Understanding Hierarchical Structure Construction Strategies and Biomimetic Design Principles: A Review

Organisms use gene and cell engineering to tailor the mineralization process and synthesize structure composites with special functions and favorable properties. This spurs scientists to design functional materials based on learning from nature. Herein, a systematic review of the biomimetic synthesis and hierarchical structure design of calcium carbonate–based minerals is presented. First, biomimetic synthesis strategies, including additive‐induced, template‐oriented, and gel‐mediated routes to direct the construction of the hierarchical structure, are reviewed. The molecular‐recognition technique and directional assembly pathway are then summarized to precisely describe the interactions between inorganic minerals and organic matter, and direct the mineral growth. Next, the underlying mineralization mechanisms governing the evolution of the complex morphology and structure are discussed. Nonclassical pathways that control mineral growth, including the theories of the amorphous phase, oriented attachment, mesocrystal formation, and liquid precursor, are concluded. Finally, herein, the applications of calcium carbonate–based minerals are discussed. Unique hierarchical structure endows minerals with special functions, including optical performance, biomedical applications, and environmental and ecological restoration. Overall, in this report, the biomimetic synthesis of calcium carbonate–based minerals is reviewed, covering the fundamental principles, construction of the hierarchical structure, underlying mechanisms of mineral growth, and functional designs.


Introduction
Under natural selection and long-term evolution, organisms can fabricate delicate structures with specific functions to meet their demands.Complex hierarchical structures and ingenious assemblies endow organisms with unique functions, including Organisms use gene and cell engineering to tailor the mineralization process and synthesize structure composites with special functions and favorable properties.This spurs scientists to design functional materials based on learning from nature.Herein, a systematic review of the biomimetic synthesis and hierarchical structure design of calcium carbonate-based minerals is presented.First, biomimetic synthesis strategies, including additive-induced, templateoriented, and gel-mediated routes to direct the construction of the hierarchical structure, are reviewed.The molecular-recognition technique and directional assembly pathway are then summarized to precisely describe the interactions between inorganic minerals and organic matter, and direct the mineral growth.Next, the underlying mineralization mechanisms governing the evolution of the complex morphology and structure are discussed.Nonclassical pathways that control mineral growth, including the theories of the amorphous phase, oriented attachment, mesocrystal formation, and liquid precursor, are concluded.Finally, herein, the applications of calcium carbonate-based minerals are discussed.Unique hierarchical structure endows minerals with special functions, including optical performance, biomedical applications, and environmental and ecological restoration.Overall, in this report, the biomimetic synthesis of calcium carbonate-based minerals is reviewed, covering the fundamental principles, construction of the hierarchical structure, underlying mechanisms of mineral growth, and functional designs.[26][27] Calcium carbonate usually exists in three anhydrous crystal forms, namely calcite, aragonite, and vaterite, and one amorphous phase, namely amorphous calcium carbonate (ACC).[30][31][32] Encouraged by the exquisite natural structure of organisms, studies have sought to imitate the morphology, structure, and functions of biominerals, which is referred to as bionics science.Increasing efforts have been focused on the structural design of biominerals and superior performance development.
Commonly, biomimetic synthesis design can be divided into three procedures: 1) understanding the structure-function relationship of natural materials; 2) extracting bionic design principles; and 3) utilizing the abundant building blocks to construct an excellent bionic structure.More importantly, biomimetic synthesis is an environmentally friendly process with low energy consumption and pollution.Recently, significant progress has been made in biomimetic mineralization.Sommerdijk et al. discussed biomimetic design based on interface-recognition theory and summarized in situ monitoring techniques in the mineralization process. [33,34]45][46] Although the biomimetic mineralization technique has become a research hot spot in the design of functional materials, a systematic report regarding the hierarchical structure design and clarification of the structure-function relationship is lacking.Here, we provide new insights regarding the biomimetic synthesis of calcium carbonate-based minerals, covering the fundamental principles and applications (Scheme 1).Section 2 briefly discusses the structures and functions of natural biominerals.Section 3 focuses on biomimetic synthesis strategies and hierarchical structure construction of calcium carbonate-based minerals.Section 4 concentrates on the mechanism of mineral growth and emphasizes the guidance of nonclassical pathways in the evolution of complex morphologies.Section 5 summarizes the functions and applications of biomimetic mineral materials.

Hierarchical Structure of Natural Minerals
Natural composites comprising fragile inorganic materials (calcium carbonate, calcium phosphate, and silicon dioxide) and soft natural polymers (polysaccharides and proteins) display unique properties. [47] Figure 1a shows the ingenious hierarchical structures in the sea urchin spine. [15]Composite materials composed of biomolecules and inorganic minerals possess attractive mechanical performance.[50][51] Natural nacre composed of aragonite (mass fraction of 95%) and organic matter (mass fraction of 5%) exhibits much higher strength and toughness than those of synthetical calcium carbonate (Figure 1b).Natural nacre possesses three structural levels: [52] the overall lamellar structure (primary structure of the pearl), the aragonite plate that uses to construct the lamellar structure (secondary structure of the pearl), and hexagonal aragonite nanocrystals to build the aragonite plate (tertiary structure of the pearl).Bones possess seven hierarchical structural levels: [53][54][55][56] amino acids and tropocollagen as the major components (level 1), Table 1.[30][31][32] mineralized collagen fibrils (level 2), fibril arrays (level 3), fibril array patterns (level 4), osteons (level 5), spongy/compact bone (level 6), and macroscopic bone (level 7). Figure 1c shows the exoskeleton of the lobster Homarus americanus, [57] for which the cuticle originates from the direct assembly of the chitinprotein fibers and ACC.The twisted plywood structure can significantly improve the hardness of the exoskeleton.The protective scale of the Arapaima gigas with the laminate structure is another representative biomineral that can resist the bite of piranhas. [58]Copyright 2012, PNAS.b) Nacre.Reproduced with permission. [177]Copyright 2015, Springer Nature.c) Lobster cuticle: I) morphology of the American lobster Homarus americanus, II) cross-section image of the cuticle, and III) assembling pathway of the hierarchical structure.Reproduced with permission. [57]Copyright 2009, John Wiley and Sons.
Two inspirations derived from the natural biominerals contribute to the design of biomimetic synthesis.1) Understanding the structure and assembly of natural minerals is essential for the design of functional materials.2) Superior combinations of natural and synthetical materials enable the fabrication of novel structural composites.Composite materials with tailored structures and excellent biocompatibility can be fabricated based on rational design.For example, the nucleation, growth, and orientation of hydroxyapatite can be precisely regulated by incorporating proteins and polypeptides.The inorganic bionic repair layer exhibits excellent mechanical strength and friction properties. [62,63]Type I collagen assembles into a triplehelical structure, inducing the directional growth of calcium phosphate in collagen fibers. [64,65][68] Nepal et al. reviewed the recent advances in bioinspired nanocomposites at multiple length scales. [69]ierarchical features such as twisted, laminated, or fibrous structures can vary from 0D to N-dimensional, thus affecting the performance of minerals.

Biomimetic Synthesis Strategies of Hierarchical Structure
Gas diffusion and chemical precipitation are two common approaches to manufacture calcium carbonate crystals, and the solution environment is of great importance in mineral regulation. [70]In this section, we summarize the biomimetic synthesis strategies and construction of the hierarchical structure of calcium carbonate-based minerals.

