Versatile bioactive polyphenolic coatings for bone tissue regeneration: from assembly strategies to biointerface interactions

Abstract

There is still a huge challenge in achieving efficient osseointegration between the implant and local bone tissue at the initial stage of implantation, because the bone–implant interface is usually exposed to abnormal microenvironments such as oxidative stress, infection, and bone homeostasis imbalance. Recently, polyphenol-inspired biointerfacial materials have received much attention for enhancing osseointegration due to their unique structural characteristics and biological functions. Polyphenolic biological coatings have shown great potential in providing adjustable physicochemical cues that improve biointerface interactions, thereby promoting bone integration and bone repair by regulating the tissue microenvironment and participating in cellular events. This review briefly outlines the regulatory effects of polyphenols on osteogenesis, introduces the interfacial adhesion mechanisms and construction strategies of polyphenolic coatings, and focuses on the biochemical and biophysical interactions occurring at the cell–polyphenol interface. Our aim is to offer guidance for the rational design of polyphenol related functional coatings and to accelerate the translation of polyphenol platforms from laboratory research into orthopedic clinical applications.

---

1. Introduction

Large segmental bone defects exceeding the critical size threshold (typically >2 cm, depending on the site) caused by high energy trauma, pathology, revision surgery, or tumor resection are difficult to heal without intervention.^1,2 Currently, more than 2.2 million bone grafting procedures are performed worldwide annually, which causes huge personal and societal healthcare burdens. More importantly, large segmental bone defects, particularly in weight-bearing bones, can dramatically reduce the long-term quality of life of patients.³ Driven by the pressing clinical needs, numerous tissue engineering materials have emerged as promising choices for bone repair over the past few decades.⁴ At present, the most common synthetic bone implant scaffolds can be broadly categorized into three major classes: metals (titanium and its alloys),⁵ polymers (polyetheretherketone, PEEK),^6,7 and bioactive ceramics (hydroxyapatite, HA).⁸ The selection of bone implant scaffolds is generally based on the functional and biological requirements of bone tissue, including biocompatibility, structural stability and sufficient mechanical supportability. However, the field of bone tissue engineering has come to a turning point in the past few years, following realization that the transformation of implant materials from bio-inert to bioactive may optimize the outcomes of bone regenerative therapy.⁹ Bioactive scaffolds represent a positive microenvironment, which can promote bone immune regulation, angiogenesis and osteogenic differentiation while maintaining the balance between osteoclastic and osteogenic processes.^10,11 Of special note, the surface characteristics of bioactive implants affect the interfacial microenvironment and interfacial cell interactions, thereby playing a vital role in directing osteogenesis.

The consensus is that osseointegration is a crucial criterion for implant success in clinical practice, representing the structural and functional connection between the living bone and the surface of the implant.¹² Osseointegration after implantation is a dynamic process, which comprises different phases of inflammation and bone formation that are impacted by the surrounding microenvironments.^13,14 Implantation of a scaffold generally triggers the foreign body reaction by M1 macrophage activation within hours after implantation, which is responsible for distinguishing and eliminating external threats. However, massive tissue damage and endocrine diseases can result in a heightened inflammatory state accompanied by the excessive accumulation of inflammatory factors and highly reactive oxygen species (ROS), thus impairing bone–implant osseointegration and long-term stability of implants.^15–17 Meanwhile, the microscopic particles produced by wear and tear of the bone implant activate the abnormal phagocytosis of macrophages, resulting in a persistent aseptic inflammatory response during the long- and medium-term implantation process.^18,19 The resultant cytokines and chemokines stimulate osteoclast activation and abnormal osteolysis at the implant and bone interface, thereby dramatically shortening the lifetime of implants.^20,21 For bone regeneration, BMSC adhesion is a critical initial step in the early osseointegration process. Upon implantation, BMSCs are recruited by chemokines and adhere onto the implant surface or surrounding extracellular matrix via adhesion molecules. Guided by specific microenvironmental cues and osteogenic induction factors, BMSCs differentiate into osteoblasts. Subsequently, these osteoblasts initiate the biomineralization process through the synthesis of the bone matrix and the deposition of hydroxyapatite crystals, which ultimately results in the formation of mature, rigid bone tissue.²² However, the bioinertness of conventional implants presents a substantial clinical challenge, hindering BMSC adhesion, colonization, and proliferation. These limitations impair osteogenic differentiation, reduce angiogenesis, and disturb the balance between osteoblasts and osteoclasts, which ultimately result in poor bone healing and implant failure.²³ Additionally, implant-related infections (IRIs) are currently considered to be the most common problems in clinical orthopedics which delay the healing process. Staphylococcus aureus is one of the main causes for bacterial biofilm formation at the bone–implant interface, which frequently leads to implant failure and osteonecrosis.^24,25

In the clinical application of orthopedic implants, advances in coating technologies have continuously enhanced osseointegration and anti-infective performance.²⁶ Currently, porous structural coatings are widely employed to improve the initial stability and bone ingrowth of implants by increasing surface porosity and roughness, thereby facilitating osteoblast adhesion and proliferation.²⁷ A representative example is the Gription™ porous metallic coating (DePuy Synthes, Johnson & Johnson), which is fabricated by metal sintering to achieve a highly interconnected pore architecture. In addition, ceramic and hydroxyapatite (HA) coatings have been extensively applied owing to their superior biocompatibility and osteoconductive properties. Clinical studies have demonstrated that HA-coated implants exhibit excellent bone integration by guiding new bone growth along the coating surface, thereby accelerating early-stage osseointegration.²⁸ At the same time, antibacterial coatings have attracted growing attention to address implant-associated infections.²⁹ Among them, antibiotic-loaded hydrogel coatings such as the Defensive Antiadhesive Coating® (Novagenit SRL) are capable of sustained local antibiotic release, forming a high-concentration antimicrobial zone around the implant to effectively prevent bacterial colonization and biofilm formation. Titanium nitride (TiN) coatings also have broad clinical application due to their dual functionality, providing both wear resistance and intrinsic antibacterial activity.³⁰ Overall, porous structural coatings, antibacterial coatings, and bioactive HA coatings represent the principal directions of current orthopedic implant surface modification. However, despite these advances, no single coating technology can simultaneously fulfill the complex biological requirements of clinical bone repair. This has led to increasing interest in next-generation interfacial coatings that can synergistically enhance mechanical stability, regulate bone immunity, promote osteogenesis, and prevent infection. Recent frontier studies have demonstrated that rational surface engineering can effectively coordinate antibacterial and osseointegration functions in orthopedic implants.³¹ For instance, Zhao et al. developed a biomimetic strategy to partially convert ZnO nanorods into Zn₃(PO₄)₂ nanostructures on titanium substrates.³² The synergistic antibacterial mechanisms, including physical penetration, ROS generation, and controlled Zn²⁺ ion release, ensured durable and broad-spectrum antibacterial activity. The optimized heterogeneous ZnO/Zn₃(PO₄)₂ surface upregulated osteogenic related genes and promoted extracellular matrix mineralization through reprogramming their configuration of cell metabolism. Remarkably, ZnO/Zn₃(PO₄)₂-coated Ti implants achieved superior osseointegration in a rabbit femur infection model, providing a valuable paradigm for balancing antibacterial and pro-osteogenic properties via surface chemical modulation. It is anticipated that more researchers will devote greater efforts to developing multifunctional coatings through advanced surface modification techniques and assembly strategies, aiming to achieve precise regulation of the bone–implant interface and to accelerate long-term osseointegration.

Polyphenol-based coatings are an emerging strategy to tailor the functional surface of implants due to their unique structural and functional features.³³ The most significant signature of polyphenols is the presence of catechol or pyrogallol groups, which allow spontaneous chemical reactions and physical interactions to induce robust surface adhesion and multidimensional platforms. Inspired by the adhesive proteins from mussels, the catechol groups in polyphenols can interact with various substrates through metal coordination, self-polymerization, hydrogen bonds, electrostatic interactions, covalent reactions, and so on.³⁴ Polyphenols are compatible structural motifs and can form a series of hybrid materials with biomacromolecules or inorganic components for constructing a bioactive engineered interface. Moreover, the polyphenol coatings show great potential for secondary modification to load bioactive molecules.³⁵ As such, a comprehensive understanding of the assembly strategies of polyphenolic coatings is necessary, which provides a crucial foundation for bone tissue engineering material design.

Functionally, the unique structural characteristics of polyphenols endow them with a variety of biological functions, including adhesiveness, antioxidation, inflammation regulation, and antibacterial properties.³⁶ Firstly, polyphenols can serve as universal organic bone adhesives to provide active binding sites for proteins and cells, thus guiding bone tissue regeneration.³⁷ Subsequently, the polyphenolic coatings on the implant aim to regulate the pathological microenvironment by eliminating excessive intracellular ROS, thus further promoting the favorable osseointegration between the implant and host bone.³⁸ Importantly, polyphenols are conducive to bone rebuilding and improve bone metabolism by balancing bone formation and bone resorption.³⁹ As for the interfacial-bio interaction, bone repair involves the active recognition and response of different types of cells to biochemical cues of the implant interface (e.g., polyphenolic ligands or specific functional groups, and the conjugated functional molecules or metal ions) and biophysical cues, including interface roughness, stiffness, and electroconductive properties. The physicochemical cues on the polyphenolic coatings can further influence cell behaviors via interface–cell interactions, including cell proliferation, migration, osteogenic differentiation, and biological mineralization. Therefore, the incorporation of polyphenols can endow implants with excellent bioactivities, which match the requirements of multistage regulation of osseointegration.⁴⁰ Based on their universal surface modification capability and multifunctional properties, polyphenol-based coatings have emerged as an effective strategy in bone tissue engineering.

This review offers a comprehensive overview of polyphenol-driven surface engineering coatings for enhancing implant osseointegration (Fig. 1). We begin by discussing the dynamic and multistage processes involved in bone defect repair, followed by an introduction to the crucial role of polyphenol compounds in promoting bone regeneration. We then summarize recent advances in constructing tailored surfaces using polyphenols. Furthermore, the review highlights that the diverse physicochemical cues of polyphenol coatings play a pivotal role in regulating cell–interface interactions during bone repair. Finally, we conclude with an outlook for the further development and construction of polyphenol-driven implant coatings and emphasize the significance of their interfacial-bio interactions in guiding bone tissue regeneration. This review offers a perspective on polyphenolic surface modification strategies for improved functional implants in bone tissue engineering, hoping to promote the clinical translation and future innovation of polyphenolic coatings.

Fig. 1 Overview of surface design and biomechanism of polyphenolic coatings for osseointegration and osteogenesis. Left: various effects of polyphenols (bioadhesion, antioxidation, anti-bacterial, anti-inflammatory, and osteogenic differentiation) in regulating osteogenesis. Right: different strategies for preparing polyphenolic coatings on various substrates. Bottom: Key factors (biochemical and biophysical interactions) influencing cell behaviors on polyphenolic coatings.

2. Bone repair and osseointegration

Following a bone defect, the status of bone healing is affected by many principal factors, including the size of the defect, the blood supply, the mechanical stability, and the severity of surrounding tissue injuries.⁴¹ In most clinical bone injuries involving larger defects, bone healing proceeds through an orchestrated multistage, secondary healing form, which mainly involves the endochondral ossification route (Fig. 2(a)).⁴² Following an injury, bone healing is a complex regenerative process that initiates with blood clotting, forming a hematoma, and is closely followed by the acute inflammatory phase (stage I: hematoma inflammation). Notably, the formed hematoma on the implant surface, which is rich in growth factors, cytokines and chemokines, has been regarded as the first natural scaffold that supports cell growth and differentiation.^43,44 Subsequently, the hematoma first allows recruitment and infiltration of neutrophils, which provides the osteoimmune microenvironment, thereby determining the subsequent bone regeneration process. Macrophages are activated by the local inflammatory milieu to a pro-inflammatory M1 phenotype, thus initiating host defense to remove the provisional fibrin matrix, the necrotic cells, and bone fragments.⁴⁵ Additionally, macrophages secrete a repertoire of inflammatory cytokines and chemokines, triggering the recruitment of mesenchymal stem cells (MSCs), chondrocytes, and fibroblasts towards the fracture site.⁴⁶ Newly formed granulation tissue is primarily composed of MSCs and the unorganized extracellular matrix (ECM), which gradually replaces the hematoma and allows ingrowth of vascular tissue by stimulating neovascularization.⁴⁷ Subsequently, the osteoimmune microenvironment promotes chondrogenic differentiation of MSCs, where the formation of a soft callus is conducive to restoring the mechanical competence of the injured bone (stage II: soft callus formation).⁴⁸ Of note, the bone defect area is still in a state of ischemia and hypoxia. The recruited bone marrow mesenchymal stem cells (BMSCs) first differentiate into chondrocytes owing to their adapted metabolism, which enables them to survive and function in environments with poor vascularization.^49,50 During this period, macrophages and fibroblasts are also involved in the deposition of the cartilage matrix and the formation of cartilage callus. Subsequently, vascular invasion into the cartilaginous callus initiates during the terminal phase of endochondral ossification and is coupled with the degradation of the callus matrix.⁵¹ The soft callus transforms into the hard callus with a large amount of woven bone under the cooperation of osteoblasts and chondroclasts (stage III: hard callus formation).⁵² Soft callus mineralization results in an increase in local mechanical strength, thereby restoring the basic mechanical support of the defective area.

Fig. 2 (a) Schematic depiction of the four phases of a typical bone healing process and cellular activities at each phase. (I) Hematoma and inflammation phase, (II) soft callus formation, (III) hard callus formation, and (IV) bone remodeling. (b) Illustration of biological events during the osseointegration process.

Thereafter, the healing process is completed by a lengthy bone remodeling phase, which eventually reconstructs the form and function of the bone to match its original mechanical properties (stage IV: bone remodeling). The remaining cartilage matrix is gradually cleared by osteoclasts, while the lamellar bone structure replaces the woven bone of the hard callus. Under the stimulation of bone stress and the regulation of various signaling pathways, the bone tissue undergoes a repeated reconstruction process of resorption, regeneration, and mineralization and finally remodels the complete bone trabecula and Haversian system.⁵³ During this period, some cytokines, such as interleukin-1α (IL-1α), interleukin-6 (IL-6), and receptor activator of nuclear factor-κB ligand (RANKL), as well as matrix metalloproteinase (MMP) and bone morphogenetic protein (BMP) family members, drive osteoclast formation and maintain bone resorption activity, thereby restoring the standard bone shape and performances.^54,55

Concurrently, beyond traditional cellular analyses and molecular signaling pathway explorations, emerging interdisciplinary technologies such as single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and artificial intelligence are reshaping our understanding of the bone healing process. By analyzing the dynamic interactions among bone metabolism, osteoimmunology, bone–multiple organ interactions, and biomechanical simulation during repair, these approaches can offer unprecedented insights into the spatiotemporal orchestration of bone regeneration and identify new targets for precision bone repair therapies.⁵⁶

Osseointegration and bone defect healing share several similar biological processes, including coagulation, immune cell recruitment, angiogenesis, bone matrix deposition, and ossification (Fig. 2(b)).^57,58 However, the nature of the interfacial connection distinguishes the two: bone healing refers to the connection between bone and bone, while osseointegration refers to the connection between the bone and the implant interface.⁵⁹ Meanwhile, osteoblasts are differentiated directly from MSCs around the implant, without endochondral ossification.^60,61 Furthermore, osseointegration is a dynamic process that involves multiple cascaded responses and is extensively influenced by many factors. Environmental factors include loading conditions, host bone characteristics, interfacial distance, local blood supply, local osteoblast and osteoclast concentrations, and systemic diseases.^62–64 Implant related factors include material composition, surface coating, topological structure, macro- and microstructure, roughness, pore size, and porosity and also have a significant impact on osseointegration.^65,66 Enhancing osseointegration critically depends on the rational design of the orthopedic implant interface, which must integrate its physicochemical properties and biological functions.⁶⁷ An ideal coating should meet the following key criteria: firstly, it must guarantee biocompatibility and avoid causing immune or foreign body reactions; secondly, it should exhibit osteoinductive properties that promote cell adhesion, proliferation, and osteogenic differentiation, eventually forming a stable bond between the implant and bone; additionally, it must maintain mechanical stability under physiological stress to prevent falling off; finally, it should have antibacterial properties to minimize the risk of infection.⁶⁸

3. Biofunctions of polyphenols and related coatings in bone regeneration

3.1 Structural characteristics and classification of polyphenols

Polyphenols, a type of organic compound widely found in plants and marine environments, have phenol as their basic skeleton and are characterized by polyhydroxy substitution of the benzene ring.⁶⁹ Till date, more than 8000 polyphenol compounds have been identified and characterized, with the majority consisting of simple phenols with a small molecular weight and phenolic derivatives with a large molecular weight. According to Haslam's classification, polyphenols can be divided into two main categories: condensed and hydrolyzable types. Condensed polyphenols include catechin, procyanidin and others. Hydrolyzable polyphenols are mainly derived from gallic acid. Polyphenols commonly used in biomedical engineering can be simply classified into three categories: dihydroxyphenols, trihydroxyphenols, as well as the dihydroxyphenol and trihydroxyphenol mixed system,⁷⁰ as shown in Fig. 3(a). Due to differences in the phenolic content and molecular structure, these compounds exhibit diverse biological, chemical, and physical properties and can interact with a variety of biomolecules and inorganic components.⁷¹

Fig. 3 (a) Representative chemical structures and classification of commonly used polyphenols applied in functional coatings. (b) Role of polyphenols in multiple stages of the bone regeneration process.

3.2 Multifunctional roles of polyphenols in bone regeneration

Polyphenols have been widely recognized as regulators of osseointegration and bone regeneration, mainly because of their multifaceted functionalities, such as excellent antioxidant, anti-inflammatory, and antibacterial properties (Fig. 3(b)).⁷² Polyphenols can directly impact cells during bone repair or regulate the surrounding microenvironment, and they can also stimulate cell behavior and response by regulating physicochemical cues at the interface. Polyphenols represent a versatile platform and play a role in bone repair through a variety of biological pathways instead of a single mechanism.⁷³ Here, we summarize the biological functions of polyphenol compounds and physicochemical signal-mediated interfacial-bio interactions from polyphenolic coatings for bone regeneration (Table 1). This section elaborates on the biological functions of polyphenol compounds in improving bone repair, focusing on their direct cellular effects and indirect modulation via the microenvironment.

Table 1 Summary of the effects of biological functions of polyphenols and physicochemical signals of the polyphenolic interface on cell behaviors during bone repair

Polyphenols	Platforms	Biological functions	Physicochemical signals	Cell behaviors	Ref.
DA	Molecules	Inhibition inflammatory osteolysis	Receptor ligand binding (D2R)	Inhibited osteoclast formation, osteoclastogenesis-related gene expression and pro-inflammatory cytokine expression in BMMs	158 and 159
	Hydrogel coating	Osteogenic activity	Receptor ligand binding (D2R)	Enhanced BMSC adhesion and osteogenic differentiation; suppressed differentiation of osteoclasts	160
PDA	Coating	—	Functional groups (–NH2)	Enhanced BMSC adhesion and proliferation; formation of a stabilized osteogenic cell population	161
		—	Functional groups (quinone, amino, hydroxyphenyl groups and aromatic ring)	Promoting protein adsorption and maintaining their natural conformation	168
		—	Roughness	Up-regulated expression of osteogenesis marker genes ALP, RUNX2, COL1A1, and OCN of hMSCs	184
		—	Roughness	Enhanced adhesion and spreading of platelets, HUVECs and macrophages	185
		—	Roughness (honeycomb-like structures)	Enhanced MSC adhesion	188
		—	Surface potential	Promoted the spreading and proliferation/differentiation of MC3T3-E1 cells	194
			Surface potential	Increased expression of integrin β1 and integrin β3 and increased M2 polarization of BMDMs	195
		—	Electrical conductivity	Promoted cell proliferation and differentiation	197 and 198
		—	Cu^2+	Increased tubular forming of HUVECs; macrophage polarization to M phenotype; enhanced macrophage-mediated osteogenesis and antibacterial activity	177–179
TA	Molecules/adhesive	Binding affinity to bone tissue and fracture fixation	—	Enhanced bone tissue adhesion	171 and 172
	Membrane	Photothermal effect	—	Bacterial killing	90
	Coating	—	Sr^2+	Upregulated the osteogenic gene expression of MC3T3-E1; macrophage polarization from the M1 to M2 phenotype; autophagy and osteogenic differentiation of MSCs	174 and 175
		—	Ce^3+/4+	Improved mitochondrial function and macrophage polarization from the M1 to M2 phenotype	176
	Coating	—	Conjugated functional molecules	Upregulated the expression of CD206; inducing morphological transition of RAW 264.7 toward a spindle-shaped morphology	171
Resveratrol	Molecules	Antioxidant; inhibition of NF-κB phosphorylation; activation of ER and MAPK signaling	—	Alleviating macrophage oxidative stress	77 and 81
				Promoted cell proliferation and osteogenic gene expression
Curcumin	Molecules	Improved osteo-immune microenvironment	—	Enhanced production of osteogenesis-related cytokine BMP-2 and TGF-β; promoted osteogenic differentiation of BMSCs	78 and 79
Ferulic acid	Molecules	Inhibition of RANKL mediated NF-κB phosphorylation and activation	—	Inhibition of osteoclast differentiation	83 and 84
Quercetin	Molecules	Triggering the estrogen receptor-mediated bone morphogenetic protein signaling	—	Increased the expression of RUNX2 and OSX; promoted osteogenic differentiation	157
EGCG	Molecules	Destroying the bacterial structure	—	Bacterial killing	86
		—	Receptor ligand binding (67LR/ZAP-70/RIG-I)	Regulating the immune function of neutrophils, monocytes/macrophages and T cells	153 and 154
	Coating	—	Functional groups (quinone, hydroxyphenyl groups and aromatic ring)	Promoted protein adsorption and maintaining their natural conformation	161
		Antioxidation; the regulation of immune microenvironment	Functional groups (catechol)	Protecting BMSC resist oxidative damage; triggering a phenotypic switch of macrophages from M1 to M2; Up-regulated expression of IL-10 and Arg-1	143
	Coating	—	Mineralization of hydroxyapatite nanocrystals	Upregulated expression of osteogenic markers (BMP2 and ITGB1); downregulated expression of osteoclast-related factors (FGF21 and IGFBP1)	93
Quercitrin/taxifolin	Coating	—	Functional groups (catechol)	Enhanced MSC adhesion and proliferation; enhanced osteogenic marker expression of RUNX2, COL1A1, and OC of MSCs	164
Catechin	Coating	—	Functional groups (catechol)	Enhanced osteogenic differentiation and mineralization of hADSCs	163
3,4-Dihydroxyhydrocinnamic acid	Coating	—	Roughness gradient surface	Adhesion of MSCs; cell spreading; osteogenic differentiation of MSCs	186
Hydroxyphenylpropionic acid	Film		Tunable stiffness	Restricted MSC spreading; up-regulated expression of COL1 and RUNX2 of MSCs	208

---

In recent years, numerous studies have revealed the significant role of polyphenolic compounds (such as resveratrol and epigallocatechin gallate) in bone tissue regeneration, including promoting osteogenic differentiation, inhibiting osteoclastic activity, enhancing angiogenesis, and modulating the immune microenvironment. Their molecular mechanisms involve the regulation of key signaling pathways, such as BMP/Smad, Wnt/β-catenin, and NF-κB.^74,75 In fact, the crucial role of polyphenols in bone integration and bone regeneration mainly depends on their antioxidant activity and inflammation regulation function, which is conducive to relieving oxidative stress and promoting bone homeostasis. The antioxidant ability of polyphenols to scavenge ROS mainly involves two mechanisms: the direct reaction with free radicals or ROS and the chelation of metal ions.⁷⁶ However, polyphenols have antioxidant effects that go beyond this, and their physiological effects are more likely due to their interactions with biomacromolecules and their influence on cellular redox signaling. For example, resveratrol is capable of defending titanium-worn-activated macrophages against oxidative stress by reducing NO production, ROS generation, and lipid peroxidation, as well as inhibition of NF-κB phosphorylation.⁷⁷ Resveratrol has also been shown to decrease oxidative enzyme activity and promote antioxidant enzyme activity, including catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), and glutathione peroxidase (GPx). Therefore, resveratrol can improve periprosthetic osteolysis and aseptic loosening through multiple pathway regulations. Polyphenols can directly interact with specific factors to take part in intracellular pathways or affect the coordination of crosstalk between macrophages and BMSCs. For instance, curcumin can improve the osteo-immune microenvironment by promoting the production of osteogenesis-related cytokines (BMP-2 and TGF-β) and also inhibit osteoclast resorption through the PI3K/AKT/Nrf2 signaling pathway.⁷⁸ Additionally, the conditioned medium of curcumin-treated macrophages has been confirmed to promote osteogenic differentiation of BMSCs, as evidenced by upregulated expression of alkaline phosphatase (ALP), runt-related transcription factor-2 (RUNX2), osteocalcin (OCN), and osteopontin (OPN), increased protein levels (RUNX2 and OCN) and formation of mineralized nodules in the co-culture assay.⁷⁹ Therefore, polyphenols promote bone regeneration through coordinated modulation of multiple mechanisms, including oxidative stress regulation, immune microenvironment homeostasis, and intercellular communication.

Osteoblasts and osteoclasts regulate each other through complex signaling pathways and secretory factors, jointly maintaining the dynamic balance of bone tissue and facilitating successful osseointegration. Polyphenols exhibit pleiotropic effects on bone homeostasis, primarily including significantly promoting osteoblast differentiation and bone formation, effectively suppressing osteoclast activation and bone resorption, and precisely modulating the bone immune microenvironment. Accumulating evidence has shown that these compounds can regulate the mitogen-activated protein kinase (MAPK) signaling cascade either directly or indirectly, thereby beneficially modulating bone metabolism.⁸⁰ In particular, resveratrol has been demonstrated to promote cell proliferation and osteogenic gene expression by inducing ER signaling and MAPK activation, which involves ERK1/2 and p38.⁸¹ On the other hand, polyphenols are able to decrease the phosphorylation of MAPKs, which is involved in the degradation of MMPs and the inhibition of inflammation-induced osteoclastogenesis through suppressing the RANKL/RANK pathway.⁸² For example, ferulic acid is capable of suppressing pro-inflammatory cytokine expression through the NF-κB pathway, while also preventing NF-κB phosphorylation and activation caused by RANKL, therein attenuating osteoclast differentiation.^83,84 Moreover, Forte et al. demonstrated that quercetin functionalized hydroxyapatite creates a positive bone repair microenvironment, supporting osteoblast proliferation and differentiation and facilitating micro-angiogenic formation in a triculture model involving osteoblast, osteoclast, and endothelial cells.⁸⁵ In particular, quercetin functionalized hydroxyapatite can upregulate the osteoprotegerin (OPG)/RANKL ratio significantly on both 7 and 14 days, with OPG acting as a decoy receptor for RANKL, suggesting marked inhibition of osteoclast differentiation.

The broad-spectrum antibacterial properties of polyphenols play a crucial role in bone regeneration, particularly in preventing implant-associated infections. By disrupting bacterial structures and interfering with microbial energy metabolism, polyphenols can effectively eliminate bacteria, thereby creating a favorable microenvironment for bone regeneration. Polyphenols exert antibacterial activity primarily by damaging bacterial membranes. Zhao et al. proved that epigallocatechin gallate (EGCG) can directly bind to the peptidoglycan of Staphylococcus aureus, which affects the structural integrity of the bacteria.⁸⁶ Furthermore, polyphenols can inhibit the synthesis of proteins, DNA, RNA, and other biological components, resulting in disorders in material metabolism and energy metabolism, which further leads to bacterial death.⁸⁷ For example, Dadi et al. demonstrated that polyphenolic compounds can inhibit the activity of ATPase and ATP synthase in Escherichia coli, thereby disrupting bacterial metabolism.⁸⁸ On the other hand, some polyphenolic compounds can form strong conjugated bonds between molecules through oxidative polymerization or combine with metal ions to form metal–polyphenol networks. The unique structure allows them to effectively exert the photothermal effect, which is crucial for their antibacterial activities.⁸⁹ In the study by Wang and co-workers, they also utilized TA for rapid chelation with Cu²⁺ to form a TA/Cu–PEG composite membrane together with PEG. This composite membrane has photothermal antibacterial properties, bacterial adhesion prevention ability, and good biocompatibility.⁹⁰

3.3 Multifunctional polyphenols for implant-tissue interface design

While numerous studies have elucidated the biological functions and underlying molecular mechanisms of polyphenols in bone tissue regeneration, their practical application in bone tissue engineering faces significant challenges. These limitations primarily stem from their inherent physicochemical properties: (1) the low water solubility of some polyphenols restricts their bioavailability,⁹¹ (2) their photosensitivity and rapid oxidation lead to insufficient chemical stability,⁹² and (3) it is difficult to meet the multistage dynamic regulation requirements of bone tissue regeneration. Collectively, these factors limit the effective loading and long-term bioactivity of polyphenols at the osseointegration interface. While polyphenolic compounds can be effectively delivered during implant-mediated osseointegration via interfacial hydrogels or nanostructures, greater importance lies in developing polyphenol-based functional network coatings that enable sustained activity via self-polymerization or molecular assembly strategies. These polyphenol-assembled coatings primarily consist of polyphenols, effectively preserving their numerous structural characteristics and biofunctional properties.

Through multiple intermolecular interactions including intra-/inter-molecular hydrogen bonding, π–π stacking, and covalent crosslinking, this coating system forms a stable network structure that exhibits exceptional environmental stability and controllability. Meanwhile, assembling polyphenols with organic/inorganic components enables the construction of a multifunctional coating system, whose multi-component synergistic effect satisfies the diverse biological demands across different stages of osseointegration.^93,94 Therefore, polyphenol-based coatings represent a novel bioactive interface that significantly enhances implant performance through the following mechanisms. Primarily, their unique chemical structures simultaneously improve implant biocompatibility and hydrophilicity. Secondly, owing to exceptional antioxidant and immunomodulatory capacities, these coatings effectively relieve early-stage oxidative stress post-implantation and establish an osteogenesis-favorable immune microenvironment. Most importantly, they promote the adhesion, proliferation, and osteogenic differentiation of BMSCs, as well as biomineralization. These synergistic effects collectively address the longstanding clinical challenge of “foreign body reaction-inadequate osseointegration” associated with conventional implants, providing an innovative solution for bone defect repair. The following sections systematically elaborate on the construction strategies and underlying mechanisms of polyphenol-based coatings, with particular emphasis on their regulatory effects on cellular behaviors at the osseointegration interface.

4. Advanced strategies to construct polyphenol-based bioactive coatings

The interfacial chemical functionality of polyphenol-based coatings primarily depends on their abundant phenolic hydroxyl groups, benzene rings, and the diverse intermolecular interactions derived from these structural features. Multiple phenolic moieties can interact with diverse materials or substrates through covalent and non-covalent approaches to enhance the functions of scaffolds. Specifically, catechol and gallocatechol moieties within polyphenols are capable of forming multiple hydrogen bonds, metal–polyphenol coordination complexes, electrostatic interactions, or covalent bonds with substrates or biomolecules. Meanwhile, the benzene ring structure facilitates π–π stacking and hydrophobic interactions. Such versatile interactions are instrumental in both providing the driving force for hybrid system assembly and ensuring robust adhesion of polyphenols onto various substrates (Fig. 4(a)). As a result, polyphenols are widely compatible structural motifs for tissue engineering materials to achieve ideal structure–function relationships.⁹⁵ In this section, we will discuss the use of various polyphenol compounds and assembly methods to construct bioactive coatings on scaffolds for improving osteogenesis. Representative approaches are summarized in Fig. 4(b).

Fig. 4 (a) Key interactions formed by polyphenols acting as building blocks, including covalent bonds, π–π interactions, hydrophobic interactions, metal coordination, electrostatic interactions, and hydrogen bonds. (b) Schematic representation of the three assembly strategies for polyphenol-based coatings on substrates.

4.1 Interfacial adhesion mechanisms of polyphenols in coating engineering

It has been widely acknowledged that the adhesion mechanism between polyphenols and substrates is related to the physical and chemical properties of the materials. Catechol interacts with metal or metal oxide surfaces primarily through the coordination bond between the oxygen atom on the hydroxyl group and the surface metal atom.⁹⁶ For example, the adhesion mechanism of catechol onto the TiO₂ surface has been thoroughly studied. At pH ∼3, catechol has the strongest binding force to the surface of TiO₂. As the pH value increases, the interface binding mechanism gradually transitions from hydrogen bonding to coordination bonding.⁹⁷ Furthermore, the oxidized catechol exhibits weaker adhesion because the quinone cannot efficiently form a hydrogen or coordination bond to the surface.⁹⁸ On hydrophobic surfaces, the van der Waals forces and the hydrophobic interactions between the catechol benzene ring and the surface play a key role in the adsorption process.⁹⁹ In addition, catechol benzene rings can form π–π stacking interactions with organic surfaces, which mainly involve substrates rich in aromatic systems. In addition, the structure and functional group density of polyphenols have significant effects on their adhesion properties. Cheng et al. reported that the introduction of phenolic groups (5–10%) into the polystyrene backbone yielded excellent underwater adhesion (up to >10 MPa) on a variety of substrates.¹⁰⁰ The results indicated that adhesion strength increased with the number of phenolic hydroxyl groups and plateaued when 4 or 5 hydroxyls were present. In addition, the position of the phenol hydroxyl group also has an important effect on the adhesion properties. For trihydroxyl or tetrahydroxyl structures, hydroxyl groups at positions 3, 4, and 5 contribute more effectively to adhesion than those at positions 2 and 6.

Different from the above monolayer deposition, polyphenol compounds are deposited on various materials primarily through oxidative polymerization during the construction of the implant coating. The oxidation process plays a key role in coating formation. Reactive quinones are produced and subsequently aggregate into high molecular weight polymers, leading to the formation of self-polymerized coatings.¹⁰¹ During the deposition process, the content of polyphenols in the reaction system is a limiting factor for further coating formation. In addition, mixing polyphenols with metal cations can drive supramolecular polymer assembly through coordination. Applying this mixture onto a solid substrate enables the rapid deposition of a nanoscale coating, the thickness of which depends on the metal-to-polyphenol ratio.¹⁰² The polyphenolic coating results in multiple functions for the implant and provides an active interface for secondary modification. According to the surface modification process, polyphenolic coating functionalization can be divided into three types: direct polymeric deposition, active bridging interfaces and co-deposited surface (Table 2).

Table 2 Summary of polyphenolic coating preparation strategies

Preparation methods	Formation mechanism	Operational complexity	Advantages	Limitations
Self-polymerization	Polyphenols undergo oxidative polymerization	Simple immersion or dip-coating	Rapid film formation	Difficult to precisely control the reaction rate and thickness
	Coordination between polyphenols and metal ions forms a 3D network		Enhances substrate hydrophilicity and interfacial adhesion	MPNs are sensitive to pH
Active bridging interfaces	Uses covalent or non-covalent interactions to build multilayer coatings through sequential assembly	Requires multiple cycles and tightly controlled reaction conditions	Well-defined layer structure with tunable functions	Tedious and time-consuming process
				Relatively low mechanical stability
Co-deposited surface	Simultaneous deposition of multifunctional components to form hybrid composite coatings	One-step reaction without layer-by-layer repetition	Simplified and efficient process with multiple functions	The functions of active molecules may be affected by the conditions of polymerization or deposition
			Good forming capability on large-area substrates

---

4.2 Direct polymeric deposition

4.2.1. Self-polymerization. Owing to its universal and efficient modification process, polyphenol self-polymerization based on mussel chemistry is an emerging technique for regulating and tailoring scaffold surface properties. Inspired by the wet adhesion properties of mussels, Lee et al. first developed a surface coating strategy based on the self-polymerization of dopamine (DA).¹⁰³ As a typical representative, DA is able to create polymer-like polydopamine (PDA) through oxidative self-polymerization driven by covalent and non-covalent bonding under mild basic pH conditions, which exhibits strong adhesion to various surfaces no matter the inorganic or organic materials. This process is an uncontrollable polymerization and involves a sequence of reactions, including the “phenol-quinone” transduction, intramolecular cyclizations, and molecular rearrangement.¹⁰⁴ Importantly, PDA serves as a versatile platform for surface modification and endows substrates with unique functions, such as biocompatibility, hydrophilicity, and durability. Generally, PDA forms under weak alkaline conditions (pH = 8.5), and both the O₂ and dopamine concentrations influence the polymerization rate. Similarly, the abundant phenolic functional groups of TA can undergo the oxidative transition to quinone under alkaline conditions and promote self-polymerization, thus exhibiting strong affinity for various substrates.^105,106 Additionally, many supporting strategies have been developed, including oxidants, biocatalysts, UV irradiation, and electrochemical actuation, which can accelerate the polymerization of polyphenols and overcome the limitations of pH and long immersion time.^107–109 For example, pre-coating a ZnO layer on the stent surface is an effective reactive oxygen (ROS) assisted polymerization strategy. The abundant ROS generation catalyzed by ZnO can accelerate the deposition of PDA on the substrate, which enhances the polymerization rate of PDA by about two orders of magnitude.¹¹⁰

Polyphenols can spontaneously polymerize on the implant surface, forming a uniform deposition layer without requiring additional processing. In one study, the PDA layer was deposited on the surfaces of three typical substances: PEEK (biopolymer), Ti (biometal) and HA (bioceramic) by DA self-initiated polymerization (Fig. 5(a)), where PDA formed strong covalent and non-covalent interactions with the substrate.¹¹¹ It can be observed from SEM images that the granular aggregates are uniformly distributed on the surface of the PDA coated samples (Fig. 5(b)). The results suggested that the implant surfaces modified by PDA coating became more hydrophilic and also exhibited excellent osteogenic differentiation as well as osseointegration performance, involving the activation of the FAK/P38 signaling pathways. Additionally, polyphenol self-polymerized coatings on metals enhance corrosion resistance. A study by Farshid et al. revealed that a uniform and crack-free PDA coating, electrodeposited on a PEO-coated AZ91 alloy, significantly increased its corrosion resistance. In addition to hydrogen bonds between magnesium hydroxide and catechol groups, the formation of metal–catechol bonds on the PDA coating helped fill surface defects.¹¹² Therefore, polyphenol-based surface modification is crucial for enhancing implant biocompatibility and effectively regulating implant interface properties.

Fig. 5 Synthesis and surface topography of the self-polymerizing polyphenolic coatings. (a) A general strategy for constructing a PDA coating. (b) SEM images of PDA coatings on PEEK, Ti and HA surfaces (bright blue arrows point out the cracks). Reproduced with permission.¹¹¹ Copyright 2019, American Chemical Society. (c) Schematic illustration of the preparation of multifunctional coatings based on gallium(III)–phenolic networks. (d) Representative FE-SEM images showing the surface micromorphology of different gallium(III)–phenolic coatings. Reproduced with permission.¹¹⁷ Copyright 2023, Elsevier.

4.2.2. Metal–polyphenol networks. Polyphenols have strong chelating ability to a variety of metal ions (Cu²⁺, Zn²⁺, Fe²⁺, Fe³⁺, Al³⁺, Zr⁴⁺, and Ti⁴⁺),¹¹³ which can be self-assembled without additional driving force. The metal–polyphenol networks (MPNs) formed through coordination extend in all directions over time and easily form a coating on a substrate surface. At low pH, most polyphenol hydroxyl groups protonate and then lead to rapid disassembly, whereas high pH favors the formation of bis- and tris-complexes, endowing MPN coatings with tunable properties. Because of the abundance of polyphenol compounds and the diversity of metal ions, MPNs offer diversified choices to design a wide range of functional coatings.^114,115

To date, various polyphenols have been used to engineer MPN coatings on orthopedic implants, including TA, EGCG, curcumin, and so on. For example, an EGCG–Mg²⁺ metal–polyphenol network coated on a titanium alloy (Ti-6Al-4V) surface improves osseointegration.¹¹⁶ Studies have shown that compared with monovalent Na⁺, divalent Mg²⁺ shows superior coating assistance capability, likely due to Mg²⁺'s ability to enhance the π-electron interactions of EGCG. EGCG-Mg²⁺ coatings can be a reliable surface modification for titanium alloy implants to enable the synergistic osteogenic effect of EGCG and Mg²⁺, thus enhancing osteogenesis and osseointegration in a rabbit tibia defect model. Similarly, Xu et al. fabricated a multifunctional gallium(III)–tannic acid (TA) coating on titanium implants by simple immersion treatment and found that the thickness of MPN coating could be controlled by adjusting the number and duration of immersion steps (Fig. 5(c)).¹¹⁷ The Ga-MPN coating spontaneously formed on the surface of titanium, with increased immersion times leading to reduced surface cracks (Fig. 5(d)). As the coating degrades, the released TA and Ga³⁺ exhibited outstanding broad-spectrum antibacterial ability. Remarkably, the resulting coating also displayed excellent near-infrared photothermal properties. Compared with uncoated Ti implants, the GA³⁺–TA coating can dramatically improve osseointegration by preventing bacterial infection, relieving oxidative stress and regulating unbalanced bone homeostasis. To further enrich the function of the orthopedic implants, MPN coatings can serve as anchors to load or graft additional bioactive molecules to match more complex pathological environments. For instance, Cu²⁺ can bond with polydopamine to form MPN coatings on the sulfonated PEEK via chelation, π–π stacking, and electrostatic interaction, which further loaded glucose oxidase (GO_x) to synergistically boost diabetic osseointegration. In a diabetic infectious microenvironment, GO_x can catalyze glucose to produce H₂O₂, and the released Cu²⁺ from coating continually catalyzes the H₂O₂ to highly bactericidal ˙OH, which improves the capability for eliminating bacteria by the enzymatic cascade reaction. Therefore, this study provides a conceptually new strategy for orchestrating diabetic infected osseointegration by combining the facilitated osteogenicity of MPNs and antibacterial activity.¹¹⁸

Different from the formation of MPNs through direct metal polyphenol coordination, the structure and morphology of MPNs are strongly influenced by surface pretreatment of metal implants. Du et al. integrated self-assembled curcumin–ferrum (Cur–Fe) nanoflowers on a Mg alloy via a facile immersion process.¹¹⁹ Notably, the plasma electrolytic oxidation (PEO) pretreatment coating on the Mg alloy provided a porous sponge-like structure and the necessary conditions for the in situ growth of nanoflowers. The prepared Cur–Fe nanoflower coating degraded slowly and continuously in the physiological environment while simultaneously improving the corrosion resistance of magnesium alloy.

4.3 Active bridging interfaces

In the second type, the polyphenolic coatings are first deposited on the substrate surface as active bridging interfaces, and then the bioactive molecules/materials are subsequently anchored to the coating via a layer-by-layer (LBL) strategy. Polyphenols are regarded as typical functional molecules to construct LBL materials due to the strong covalent and non-covalent interactions with various species. First, the phenolic hydroxyl groups in the polyphenol coating serve as effective anchoring sites for various functional groups, such as epoxy and boronic acid moieties.¹²⁰ Based on the dynamic nature of boronate ester chemistry, cis-diol structural units in polyphenols can react with boronic acid to form reversible covalent bonds, thereby creating stimuli-responsive boronic acid–polyphenol networks.¹²¹ Similarly, owing to the high reactivity of oxidized catechol moieties (quinones), polyphenolic coatings offer the reactive sites for conjugating amino- or thiol-containing compounds via Michael addition or Schiff-base reactions,^122,123 thereby expanding additional covalent modification routes for coatings. For example, TA mediated LBL self-assembly was used to load the biomineralization inducer (8DSS) on the surface of titanium implants via covalent linkage, which was proposed to promote osseointegration.¹²⁴ Moreover, polyphenols can be electrostatically assembled with cationic compounds,¹²⁵ and this interaction is responsive to the surrounding environment (such as pH and temperature). In Zhuk's work,¹²⁶ poly-tannic acid (PTA) coating was combined with cationic antibiotics, including polymyxin B, gentamicin, and tobramycin, via the electrostatic interactions, ultimately fabricating a bio-responsive and controlled-release antibacterial film.

Apart from polymers or active molecules, the polyphenolic coatings have been applied as intermediates to bridge cells, proteins, and DNA molecules due to their strong interactions with biomolecules (e.g., covalent bonds and hydrogen bonds).^127,128 For example, the phenol hydroxyl group of TA is bonded to the phosphoric acid backbone of DNA or the carbonyl group of the peptide chain by hydrogen bonding.¹²⁹ Dong et al. conducted the studies to anchor the RBC membrane homogeneously on the TA oxidative polymerization coating, which endowed the substrates with excellent biocompatibility and macrophage immunomodulatory capability (Fig. 6(a)). This cell membrane coupling strategy with PTA as the bridging layer can be applied to modify various irregularly shaped orthopedic and dental implants.¹³⁰

Fig. 6 Polyphenolic active interfaces and co-deposition strategies. (a) Schematic diagram of the fabrication process of the pTA-assisted cell membrane-based coating. Reproduced with permission.¹³⁰ Copyright 2019, American Chemical Society. (b) Schematic illustration of the preparation of antibacterial coatings on titanium implants by using the co-deposition strategy of catecholins and polyamines. Reproduced with permission.¹⁴¹ Copyright 2020, Elsevier. (c) SEM images of surfaces of the pristine Ti and catechol-ε-poly-L-lysine painted Ti substrate. (d) The preparation process of silica coatings on 3D printed PCL scaffolds mediated by co-deposition of EGCG and PEI. Reproduced with permission.¹⁴³ Copyright 2023, John Wiley and Sons.

Besides, polyphenolic coatings can be applied as universal biomineralization interfaces to immobilize the functional inorganic materials on various substrate surfaces. A biomineralization strategy for polydopamine-assisted hydroxyapatite formation (pHAF) has been developed to readily integrate inorganic hydroxyapatite on a variety of surfaces regardless of the material type.¹³¹ During the dip coating process, the abundant catecholamine moieties of polydopamine can induce the nucleation of hydroxyapatite by bonding Ca²⁺ at the interface. The study demonstrated that when proanthocyanidins, myricetin, resveratrol, and kaempferol were applied as primers at the implant–dentin bonding interface, they all facilitated the oriented deposition of amorphous calcium phosphate (ACP) nanoparticles, consequently forming a homogeneous mineralization layer.¹³² Notably, myricetin and resveratrol exhibit superior capability to further induce biomimetic remineralization within the hybrid layer, thus enhancing both the bonding strength and long-term stability at the implant–dentin interface. This finding expands the available strategies for constructing functional mineralized coatings on implant surfaces. The strong interactions between PDA and CaP biominerals enable the formation of hydroxyapatite crystals aligned with the c-axis, which has the same growth pattern as natural biominerals. Meanwhile, epigallocatechin gallate (EGCG) coatings have also been reported for induction of hydroxyapatite deposition on magnesium alloys, which is intended to improve the corrosion resistance and biocompatibility.¹³³ As reported, Zhang et al. designed a self-polymerized PDA coating for depositing hydroxyapatite (HA) on Zn–1Mg porous scaffolds. The prepared HA/PDA composite coating was an effective physical barrier to retard the corrosion, facilitating the optimization of the degradation behavior of Zn–1Mg porous scaffolds.¹³⁴

Additionally, polyphenols are also proven to have in situ reduction capacity and serve as reducing and stabilizing agents for the green synthesis of metallic nanomaterials. For instance, the polycaffeic acid coating formed on the surface of the titanium foil with UV assistance could immobilize and reduce Ag⁺ to silver particles by its catechol moiety, thus creating an antibacterial surface to mitigate the bacterial infection in implant procedures.¹³⁵ Meanwhile, polyphenols and their derivatives, including polydopamine (PDA),¹³⁶ PTA,¹³⁷ and lignin,¹³⁸ actively enhance the in situ reduction process of metal ions. Thus, polyphenols can serve as active interfaces to further mediate the formation of organic or inorganic coatings on implant surfaces.

4.4 Co-deposited surface

The co-deposited method simplifies the surface modification process into one step compared with the aforementioned LBL strategy, where polyphenols are coupled/mixed with functional molecules or materials and then deposited onto the substrates integrally. A wide variety of molecules, including polymers, proteins and silane coupling agents, have generally been utilized in the co-deposition process. It is noteworthy that the structures, morphologies and polymerization rates of polyphenol hybrid coatings can be regulated by additives during the deposition process. Yang and coworkers proposed an innovative strategy involving the co-deposition process of L-DOPA and polyethyleneimine (PEI) to significantly accelerate the preparation process of mussel-inspired coatings.¹³⁹ The research proved that PEI crosslinking with intermediates of oxidized L-DOPA resulted in a highly effective acceleration of the formation of L-DOPA/PEI aggregates through Michael addition and Schiff-base reactions. Therefore, tuning the concentration of PEI can flexibly control the growth rate and particle size of LDOPA/PEI aggregates in the co-deposition system. The L-DOPA/PEI coating forms four times faster than the PDA, and it has both super-hydrophilic properties and antibacterial functions. Similarly, it has been reported that the mixture of TA and hydrolysable 3-aminopropyltriethoxysilane (APTES) could assemble hierarchical layer-colloidal nanosphere coatings on highly hydrophobic surfaces by a simple dip-coating method.¹⁴⁰

Co-deposited coatings constructed with polyphenols and polymers, biomacromolecules or micromolecules have been studied as a universal route for guiding bone regeneration and have consequently attracted extensive attention. For example, Xu et al. constructed a catechol-ε-poly-L-lysine (EPLC) coating on the Ti surface by a single-step strategy (Fig. 6(b)), where catechol and polyamines were copolymerized via Schiff base reactions in alkaline solutions. The prepared EPLC coating could be easily attached to the surface of various substrates, endowing the Ti surface with microstructures (Fig. 6(c)) and unique antibacterial properties, while also increasing its osteoconductivity.¹⁴¹ Similarly, a co-deposition coating consisting of TA and polypyrrole nanoparticles was fabricated by hydrogen bonding interaction in the research of Wang et al.¹⁴² The uniform and photo-responsive antibacterial coating could be deposited onto solid materials in a substrate-independent manner.

Remarkably, co-deposited coatings can often be used as a bridge interface to further introduce other molecules, achieving the integration of multiple functions. Xiao et al. pre-constructed an EGCG/PEI (polyethyleneimine) co-deposited coating on a 3D printed PCL scaffold. Here, the negatively charged silicic acid combined with the highly positively charged EGCG/PEI coating assembled to form multilayer nanostructured silica on its surface (Fig. 6(d)).¹⁴³ The introduction of EGCG presented a favorable immune microenvironment for osteogenesis, while the release of silicon ions accelerated osteogenesis and vascular network reconstruction by activating a series of signaling pathways. More recently, the biomimetic adhesion and clickable molecular linkage coating was fabricated on Ti implants by Ge and coworkers, which was achieved through the one-step deposition process of a levodopa peptide with a bioclickable dibenzocyclooctyne group [(DOPA)6-PEG5-DBCO].¹⁴⁴ The dual-functional adhesive coating allowed for stable tethering of pre-osteogenic MSC-derived extracellular vesicles, ultimately enhancing osseointegration on the Ti implants by regulating the expression of osteogenic genes and macrophage polarization through multiple pathways.

4.5 Stability of polyphenolic coatings

Polyphenol-based surface engineering has emerged as a highly versatile strategy for fabricating multifunctional coatings, demonstrating broad applicability across various substrates, including metals, polymers, and ceramics.^145,146 For instance, the copolymerization of catechol derivatives with terminal amino ligands facilitates the formation of functional coatings that exhibit both exceptional biocompatibility and potent antimicrobial properties. This innovative approach has been applied to surface modification of various medical materials, ranging from paper and cotton dressings to polypropylene.¹⁴⁷

In the field of implants, the stability of polyphenolic coatings is of vital importance. It is defined as the ability to maintain mechanical properties, chemical structure, and functional characteristics over extended periods in physiological environments, which directly affects the long-term performance and biocompatibility of implants. Current research on the stability of polyphenolic coatings primarily focuses on their chemical degradation and release behaviors under simulated physiological conditions. For instance, researchers evaluated the stability of an alkyl- and quaternary ammonium-co-substituted tannic acid (TA) coating (AQTA) through in vitro leaching experiments. After immersing AQTA-coated polyurethane (TPU) sheets in physiological saline for 3 days, the content of TA derivatives in the leaching solution was measured. The results demonstrated excellent stability of the AQTA coating, with TA leaching rates of both TPU-A100 and TPU-A150 less than 1%.¹⁴⁸ Similarly, the metal–tannic acid composite coating loaded with metformin on the degradable zinc-based substrate exhibited outstanding stability. The coating formed a complete and uniform corrosion product layer on the surface in long-term corrosion immersion tests. In contrast, the tannic acid/metformin coating, which relies on hydrogen bonding and electrostatic interactions, tended to detach during prolonged immersion, resulting in an uneven distribution of corrosion products on the substrate surface.¹⁴⁹ Collectively, coating stability is closely related to its thickness and crosslinking density. A higher crosslinking density effectively enhances molecular immobilization, while an appropriate coating thickness helps balance mechanical strength and release kinetics.

Furthermore, to ensure that the implant can resist repeated mechanical loading during surgical implantation, the polyphenolic coating on its surface must exhibit excellent chemical stability, mechanical stability, and adhesion strength to the substrate. Du et al. developed a catechol-modified polyallylamine (CPA) coating inspired by Mytilus edulis foot protein-5, in which the synergistic interaction between catechol and polyamine groups enables the formation of an interpenetrating and entangled network structure. This “reinforced-concrete-like” coating exhibits outstanding chemical and mechanical stability, surpassing conventional PDA coatings. In particular, it maintained its structural integrity even after exposure to harsh chemical conditions and high-frequency ultrasonic treatment.¹⁴⁶ Ho et al. systematically investigated the bonding performance of PDA coatings and hybrid PDA–SiO₂ coatings with varying compositions on titanium implant surfaces. The results revealed that the shear bond strengths of pure PDA and 20SiPDA hybrid coatings were 3.1 ± 0.5 MPa and 3.4 ± 0.5 MPa, respectively.¹⁵⁰ Nevertheless, this bonding strength proves to be insufficient for orthopedic implants, falling notably below that of hydroxyapatite/titanium (HA/Ti) composite coatings (>10 MPa) fabricated on Ti-6Al-4V alloy substrates, as reported in the literature.¹⁵¹ Therefore, it is imperative to optimize the interfacial bonding performance between polyphenolic coatings and substrates to enhance the long-term stability of the coatings and meet the application requirements in implant materials.

5. Polyphenol-based bone–implant interface in regulating cell behaviors

As discussed above, polyphenolic coatings have garnered significant interest as potential functional interfaces for bone tissue engineering. More profoundly, bone regenerative processes generally rely on the interplay between bioactive interfaces and the adjoining cells. First, the dynamic interactions between the cells and the implant interface occurs continuously throughout the healing process. These polyphenol-mediated chemical signals, including membrane surface receptor protein, functional groups and ion enrichment, activate specific signaling pathways and manipulate cell fate. In addition, polyphenol-based functional coatings have adjustable physical properties, such as surface roughness, stiffness, and electrical conductivity, which can provide a versatile environment to guide cell behaviors. Hence, understanding how the polyphenol interface interacts with the cell system and the corresponding cell behaviors is crucial for designing safer and more effective coatings for osteogenic application. In this section, we will discuss how polyphenolic coating directs cellular behaviors during osteogenesis from both biochemical and biophysical perspectives.

5.1 Biochemical interaction

New bone formation initiates at the implant surface. The introduction of an extra implant interface is a novel element in the bone environment, where various chemical responses and cell behaviors at the bone–implant interface are of great significance to osseointegration.⁶⁰ Polyphenol-based coatings achieve multifunctional synergistic regulation at biomaterial interfaces through their distinctive chemical properties. These functionalities include receptor-mediated cell recognition, cell adhesion, immunomodulation of the microenvironment, biomineralization, protein adsorption, and osteogenic differentiation. Specifically, the recognition of cell surface receptors and cellular adhesion are primarily attributed to multiple non-covalent interactions, such as hydrogen bonding and hydrophobic interactions, occurring between the phenolic hydroxyl/aromatic ring structures of polyphenol molecules and proteins.¹⁵² Concurrently, polyphenol-based coatings synergistically capture extracellular matrix proteins, such as fibronectin, through both covalent crosslinking (e.g., Michael addition and Schiff base reactions) and non-covalent interactions, thereby creating an optimal microenvironment for cell adhesion. Significantly, the phenolic hydroxyl groups in polyphenols not only confer the coatings with notable anti-inflammatory and antioxidant capabilities but also play a crucial role in biomineralization processes. Based on these, the introduction of metal ions and functional molecules through dynamic molecular interactions or covalent conjugation can further modulate cellular behaviors at the interface. Collectively, these combined properties regulate cellular adhesion behaviors, signal transduction pathways, and immune responses, ultimately exerting profound effects on implant osseointegration. At the molecular level, the chemical signaling at implant surfaces originates from two primary sources: the direct functionality of polyphenolic ligands or specific functional groups, and the regulatory effects of conjugated functional molecules or metal ions.

5.1.1 Interfacial polyphenolic ligands or functional groups.
5.1.1.1. Receptor-mediated signaling at the biointerface. Natural polyphenols can interact with both extracellular and intracellular targets via specific receptors, initiating signal transduction pathways and downstream biological responses. Generally, each type of polyphenol can recognize and bind to one or more receptors on different cell types. As reported, epigallocatechin gallate (EGCG) targets three important cellular receptors, including the 67 kDa laminin receptor (67LR), zeta chain-associated 70 kDa protein (ZAP-70), and retinoic acid-inducible gene (RIG-I), which are widely expressed on neutrophils, monocytes/macrophages and T cells.¹⁵³ Especially in terms of inflammation regulation, EGCG remarkably reduces LPS-induced activation of TLR4 downstream signaling pathways through the 67 kDa laminin receptor, thus alleviating excessive inflammation.¹⁵⁴ In addition to immunoregulation, polyphenols can exert a beneficial influence on vascular and osteogenic functions through receptor-mediated signaling. Resveratrol has been reported to bind to estrogen receptors α and β (ERα and ERβ) and enhance the transcriptional activity, thereby stimulating MAPK and endothelial nitric oxide synthase (eNOS) activity to promote endothelial nitric oxide synthesis and vascular remodeling.¹⁵⁵ Similarly, quercetin has been demonstrated to promote osteogenic differentiation by triggering the estrogen receptor-mediated bone morphogenetic protein (BMP) signaling, thereby upregulating osteogenic transcription factors such as RUNX2 and Osterix (OSX), which are essential for bone formation.^156,157

Dopamine, another representative polyphenolic compound, transduces biological signals through seven-transmembrane G protein-coupled receptors, including five receptor members from D1R to D5R.¹⁵⁸ Importantly, the anti-inflammatory and anti-osteolytic effects of dopamine are primarily mediated through the inhibition of pro-inflammatory cytokine expression in bone-marrow-derived macrophages (BMMs) via the D2-like-receptor pathway. It has been demonstrated by Hanami et al. that DA inhibits osteoclast formation and osteoclastic bone resorption in a direct D2-like receptor (D2R)-dependent manner.¹⁵⁹ Building upon these molecular mechanisms, controlled-release coatings incorporating polyphenolic compounds have been engineered to achieve precise modulation of the bone–implant interface. Wang et al. fabricated a hydrogel coating on a titanium substrate that continuously and steadily released DA, where the DA loading concentration of 100 µM optimally balanced osteoclast inhibition and osteogenic promotion. Notably, hBMSCs cultured on the DA-loaded coating showed enhanced cell spreading with more extensive filamentous pseudopodia formation, which is attributed to DA-mediated cell adhesion (Fig. 7(a)). Moreover, the DA loaded hydrogel coatings inhibit phosphorylation of AKT and NF-κB via the activation of the D2 receptor signaling pathway (Fig. 7(b)), which results in the reduced expression and weakened nuclear translocation of NFATc1, thereby suppressing osteoclast maturation and differentiation.¹⁶⁰

Fig. 7 Cell behaviors mediated through interfacial polyphenolic ligands or functional groups. (a) SEM images of hBMSCs grown on a DA-loaded hydrogel coating. (b) Schematic illustration shows that DA-loaded hydrogel coatings regulate bone remodeling through dopamine receptor mediated osteogenic differentiation. Reproduced with permission.¹⁶⁰ Copyright 2021, Elsevier. (c) SEM images of RAW264.7 cells on the scaffolds. (d) Immunofluorescence staining images of iNOS and CD206 in RAW264.7 cells. (e) Gene expression of RAW 264.7 cells. Reproduced with permission.¹⁴³ Copyright 2022, John Wiley and Sons. (f) Schematic illustration of a catechin hydrate surface coating for enhanced osteogenesis. (g) Alizarin red staining for evaluating calcium deposition in osteogenically differentiated hADSCs, scale bar = 200 µm. (h) XPS analysis of Ca 2p peaks on uncoated and catechin-coated substrates. Reproduced with permission.¹⁶³ Copyright 2017, American Chemical Society. (i) Schematic diagram of a polyphenol-modified Ti bioactive surface through covalent immobilization and drop casting. Gene expression of osteogenic markers, including RUNX2 (j), osteocalcin (OC) (k), osteogenic collagen (COL1A1) (l), and ALP activity (m) in hUC-MSCs cultured on polyphenol-modified surfaces. Reproduced with permission.¹⁶⁴ Copyright 2015, John Wiley and Sons.

5.1.1.2. Functional group-driven modulation of cellular behaviors. Beyond receptor–mediated interactions, the surface chemistry of polyphenol-based coatings exerts profound effects on cellular adhesion, morphology, and fate determination. Polyphenols are rich in functional groups, including catechol, pyrogallol, carboxyl, and amino moieties, which can establish hydrogen bonds, coordinate metal ions, or form covalent linkages with biomolecules. These functionalities provide dynamic anchoring sites that mediate interfacial interactions and regulate gene expression related to cell adhesion and differentiation during osteogenesis. A study indicated that when a series of PDA coatings at various concentrations were coated on the polydimethylsiloxane (PDMS) surface, the cell adhesion could be significantly enhanced more than 40-fold.¹⁶¹ Notably, the coating prepared with 0.01% PDA continuously promoted the adhesion and proliferation of BMSCs, eventually forming a layer of stable osteogenic cell population in long-term culture. Ninhydrin-based colorimetric assay verified the presence of free amine groups on PDA coatings, where the highest amount of nitrogen was observed at 0.100% (w/v). The main contribution of amine groups was to enhance initial cell adhesion, while the surfaces with lower amine contents were more favorable for sustained BMSC growth. Moreover, the PDA coating formed rapidly (1 h) on the PDMS surface enhanced the stability of BMSC adhesion and osteogenic differentiation through the promotion of α-5 integrin expression and activating the PI3K signaling pathway.

Of special note, the type of polyphenol-based surface functionalization also significantly influences the immune cell behaviors at the interface. For instance, phenolic hydroxyl groups of EGCG remained after the formation of EGCG/PEI co-deposition coating, which endowed the scaffold with promising antioxidant capability.¹⁴³ Hence, hybrid coating with EGCG could effectively protect BMSCs from H₂O₂ mediated oxidative damage and provided a favorable immune microenvironment for osteogenesis. The remarkable ROS scavenging properties of EGCG are deemed to mediate immune regulation by helping macrophages to reverse their inflammatory status. Experimental results revealed that RAW264.7 macrophages cultured on EGCG/silica-coated surfaces exhibited typical M2-like characteristics, including the spindle-shaped morphology and enhanced cell spreading (Fig. 7(c)). In contrast, the control group maintained an M1-polarized state, as evidenced by the elevated expression of inducible nitric oxide synthase (iNOS), a marker of pro-inflammatory macrophages (Fig. 7(d) and (e)). In addition, gene expression analysis via qPCR further confirmed this phenomenon, showing that the EGCG/silica coating downregulated the expression of pro-inflammatory genes (TNF-α and IL-1β) and upregulated the expression of M2-related genes (IL-10 and Arg-1).

Moreover, catechol groups in polyphenols can effectively accelerate the biomineralization process.¹⁶² For instance, Lee and colleagues further investigated the pivotal role of polyphenol coating-mediated biomineralization in regulating cellular behaviors (Fig. 7(f)).¹⁶³ In particular, the catechin-coated groups exhibited a greater amount of calcium deposition with alizarin red staining, suggesting enhanced osteogenic differentiation and mineralization of hADSCs (Fig. 7(g)). XPS analysis further confirmed that the catechin coating mediated mineralization on the substrate surface through its active functional groups (Fig. 7(h)). Based on this, the deposition of hydroxyapatite nanocrystals created a favorable extracellular matrix microenvironment for osteogenesis-related cells, which is conducive to enhancing osseointegration between the implant and the host bone tissue. A recent study has further demonstrated that the polyphenol–hydroxyapatite hybrid system exhibited remarkable synergistic biological effects. Notably, the tea polyphenol-functionalized micro-/nano-hydroxyapatite bioceramic (TP-nwHA) provided abundant anchor sites for MSC attachment and spreading due to its unique surface characteristics.⁹³ Moreover, the TP-nwHA scaffold exhibited dual regulatory effects on MSCs, significantly upregulating the expression of osteogenic markers (BMP2 and ITGB1) while downregulating osteoclast-related factors (FGF21 and IGFBP1). These results confirmed that biomimetic hydroxyapatite bioceramics, when combined with polyphenols, can effectively regulate bone tissue regeneration via the MAPK signaling pathway.

The fabrication strategy of polyphenol coatings plays a decisive role in determining their interfacial functionality, as differences in bonding chemistry and exposure of active groups can profoundly affect subsequent cellular responses. Córdoba and coworkers fabricated two kinds of functionalized Ti surfaces with quercitrin and taxifolin, covalent immobilization coating and drop casting prepared coating, and further compared their biological activity (Fig. 7(i)).¹⁶⁴ The results indicated that the covalently modified surface exhibited higher cell adhesion and/or proliferation, enhanced the osteogenic marker expression of RUNX2, COL1A1, and osteocalcin (OC) as well as increased ALP activity compared to the physically drop-cast surface (Fig. 7(j)–(m)). These differences in surface biological activity can be attributed to several factors. On the one hand, polyphenols are almost completely released from the drop-cast surface after 1 h of incubation, making it difficult to exert sustained effects. On the other hand, polyphenols were immobilized on the covalently modified surface by carbonyl groups, thereby exposing a large number of catechol groups that can bind to cells. In contrast, on the drop-cast surface, polyphenols are anchored through the catechol group to the Ti substrate, leading to the exposure of calcium chelating sites.

5.1.1.3. Protein adsorption and interfacial biological regulation. It is widely accepted that cellular responses to implants are largely mediated by protein adsorption in the early stage of osseointegration.¹⁶⁵ Protein adsorption can be affected by the interactions between functional groups in polyphenol coatings and amino acid residues in proteins through hydrogen, ionic, and covalent bonds. Weber et al. investigated the impact of surface coatings composed of TA and pyrogallol (PG) on the host response. The results indicated that TA and PG coatings altered the initial blood protein layer formation, thereby improving the hemocompatibility of titanium surfaces and potentially reducing oxidative stress during tissue integration.¹⁶⁶

Importantly, catechol, carboxyl, or amino groups in polyphenol coatings can enhance the hydrophilicity of the substrate surface, thereby helping to maintain the natural conformation of adsorbed proteins. In contrast, highly hydrophobic surfaces cause an irreversible build-up of non-functional and denatured proteins, resulting in protein fouling.¹⁶⁷ A superhydrophilic nanocoating with passivated protein-adsorption properties was constructed by utilizing dopamine, EGCG, and Cu²⁺ in a representative study (Fig. 8(a)).¹⁶⁸ This coating was hierarchical in function, acting as a superhydrophilic antifouling coating on the macroscale, while the active groups (quinone, amino, hydroxyphenyl groups and aromatic rings) promoted protein adsorption on the microscale. Fibrinogen continuously adsorbed onto the PDA/EGCG/Cu surface as the incubation time increased, effectively maintaining its native conformation (Fig. 8(b) and (c)). In contrast, fibrinogen molecules on the PLA surface underwent obvious conformational changes (Fig. 8(d)). Hence, the polyphenol-mediated adhesive surface enables control over the biological response by signaling through immobilized proteins and other biomolecules, thereby leading to the integration between the implant surface and the local bone tissue. During the initial bone healing process, polyphenols can act as effective bioadhesives and may significantly contribute to cell bio-adhesion, which is the crucial step in initiating cell–interface interactions. In their research, Liu et al. confirmed that the multilayer-structured microparticles with an outermost tannic acid (TA) layer showed significant advantages in platelet adhesion/activation and red blood cell (RBC) aggregation, which may be attributed to the moderate interaction between the outer structure and plasma proteins.¹⁶⁹ Overall, the interfacial functional groups and hydrophilic microenvironment introduced by polyphenol coatings orchestrate protein adsorption and subsequent cell adhesion, thereby affecting the downstream biological events of bone integration.

Fig. 8 Interfacial chemically mediated protein adsorption behavior. (a) Surface wettability of PLA, PDA, and PDA/EGCG/Cu coatings evaluated by measuring water contact angles. Fluorescence intensity (b) and images (c) after FITC-hFg was incubated with PLA, PDA, and PDA/EGCG/Cu surfaces. (d) Activity of Fg-γ after 24 h of fibrinogen adsorption. Reproduced with permission.¹⁶⁸ Copyright 2024, John Wiley and Sons. (e) Schematic diagram of the multiple dynamic interactions among TA, ABL, and Zn^II and their receptor–ligand binding free energies. (f) TA and ABL peptides have four representative interactions. Reproduced with permission.¹⁷⁰ Copyright 2024, Elsevier.

5.1.2 Conjugated functional molecules or metal ions. Polyphenol-based preloading strategies offer novel technical approaches for regulating cellular behaviors at the implant–tissue interface. The polyphenolic coating offers unique advantages for preloading bioactive molecules, enabling efficient loading of osteogenic proteins, therapeutic peptides, or pharmaceutical agents to modulate bone formation. Inspired by the structure of the zinc finger motif, Xu et al. designed a multifunctional coating on the implant surface (ABL@ZnTA) by engineering an integrative peptide–metal–phenolic network.¹⁷⁰ The ABL@ZnTA nanocoating effectively maintains the structural stability of ABL peptide's α-helix through electrostatic/hydrogen bond interactions (93.9%) between polyphenols and the ABL peptide (Fig. 8(e) and (f)), significantly enhancing drug loading efficiency and sustained release. In an LPS-induced inflammatory environment, osteoblasts (MC-3T3) cultured on ABL@ZnTA coating demonstrated markedly elevated expression levels of osteogenesis-related genes, including Runx2, ALP, and COL1. Similarly, a dual-functional implant system (Ti-PR) was developed through a polytannic acid (PTA)-mediated Michael addition reaction, covalently grafting a cationic antimicrobial agent (PHMG) and an osteogenesis-promoting peptide (arginine–glycine–aspartate, RGD) onto titanium implant surfaces.¹⁷¹ The results demonstrated that RGD-modified surfaces significantly induced morphological transition of RAW 264.7 toward a spindle-shaped morphology and markedly upregulated the expression of the M2 phenotype marker CD206. In the competitive cell-bacteria colonization assay, this bifunctional coating simultaneously enhanced the adhesion and spreading of MSCs while inducing apoptosis in most bacteria. This synergistic effect stems from the combined action of PHMG and RGD, endowing the implant surface with dual biological properties of antibacterial capability and pro-osteogenic potential. Furthermore, polyphenols can be functionally integrated with inorganic components and polymers to enhance the overall performance of composite materials. A representative example is TA, which can drive the molecular arrangement of silk fibroin (SF) and hydroxyapatite (HA) to form a bioinspired bone adhesive. This adhesive provides strong fracture fixation while simultaneously promoting bone regeneration.

Metal ion-based therapeutic strategies exert multiple regulatory effects on bone metabolism by modulating osteoclast differentiation, promoting bone mineralization, and stimulating angiogenesis. It is widely known that MPNs as supramolecular complexes on the surface of implants gradually degrade in the physiological environment, thus continuously releasing polyphenols and metal ions. A variety of metal ions, including Mg²⁺, Zn²⁺, Sr²⁺, Ce³⁺, Cu²⁺, and others, play an active role in bone repair due to their unique biological activities.¹⁷³ Taking Sr²⁺ as an example, the as-constructed TA-Sr coating on Ti implants could synergistically create a favorable osteoimmune microenvironment to promote osseointegration and osteogenesis.¹⁷⁴ Notably, with the increase in the number of TA-Sr coatings, the adhesion, spreading, and recruitment of BMSCs were significantly improved, which might be attributed to the synergistic effect between TA and Sr (Fig. 9(a) and (b)). The powerful osteogenic differentiation effect was observed in Ti@TA-Sr-8, which dramatically upregulated the osteogenic gene expression (ALP, Collagen Type I, and RUNX2) of MC3T3-E1. In particular, TA-Sr-8 regulated macrophage polarization from the M1 to the M2 phenotype, which was accompanied by the suppression of CD86 and iNOS (both M1 markers) and an increase in CD206 (M2 marker) (Fig. 9(c)–(e)). Meanwhile, mineralized bone formation was further increased surrounding Ti@TA-Sr-8 compared with the Ti implant (Fig. 9(f)). Similarly, Sr²⁺ exhibited a burst release on the first day in a strontium- caffeic acid self-polymerization coating, whereas its sustained release time could reach up to 21 days, thus achieving long-term osteogenesis promotion (Fig. 9(g)). Interestingly, the LC3 protein content of MSCs was significantly increased in the coating of caffeic acid with a grafted deferoxamine-Sr (T-CS-D) group, suggesting the occurrence of autophagy, which thus promoted the self-renewal and osteogenic differentiation of MSCs (Fig. 9(h)). The results of the in vivo osteogenic effect indicated that the dense bone matrix around the implant was obviously visible in the T-CS-D groups (Fig. 9(i)), while the control group showed thinner and discontinuous new bone. The osteogenesis-related differentially expressed genes showed that the expression of essential genes SPP1 and COL1A2 exhibited the highest levels in Sr²⁺ containing coatings (Fig. 9(j)).¹⁷⁵

Fig. 9 Ionic effect-mediated cell behaviors. (a) Morphology of BMSCs after 24 h of culture on the Ti and Ti@TA-Sr-n surface. (b) Crystal violet staining images of BMSCs that migrated to the proximal surface toward the Ti and Ti@TA-Sr-n. (c)–(e) Representative immunofluorescence images of macrophages cultured on the Ti and Ti@TA-Sr-8 surface for 24 h: (c) iNOS (M1 marker, red), (d) CD86 (M1 marker, green), and (e) CD206 (M2 marker, green). (f) 3D reconstructed micro-CT images of new bone around Ti and Ti@TA-Sr-8 implants. Reproduced with permission.¹⁷⁴ Copyright 2024, John Wiley and Sons. (g) Schematic illustration of the osseointegration mechanism of the DFO-CA/Sr modified Ti implant. (h) Western blot images of LC3-I and LC3-II expression of MSCs cultured on the different Ti substrate surfaces. (i) Hematoxylin–eosin (H&E) staining images of the new bone area. (j) Circular heatmap showing the expression levels of key genes related to osteogenesis. Reproduced with permission.¹⁷⁵ Copyright 2023, John Wiley and Sons.

Cerium ions (Ce³⁺/Ce⁴⁺) exhibit unique biological effects in immune regulation. The transition between Ce³⁺ and Ce⁴⁺ facilitates intracellular ROS scavenging and oxidative stress regulation. Cerium has also been immobilized on substrate surfaces through coordination with TA to form a biofunctional interface.¹⁷⁶ Rather than directly acting on the osteoclasts and osteoblasts, Ce–TA coatings have the capacity to improve mitochondrial function and reprogram macrophages from the M1 to the M2 phenotype. This immunomodulatory activity remodels the regenerative microenvironment and accelerates bone regeneration. Cu²⁺ exhibits remarkable multifunctional biological properties. Extensive research has demonstrated that Cu²⁺ released from biomaterials could not only regulate pro-vascular-related gene expression and induce osteoblastic differentiation but also effectively kill bacteria on and around implants. For instance, metal–phenolic network coatings on PEEK, formed via the self-assembly of Cu²⁺ and PDA, have been developed to accelerate osteogenesis, promote angiogenesis and exert antibacterial effects.¹⁷⁷ The increased ALP activity and collagen of rBMSCs witnessed the direct pro-osteogenic effect of Cu chelated in the coating and released locally. Moreover, the DA-Cu(II) coating can exert an immunomodulatory effect on macrophages, which effectively promoted the expression of osteogenesis-related genes (ALP, BMP2, COL1, and OCN). Furthermore, Liu et al. designed a mussel-inspired “built-up” surface chemistry coating by sequentially heaping a Cu-dopamine network and grafting an osteogenic growth peptide layer. The resulting composite coating endowed PEEK with excellent antibacterial properties as well as synergistic osteogenic and angiogenic abilities, markedly promoting bone regeneration and osseointegration both in vitro and in vivo.¹⁷⁸ More importantly, the pH-responsive MPN can control the release of metal ions. The release of Cu²⁺ from the co-deposition coating of PDA and copper–citrate nanoclusters could promote osteogenesis and vascularization in the physiological environment, whereas the acidification of bacteria could trigger the rapid release of Cu²⁺, thereby enhancing the bactericidal effect.¹⁷⁹

5.2 Biophysical interaction

During the construction of bioactive interfaces for regenerative medicine, numerous studies have highlighted the key role of physical signals in regulation of the extracellular microenvironment (ECM) and cell behavior. Among biointerface properties, stiffness, roughness, wettability, and electroconductive properties are crucial physical parameters. When attached to the surface of biomaterials, cells can perceive the external mechanical signals generated at the cell–biomaterial interface, which are potent for cell biology regulation via mechanotransduction signaling cascades.^180,181

5.2.1 Surface roughness. Surface roughness of an implant, ranging from micro- to nanoscale, is a typical biointerface characteristic and has significant impacts on cell adhesion, cell behavior, and osseointegration.^182,183 For polyphenolic coatings, surfaces with different roughness values (Ra) could be obtained by adjusting the experimental parameters. For instance, cefotaxime sodium (CS)-loaded PDA coatings were fabricated onto Ti substrate surfaces by He et al., and they found that the surface roughness of the coating was controlled by the polymerization time.¹⁸⁴ Owing to the formation of micro-/nanoscale particles, the roughness of the Ti surface gradually transformed from smooth surfaces (R_a = 128.47 ± 5.06 nm) to “minimally rough” (R_a = 569.47 ± 30.27 nm) after polymerization of 30 min (Fig. 10(a)). Although roughness and hydrophilicity are two independent factors, hydrophilicity can be generally increased by roughening the surface. Notably, human mesenchymal stem cells (hMSCs) cultured on PDA/CS-decorated Ti surfaces displayed the up-regulated expression of osteogenesis marker genes ALP, RUNX2, COL1A1, and OCN on day 21, which may be attributed to the combination of surface roughness and the osteoinductivity of PDA (Fig. 10(c)–(f)). In another study, researchers explored the surface modification of poly(dimethylsiloxane) (PDMS) with a composite of hyaluronic acid and PDA. After PDA deposition, the surface roughness increased to 7.52 nm and exhibited a vein-like texture, whereas the roughness further decreased with the increase in the hyaluronic acid concentration. Particularly, the platelets, endothelial cells (HUVECs) and macrophages all exhibited the highest density and spreading morphology on PDA-coated PDMS.¹⁸⁵ Additionally, on a catecholic polyglycerol coating that exhibited the roughness gradient ranging from nano- to microscale, Hou et al. investigated the impact of roughness on human MSC behavior and mechanotransduction.¹⁸⁶ A broad range of surface topographies was achieved by a one-step-tilted dip-coating approach during the coating, which was controlled by the number and density of aggregates (Fig. 10(g) and (h)). More importantly, adhesion of MSCs showed a biphasic manner with roughness, where the level of YAP nuclear accumulation, filopodia length as well as cellular and nuclear tension generation increased with the increasing roughness till the intermediate roughness region and then decreased slowly (Fig. 10(i) and (j)). Because of this, the surface roughness in the intermediate region has the potential to promote osteogenic differentiation of MSCs. It is also revealed that the cell spreading state appeared to have a negative linear correlation with the interfacial roughness (approximately 50 nm to 1 µm) (Fig. 10(k) and (l)). Similarly, Steeves and Variola investigated structure–function relationships with two PDA coatings (sPDA and rPDA) by varying one critical parameter (stationary deposition and rotation) during the deposition.¹⁸⁷ Compared with sPDA, hMSCs on rPDA exhibited a remarkable increase in the proportion of the more elongated and multipodal morphologies, which were associated with the surface-scattered micro-/nano-scale particles.

Fig. 10 Cells sense and respond to interfacial roughness. (a) SEM and AFM images of the pristine and PDA/CS-coated Ti samples polymerized for 15, 30, and 60 min, scale bar = 100 µm. (b) F-actin (red) expression in hUMSCs on the Ti substrate surfaces was visualized by immunofluorescence staining, scale bar = 50 µm. (c)–(f) Expression of osteogenic gene markers in hUMSCs measured by RT-PCR analysis: (c) ALP, (d) RUNX2, (e) COL1A1, and (f) OCN. Reproduced with permission.¹⁸⁴ Copyright 2022, American Chemical Society. (g) Schematic representation of the fabrication of the roughness gradient via a one-step tilted dip-coating approach. (h) SEM and AFM 3D images of the surface morphology of the roughness gradient at different positions, scale bar = 5 µm for SEM images and 10 µm for AFM images. Focal adhesion area (i) and length (j) of MSCs indicated by paxillin immunostaining. (k) The effects of different surface roughness levels on cell fate. (l) SEM images of the adhered MSC morphology on the roughness gradient surface, scale bar = 15 µm, inset bar = 5 µm. Reproduced with permission.¹⁸⁶ Copyright 2020, John Wiley and Sons.

Apart from interfacial roughness, polyphenolic materials can also engineer surface topology to modulate cell adhesion and proliferation. Chen et al. prepared PDA engineered films via DA polymerization at the air–water interface of the particle templates, resulting in regular patterns and grooves with honeycomb-like structures. The results showed that MSC attachment was enhanced on grooved PDA films compared to that on the nonpatterned films, which is likely attributable to the increased cell–material interfacial contact area provided by the grooves.¹⁸⁸ Moreover, different cell types perceive surface roughness differently and then respond via mechanotransduction-mediated gene regulation. Zhu and others have shown that human dental pulp mesenchymal stem cells (DPSCs) on the coating with relatively high roughness exhibited higher viability than MC3T3-E1 cells.¹⁸⁹ This finding highlights the importance of considering cell type-specific responses to surface roughness when designing and optimizing polyphenol-based implant surface modifications.

5.2.2 Electroconductive properties. Endogenous electrical signals can elicit and participate in various biological activities, serving as a crucial pathway in intercellular communication and regulation of tissue repair processes.^190,191 Specifically, an increasing body of research has revealed that endogenous electronegative potentials are generated rapidly after a bone defect, which can regulate cell proliferation and differentiation, thereby mediating bone defect repair.¹⁹² From a structural perspective, PDA could achieve reversible electron exchange by electrically inducing molecular transformation between the phenolic and quinone groups.¹⁹³ Tan et al. reported that PDA coatings on Ti substrates respond to external electrical stimulation and could reversibly switch between oxidized and reduced states by applying periodic potentials of +0.50 and −0.10 V, thereby generating quinone and phenolic groups.

Notably, the quinone groups of PDA coating in the oxidation state significantly promoted the spreading and proliferation of MC3T3-E1 cells, while the PDA in the reduced state improved osteogenic differentiation.¹⁹⁴ In another experiment conducted by Li and co-workers, PDA was employed to functionalize the Ti surface to decrease its surface potential.¹⁹⁵ They found that bone marrow-derived monocytes (BMDMs) cultured on Ti-P2# with low surface potential (approximately −100 mV) tended to polarize toward the M2 phenotype by inhibition of the PI3K-Akt-mTOR signaling pathway, thus promoting osteogenic differentiation of C3H10T1/2. Moreover, the low surface potential could promote the upregulation of integrin β1 and integrin β3 of BMDMs to resist the repulsive force.

Moreover, PDA coatings can mainly serve as auxiliary structural building blocks to improve the electrochemical and biological properties of conductive polymers (e.g., polypyrrole (PPy) chain or carbon microfiber). Previous studies have demonstrated that the presence of dopamine not only facilitates the in situ electrochemical copolymerization with pyrrole by acting as an electron mediator but also greatly improves electrical performance.¹⁹⁶ The electrodes coated with PDA/PPy exhibited significantly lower impedances compared to the electrodes coated with PPy, thus facilitating the charge transfer between the electrode and cells/tissues.¹⁹⁷ Specifically, PDA/PPy films on electrodes led to enhanced proliferation and myogenic differentiation of C2C12 myoblasts than PPy films. Similarly, the electrical conductivity of the carbon fiber sponge-based scaffold was further improved from 32.6 to 128.2 S m⁻¹ by polydopamine coating, which enhanced the differentiation of PC-12 cells under electrical stimulation.¹⁹⁸ In another study, Xie et al. fabricated the conductive PDA-PPy microcapsules on porous Ti scaffold surfaces using electrochemical deposition (Fig. 11(a)). BMSCs on PDA-PPy films exhibited a good spreading under electrical stimulation (ES), as shown in Fig. 11(b) and (c). Compared with PPy films and Ti, BMSCs on the PDA-PPy microcapsules have higher proliferation and ALP activity under the same ES potentials, which may be contributed to the enhanced biocompatibility and the intensified electrical signals of PDA.¹⁹⁹ The inclusion of PDA not only neutralizes the positive charge of the PPy backbone but also forms π–π stacking with PPy to support electron movement. Apart from PDA, TA cross-linked and doped PPy hydrogels also exhibited a higher current response and a lower impedance than pristine PPy.²⁰⁰ Therefore, polyphenols may broaden and improve the biomedical applications of a range of conductive polymers, such as polyaniline.

Fig. 11 The effect of electroconductive properties and stiffness on cell behaviors. (a) Schematic representation of the construction process of DEX-loaded PDA-PPy-MCs. (b) Schematic illustration of the high-throughput stimulation of BMSCs. (c) Fluorescence staining images of BMSCs on Ti, PPy-films, PDA-PPy-films and PDA-PPy-MCs at different ES potentials. Reproduced with permission.¹⁹⁹ Copyright 2017, Springer Nature. (d) The mechanism and construction process of dynamic stiffening hydrogels are displayed, and their capacity to induce osteogenic differentiation of MSCs in vitro and promote bone remodeling in vivo has been systematically evaluated. (e) 3D reconstructed cell images with front and side views. (f) Immunofluorescence staining of Col-I and RUNX2 reveals the osteogenic differentiation in MSC-laden hydrogels. Reproduced with permission.²⁰⁸ Copyright 2023, John Wiley and Sons.

5.2.3 Stiffness. A large number of studies proved that the stem cells can sense the specific stiffness to which the cells are subjected, which mainly initiates the mechanotransduction pathway and activates YAP translocation between the cytoplasm and nuclei to adjust their differentiation trend.^201,202 For example, when MSCs were inoculated on a high-stiffness substrate (≈3 MPa), which is favorable for osteoblast differentiation, chondrocyte differentiation is more likely to occur on a low-stiffness substrate (130 kPa).^203,204 Polyphenols have been extensively investigated as biocompatible crosslinking agents in adjusting the interface stiffness. A representative example involves collagen-based hydrogels, where the incorporation of proanthocyanidins (PA) significantly enhances mechanical stiffness in a concentration-dependent manner. The stiffness of the hydrogel increases gradually with the PA concentration.²⁰⁵ In contrast to conventional rigid scaffolds, scaffold-free microtissues present considerable challenges in tissue regeneration due to their inherent mechanical insufficiency. To address this limitation, Yang et al. developed a strategy by applying PA pretreatment of 3D spheroids derived from dental pulp stem cells (DPSCs). The results revealed that PA-mediated surface crosslinking markedly improved microtissue surface stiffness and effectively suppressed contraction behavior.²⁰⁶ This unique regulatory mechanism opens new possibilities for enhancing biological modulation during pulp regeneration. Therefore, polyphenols exhibit the capability to precisely modulate implant surface stiffness through controlled crosslinking. For instance, Yang and coworkers developed the TA/(gelatin) gel multilayered film by the layer-by-layer method on various substrates as a potential bone implant coating.²⁰⁷ The stiffness of the TA/gel multilayer film was regulated by the different assembled conditions, where the (TA/gel)_4-0.15M exhibited the highest modulus up to 49.2 MPa, which far exceeds the modulus of most reported bio-polymeric films. Additionally, polyphenols have been widely designed as a molecular glue in strengthening the stiffness of the hydrogel through multiple covalent and noncovalent interactions.

Furthermore, polyphenols facilitate the dynamic modulation of hydrogel mechanical properties via synergistic covalent bonding and non-covalent interactions. For instance, a dynamically stiffened hydrogel system was constructed by Li et al. based on the hydroxyphenylpropionic acid and glycidyl methacrylate grafted gelatin macromer (Fig. 11(d)).²⁰⁸ The delayed and controllable stiffening of 3D hydrogels was achieved by horseradish peroxidase/H₂O₂ triggered phenol hydroxyl crosslinking and photo-crosslinking reactions. Notably, MSC spreading was restricted due to the high stiffness in the dynamic stiffening hydrogel, while MSC exhibited higher expression levels of COL1 and RUNX2 under stiffening treatment than all static hydrogel groups (Fig. 11(e) and (f)). Hence, the dynamic stiffness changes of the matrix play a pivotal role in modulating cellular behaviors.

It is worth noting that the interfacial mechanical strength of polyphenol-coated scaffolds significantly differs from their bulk mechanical properties. For instance, a thin PDA layer (thickness: 393.7 nm) formed via self-polymerization on PEEK surfaces showed negligible effects on both the yield load and overall stiffness of the substrate.²⁰⁹ In another study, surface engineering of medical grade polycaprolactone (mPCL) through sequential deposition of human serum albumin (HSA) and tannic acid (TA) was demonstrated to effectively improve surface mechanical properties.²¹⁰ Nanoindentation tests revealed that both HSA/TA-modified surfaces exhibited higher Young's modulus (4–8 GPa) in comparison to the unmodified surfaces. The substrate material significantly influences the measured interfacial mechanical properties, with this effect being predominantly regulated by multiple factors including the coating thickness and interfacial interaction forces. Consequently, the interfacial mechanical signals perceived by cells likely represent a combined effect of both the coating and the substrate.

5.3 Limitations of interface biological functions

The aforementioned studies demonstrate that polyphenol-based coatings exhibit significant application potential in osteoimmunomodulation, osteogenic differentiation, and biomineralization. Nevertheless, their practical biological functions still face several critical challenges, particularly in terms of antibacterial efficacy and vascularization regulation. Further investigation is required to fully understand the antibacterial properties of polyphenol-based coatings and their optimization strategies. During coating assembly, the molecular structure of polyphenols may undergo alterations that reduce the availability of antibacterial active sites. Moreover, coating immobilization significantly restricts the mobility of polyphenol molecules, limiting sufficient contact between molecules and bacterial cell membranes and consequently compromising their antimicrobial efficacy. For instance, poly(tannic acid) (PTA) coatings directly modified on titanium implants exhibited only modest antibacterial activity, demonstrating an inhibition rate of 31.79% ± 7.24% against S. aureus.¹¹⁷ Notably, the introduction of metal ions can substantially enhance antimicrobial performance, as evidenced by gallium(III)–tannic acid composite coatings achieving approximately 78% inhibition against S. aureus. More remarkably, under near-infrared (NIR) laser irradiation, these coatings generate pronounced photothermal effects, enabling near-complete bacterial eradication (>99%) and demonstrating excellent on-demand antibacterial capability. Similarly, PTA-RGD coatings on poly(lactic acid) (PLA) scaffolds exhibited poor antibacterial efficacy against E. coli, with the antibacterial rate below 20%.²¹¹ However, subsequent covalent conjugation with the antimicrobial agent poly(hexamethylene guanidine) (PHMG) significantly improved the antibacterial efficiency to over 90%. These findings collectively highlight the limitations of single-component polyphenol coatings and underscore the importance of advanced surface engineering strategies to enhance their antibacterial performance.

Polyphenolic coatings exhibit remarkable complexity in regulating vascularization during osseointegration. For instance, by activating autophagy pathways in HUVECs, resveratrol reduces ANG2/hypoxia-triggered apoptosis, ultimately improving HUVEC activity and promoting angiogenesis.²¹² Conversely, certain polyphenols, such as quercetin, inhibit vascularization by suppressing eNOS activity and inducing early M-phase cell cycle arrest.²¹³ The vascular regulatory effects of polyphenol coatings demonstrate a significant concentration dependence and structural specificity. For example, in the poly(lactic-co-glycolic acid)/MgO/quercetin artificial periosteum system, a 0.1 wt% quercetin concentration significantly enhanced tubule formation and upregulated Vegfa and Vwf expression, whereas a 1% concentration exhibited inhibitory effects.²¹⁴ Therefore, precise dosage control is essential for polyphenol coating-mediated vascular regulation. In another study, the MPN coating formed by PC and Fe(III) assembly demonstrated negligible promotion of endothelial cell migration and even suppressed CD31 expression.²¹⁵ In contrast, triple-functional peptide co-modification of the MPN coating significantly enhanced these pro-angiogenic indicators, confirming the superiority of composite modification strategies. Notably, the interfacial chemical properties of polyphenol coatings play an important role in vascularization behavior. PDA coatings subjected to 150 °C heat treatment (PDA-2#), which exhibited increased quinone (C=O) content and reduced phenolic hydroxyl/primary amine groups, demonstrate optimal pro-angiogenic performance.²¹⁶ Compared with untreated PDA, PDA-2# coatings enhanced HUVEC adhesion and migration, improved tubule formation, and upregulated VEGF secretion and angiogenesis-related gene expression. These studies underscore the complex structure–function relationship of polyphenols, where their vascular regulatory effects depend not only on specific chemical structures but also on material–microenvironment interactions. Therefore, in the design of bone implant interface coatings, systematic optimization of the polyphenol type, concentration, and surface chemistry is essential to achieve precise vascular regulation.

6. Conclusions and perspectives

Bone tissue engineering strategies are now intertwined with biology and engineering, generally employing the biomaterials to create biocompatible, bioactive, or biomimetic platforms for tissue regeneration. This review provides a comprehensive discussion of the significant role of polyphenols in the complex physiological processes of osseointegration and osteogenesis and highlights their broad potential for optimizing implant surface modification techniques. For polyphenol-based implant coatings, we systematically summarize a variety of innovative fabricating strategies, including direct polymeric deposition, active bridging interfaces and co-deposited surfaces. Polyphenol coatings, with their distinctive structural characteristics and versatile surface properties, provide a tunable physicochemical microenvironment for tissue regeneration interfaces. At the chemical level, these coatings function through mechanisms including interfacial cell receptor recognition, active functional groups, and interfacial chemistry mediated biomineralization and protein adsorption. Notably, their surface conjugation with metal ions or functional molecules further diversifies their biological functionalities. At the physical level, coating properties such as stiffness, surface roughness, and electrical conductivity regulate cellular adhesion behaviors, proliferative activity, and differentiation fate through cell signal transduction pathways.

The core objective of polyphenol-based surface modification is to construct a bioactive interface that meets the critical requirements of osseointegration through structural and functional engineering. Primarily, the intrinsic biological functions of polyphenols can modulate interfacial oxidative stress to improve the osteoimmune microenvironment, while simultaneously guiding cellular behavior at the interface via biochemical and biophysical signaling. On the other hand, polyphenol coatings serve as versatile active interfaces amenable to diverse engineering modifications. Functional components such as growth factors, antimicrobial agents, and hydroxyapatite can be incorporated through covalent or non-covalent interactions to synergistically regulate bone regeneration processes with polyphenols. Thus, through a dual mechanism of “bioactivity + interface customization,” polyphenols enable osseointegration regulation spanning from molecular to tissue levels. Their key value resides in transforming traditional implant interfaces from passive surfaces to actively modulated ones, offering an innovative solution for complex bone defect repair.

It is important to note that numerous challenges still need to be overcome in the development and application of polyphenol-based implant coatings. (1) Polyphenol compounds not only exhibit extensive biological activities but also have great potential for application in tissue engineering scaffolds. Nevertheless, due to the diverse chemical structures, the selection of polyphenols is often imprecise, mainly because of the limited understanding of their structure–property relationship. Consequently, there is an urgent need to advance fundamental scientific research and conduct in-depth analysis of the intrinsic correlations between the structure and functional properties of polyphenols. Such efforts will establish a theoretical and scientific foundation for the precise screening and application of polyphenols. (2) Existing studies predominantly emphasize the biological activity of polyphenol coatings, often overlooking the crucial aspects of their mechanical properties and surface adhesion for bone implants. These key yet often overlooked factors include coating bonding strength, shear stress, fracture toughness, frictional resistance, fatigue, and the potential impact of coating degradation products, which are closely associated with the implant's osseointegration effect and its long-term service performance in vivo. Moreover, to further enhance the binding strength between polyphenolic coatings and biological tissues, covalent bonding or mechanical interlocking structures can be introduced, thereby significantly improving the interfacial mechanical stability. More importantly, future studies should evaluate the in vitro degradation and release behavior of polyphenols in physiologically relevant media to better recapitulate the actual conditions of bone defect microenvironments. (3) The primary challenge is the need for in-depth and systematic scientific studies to validate the in vivo functionality of polyphenol-based coatings. Studying polyphenols under static conditions makes it difficult to fully capture their actual performance due to the complex and varying cellular microenvironment and the dynamic balance of the physiological conditions in vivo. This limitation has hindered our understanding of the underlying biological mechanism by which polyphenols regulate cell fate. (4) It is particularly important to explore how polyphenol-based coatings can achieve exquisite synergy and balance in the complex, multi-stage process of anti-inflammation, anti-infection, and promoting bone integration. Therefore, the function of the polyphenolic coatings can be further designed to respond to exogenous/endogenous stimuli, thus ensuring that the coating dynamically adapts and accurately matches the specific needs of bone repair. Overall, polyphenol-based implant coatings have shown great potential and advantages in bone repair and regeneration, particularly through continued development and precise clinical translation.

Conflicts of interest

The authors declare no conflicts of interest.

Data availability

All data underlying this review are available through the original publications as cited. No new datasets were generated or analyzed beyond those already published and cited herein. We have added copyright attribution statements to the figure captions for all images cited in this manuscript. The license documentation for these figures is available upon request.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant no. 22302159, 32071327, 32301130, and 82172396), the Science Fund for Distinguished Young Scholars of Shaanxi (grant no. 2024JC-JCQN-31), the Key Research and Development Program of Shaanxi (grant no. 2023-LL-QY-44), and the Qin Chuangyuan Cited High-level Innovation and Entrepreneurship Talent Project (grant no. QCYRCXM-2022-276).

References

1. G. L. Koons, M. Diba and A. G. Mikos, Nat. Rev. Mater., 2020, 9, 584–603.
2. J. J. Li, M. Ebied, J. Xu and H. Zreiqat, Adv. Healthcare Mater., 2018, 7, 1701061.
3. P. Feng, R. Zhao, W. Tang, F. Yang, H. Tian, S. Peng, H. Pan and C. Shuai, Adv. Funct. Mater., 2023, 33, 2214726.
4. G. Turnbull, J. Clarke, F. Picard, P. Riches, L. Jia, F. Han, B. Li and W. Shu, Bioact. Mater., 2018, 3, 278–314.
5. A. Hariharan, P. Goldberg, F. Schell, U. Hempel, F. Striggow, M. Hantusch, M. Medina-Sánchez, A. F. Lasagni and A. Gebert, Adv. Funct. Mater., 2024, 34, 2310607.
6. J. Zheng, H. Zhao, Z. Ouyang, X. Zhou, J. Kang, C. Yang, C. Sun, M. Xiong, M. Fu, D. Jin, L. Wang, D. Li and Q. Li, Composites, Part B, 2022, 232, 109508.
7. W. Zheng, D. Wu, Y. Zhang, Y. Luo, L. Yang, X. Xu and F. Luo, Biomater. Adv., 2023, 154, 213607.
8. Q. Zhang, L. Ma, X. Ji, Y. He, Y. Cui, X. Liu, C. Xuan, Z. Wang, W. Yang, M. Chai and X. Shi, Adv. Funct. Mater., 2022, 32, 2204182.
9. X. Niu, N. Li, Z. Du and X. Li, Bioact. Mater., 2023, 20, 574–597.
10. M. N. Collins, G. Ren, K. Young, S. Pina, R. L. Reis and J. M. Oliveira, Adv. Funct. Mater., 2021, 31, 2010609.
11. N. Amiryaghoubi, M. Fathi, N. N. Pesyan, M. Samiei, J. Barar and Y. Omidi, Med. Res. Rev., 2020, 40, 1833–1870.
12. M. B. Guglielmotti, D. G. Olmedo and R. L. Cabrini, Periodontology, 2019, 79, 178–189.
13. S. Shirazi, S. Ravindran and L. F. Cooper, Biomaterials, 2022, 291, 121903.
14. Y. Zheng, A. Gao, J. Bai, Q. Liao, Y. Wu, W. Zhang, M. Guan, L. Tong, D. Geng, X. Zhao, P. K. Chu and H. Wang, Bioact. Mater., 2022, 14, 364–376.
15. H. Newman, Y. V. Shih and S. Varghese, Biomaterials, 2021, 277, 121114.
16. Q. Gu, H. Yang and Q. Shi, J. Orthop. Translat., 2017, 10, 86–93.
17. K. Schmidt-Bleek, H. Schell, N. Schulz, P. Hoff, C. Perka, F. Buttgereit, H. D. Volk, J. Lienau and G. N. Duda, Cell Tissue Res., 2012, 347, 567–573.
18. T. D. Zaveri, N. V. Dolgova, J. S. Lewis, K. Hamaker, M. J. Clare-Salzler and B. G. Keselowsky, Biomaterials, 2017, 115, 128–140.
19. X. Cui, Y. Shan, J. Li, M. Xiao, Y. Xi, J. Ji, E. Wang, B. Zhang, L. Xu, M. Zhang, Z. Li and Y. Zhang, Adv. Funct. Mater., 2024, 34, 2403759.
20. F. Loi, L. A. Córdova, J. Pajarinen, T. H. Lin, Z. Yao and S. B. Goodman, Bone, 2016, 86, 119–130.
21. S. B. Goodman, Z. Yao, M. Keeney and F. Yang, Biomaterials, 2013, 34, 3174–3183.
22. B. Cai, D. Lin, Y. Li, L. Wang, J. Xie, T. Dai, F. Liu, M. Tang, L. Tian, Y. Yuan, L. Kong and S. G. F. Shen, Adv. Sci., 2021, 8, 2100584.
23. Z. Wang, C. Li, J. Xu, K. Wang, X. Lu, H. Zhang, S. Qu, G. Zhen and F. Ren, Chem. Mater., 2015, 27, 848–856.
24. H. Li, S. Zhang, S. Huo, H. Tang, B. E. Nie, X. Qu and B. Yue, J. Orthop. Translat., 2020, 21, 66–72.
25. E. A. Masters, B. F. Ricciardi, K. L. d M. Bentley, T. F. Moriarty, E. M. Schwarz and G. Muthukrishnan, Nat. Rev. Microbiol., 2022, 20, 385–400.
26. S. Bohara and J. Suthakorn, Biomater. Res., 2022, 26, 26.
27. C. N. Kelly, T. Wang, J. Crowley, D. Wills, M. H. Pelletier, E. R. Westrick, S. B. Adams, K. Gall and W. R. Walsh, Biomaterials, 2021, 279, 121206.
28. S. Ibuchi, N. Imai, Y. Horigome, Y. Hirano, K. Kimura and H. Kawashima, Medicina, 2024, 60, 1154.
29. X. Chen, J. Zhou, Y. Qian and L. Zhao, Mater. Today Bio., 2023, 19, 100586.
30. R. P. van Hove, I. N. Sierevelt, B. J. van Royen and P. A. Nolte, BioMed Res. Int., 2015, 2015, 485975.
31. S. Mo, K. Tang, Q. Liao, L. Xie, Y. Wu, G. Wang, Q. Ruan, A. Gao, Y. Lv, K. Cai, L. Tong, Z. Wu, P. K. Chu and H. Wang, Mater. Horiz., 2023, 10, 881–888.
32. F. Zhao, A. Gao, Q. Liao, Y. Li, I. Ullah, Y. Zhao, X. Ren, L. Tong, X. Li, Y. Zheng, P. K. Chu and H. Wang, Adv. Funct. Mater., 2024, 34, 2311812.
33. V. C. Cajiao Checchin, A. Gonzalez, M. Bertuola and M. A. Fernández Lorenzo de Mele, Prog. Org. Coat., 2022, 172, 107068.
34. J. Zhou, Z. Lin, Y. Ju, M. A. Rahim, J. J. Richardson and F. Caruso, Acc. Chem. Res., 2020, 53, 1269–1278.
35. J. Guo, T. Suma, J. J. Richardson and H. Ejima, ACS Biomater. Sci. Eng., 2019, 5, 5578–5596.
36. Y. Guo, Q. Sun, F. G. Wu, Y. Dai and X. Chen, Adv. Mater., 2021, 33, 2007356.
37. Q. Li, B. Tang, X. Liu, B. Chen, X. Wang, H. Xiao and Z. Zheng, Adv. Healthcare Mater., 2024, 13, 2301870.
38. E. Torre, Phytochem. Rev., 2017, 16, 1183–1226.
39. Y. Li, L. Li, X. Li, B. Luo, Q. Ye, H. Wang, L. Yang, X. Zhu, L. Han, R. Zhang, H. Tian and P. Wang, Front. Pharmacol., 2022, 13, 1017538.
40. H. Wu, C. Zhao, K. Lin and X. Wang, Front. Bioeng. Biotechnol., 2022, 10, 952500.
41. M. A. Fernandez-Yague, S. A. Abbah, L. McNamara, D. I. Zeugolis, A. Pandit and M. J. Biggs, Adv. Drug Delivery Rev., 2015, 84, 1–29.
42. G. N. Duda, S. Geissler, S. Checa, S. Tsitsilonis, A. Petersen and K. Schmidt-Bleek, Nat. Rev. Rheumatol., 2023, 19, 78–95.
43. L. Xiao, Y. Ma, R. Crawford, J. Mendhi, Y. Zhang, H. Lu, Q. Zhao, J. Cao, C. Wu, X. Wang and Y. Xiao, Mater. Today, 2022, 54, 202–224.
44. L. Bai, P. Chen, Y. Zhao, R. Hang, X. Yao, B. Tang, C. Liu, Y. Xiao and R. Hang, Biomaterials, 2021, 278, 121162.
45. C. Schlundt, T. El Khassawna, A. Serra, A. Dienelt, S. Wendler, H. Schell, N. van Rooijen, A. Radbruch, R. Lucius, S. Hartmann, G. N. Duda and K. Schmidt-Bleek, Bone, 2018, 106, 78–89.
46. C. Schlundt, H. Fischer, C. H. Bucher, C. Rendenbach, G. N. Duda and K. Schmidt-Bleek, Acta Biomater., 2021, 133, 46–57.
47. A. Ho-Shui-Ling, J. Bolander, L. E. Rustom, A. W. Johnson, F. P. Luyten and C. Picart, Biomaterials, 2018, 180, 143–162.
48. Y. Zhang, T. Böse, R. E. Unger, J. A. Jansen, C. J. Kirkpatrick and J. J. J. P. van den Beucken, Cell Tissue Res., 2017, 369, 273–286.
49. W. Liu, L. Li, Y. Rong, D. Qian, J. Chen, Z. Zhou, Y. Luo, D. Jiang, L. Cheng, S. Zhao, F. Kong, J. Wang, Z. Zhou, T. Xu, F. Gong, Y. Huang, C. Gu, X. Zhao, J. Bai, F. Wang, W. Zhao, L. Zhang, X. Li, G. Yin, J. Fan and W. Cai, Acta Biomater., 2020, 103, 196–212.
50. A. R. Armiento, L. P. Hatt, G. Sanchez Rosenberg, K. Thompson and M. J. Stoddart, Adv. Funct. Mater., 2020, 30, 1909874.
51. J. Zhou, Z. Zhang, J. Joseph, X. Zhang, B. E. Ferdows, D. N. Patel, W. Chen, G. Banfi, R. Molinaro, D. Cosco, N. Kong, N. Joshi, O. C. Farokhzad, C. Corbo and W. Tao, Exploration, 2021, 1, 20210011.
52. A. Schindeler, M. M. McDonald, P. Bokko and D. G. Little, Semin. Cell Dev. Biol., 2008, 19, 459–466.
53. B. Chang and X. Liu, Tissue Eng., Part B, 2021, 28, 261–278.
54. Y. Wang, H. Zhang, Y. Hu, Y. Jing, Z. Geng and J. Su, Adv. Funct. Mater., 2022, 32, 2208639.
55. H. Niu, Y. Ma, G. Wu, B. Duan, Y. Wang, Y. Yuan and C. Liu, Biomaterials, 2019, 216, 119216.
56. L. Tong, A. J. v Wijnen, H. Wang and D. Chen, Innovation Life, 2024, 2, 100078.
57. J. Xie, D. Rittel, K. Shemtov-Yona, F. A. Shah and A. Palmquist, Acta Biomater., 2021, 131, 415–423.
58. A. L. Overmann, C. Aparicio, J. T. Richards, I. Mutreja, N. G. Fischer, S. M. Wade, B. K. Potter, T. A. Davis, J. E. Bechtold, J. A. Forsberg and D. Dey, J. Orthop. Res., 2020, 38, 1445–1454.
59. T. Albrektsson and A. Wennerberg, Clin. Implant Dent. Relat. Res., 2019, 21, 4–7.
60. F. A. Shah, P. Thomsen and A. Palmquist, Acta Biomater., 2019, 84, 1–15.
61. C. Colnot, D. M. Romero, S. Huang, J. Rahman, J. A. Currey, A. Nanci, J. B. Brunski and J. A. Helms, J. Dent. Res., 2007, 86, 862–867.
62. A. Shibamoto, T. Ogawa, J. Duyck, K. Vandamme, I. Naert and K. Sasaki, Int. J. Oral Sci., 2018, 10, 6.
63. Y. Li, S. He, Y. Hua and J. Hu, J. Biomed. Mater. Res., Part B, 2017, 105, 2426–2432.
64. B. Wang, Y. Huang, Q. Cai, Z. Du and X. Li, Composites, Part B, 2024, 274, 111282.
65. Z. Jia, X. Xu, D. Zhu and Y. Zheng, Prog. Mater. Sci., 2023, 134, 101072.
66. P. Feng, R. He, Y. Gu, F. Yang, H. Pan and C. Shuai, Mater. Horiz., 2024, 11, 590–625.
67. M. Yu, H. Yang, B. Li, R. Wang and Y. Han, Chem. Eng. J., 2023, 454, 140141.
68. B. G. X. Zhang, D. E. Myers, G. G. Wallace, M. Brandt and P. F. M. Choong, Int. J. Mol. Sci., 2014, 15, 11878–11921.
69. X. Zhang, Z. Li, P. Yang, G. Duan, X. Liu, Z. Gu and Y. Li, Mater. Horiz., 2021, 8, 145–167.
70. S. Quideau, D. Deffieux, C. Douat-Casassus and L. Pouységu, Angew. Chem., Int. Ed., 2011, 50, 586–621.
71. J. Guo, B. L. Tardy, A. J. Christofferson, Y. Dai, J. J. Richardson, W. Zhu, M. Hu, Y. Ju, J. Cui, R. R. Dagastine, I. Yarovsky and F. Caruso, Nat. Nanotechnol., 2016, 11, 1105–1111.
72. P. Hobbi, O. V. Okoro, L. Nie and A. Shavandi, Mater. Today Sustain., 2023, 24, 100541.
73. H. Cao, L. Yang, R. Tian, H. Wu, Z. Gu and Y. Li, Chem. Soc. Rev., 2022, 51, 4175–4198.
74. Y. Chen, W. Gan, Z. Cheng, A. Zhang and P. Shi, Mater. Today Bio., 2024, 24, 100920.
75. A. Hanga-Farcas, F. Miere, G. A. Filip, S. Clichici, L. Fritea, L. G. Vicas, E. Marian, A. Pallag, T. Jurca, S. M. Filip and M. E. Muresan, Plants, 2023, 12, 2055.
76. X. Gao, Z. Xu, G. Liu and J. Wu, Acta Biomater., 2021, 119, 57–74.
77. G. Luo, Z. Li, Y. Wang, H. Wang, Z. Zhang, W. Chen, Y. Zhang, Y. Xiao, C. Li, Y. Guo and P. Sheng, Inflammation, 2016, 39, 775–785.
78. J. H. Kim, S. C. Gupta, B. Park, V. R. Yadav and B. B. Aggarwal, Mol. Nutr. Food Res., 2012, 56, 454–465.
79. S. Chen, H. Liang, Y. Ji, H. Kou, C. Zhang, G. Shang, C. Shang, Z. Song, L. Yang, L. Liu, Y. Wang and H. Liu, Front. Cell Dev. Biol., 2021, 9, 634650.
80. Z. Su, B. Yao, G. Liu and J. Fang, J. Nutr. Biochem., 2024, 123, 109488.
81. Z. Dai, Y. Li, L. D. Quarles, T. Song, W. Pan, H. Zhou and Z. Xiao, Phytomedicine, 2007, 14, 806–814.
82. A. Huang, Y. Honda, P. Li, T. Tanaka and S. Baba, Int. J. Mol. Sci., 2019, 20, 6042.
83. H. M. Doss, C. Dey, C. Sudandiradoss and M. K. Rasool, Life Sci., 2016, 148, 201–210.
84. H. M. Doss, S. Samarpita, R. Ganesan and M. Rasool, Life Sci., 2018, 207, 284–295.
85. L. Forte, P. Torricelli, E. Boanini, M. Gazzano, K. Rubini, M. Fini and A. Bigi, Acta Biomater., 2016, 32, 298–308.
86. W. H. Zhao, Z. Q. Hu, Y. Hara and T. Shimamura, Antimicrob. Agents Chemother., 2002, 46, 2266–2268.
87. M. Efenberger-Szmechtyk, A. Nowak and A. Czyzowska, Crit. Rev. Food Sci., 2021, 61, 149–178.
88. P. K. Dadi, M. Ahmad and Z. Ahmad, Inhibition of ATPase activity of Escherichia coli ATP synthase by polyphenols, Int. J. Biol. Macromol., 2009, 45, 72–79.
89. Y. Li, Y. Miao, L. Yang, Y. Zhao, K. Wu, Z. Lu, Z. Hu and J. Guo, Adv. Sci., 2022, 9, 2202684.
90. Y. Wang, Y. Zou, Y. Wu, T. Wei, K. Lu, L. Li, Y. Lin, Y. Wu, C. Huang, Y. Zhang, H. Chen and Q. Yu, ACS Appl. Mater. Interfaces, 2021, 13, 48403–48413.
91. J. A. Zokti, B. S. Baharin, A. S. Mohammed and F. Abas, Molecules, 2016, 21, 940.
92. Y. Liu, Y. Shi, M. Zhang, F. Han, W. Liao and X. Duan, Eur. J. Med. Chem., 2024, 266, 116141.
93. R. Zhao, H. Qian, X. Zhu, X. Zhang, Z. Chen and X. Yang, Adv. Funct. Mater., 2024, 34, 2401566.
94. K. Huo, W. Liu, Z. Shou, H. Wang, H. Liu, Y. Chen, X. Zan, Q. Wang and N. Li, Adv. Sci., 2025, 12, 2412194.
95. H. Wang, C. Wang, Y. Zou, J. Hu, Y. Li and Y. Cheng, