023; 9(1):1–19; doi: 10.1021/acsbiomaterials.2c00884

61.

Frassanito

, Beez

. Cranial repair in children: Techniques, materials, and peculiar issues. Adv Tech Stand Neurosurg, 2024; 49:307–326; doi: 10.1007/978-3-031-42398-7_14

62.

Mannella

, Faedo

, Fumagalli

, et al. Long-term follow-up of custom-made porous hydroxyapatite cranioplasties: Analysis of infections in adult and pediatric patients. J Clin Med, 2024; 13(4):1133; doi: 10.3390/jcm13041133

63.

Zaed

, Cardia

, Stefini

. From reparative surgery to regenerative surgery: State of the art of porous hydroxyapatite in cranioplasty. Int J Mol Sci, 2022; 23(10):5434; doi: 10.3390/ijms23105434

64.

Xie

, Wang

, Zhang

, et al. Developing new mg alloy as potential bone repair material via constructing weak anode nano-lamellar structure. J Magnesium Alloys, 2023; 11(1):154–175; doi: 10.1016/j.jma.2022.08.011

65.

Zhang

, Ding

, Wang

, et al. Study on degradation behavior of porous magnesium alloy scaffold loaded with rhbmp-2 and repair of bone defects. J Mater Res Technol, 2024; 30:6498–6507; doi: 10.1016/j.jmrt.2024.04.227

66.

, Shen

, Liu

, et al. Biodegradable zn-2cu-0.5zr alloy promotes the bone repair of senile osteoporotic fractures via the immune-modulation of macrophages. Bioact Mater, 2024; 38:422–437; doi: 10.1016/j.bioactmat.2024.05.003

67.

Dong

, Zhang

, Zhou

, et al. 3D-printed mg-incorporated pcl-based scaffolds: A promising approach for bone healing. Mater Sci Eng C Mater Biol Appl, 2021; 129:112372; doi: 10.1016/j.msec.2021.112372

68.

Huo

, Li

, Jiang

, et al. Porous Mg-Zn-Ca scaffolds for bone repair: A study on microstructure, mechanical properties and in vitro degradation behavior. J Mater Sci Mater Med, 2024; 35(1):22; doi: 10.1007/s10856-023-06754-y

69.

Zhang

, Lin

, Meng

, et al. 3D gel-printed porous magnesium scaffold coated with dibasic calcium phosphate dihydrate for bone repair in vivo. J Orthop Translat, 2022; 33:13–23; doi: 10.1016/j.jot.2021.11.005

70.

Chen

, Zhou

, Fan

, et al. 3d printing for bone repair: Coupling infection therapy and defect regeneration. Chem Eng J, 2023; 471:144537; doi: 10.1016/j.cej.2023.144537

71.

, Sun

, Wang

, et al. Effects of mgo nanoparticle addition on the mechanical properties, degradation properties, antibacterial properties and in vitro and in vivo biological properties of 3d-printed zn scaffolds. Bioact Mater, 2024; 37:72–85; doi: 10.1016/j.bioactmat.2024.03.016

72.

Zhou

, Liang

, Jiang

, et al. Magnesium-based biomaterials as emerging agents for bone repair and regeneration: From mechanism to application. J Magnesium Alloys, 2021; 9(3):779–804; doi: 10.1016/j.jma.2021.03.004

73.

Christie

, Musri

, Djustiana

, et al. Advances and challenges in regenerative dentistry: A systematic review of calcium phosphate and silicate-based materials on human dental pulp stem cells. Mater Today Bio, 2023; 23:100815; doi: 10.1016/j.mtbio.2023.100815

74.

, Ye

, Liu

, et al. An overview on bioactive glasses for bone regeneration and repair: Preparation, reinforcement, and applications. Tissue Eng Part B Rev, 2025; 10; doi: 10.1089/ten.teb.2024.0272

75.

Alshareef

, Alshareef

, Vasas

, et al. Pediatric cranioplasty using hydroxyapatite cement: A retrospective review and preliminary computational model. Pediatr Neurosurg, 2022; 57(1):40–49; doi: 10.1159/000520954

76.

De Santis

, Russo

, Rau

, et al. Design of 3D additively manufactured hybrid structures for cranioplasty. Materials (Basel), 2021; 14(1):181; doi: 10.3390/ma14010181

77.

Bhat

, Uthappa

, Altalhi

, et al. Functionalized porous hydroxyapatite scaffolds for tissue engineering applications: A focused review. ACS Biomater Sci Eng, 2022; 8(10):4039–4076; doi: 10.1021/acsbiomaterials.1c00438

78.

, Zhao

, Yan

, et al. Advances in magnesium-containing bioceramics for bone repair. Biomater Transl, 2024; 5(1):3–20; doi: 10.12336/biomatertransl.2024.01.002

79.

Sun

, Thakur

. Bio-ceramics and bio-glasses for orthopedics and tissue engineering. In: Integrated Nanomaterials and Their Applications. Springer. 2023, 12: 177–200; doi: 10.1007/978-981-99-6105-4_9

80.

Surana

, Dhull

, Arya

, et al. Bio-ceramics application in dentistry. Bioinformation, 2024; 20(2):136–139; doi: 10.6026/973206300200136

81.

Jung

J-W

, Kim

D-S

, Lee

J-K

, et al. Advanced α-csh/β-tcp-based injectable paste with magnesium hydroxide and vitamin d-incorporated plga microspheres for bone repair. Mater Today Adv, 2023; 20:100447; doi: 10.1016/j.mtadv.2023.100447

82.

Budharaju

, Suresh

, Sekar

, et al. Ceramic materials for 3d printing of biomimetic bone scaffolds – current state-of-the-art & future perspectives. Materials & Design, 2023; 231:112064; doi: 10.1016/j.matdes.2023.112064

83.

, Gao

, Zhou

, et al. Bioactive pore-forming bone adhesives facilitating cell ingrowth for fracture healing. Adv Mater, 2020; 32(10):e1907491; doi: 10.1002/adma.201907491

84.

, Ma

, Yuan

, et al. Cranial suture regeneration mitigates skull and neurocognitive defects in craniosynostosis. Cell, 2021; 184(1):243–256 e218; doi: 10.1016/j.cell.2020.11.037

85.

, Wang

, Zhang

, et al. Biomimetic periosteum-bone substitute composed of preosteoblast-derived matrix and hydrogel for large segmental bone defect repair. Acta Biomater, 2020; 113:317–327; doi: 10.1016/j.actbio.2020.06.030

86.

Tian

, Wu

, Qin

, et al. Composite materials combined with stem cells promote kidney repair and regeneration. Composites Part B: Eng, 2024; 275:111278; doi: 10.1016/j.compositesb.2024.111278

87.

, Dai

, Zhang

, et al. Pore size of 3d-printed polycaprolactone/polyethylene glycol/hydroxyapatite scaffolds affects bone regeneration by modulating macrophage polarization and the foreign body response. ACS Appl Mater Interfaces, 2022; 14(18):20693–20707.

88.

Liu

, Sun

, Zhu

, et al. Microstructures and properties of polycaprolactone/tricalcium phosphate scaffolds containing polyethylene glycol fabricated by 3D printing. Ceram Int, 2022; 48(16):24032–24043.

89.

, Wang

, et al. High-strength porous polyetheretherketone/hydroxyapatite composite for the treatment of bone defect. Composites Communications, 2023; 38:101473.

90.

, Yuan

, Lin

, et al. An injectable bone paste of poly (lactic acid)/zinc-doped nano hydroxyapatite composite microspheres for skull repair. Colloids Surf B Biointerfaces, 2024; 239:113969; doi: 10.1016/j.colsurfb.2024.113969

91.

, Ma

, Han

, et al. Microbially catalyzed biomaterials for bone regeneration. Adv Mater, 2021; 33(49):e2104829; doi: 10.1002/adma.202104829

92.

Shen

, Zhang

, Gu

, et al. Sequential and sustained release of sdf-1 and bmp-2 from silk fibroin-nanohydroxyapatite scaffold for the enhancement of bone regeneration. Biomaterials, 2016; 106:205–216; doi: 10.1016/j.biomaterials.2016.08.023

93.

Yao

, Cosme

, Xu

, et al. Three dimensional electrospun PCL/PLA blend nanofibrous scaffolds with significantly improved stem cells osteogenic differentiation and cranial bone formation. Biomaterials, 2017; 115:115–127; doi: 10.1016/j.biomaterials.2016.11.018

94.

Wang

, Wang

, et al. Endothelialized microvessels fabricated by microfluidics facilitate osteogenic differentiation and promote bone repair. Acta Biomater, 2022; 142:85–98; doi: 10.1016/j.actbio.2022.01.055

95.

Zhang

, Liao

, Cui

. Hierarchical self-assembly of nano-fibrils in mineralized collagen. Chem Mater, 2003; 15(16):3221–3226.

96.

Wang

X-M

, Cui

F-Z

, Ge

, et al. Alterations in mineral properties of zebrafish skeletal bone induced by liliputdtc232 gene mutation. J Cryst Growth, 2003; 258(3–4):394–401; doi: 10.1016/s0022-0248(03)01543-4

97.

Cui

, Wang

, Cai

, et al. Conformation change of collagen during the initial stage of biomineralization of calcium phosphate. J Mater Chem, 2008; 18(32):3835; doi: 10.1039/b805467c

98.

Wang

, Cui

, Ge

, et al. Hierarchical structural comparisons of bones from wild-type and liliputdtc232 gene-mutated zebrafish. J Struct Biol, 2004; 145(3):236–245; doi: 10.1016/j.jsb.2003.10.028

99.

Kolliopoulos

, Harley

. Mineralized collagen scaffolds for regenerative engineering applications. Curr Opin Biotechnol, 2024; 86:103080; doi: 10.1016/j.copbio.2024.103080

100.

, Du

, Ruan

, et al. Bioinspired mineralized collagen scaffolds for bone tissue engineering. Bioact Mater, 2021; 6(5):1491–1511; doi: 10.1016/j.bioactmat.2020.11.004

101.

Oosterlaken

, Vena

, De With

. In vitro mineralization of collagen. Adv Mater, 2021; 33(16):e2004418; doi: 10.1002/adma.202004418

102.

Peng

, Zhang

, Wang

, et al. Guided bone regeneration in long-bone defect with a bilayer mineralized collagen membrane. Collagen & Leather, 2023; 5(1):36–49; doi: 10.1186/s42825-023-00144-4

103.

Tuoyu

, Shuo

, Bo

, et al. Clinical application of mineralized collagen biomimetic bone materials in skull defect repair surgery. Chinese J Reparative Reconstructive Surgery, 2024; 38(12):1427–1432; doi: 10.7507/1002-1892.202405012

104.

Mac

, Chan

, Lin

, et al. Engineering a biomimetic bone scaffold that can regulate redox homeostasis and promote osteogenesis to repair large bone defects. Biomaterials, 2022; 286:121574; doi: 10.1016/j.biomaterials.2022.121574

105.

Seok

H-S

, Herr

, Chung

J-H

, et al. The effect of composite graft with deproteinized bovine bone mineral and mineralized solvent-dehydrated bone on exophytic bone formation in rabbit calvarial model. Tissue Eng Regen Med, 2014; 11(6):467–475; doi: 10.1007/s13770-014-9055-5

106.

Weiner

, Wagner

. The material bone: Structure-mechanical function relations. Annu Rev Mater Sci, 1998; 28(1):271–298; doi: 10.1146/annurev.matsci.28.1.271

107.

Launey

, Chen

, Mckittrick

, et al. Mechanistic aspects of the fracture toughness of elk antler bone. Acta Biomater, 2010; 6(4):1505–1514; doi: 10.1016/j.actbio.2009.11.026

108.

Monn

, Vijaykumar

, Kochiyama

, et al. Lamellar architectures in stiff biomaterials may not always be templates for enhancing toughness in composites. Nat Commun, 2020; 11(1):373; doi: 10.1038/s41467-019-14128-8

109.

Zhang

, Huang

, Liao

, et al. Nucleation sites of calcium phosphate crystals during collagen mineralization. J American Ceramic Soci, 2003; 86(6):1052–1054; doi: 10.1111/j.1151-2916.2003.tb03422.x

110.

Simon

, Gruner

, Worch

, et al. First evidence of octacalcium phosphate@osteocalcin nanocomplex as skeletal bone component directing collagen triple-helix nanofibril mineralization. Sci Rep, 2018; 8(1):13696; doi: 10.1038/s41598-018-31983-5

111.

Niu

L-N

, Jee

, Jiao

, et al. Collagen intrafibrillar mineralization as a result of the balance between osmotic equilibrium and electroneutrality. Nat Mater, 2017; 16(3):370–378; doi: 10.1038/nmat4789

112.

, Xu

, Liu

, et al. An instantly fixable and self-adaptive scaffold for skull regeneration by autologous stem cell recruitment and angiogenesis. Nat Commun, 2022; 13(1):2499; doi: 10.1038/s41467-022-30243-5

113.

Zhao

, Zheng

, Xiong

, et al. Hierarchically engineered artificial lamellar bone with high strength and toughness. Small Struct, 2023; 4(3):2200256; doi: 10.1002/sstr.202200256

114.

Kong

, Zhao

, Xiong

, et al. Multiscale engineered artificial compact bone via bidirectional freeze-driven lamellated organization of mineralized collagen microfibrils. Bioact Mater, 2024; 40:168–181; doi: 10.1016/j.bioactmat.2024.02.005

115.

Robin

, Mouloungui

, Castillo Dali

, et al. Mineralized collagen plywood contributes to bone autograft performance. Nature, 2024; 636(8041):100–107; doi: 10.1038/s41586-024-08208-z

116.

Yuan

, Feng

, Wang

, et al. Sword and board in one: A bioinspired nanocomposite membrane for guided bone regeneration. Adv Mater, 2025:e2504577; doi: 10.1002/adma.202504577

117.

Zheng

, Zhao

, Yang

, et al. Biphasic mineralized collagen-based composite scaffold for cranial bone regeneration in developing sheep. Regen Biomater, 2022; 9:rbac004; doi: 10.1093/rb/rbac004

118.

Wang

, Yang

, Huo

, et al. Engineering single-atomic iron-catalyst-integrated 3d-printed bioscaffolds for osteosarcoma destruction with antibacterial and bone defect regeneration bioactivity. Adv Mater, 2021; 33(31):e2100150; doi: 10.1002/adma.202100150

119.

Wang

, Jiang

, Zhang

, et al. Biomimetic nanosilica-collagen scaffolds for in situ bone regeneration: Toward a cell-free, one-step surgery. Adv Mater, 2019; 31(49):e1904341; doi: 10.1002/adma.201904341

120.

Wang

, Zhao

, Tang

, et al. Multifunctional nanoengineered hydrogels consisting of black phosphorus nanosheets upregulate bone formation. Small, 2019; 15(41):e1901560; doi: 10.1002/smll.201901560

121.

Song

, Hu

, Liu

, et al. Design and fabrication of drug-loaded alginate/hydroxyapatite/collagen composite scaffolds for repairing infected bone defects. J Mater Sci, 2023; 58(2):911–926; doi: 10.1007/s10853-022-08053-3

122.

, Chen

, Guo

, et al. Collagen mineralization and its applications in hard tissue repair. Mater Chem Front, 2021; 5(19):7071–7087; doi: 10.1039/D1QM00901J

123.

Zhu

, Li

, Yao

, et al. Advances in osseointegration of biomimetic mineralized collagen and inorganic metal elements of natural bone for bone repair. Regen Biomater, 2023; 10:rbad030; doi: 10.1093/rb/rbad030

124.

Nalla

, Kinney

, Ritchie

. Mechanistic fracture criteria for the failure of human cortical bone. Nat Mater, 2003; 2(3):164–168; doi: 10.1038/nmat832

125.

Ritchie

. The conflicts between strength and toughness. Nat Mater, 2011; 10(11):817–822; doi: 10.1038/nmat3115

126.

Motomichi

, Meimei

, Dirk

, et al. Bone-like crack resistance in hierarchical metastable nanolaminate steels. Science (1979), 2017; 355:1055–1057; doi: 10.1126/science.aal2766

127.

Gupta

, Wagermaier

, Zickler

, et al. Nanoscale deformation mechanisms in bone. Nano Lett, 2005; 5(10):2108–2111; doi: 10.1021/nl051584b

128.

Liu

, Weng

, Zhai

, et al. Hydration-induced nano- to micro-scale self-recovery of the tooth enamel of the giant panda. Acta Biomater, 2018; 81:267–277; doi: 10.1016/j.actbio.2018.09.053

129.

Wilkerson

, Gludovatz

, Ell

, et al. High-temperature damage-tolerance of coextruded, bioinspired (“nacre-like”), alumina/nickel compliant-phase ceramics. Scr Mater, 2019; 158:110–115; doi: 10.1016/j.scriptamat.2018.08.046

130.

Wilkerson

, Gludovatz

, Watts

, et al. A study of size effects in bioinspired, “nacre-like”, metal-compliant-phase (nickel-alumina) coextruded ceramics. Acta Mater, 2018; 148:147–155; doi: 10.1016/j.actamat.2018.01.046

131.

Koester

, Ager

3rd , Ritchie

. The true toughness of human cortical bone measured with realistically short cracks. Nat Mater, 2008; 7(8):672–677; doi: 10.1038/nmat2221

132.

Launey

, Buehler

, Ritchie

. On the mechanistic origins of toughness in bone. Annu Rev Mater Res, 2010; 40(1):25–53; doi: 10.1146/annurev-matsci-070909-104427

133.

Chen

, Tang

, Jia

, et al. Graphene oxide bulk material reinforced by heterophase platelets with multiscale interface crosslinking. Nat Mater, 2022; 21(10):1121–1129; doi: 10.1038/s41563-022-01292-4

134.

Zhao

, Liu

, Wei

, et al. Multiscale engineered artificial tooth enamel. Science, 2022; 375(6580):551–556; doi: 10.1126/science.abj3343

135.

Yang

, Wu

, Guan

, et al. Enhancing the mechanical toughness of epoxy-resin composites using natural silk reinforcements. Sci Rep, 2017; 7(1):11939; doi: 10.1038/s41598-017-11919-1

136.

Reznikov

, Bilton

, Lari

, et al. Fractal-like hierarchical organization of bone begins at the nanoscale. Science, 2018; 360(6388):eaao2189; doi: 10.1126/science.aao2189

137.

Zhao

, Tan

, Ji

, et al. In situ study of cementite deformation and its fracture mechanism in pearlitic steels. Materials Sci Eng: A, 2018; 731:93–101; doi: 10.1016/j.msea.2018.05.114

138.

Zhao

, Xiang

, Tan

, et al. Microstructure transformation on pre-quenched and ultrafast-tempered high-strength multiphase steels. Materials (Basel), 2019; 12(3):396; doi: 10.3390/ma12030396

139.

Zhao

, Tan

, Ji

, et al. Microstructural dependence of anisotropic fracture mechanisms in cold-drawn pearlitic steels. Materials Sci Eng: A, 2018; 735:250–259; doi: 10.1016/j.msea.2018.08.044

140.

Zhang

, Wu

, Sun

, et al. Hybrid materials from ultrahigh‐inorganic‐content mineral plastic hydrogels: Arbitrarily shapeable, strong, and tough. Adv Funct Materials, 2020; 30(19):201910425; doi: 10.1002/adfm.201910425

141.

Peng

, Huang

, Cao

, et al. Inverse nacre-like epoxy-graphene layered nanocomposites with integration of high toughness and self-monitoring. Matter, 2020; 2(1):220–232; doi: 10.1016/j.matt.2019.08.013

142.

, Chang

, Zhu

, et al. 3d printing of bioinspired biomaterials for tissue regeneration. Adv Healthc Mater, 2020; 9(23):e2000208; doi: 10.1002/adhm.202000208

143.

Tan

, Gan

, Wang

, et al. Applications of 3d bioprinting in tissue engineering: Advantages, deficiencies, improvements, and future perspectives. J Mater Chem B, 2021; 9(27):5385–5413; doi: 10.1039/D1TB00172H

144.

Mai

, Popov

, Mishina

, et al. 3D printing in pediatric neurosurgery: Experimental study of a novel approach using biodegradable materials. Childs Nerv Syst, 2024; 40(6):1881–1888; doi: 10.1007/s00381-024-06342-7