Additive-Induced Strategy
73] Additives play an important role in the morphology and hierarchical structure regulations of biominerals. [74]Duchstein et al. pointed out that additives can stabilize the solution through interactions with prenucleation clusters (PNCs), thereby modulating calcium carbonate mineralization. [75][78] In situ nucleation monitoring has also shown that superstructures of composites are dependent on complex interactions between additives and minerals. [79]Olafson et al. described additives as modifiers with different molecular sizes, structures, and chemical compositions. [72]They classified modifiers into three types: ions, molecules, and macromolecules (Figure 2).Compared to ions and molecules, macromolecules possess multiple binding moieties and provide more sites for solute attachment. [80,81]1.1.Small-Molecular Additives Small-molecular additives are typically used in the mineralization process to modulate the structure and morphology of minerals.For example, by embedding the aspartic acid and glycine into calcite crystals, the hardness of inorganic minerals can be improved significantly and is positively correlated with the amount of additives.[82] Another interesting case is that the chiral additive can induce helical or twisted growth of achiral crystals.[83] This is a common phenomenon in organisms where chirality has been found in many hardened structures, such as invertebrate marine and terrestrial organisms, notably helical gastropod shells and now-extinct ammonites.[84] However, although the chiral additives can induce the handedness of the minerals, the knowledge of how the chiral molecules can orient the nanosized "building block" and form the hierarchical architectures remains elusive.[85] Based on these considerations, Jiang et al. used the additive-oriented strategy to adjust the handedness of calcium carbonate minerals.[86] The results clarify that the direction of the spirally oriented crystal platelets is in line with the chirality of the amino acid enantiomers.Figure 3e,f shows scanning electron microscope (SEM) images of the chiral toroid platelets under the induction of L-and D-aspartic acid, respectively.The chiral suprastructures on the calcium carbonate minerals are formed due to the mineral-amino acids interactions.To further understand the roles of additives on the morphology of calcium carbonate minerals, high-magnification SEM is used to capture the nanoparticle tilting under selective adsorption of the enantiomers (Figure 3g,h).Figure 3i shows a highresolution transmission electron microscope (TEM) image of the growing platelet edge under the regulation of L-aspartic acid, where the nanohexagons and an internal lattice structure can be observed.Combined with experiments and theoretical analyses, the authors proposed a nanoparticle tilting mechanism to interpret the chirality of minerals under different enantiomers.The nanoparticle tilting ("mother" subunit nanoparticle) is produced on the suprastructures of calcium carbonate after binding with the chiral amino acids.Then, the "daughter" nanoparticle can adsorb onto the "mother" subunit nanoparticle and grow continuously. Therfore, chiral signals can be transferred from the amino acid molecules to the macroscopic scale.Subsequently, Jiang et al. discovered that the enantiomer ratio of the mixed nonracemic amino acid determined the homochiral suprastructures of vaterite biominerals.[87] This chirality dominant effect suggests the handedness of vaterite helicoids depends on the majority of the enantiomers in the mixtures. Figue 3j,k shows SEM images of the vaterite crystals in the presence of different enantiomeric excess (e.e.L ) (j) e.e. L = 0%, k) e.e.L = 20%, l) e.e.L = 40%). The xperiments illustrate that homochiral vaterite helicoids can maintain the same enantiomer ratio as the initial growth solution.Furthermore, Jiang et al. discovered that the chiral morphology of biomineral switched spontaneously under the induction of the homochiral L-amino acid.[88] Cross-sectional SEM images indicate that the interior of the chiral vaterite helicoid is composed of an initial core disc/dome and an inclined platelet region (Figure 3m).After monitoring the thickness and morphology of the helical minerals in real time, a two-stage chiral switch mechanism, i.e., layer inclination and rotation stages, is proposed to rationalize the biomineralized structures (Figure 3n).The layer rotation stage determines the successive chiral switching process in biominerals.Except for the work from Jiang et al., De Yoreo et al. also studied the effect of chiral amino acids on calcite growth.[89] The symmetric growth of calcite is broken under the participation of enantiomers. Calcte morphology is determined by the chirality of amino acids and the corresponding interactions with minerals.In other words, the macroscopic shape of calcite reflects the chirality of the additives.Tremel et al. emphasized that the adsorption of chiral amino acids on calcium carbonate can produce 2D chiral arrangements on the mineral surface.[90] They synthesized peptide chains with various types of amino acids to induce polymorphs of calcium carbonate minerals.[91]

Macromolecular Additives
Macromolecules are the main substances that direct the growth of minerals and regulate the polymorphs in organisms.Common macromolecular additives are proteins, polypeptides, polysaccharides, and polymers. [92]Cölfen et al. reported the first case of spherical vaterite cores surrounded by equatorial loops with calcite nanobricks. [93]Poly(sodium 4-styrenesulfonate) and folic acid are used to control the structure and morphology of the calcium carbonate minerals.Figure 3r-t shows the morphologies of the vaterite microspheres at 16 h, 1 day, and 2 days, respectively.The formation of ACC nanoparticles occurs first.Then, the vaterite platelets are prepared through the aggregation of the ACC nanoparticles (Figure 3r).The nanoparticles are predominantly attached to the surfaces of the intermediate vaterite plate, and the equatorial loop forms after mineralizing for 1 day (Figure 3s).After 2 days, microspheres with brick-like superstructures along the equator gradually form (Figure 3t). Figure 3u shows a high-resolution SEM image of the equatorial loop.These images and selected-area electron diffraction illustrate that the resultant calcite equatorial loop evolves from the vaterite intermediate.
Double-hydrophilic block copolymers (DHBCs) and doublehydrophilic graft copolymers (DHGCs) are two common macromolecules used in the mineralization process. [94]The hydrophilic side of DHBC can interact strongly with the surface of inorganic minerals, whereas the other side is used to improve solubility. [95]HGC is also a soluble macromolecular additive.One side of DHGC can adsorb onto the crystal surface through intermolecular interactions, whereas the other side is hydrophilic, forming brushes on the crystal surface and extending into the solution. [96,97]Cölfen et al. discovered that the morphology of calcium carbonate can change from a rhomboid shape to a rosette-like shape by the regulation of copolymers (Figure 3o-q). [98]The structure and morphology of the minerals depend on the special interactions between the additive molecules and the crystal faces of the minerals.The authors proposed that DHBC can bind with Ca 2þ to regulate the structure of minerals. [99]Using DHBC as the directing agent, they designed the hollow superstructures of calcium carbonate minerals based on the self-assembly technique and concentration gradient strategy. [100]Except for the modulations of mineral morphologies, macromolecular additives can also impact the polymorphs of calcium carbonate. [101,102]Kim et al. incorporated pH-responsive anionic double-block copolymer micelles into calcite crystals to improve the hardness of the minerals. [103]06][107]

Ion Additives
Lastly, we discussed the effects of ion additives on mineral growth.Various metal ions such as Mg 2þ , Na þ , Sr 2þ , Mn 2þ , and Pb 2þ can influence the mineralization process.For example, Mg 2þ can occupy the location of Ca 2þ in the crystal lattice, thereby restricting calcite growth and favoring the aragonite formation. [108]Specifically, calcium carbonate tends to form prismatic calcite at a low concentration of Mg 2þ but favors dumbbellshaped aragonite under higher concentrations. [33,109]This stems from the improved thermodynamic stability of aragonite when  [114] Copyright 2015, American Chemical Society.e-n) Handedness regulation of the biominerals by the induction of the amino acid enantiomers.e-i) Chiral morphology regulations given the nanoparticle tilting theory.e,f ) SEM images of the platelets under the selective adsorption of the L-aspartic acid (e) and D-aspartic acid (f ).g,h) High-magnification SEM images showing the nanoparticle tilting under the induction of the chiral enantiomers g) L-aspartic acid and h) D-aspartic acid).i) transmission electron microscope (TEM) image of the growing platelet edge.Reproduced with permission. [86]Copyright 2017, Springer Nature.j-l) SEM images of the chiral vaterite helicoid by the induction of enantiomeric mixtures (L-aspartic acid is the major enantiomer), e.e.L , j) 10%, k) 20%, and l) 40%.Reproduced with permission. [87]Copyright 2019, Springer Nature.m,n) Chiral switching by the induction of a single-amino-acid enantiomer.m) SEM image of the cross section of the chiral vaterite helicoid, n) Schematic illustration of the chiral switching.Reproduced with permission. [88]incorporating Mg 2þ .[112][113] Nindiyasari et al. discussed the effects of Mg 2þ on calcite morphology in a gel environment. [114]Figure 3a-d illustrates the SEM images of the calcite morphologies in (a,b) Mg-free and (c,d) Mg-rich environments.The experiments show that fewer misoriented subunits exist in a single crystal or radial aggregate in the absence of Mg 2þ , while calcite has a rough surface in Mgrich environments.They also discovered that the gel had fewer effects on morphology selection without Mg 2þ .Ihli et al. revealed the synergistic roles of lysine and Mg 2þ on mineral growth using Bragg coherent diffraction imaging. [115]Parker et al. used molecular dynamics simulations to analyze the adsorption behaviors of additives on the surface of calcite. [116]Simulations indicate that a flat perfect surface is not favorable for adsorption and an additional electrostatic driving force is necessary to overcome the energy barriers.Mann et al. discovered that a higher concentration of sodium polyphosphate (>1 g L À1 ) can inhibit aragonite formation and favor platelike vaterite and bundle-like calcite. [117]n summary, molecular additives can control the crystallization process through the interactions between the functional groups and crystal faces.Ion additives are used to stabilize ACC, vaterite, and aragonite.The synergistic roles of the additives influence the morphology and functions of inorganic minerals.Other additives such as metallic oxides can also endow minerals with special functions.For example, Kim et al. embedded Fe 3 O 4 and ZnO nanoparticles into single-calcite crystals, to endow the magnetic and optical properties of composites. [118]

Template-Directed Strategy
In addition to the additive-induced strategy, templates with special functional surfaces can be used to regulate the hierarchical structure and morphology of minerals.Organic templates can lower the energy barrier of heterogeneous (HEN) nucleation through electrostatic interactions or orientational matching with the mineral surfaces.This section reviews three types of templates for the modulation of the mineralization process.

Langmuir Monolayers
Langmuir monolayer is the template that floats on aqueous subphases.Template surfaces are composed of acidic functionalities, such as carboxylic, phosphate, and sulfate groups. [119]Abundant functional groups provide unique nucleation sites for calcium carbonate growth. [120]Inorganic substrates and organic molecules on Langmuir monolayers can compensate for geometric mismatches through rearrangement. [33]Figure 4a shows the phase-transition process induced by amphiphilic porphyrin templates. [121]Du et al. prepared calcium carbonate nanoparticles on a bovine serum albumin Langmuir monolayer, [122] and discovered the existence of ACC in the multistep crystallization process. [123]The lattice match between calcium carbonate and the Langmuir monolayer is of great importance in the synthesis of composite materials.Lee et al. prepared ACC precipitates with uniform size at the gas-liquid interface (Figure 4b). [124]In addition to the particles, the Langmuir monolayer template can also be used to synthesize films.For example, Langmuir monolayer-enriched stearic acid directs the formation of calcium phosphate thin films. [125]

Self-Assembled Monolayers
In contrast to the Langmuir monolayer floating on a gas-solution interface, self-assembled monolayers (SAMs) can carry abundant functional groups on solid substrates.SAMs consist of a molecular head group, an alkyl chain, and an end group.The molecular head groups can combine with the surface substrate through covalent (Si-O, Au-S) or ionic (Co-Ag) bonds.The active molecules can occupy special positions and pack orderly and tightly on the substrate surface via van der Waals forces between the alkyl chains.The end groups of molecules determine the physicochemical properties and functions of SAMs.128] Among the various types of SAMs, Au is the most common substrate.Kuther et al. controlled the growth of calcite, vaterite, and aragonite crystals on the Au substrate enriched with an alkylthiol group. [129]The crystal forms of the calcium carbonate depend on the thiol chain length and reaction temperature.Kim et al. synthesized the calcium carbonate on SAMs, whereby Au and 4-mercaptobenzoic acid (4-MBA) were the substrate materials and the stabilizing ligand, respectively. [130]Figure 4e,f shows the morphologies of calcium carbonate in the (e) presence and (f ) absence of the 4-MBA-capped Au nanoparticles.The hexahedron-shaped particles transfer to a ceramic-like shape under the orientation of the templates.Nielsen et al. compared two types of SAMs for mineralizing calcium carbonate: CO 2 -in diffusion (Figure 4c) and the Kitano method (Figure 4d). [131]For the CO 2 -in diffusion approach, the SAM-bearing substrate is placed in a Ca-based solution, whereby Ca 2þ typically binds first with the functional groups of the template, and then CO 2 forms carbonate at high pH and reacts with Ca 2þ to form calcium carbonate.In the Kitano method, CO 2 is first injected into the saturation solution, and then the SAMs substrate is immersed in the supersaturation solution.Space confinement is another template technique.Meldrum et al. designed a "crystal hotel" microfluidic device to confine the reaction volumes and prepare the welldefined shape particles. [132]They etched thin films with cylindrical cavities of different diameters to deposit calcium carbonate and found that the amount of aragonite depended on the pore size.

Cellulose-Based Mineralization
Except for the template-directed crystal growth based on Langmuir monolayers and SAMs, cellulose is a green template for mineral deposition. [133]Matsumura et al. discovered that liquid-crystalline chitin whiskers can form helically ordered polymer network templates for calcium carbonate mineralization. [134]igure 5a shows the self-assembly of chitin whiskers, whereby the liquid crystalline structure can be stabilized by incorporating an acidic polymer, poly(acrylic acid) (PAA).Mineralization is carried out by soaking the chitin/PAA templates in the ACC precursor solution.Figure 5b shows the cross-sectional SEM image of the template after 7 days of mineralization, and the helical and homogeneous (HON) structure is analogous to the exoskeleton of crustaceans.[137][138] Cölfen et al. proposed an artificial molting strategy to synthesize biophotonic-structure materials. [139]The fabrication process is divided into the self-assembly of CNCs and ACC mineralization.PAA is incorporated to stabilize the liquid-crystalline structure of CNCs and combine with Ca 2þ , thus favoring the deposition of calcium carbonate (Figure 5c).The composite materials exhibit tunable mechanical properties (Figure 5e) and excellent photonic performances (Figure 5d,f ).After mineralization for 3 h, the composite film is elastic, strong, stiff, and iridescent (Figure 5e).The swelling performance is tunable by controlling the amount of PAA (Figure 5f ).In addition, the mineralized films can reflect lefthanded polarized light with an asymmetry factor of 0.8 (Figure 5d).Wu et al. used carboxylated nanocellulose to stabilize ACC. [140]The fabricated carboxylated nanocellulose-ACC dispersions can form transparent composite films with extremely high strength and toughness.Figure 5g illustrates ACC growth on carboxylated nanocellulose.28] Types Substrate materials Self-assembly groups  Reproduced with permission. [121]Copyright 1998, American Chemical Society.b) Preparation of amorphous calcium carbonate (ACC) precipitates.Reproduced with permission. [124]Copyright 2012, Springer Nature.c-f ) Controlling of mineralization process on the template of self-assembled monolayers (SAMs).c,d) Two patterns of SAMs: c) CO 2 -in diffusion and d) Kitano methods.Reproduced with permission. [131]Copyright 2013.e,f ) Morphology of calcium carbonate crystals, in the e) present and f ) absence of SAMs.Reproduced with permission. [130]Copyright 2002.John Wiley and Sons.
bridging on the improvement of the toughness performance (Figure 5h).

Gel-Mediated Strategy
Gel-mediated biomineralization has been confirmed in various biological tissues such as coral, [141] mollusk shells, [142] otoliths, [143] and tooth enamel. [144]Characterized by its viscoelasticity and fluidity, gel is a substance with both solid and liquid properties.The organic matrix can be incorporated into the crystals through interactions between the gel network and the solute molecules.Gels can be classified into physical or chemical types.In physical gels, networks are mainly formed through physical entanglement and noncovalent intermolecular forces.Networks of chemical gels are formed by covalent bonds, such as UV light reactions or free-radical polymerization by chemical initiators. [70]Figure 6a,b shows SEM images of hydrogels of different solid contents a) 5 wt%; b)10 wt%), whereby the gel with higher density possesses smaller pores. [145]During the gelmediated mineralization process, the structure and morphology of the minerals depend on the interactions between the gels and solute.
The gel can provide special microenvironments for mineral growth.That is, the unique 3D porous gel network determines the crystal nucleation and growth.Therefore, elucidating the mechanism of gel-mediated crystal growth is important for designing biomimetic synthesis.Estroff et al. discovered that solute diffusion and crystal growth depended on the gel strength and crystal growth kinetics. [146]The competition between the strength of the hydrogel network and the growing crystals determines whether the gel particles can integrate into the minerals (Figure 6g).The experiments reveal that anisotropic agarose gel Reproduced with permission. [134]Copyright 2015, Wiley-VCH Verlag.c-f ) Construction of the biomimetic biophotonic structural materials.c) Illustration of the artificial molting processing.d) Photos of the film under the left-and right-hand polarized light.e) Performance of the composite films after mineralization 3 h.f ) Swelling performance tests when adding different amounts of poly(acrylic acid) (PAA).Reproduced with permission. [139]opyright 2022, John Wiley and Sons.g,h) ACC mineralization on the rigid carboxylated networks.g) Illustration of ACC growth on the carboxylated networks.h) SEM image of fraction cross section of the composite film.Reproduced with permission. [140]Copyright 2008, Elsevier.c-f ) Synthesis and performance of the composite functional calcium carbonate crystals.c) Preparation of the functional materials.d-f ) Images of the calcite crystals that grow in different environments.d) Diamagnetic and colorless crystals grown in the agarose gel.e) Colored crystals grown in the agarose gel-enriched Au nanoparticles.f ) Colored and paramagnetic crystals grown in the agarose gel enriched both Fe 3 O 4 and Au nanoparticles.Reproduced with permission. [152]Copyright 2014, John Wiley and Sons.g) Mechanism of crystal growth in the gel network, competitions between the gel strength and kinetics of crystal growth.Reproduced with permission. [146]opyright 2009, John Wiley and Sons.h-k) SEM images of the calcite-agar aggregates under different conditions: h) 0.5 wt% agar, 0.5 M reagent solutions; i) 0.5 wt% agar, 0.1 M reagent solutions; j) 2 wt% agar, 0.5 M reagent solutions; and k) 2 wt% agar, 0.1 M reagent solutions.Reproduced with permission. [147]Copyright 2018, American Chemical Society.l) The growth of calcite aggregates in different densities of alginate gels.Reproduced with permission. [148]Copyright 2011, Academic Press Inc. m-q) Mineralization of the calcium carbonate on the hydrogel composite membranes.m) Biomimetic synthesis of minerals on the hydrogel composite membranes.n-q) SEM images of the composites on different hydrogel substrates: n) virgin polypropylene (PP), o) [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) ammonium hydroxide/N, N 0 -methylene bisacrylamide (SPE/MBA) HCMs, p) acrylic acid-co-2-hydroxyethyl methacrylate/ethylene glycol dimethacrylate (AA-co-HEMA/EGDMA) HCMs, and q) MAA-co-HEMA/ PEGDMA HCMs.Reproduced with permission. [150]Copyright 2016, John Wiley and Sons.r) Synthesis of the oriented anisotropic calcite nanoparticles.Reproduced with permission. [149]Copyright 2023, John Wiley and Sons.(Scale bars: a,b) 50 μm).
networks can produce calcite composites with anisotropic structures.In addition, the morphologies of the minerals depend on the gel density and solution environments (Figure 6h-k). [147]A higher gel concentration results in the formation of radial calcite aggregates.In comparison, the crystal morphology is less distorted and rhombohedral at a lower gel density.Ma et al. established a growth model to explain the roles of gel on the morphology, size, and surface roughness of calcium carbonate. [148]ombined with the thermogravimetric analysis and Fouriertransform infrared spectroscopy, they proposed that selective nucleation and confined crystallization codetermined the structure of minerals under the gel-oriented route (Figure 6l).Dong et al. synthesized a series of soft and deformable gels to prepare nanogel calcite composites (Figure 6r). [149]The nanogel particles with different cross-linking degrees are embedded in calcite.Di Profio et al. designed a hydrogel composite membrane (HCM)based strategy to regulate mineral growth. [150]The functional groups on the membrane surface provide the mineralization sites to combine with Ca 2þ (Figure 6m).The composite membranes can reduce the diffusion rate of CO 2 and reaction rate, which benefits the complex morphology evolution of the minerals.The minerals can exhibit different morphologies when grown on different gel substrates (Figure 6n-q ammonium hydroxide/N, N 0 -methylene bisacrylamide [SPE/MBA]; p) acrylic acid-co-2-hydroxyethyl methacrylate/ethylene glycol dimethacrylate [AA-co-HEMA/ EGDMA]; and q): methacrylic acid (MAA)-co-HEMA/EGDMA).This bioinspired synthesis technique based on hydrogel microenvironments can control the morphology through the cooperative effects of carboxyl and hydroxyl groups.Moreover, the gelmediated process can also synthesize minerals with special functions, [114,147,151] such as magnetic, [118,152] superior mechanical, [82,153,154] and optical properties. [32,152,155,156]For example, Liu et al. incorporated Au and Fe 3 O 4 nanoparticles into calcite crystals in an agarose gel environment to prepare composites with colored and paramagnetic responses (Figure 6c-f ). [152]n summary, both additive engineering and template effects can control the hierarchical structure through interactions between the solute molecules and functional groups of organic matrices.On this basis, gel control can provide a confined space to decrease solute diffusion and the reaction rate, which supports the morphology evolution.Synergistic mineralization is a common pathway for fabricating biominerals with tailored functions and hierarchical structures.159][160]

Assembly Strategies of Biomimetic Structural Materials
The exquisite structures and functions of organisms encourage scientists to synthesize biomimetic materials.Aizenberg et al. proposed three levels in biomimetic synthesis: [8] level 1: understanding the correlations of structure-function in biological materials; level 2: exploring the physicochemical principles in the structure construction; and level 3: manufacturing the biomimetic materials based on the above principles.Compared with the composition analysis of the natural minerals, simulation of the hierarchical structure is a significant challenge.In this section, we summarize two assembly strategies for biomimetic structural materials: molecular recognition and directional assembly.

Molecular-Recognition Technique
The molecular-recognition technique refers to the regulation of crystal morphology or structure at the molecular level.In organisms, gene expression can determine the assembly and stacking of inorganic minerals, thus affecting the structure and functions. [53,161,162]This suggests that molecular-recognition techniques can be used to create biominerals by cleverly designing interactions between organic matrices and inorganic materials.From the perspective of biology, programmed gene expression controls ordered multistage assemblies within specific space and time.However, selective gene expression is common in organisms but is difficult to control in biomimetic synthesis.In contrast, inorganic mineral deposition can be induced in existing organic matrix frameworks.Organic templates can be designed manually or as natural products such as frames after pearl layer demineralization. [163]Acidic biomacromolecules such as PAA, polyaspartic acid, and block copolymer can readily induce inorganic mineral deposition. [85,164,165]Gal et al. considered that the interactions between soluble organic molecules and inorganic minerals can direct the mineralization process at specific sites. [166]Organic matter can regulate the structure of inorganic materials or participate in the synthesis of composite materials by combining them with inorganic components.For example, the majority of gastropod shells possess right-handed coiling modes. [84,167]This is because the β-chitin molecules can assemble into the supramolecular chitin and act as the organic substrates to control the growth of inorganic minerals. [168]

Directional Assembly Strategy
Although molecular-recognition techniques can regulate the structure and morphology of minerals, it is difficult to precisely duplicate the complex interactions between the organic matrix and inorganics in vitro.Moreover, accurate molecular recognition or adsorption on unique sites is also challenging. [69,169]herefore, the directional assembly strategy is proposed, which emphasizes the unique template structure design but involves less recognition at the molecular level.Figure 7b illustrates layer-by-layer (LBL) self-assembly, which is a continuous alternative adsorption process for inorganic minerals and organic matrices through weak interaction forces. [170]This technique can precisely regulate the bionic structure at the molecular or nanoscale level and is suitable for the fabrication of natural minerals and composite films. [105,171]Another common assembly strategy utilized in biomimetic mineralization is the ice-template technique (Figure 7a). [172]A layer-to-layer stacking inorganic phase is formed when removing the solution from the framework during ice formation.The organic polymer is then refilled into the spaces between the inorganic layers.Notably, surface modification of the inorganic layer is necessary to fill the organic polymer phase filling. [67]Yu et al. applied the ice template technique to  [173] Copyright 2016, American Association for the Advancement of Science.b) Layer-by-layer selfassembly strategy for the preparation of hybrid mesh of graphene oxide-calcium carbonate.Reproduced with permission. [170]Copyright 2020, American Chemical Society.c) Freeze-casting technique.Reproduced with permission. [177]Copyright 2015, Springer Nature.d) Brushing-induced assembly strategy.Reproduced with permission. [179]Copyright 2018, Oxford University Press.e) Evaporation-induced self-assembly via lamination technique.Reproduced with permission. [47]Copyright 2017, Springer Nature.f ) Dual-network interfacial design strategy.Reproduced with permission. [180]Copyright 2019, Elsevier.g) Additive-manufacturing technology.Reproduced with permission. [177]Copyright 2015, Springer Nature.direct calcium carbonate mineralization, and the composite materials have similar microstructures and compositions to natural pearls. [173][176] The 3D printing technology can be used to fabricate macrostructural blocks similar to natural materials.Figure 7c shows the freeze-casting technique used to build the architectures and create layered porous materials. [177,178]Recently, Yu et al. proposed several strategies to create the hierarchical structure materials, such as brushing-induced assembly (Figure 7d), [179] evaporationinduced self-assembly (Figure 7e), [47] and dual-network interfacial design (Figure 7f ). [180]They also proposed biomimetic matrix-directed mineralization to fabricate artificial nacre with multiple functions, whereby the functional nanoparticles were incorporated into platelets. [181]To precisely manipulate the microscale structure, Bai et al. proposed a bidirectional freezing technique to mimic the architecture of a nacre, whereby products with dimensions of 4 Â 8 Â 25 mm are fabricated. [182]Xiao et al. synthesized prismatic-type thin films of calcium carbonate to mimic the tissues in mollusk shells. [183]The excellent performance of the synthesized composites highlights the importance of the granular transition layer in prismatic layer growth.The shear flow-induced alignment of nanosheets is also a certified approach for fabricating functional films with high uniformity and mechanical performance. [104,184,185]

Hierarchical Structure Evolution Mechanisms
Miraculous hierarchical structure materials with various functions have attracted considerable interest, especially their formation routes.Understanding the evolution of complex structures or the morphology of minerals is important for guiding the mineralization process.The classical and nonclassical mechanisms can explain the mineral growth process (Figure 8). [38]ompared with the building blocks of monomers and ions in classical processes, particle attachment, such as complexes, [186] clusters, [187] nanoparticles, [40] amorphous, [188] and liquid, [189] is more common in the nonclassical pathways.In this section, we briefly review classical nucleation theory (CNT) and focus on nonclassical pathways in biomimetic mineralization.

Classical Crystallization Pathway
According to CNT, solute molecules or ions can continuously collide and gather in a certain supersaturated solution and then form crystals after overcoming the activation energy barriers.Figure 10a provides a schematic illustration of Ostwald ripening (OR), whereby the small crystals tend to dissolve and adsorb onto the surface of large crystals.The total free energy consists of a decrease in bulk free energy and an increase in surface energy.The two types of free energy compete and codetermine the formation of solute clusters.The crystal nucleus begins to form when the total free energy decreases.The crystal nucleus size at this time is the critical size. [190]Cölfen et al. pointed out that pre-nucleation clusters can form even in an undersaturated solution prior to nucleation. [37]Nucleation from a solution can be classified as HON or HEN.HON refers to the uniform formation of new nuclei, whereas HEN requires nucleation sites from foreign particles.During biomineralization, the organic matter often functions as HEN sites to support crystal nucleation and mineral growth. [191,192]

Nonclassical Crystallization Pathways
Most mineralization processes are controlled by nonclassical pathways, as evidenced by the complex morphology and hierarchical structure, [35,36] such as curved surfaces. [193]In this section, four nonclassical routes that contribute to the design and understanding of the biomineralization process are summarized.

Amorphous Precursor
Increasing evidence suggests that the amorphous precursor is a common intermediate for biomineral materials such as chiton tooth, [194] nacre, [195] and skeleton. [196,197]The solute in the amorphous phase can be readily transported to specific sites and accommodate more "impurities" (e.g., proteins, amino acids, or ions). [198]The tailored functions are then provided through the combination and realignment between the "impurities" and solute molecules. [155,199,200][203][204] Therefore, organisms seek to regulate their surrounding environments, such as pH, solvents, and space limitations, to stabilize the amorphous phase.Beniash et al. discovered amorphous calcium phosphate in the enamel. [188]Similar cases were also reported in echinoderm spicules, spines, mollusk shells, fin bones, and chiton teeth. [205]igure 10f,h shows the formation of amorphous nanoparticles through the aggregation of nanoclusters.Politi et al. [13,206,207] observed hydrated and anhydrous ACC in adult sea urchin spines and revealed the phase-transition process of ACC during mineral formation.Beniash et al. [208] discovered that sea urchin Reproduced with permission. [38]Copyright 2015, American Association for the Advancement of Science.
spicules were composed of the ACC and a single crystal of calcite.The surroundings can participate in mineral transport and mineralization regulations.They also demonstrated the existence of an amorphous phosphate phase in the mineral formation. [188,209]e Yoreo et al. [41] observed the nucleation process of calcium carbonate and recorded the phase transition from ACC to the crystalline phases.Amorphous minerals are usually hydrated, whereas the crystalline form is often anhydrous or have low water content.Figure 9a shows the relative energy stabilities of different forms of calcium carbonate, with the thermodynamic stability increasing from ACC to calcite. [210]Navrotsky et al. found that the dehydration of ACC occurred before skeleton formation in sea urchin larvae, suggesting that water participates in atom rearrangement. [210]The entire phase transition of calcium carbonate undergoes the following sequences: more metastable hydrated ACC, less metastable hydrated ACC, anhydrous ACC, biogenic anhydrous ACC, vaterite, aragonite, and calcite. [43,210]Figure 9b shows the evolution of the mineral phases in sea urchin spicules from hydrated ACC to calcite. [201]Tao et al. explored the shell molt of crustaceans and suggested cooperative effects of aspartic acid and Mg 2þ on the mineralization process. [17]The phase transition from ACC to calcite during the molting process is shown in Figure 9c.Yu et al. reported that ACC nanospheres can be synthesized in a water-deficient organic solvent system. [211]hey suggested that ACC nanospheres were composed of smaller nanosized clusters.

Oriented Attachment
In addition to amorphous precursors, nanoparticle aggregation is another nonclassical pathway to synthesize nanowires with complex morphologies. [212,213]The particle aggregation process is namely oriented attachment (OA). [40,214,215]OA is a "matchand-dock" process, whereby the primary particle can attach and fuse on the given crystal surface with a specific alignment (Figure 10b). [216,217]The decrease in surface energy can favor the merging of particles into a single crystal. [218]The first case of OA was reported by Penn et al. with titanium dioxide in 1998. [214]Since then, more cases of OA mechanism have been confirmed in biomineralization and synthetic crystals such as metal oxides, semiconductors, and gold. [14,212]Compared with the amorphous phase that can readily be transferred into the crystal with the same orientation, nanoparticles directed by OA can adjust their orientations.Therefore, the assemblies display well-defined sizes and fewer defects. [219]Xue et al. established the kinetic models of OA and discussed the competition between OA and OR, where OA is closely related to surface chemistry and growth conditions. [220]De Yoreo et al. observed the OA process directly using in situ liquid TEM, and the assemblies showed the same orientation and a clear boundary. [221]igure 10d,e visualizes the particle attachment process, and the surface of particles (I and II) makes transient contacts and orientations before attaching.However, in some cases, there Reproduced with permission. [210]Copyright 2010, PNAS.b) Red (hydrated ACC), green (ACC), and blue (calcite) maps of spicules extracted at 36, 48, and 72 h after fertilization.Reproduced with permission. [201]Copyright 2012, PNAS.c) Morphology and phase of cuticles at different molt stages.Reproduced with permission. [17]Copyright 2009, PNAS.
is evidence that there are no exact or visible boundaries in rough crystals, which contradicts the OA mechanism. [222]Thereby, another nucleation mechanism, random attachment (RA), has been proposed to explain the agglomeration behaviors. [43]The schematic illustration of RA is shown in Figure 10c, whereby particle attachment and crystal growth can occur on the nonoriented growth front. [223]Tang et al. discovered that the inherent surface stress plays an important role in particle agglomeration and results in the formation of a single crystal by grain-boundary migration (Figure 10g). [223]The particle agglomeration process can be visualized successfully using high-precision images with advanced online monitoring devices.More deep explorations and understanding of OA processes are necessary, rather than relying only on the driving force or energy transformation. [224,225]

Mesocrystal Formation
Mesocrystal is composed of nanocrystals with the same orientation along a certain direction. [226][230] The ordered alignment of nanoparticles can significantly enhance the hardness of minerals. [231]Several strategies have been proposed to induce mesocrystal formation.First is the orderly arrangement of nanoparticles under the regulations of organic matter.[234] The coral formation is a representative example, where the nanocrystalline particles can grow on the fibrous organic matrixes and finally transform into an ordered aragonite mesocrystal. [141]Another strategy is under the regulation of the external physical fields, whereby the nanoparticles can assemble into mesocrystal without interactions with the organic templates.[237] Mineral bridging can also guide mesocrystal formation. [238]For example, the shell nacre is composed of the layered structural aragonite, where organic matter is incorporated between the layers.The organic matter connects through the pores to form the aragonite layers with the same orientation. [229]chwahn et al. used dynamic light scattering and timeresolved small-angle neutron scattering to monitor the formation of the alanine mesocrystal and the transition process to a single crystal. [239]The experiments reveal that compact single crystals originate from the aggregation of mesocrystal nanoparticles.Figure 10i-k shows the TEM images of mesocrystal formation, whereby the number of primary particles residing in the mesocrystal increases continuously. [215]The mesocrystal initiates with the amorphous precursor in vesicles or other structures in vivo Reproduced with permission. [304]Copyright 2014, Royal Society of Chemistry.b-n) Nonclassical crystallization process.b) Schematic diagram of orientation attachment.Reproduced with permission. [305]Copyright 1999, Elsevier.Schematic diagram of c) random aggregation of building blocks.Reproduced with permission. [223]Copyright 2016, John Wiley and Sons.d-h) Records of particle movement in nonclassical processes via TEM.d,e) Orientation attachment over time: d) t = 0 s and e) t = 52.75s.Reproduced with permission. [40]Copyright 2012, American Association for the Advancement of Science.f ) Amorphous precursor.Reproduced with permission. [186]Copyright 2013, Springer Nature.g) Random aggregation.Reproduced with permission. [223]Copyright 2016, John Wiley and Sons.h) Nanoclusters aggregation to form the spherical amorphous nanoparticles.Reproduced with permission. [306]Copyright 2012, Wiley-VCH.i-k) Mesocrystal formation and evolution process: i) 5 days, j) 10 days, and k) 24 days.Reproduced with permission. [215]Copyright 2010, American Chemical Society.l-n) Polymer-induced liquid precursor under different time: l) t = 150-200 min, m) t = 200-250 min, and n) t = 250-300 min.Reproduced with permission. [247]Copyright 2018, Springer Nature.(Scale bar: d,e) 2 nm and f ) 50 nm, the scale bar of inset: 100 nm; g) 5 nm and h) 50 nm, the scale bar of inset: 10 nm; i-k) 50 nm, l,m) 20 nm, n) 500 nm, and inset of (l) 5 nm).
and then transforms into oriented nanocrystals.The mesocrystal intermediates then fuse into oriented aggregates and form new crystals.This finding indicates a close connection between the mesocrystal and oriented aggregation.Mesocrystal originating from an ordered arrangement of nanoparticles can form a single crystal through oriented aggregation.Seto et al. studied the hierarchical structure of adult sea urchin spines. [240]The spine is composed of Mg-calcite nanocrystals, and the surrounding ACC precursor particles involved in the formation of mesocrystal.

Liquid Precursor
Polymer-induced liquid precursor (PILP) refers to the liquidliquid separation process under the induction of a soluble polymer when solution supersaturation exceeds a critical value. [241,242]The polymer and calcium carbonate can initially form small droplets, adsorb onto the substrate to form thin films, and finally transfer to the crystals. [243]Bewernitz et al. suggested that organisms can utilize the charged polyelectrolytes to guide the crystal growth through the intermediate liquid phase, this process is deemed as PILP. [244]Several in situ microscopic observations have successfully captured the presence of PILP. [211,245]e Yoreo et al. proposed the theory of liquid-liquid binodal separation and established the mechanism of liquid-liquid separation. [42]They suggested that coalescence and solidification at the nanoscale can lead to the formation of a solid phase.Kim et al. demonstrated that PILP theory can guide the synthesis of mineral films on the functionalized organic template by adding the polyanionic process-directing agents. [245]Bahn et al. discovered that the Pif80 protein extracted from pearl oysters can interact with Ca 2þ to stabilize the PILP process. [246]Figure 10l-n shows TEM images of the thin film of calcium carbonate with the time evolution based on the PILP theory. [247]Figure 10l shows images of the nanoparticles at 150 min, which consist of assemblies of %2 nm subunits (inset of Figure 10l).The nanoparticles subsequently grow and aggregate into a larger size but still cannot form continuous objects, such as liquid droplets (Figure 10m).Further aggregation is observed after 250 min (Figure 10n).This finding demonstrates that PlLP is the assembly of ACC clusters, whereby the surface properties determine the liquid-like behavior.This discovery provides novel insights regarding the biopolymer-stabilized nanogranular phase in biomineralization.Wolf et al. discovered that ovalbumin can stabilize transient precursors. [242]They suggested that the polymer controlled the PILP by affecting droplet stability and demulsification, rather than the "induction."Recent studies have demonstrated that ions or monomers can form stable cluster structures through interactions.These clusters can nucleate and form solid particles when the supersaturation exceeds a certain value.The stable clusters that do not form an evident phase interface with the solution are considered the PNCs.Bewernitz et al. linked the PILPs with PNCs and argued that the charged polyelectrolytes may stabilize liquid PNCs and thereof impact nucleation and the formation of ACC. [244]Cölfen et al. discovered the stable PNCs in calcium carbonate in 2008. [248]They revealed that a lower pH promoted stabilization of the PNCs and that the PNCs tended to transfer into the relatively stable ACC following conversion into calcite. [249]n summary, most cases of mineral growth are guided by the aforementioned nonclassical pathways.In some cases, various nonclassical processes can guide calcium carbonate mineralization synergistically.For example, Yu et al. synthesized Mg-calcite mesocrystal, which originates from the agglomeration of ACC through the oriented aggregation process. [250]

Applications of Biomimetic Materials
253] Scientists utilized biomimetic synthesis strategies to mimic the structure of natural minerals and design smart materials with excellent performances.Based on the theory of biomimetic mineralization, Yang et al. reviewed recent progress on core-shell nanoparticles for drug delivery systems, covering the synthesis routes of silica-and calcium-based nanoparticles and their corresponding functions. [254]Wegst et al. reviewed the design pathways of natural structural materials and discussed difficulties in the manufacturing process. [177]57][258]

Improvement of Mechanical Performance
Natural materials are composed of fragile inorganic minerals and soft polymers, and the hierarchical structure can endow materials with excellent properties.Several representative natural products, such as teeth, [259,260] skeletons, [261,262] and shell nacre, [173,263] have displayed excellent mechanical performances.Inspired by natural minerals, scientists have used biomimetic synthesis strategies to optimize the mechanical performance of composites.For example, composite materials with nacremimetic lamellar and brick-and-mortar architectures exhibit huge potential for application in dental recovery. [106]Monn et al. used computational fracture mechanics simulations to calculate the increase in toughness in layer architectures. [264]akashima et al. synthesized organic-inorganic hybrid materials composed of chitin, proteins, and calcium carbonate (Figure 11a). [265]The fusion protein is formed by the calcitebinding peptide and chitin-binding domain, whereby calcium carbonate can adsorb and grow on the sites of the chitin matrix.Twisted stacking or symmetry-breaking alignment is a common strategy to optimize the mechanical performance of composites.Yu et al. improved the fracture toughness of artificial nacre materials using an extrinsic toughening strategy. [266]Nacre that incorporates nanoparticles can display prominent toughness compared to biomimetic ceramics (Figure 11b-d).The incorporation of chiral organic molecules can also significantly affect the strength and toughness of materials.Figure 11e shows the chiral additives on the regulation of mineral properties. [267]Compared with the D-enantiomer, the minerals combined with the L-enantiomer exhibit better mechanical performances, suggesting the importance of chiral selectivity in the mineralization process.Tremel et al. discovered that macromolecular additives can create defects in the crystal lattice and strengthen the crystal against fracture. [268]

Design of Optical Materials
The design of functional optical materials gradually gains increasing interest.The properties of optical functional materials depend on their composition and structure.Many organisms have gradually evolved various fine hierarchical structures and special functions. [269]For example, unique optical properties can provide functions for organisms, such as protection, mating, and information transfer. [270,271]Figure 12a-d shows the appearance and skeletal structure of two species of Ophiocomid brittle stars, with different features of photosensitivity. [32]Ophiocoma pumila exhibits no color change and little reaction, whereas Ophiocoma wendtii is an extremely photosensitive species.Aizenberg et al. revealed that the light sensitivity of species is correlated with the 3D mesh skeletal structure of the dorsal arm plates, [32] that is to say, the structure and arrangement of calcite crystals.
Elucidating the structure and functions of organisms is the first procedure in understanding the biomimetic synthesis process. [272,273]For example, inspired by the butterfly, England et al. created an artificial photonic material to mimic the reverse colororder diffraction effect, which has wide applications in biosensing, photovoltaic systems, and light-emitting diodes. [274]Another representative optical application is in chiral signal development.[277]   .Reproduced with permission. [265]Copyright 2021, American Chemical Society.b-d) Preparation of the nanoparticles-incorporated artificial nacre with excellent toughness: b) artificial nacre, c) nacre-mimetic structure, and d) combination of aragonite platelet with nanoparticles.Reproduced with permission. [266]Copyright 2022, John Wiley and Sons.e) The incorporation of chiral molecules on the mechanical performance regulation of minerals.Reproduced with permission. [267]Copyright 2020, American Chemical Society.chiral photonic crystals by Langmuir-Schaefer assembly of colloidal inorganic nanowires, where the composite materials show different colors when changing the stacking angles. [278]igure 12e shows the nanoparticle synthesis of functional calcite/metal oxide. [118]The incorporation of magnetite and zincite nanoparticles endows the composites with excellent magnetic and optical properties.Yu et al. proposed a matrix-directed mineralization strategy in which more functions can be assembled into artificial nacre through the incorporation of unique nanoparticles (Figure 12f ). [181]Figure 12g is the image of the synthesized photoluminescence-responsive artificial nacre.Although biomimetic optical functional materials have been successfully fabricated, the complexity of the optical structure restricts their design.Further studies should concentrate on the development of advanced optical functional materials and the design of biological templates.

Biomedical Applications
Inorganic materials have great potential for biomedical applications.Biomineralization techniques can repair pathologies such as osteoporosis, [279] enamel restoration, [280] angiocardiopathy, [281] and cataracts. [282]For example, vaterite is associated with pathologically calcified tissues in humans, including pancreatic stones, calcified heart valves, and gallstones. [88,283,284][287] Calcium carbonate-based nanomaterials have numerous advantages, including low cost, ease of synthesis and surface modification, excellent biocompatibility, and strong absorbability and interactions.290] Moreover, by undergoing a simple mineralization strategy, the functional groups or guest molecules can be encapsulated into calcium carbonate nanomaterials.For example, Begum et al. successfully encapsulated antibiotics in the microstructure of calcium carbonate to synthesize drug-loaded inorganic materials. [291]Moreover, the polymer electrolyte can be grafted onto calcium carbonate nanoparticles, which significantly increases the binding between the cells and calcium carbonate particles.Kong et al. packaged functional groups and guest molecules into nanoparticles to prepare pH-responsive calcium carbonatephospholipid-acetylated dextran (CaCO 3 @ POPC-AcDX) for cancer treatment (Figure 13a). [292]The multifunctional composite particle has versatile molecular-targeted therapeutic applications.
Compared to the crystalline phase, ACC has more applications in biomedical fields and usually acts as a pH-responsive nanocarrier for cancer therapy. [124,293,294]However, the instability of ACC nanoparticles in an aqueous solution limits their applications in the biomedical field.One strategy for stabilizing ACC is the introduction of biocompatible organic molecules.The organic molecules can act as stabilizers and form hybrid materials with nanoparticle carriers.Wang et al. proposed a locking/unlocking strategy for cancer treatment. [295]An oleic acid molecular layer and polyethylene glycol are introduced into the ACC to form the composite nanoparticles.The drug molecule doxorubicin (DOX) is then loaded onto the nanoparticle to kill cancer cells.Another strategy for stabilizing ACC is surface coating.Zhao et al. synthesized a novel nanoreactor of ACC-DOX-silica, whereby the pH-sensitive feature could direct precise drug Reproduced with permission. [32]Copyright 2001, Springer Nature.e) Preparation of the functional nanoparticle composites formation.Reproduced with permission. [118]Copyright 2014, Royal Society of Chemistry.f,g) Fabrication of the multifunctional artificial nacre.f ) Illustration of the matrix-directed mineralization process.g) Photos of the artificial nacre.Reproduced with permission. [181]Copyright 2022, China University of Science and Technology.(Scale bar: a,c) 1 cm and b,d) 10 μm).
delivery and cancer treatment (Figure 13b). [293]Guest molecular modification and assembly can broaden the applications of calcium carbonate materials in the biomedical field.Compared with the crystals, ACC offers advantages in drug delivery systems because of its smaller particle size, ease of fabrication, and regulation.

Environment and Ecological Restoration
Finally, we reviewed the biomineralization techniques in the environment and ecological restoration.Facing the rapid development of industrial production, it is necessary to develop green and environmental techniques to reduce the emission of greenhouse gas.Biologically induced mineralization techniques have become an attractive CO 2 -fixation process. [296,297]icroorganisms can produce carbonic anhydrase to fix CO 2 and then form specific minerals of calcite and aragonite. [298]igure 13c is a formation illustration of calcium carbonate mineralization that is induced by urease bacteria. [299]CO 2 fixation through the mineralization technique is a rapid process without the issues of transport and leakage. [300]Compared to cement-mixed underground backfill materials, the formation of calcium carbonate induced by microorganisms is deemed an environmental-friendly technology. [301]nother application is the preparation of anticorrosive coatings in the ocean.Damage to reinforced concrete structures caused by marine biological fouling and corrosion is becoming increasingly serious. [302]Biomineralization technology can solve these problems through the design of anticorrosive coatings with different surface structures. [303]The dense inorganic layer of the composites can effectively reduce corrosion.Moreover, the nanostructure of the coating endows the materials with excellent hydrophobic, oil-phobic, and antifouling properties.For example, Xiao et al. applied a biomimetic mineralization strategy to prepare calcium carbonate thin films, and the synthesis layer displays comparable hardness and excellent superoleophobicity. [183]

Conclusions and Perspectives
Originating from a delicate structural design, biological minerals exhibit unique functions and even better performance than synthetical materials, prompting scientists to learn from nature.@ POPC-AcDX).Reproduced with permission. [292]opyright 2016, Wiley-VCH.b) ACC-doxorubicin (DOX)@silica nanoreactor.Reproduced with permission. [293]Copyright 2015, John Wiley and Sons.c) Schematic illustration of the calcium carbonate precipitation by the urease bacteria.Reproduced with permission. [299]Copyright 2010, Elsevier.
Therefore, elucidation of the correlation of structure-function is important for biomimetic design.In this study, we focus on the biomimetic synthesis of calcium carbonate-based minerals and highlight hierarchical structure construction and functional material design.
First, we discuss the delicate construction of the hierarchical structure using additive-induced, gel-mediated, and templateoriented strategies.Additive engineering and template strategies primarily regulate the hierarchical structure through interactions between inorganic minerals and organic matter.On this basis, the gel-mediated process provides a confined space for solute diffusion and a relatively low reaction rate, favoring the evolution of complex morphology.However, it remains difficult to guide calcium carbonate growth at specific sites using molecularrecognition techniques alone.Thereby, this report reviews common matrix-directed mineralization pathways, including LBL self-assembly, ice-template technique, additive manufacturing, and brushing-induced assembly strategy, to guide mineral assemblies.Next, the underlying mineralization mechanisms governing the hierarchical structure and functions are reviewed.The complex morphologies of minerals are mainly directed by nonclassical pathways, including the amorphous phase, OA, mesocrystal formation, and liquid precursors.Finally, recent efforts regarding calcium carbonate-based minerals in biomimetic material design are highlighted, mainly covering optical functions, biomedical development, and environmental restoration.
Overall, this review can lead to a better understanding of the biomimetic design process.One main challenge is to maintain the excellent performance of biominerals when scaling up.Other key points that need to be addressed include 1) developing strategies to integrate diverse molecules, ions, and polymers into minerals; 2) designing novel assembly techniques to reduce preparation time; and 3) elucidating the intrinsic correlation of structure-function, thus designing hierarchical materials with features superior to the current state-of-the-art materials.

Figure 1
lists several representative examples of calcium carbonate-based natural minerals in organisms.

Figure 1 .
Figure 1.Representative examples of calcium carbonate-based minerals with hierarchical structure in organisms.a) Sea urchin spine.Reproduced with permission.[15]Copyright 2012, PNAS.b) Nacre.Reproduced with permission.[177]Copyright 2015, Springer Nature.c) Lobster cuticle: I) morphology of the American lobster Homarus americanus, II) cross-section image of the cuticle, and III) assembling pathway of the hierarchical structure.Reproduced with permission.[57]Copyright 2009, John Wiley and Sons.

Figure 3 .
Figure 3.The regulation of hierarchical structures of calcium carbonate-based minerals using additives.a-d) Effects of the ion additives on the morphology of calcium carbonate: a,b) calcite growth in Mg free and c,d) Mg-rich environments.a,c) scanning electron microscope (SEM) images of the aggregates, and b,d) high-resolution SEM images of the crystal surface.Reproduced with permission.[114]Copyright 2015, American Chemical Society.e-n) Handedness regulation of the biominerals by the induction of the amino acid enantiomers.e-i) Chiral morphology regulations given the nanoparticle tilting theory.e,f ) SEM images of the platelets under the selective adsorption of the L-aspartic acid (e) and D-aspartic acid (f ).g,h) High-magnification SEM images showing the nanoparticle tilting under the induction of the chiral enantiomers g) L-aspartic acid and h) D-aspartic acid).i) transmission electron microscope (TEM) image of the growing platelet edge.Reproduced with permission.[86]Copyright 2017, Springer Nature.j-l) SEM images of the chiral vaterite helicoid by the induction of enantiomeric mixtures (L-aspartic acid is the major enantiomer), e.e.L , j) 10%, k) 20%, and l) 40%.Reproduced with permission.[87]Copyright 2019, Springer Nature.m,n) Chiral switching by the induction of a single-amino-acid enantiomer.m) SEM image of the cross section of the chiral vaterite helicoid, n) Schematic illustration of the chiral switching.Reproduced with permission.[88]Copyright 2018, American Association for the Advancement of Science.o-q) Macromolecular-mediated calcium carbonate structure evolution from block shape to spherules-like with the increase of additive concentration: o) Ca: S = 500:1, p) Ca: S = 125:1, and q) Ca: S = 25:1.Reproduced with permission.[98]Copyright 2007, American Chemical Society.r-u) The evolution of heterostructured calcium carbonate microspheres, SEM images of microspheres at r) 16 h, s) 1 day, and t) 2 days; u) high-resolution SEM image of the equatorial loop.Reproduced with permission.[93]Copyright 2013, John Wiley and Sons Ltd. (Scale bar: e,f ): 2 μm, g,h) 300 nm, i) 5 nm; e) top image: 4 μm; and low image: 1 μm).

Figure 4 .
Figure 4. Template-directed formation of the calcium carbonate-mineralization process.a,b) Mineral growth on the templates of Langmuir monolayers.a) Phase transition of calcium carbonate.Reproduced with permission.[121]Copyright 1998, American Chemical Society.b) Preparation of amorphous calcium carbonate (ACC) precipitates.Reproduced with permission.[124]Copyright 2012, Springer Nature.c-f ) Controlling of mineralization process on the template of self-assembled monolayers (SAMs).c,d) Two patterns of SAMs: c) CO 2 -in diffusion and d) Kitano methods.Reproduced with permission.[131]Copyright 2013.e,f ) Morphology of calcium carbonate crystals, in the e) present and f ) absence of SAMs.Reproduced with permission.[130]Copyright 2002.John Wiley and Sons.

Figure 5 .
Figure 5.The growth of the minerals on the cellulose-based templates.a,b) Design of the helically ordered chitin/calcium carbonate hybrid materials.a) Illustration of the calcium carbonate mineralization on the template of chitin.b) SEM image of the organic template after mineralization for 7 days.Reproduced with permission.[134]Copyright 2015, Wiley-VCH Verlag.c-f ) Construction of the biomimetic biophotonic structural materials.c) Illustration of the artificial molting processing.d) Photos of the film under the left-and right-hand polarized light.e) Performance of the composite films after mineralization 3 h.f ) Swelling performance tests when adding different amounts of poly(acrylic acid) (PAA).Reproduced with permission.[139]Copyright 2022, John Wiley and Sons.g,h) ACC mineralization on the rigid carboxylated networks.g) Illustration of ACC growth on the carboxylated networks.h) SEM image of fraction cross section of the composite film.Reproduced with permission.[140]Copyright 2023, American Chemical Society.

Figure 6 .
Figure 6.Gel-oriented mineralization process.a,b) SEM images of the freeze-dried polyacrylamide hydrogel sample under different solid contents: a) 5 wt% and b) 10 wt%.Reproduced with permission.[145]Copyright 2008, Elsevier.c-f ) Synthesis and performance of the composite functional calcium carbonate crystals.c) Preparation of the functional materials.d-f ) Images of the calcite crystals that grow in different environments.d) Diamagnetic and colorless crystals grown in the agarose gel.e) Colored crystals grown in the agarose gel-enriched Au nanoparticles.f ) Colored and paramagnetic crystals grown in the agarose gel enriched both Fe 3 O 4 and Au nanoparticles.Reproduced with permission.[152]Copyright 2014, John Wiley and Sons.g) Mechanism of crystal growth in the gel network, competitions between the gel strength and kinetics of crystal growth.Reproduced with permission.[146]Copyright 2009, John Wiley and Sons.h-k) SEM images of the calcite-agar aggregates under different conditions: h) 0.5 wt% agar, 0.5 M reagent solutions; i) 0.5 wt% agar, 0.1 M reagent solutions; j) 2 wt% agar, 0.5 M reagent solutions; and k) 2 wt% agar, 0.1 M reagent solutions.Reproduced with permission.[147]Copyright 2018, American Chemical Society.l) The growth of calcite aggregates in different densities of alginate gels.Reproduced with permission.[148]Copyright 2011, Academic Press Inc. m-q) Mineralization of the calcium carbonate on the hydrogel composite membranes.m) Biomimetic synthesis of minerals on the hydrogel composite membranes.n-q) SEM images of the composites on different hydrogel substrates: n) virgin polypropylene (PP), o)[2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) ammonium hydroxide/N, N 0 -methylene bisacrylamide (SPE/MBA) HCMs, p) acrylic acid-co-2-hydroxyethyl methacrylate/ethylene glycol dimethacrylate (AA-co-HEMA/EGDMA) HCMs, and q) MAA-co-HEMA/ PEGDMA HCMs.Reproduced with permission.[150]Copyright 2016, John Wiley and Sons.r) Synthesis of the oriented anisotropic calcite nanoparticles.Reproduced with permission.[149]Copyright 2023, John Wiley and Sons.(Scale bars: a,b) 50 μm).

Figure 7 .
Figure 7. Schematic illustration of different directional assembly strategies on the construction of biomimetic materials.a) Ice-template strategy for the synthesis of nacre.Reproduced with permission.[173]Copyright 2016, American Association for the Advancement of Science.b) Layer-by-layer selfassembly strategy for the preparation of hybrid mesh of graphene oxide-calcium carbonate.Reproduced with permission.[170]Copyright 2020, American Chemical Society.c) Freeze-casting technique.Reproduced with permission.[177]Copyright 2015, Springer Nature.d) Brushing-induced assembly strategy.Reproduced with permission.[179]Copyright 2018, Oxford University Press.e) Evaporation-induced self-assembly via lamination technique.Reproduced with permission.[47]Copyright 2017, Springer Nature.f ) Dual-network interfacial design strategy.Reproduced with permission.[180]Copyright 2019, Elsevier.g) Additive-manufacturing technology.Reproduced with permission.[177]Copyright 2015, Springer Nature.

Figure 8 .
Figure 8. Schematic representation of classical (monomer or ion) and nonclassical (higher-order species as particles) crystallization pathways.Reproduced with permission.[38]Copyright 2015, American Association for the Advancement of Science.

Figure 11 .
Figure 11.Optimization of mechanical performance via the mineralization strategy.a) Fabrication of the organic-inorganic composite materials via the incorporation of the calcite-binding peptide (CaBP) into the chitin-binding domain (ChBD).Reproduced with permission.[265]Copyright 2021, American Chemical Society.b-d) Preparation of the nanoparticles-incorporated artificial nacre with excellent toughness: b) artificial nacre, c) nacre-mimetic structure, and d) combination of aragonite platelet with nanoparticles.Reproduced with permission.[266]Copyright 2022, John Wiley and Sons.e) The incorporation of chiral molecules on the mechanical performance regulation of minerals.Reproduced with permission.[267]Copyright 2020, American Chemical Society.

Figure 12 .
Figure 12.Optical functions development of calcium carbonate-based minerals.a-d) The appearance of the Ophiocomid brittle stars.a) Lightindifferent species (Ophiocoma pumila) with color-insensitive from the day (left) to night (right).c) Light-sensitive species (Ophiocoma wendtii) with color change, from the day (left) to night (right).SEM image of the peripheral layer of the dorsal arm plate in b) Ophiocoma pumila and d) Ophiocoma wendtii.Reproduced with permission.[32]Copyright 2001, Springer Nature.e) Preparation of the functional nanoparticle composites formation.Reproduced with permission.[118]Copyright 2014, Royal Society of Chemistry.f,g) Fabrication of the multifunctional artificial nacre.f ) Illustration of the matrix-directed mineralization process.g) Photos of the artificial nacre.Reproduced with permission.[181]Copyright 2022, China University of Science and Technology.(Scale bar: a,c) 1 cm and b,d) 10 μm).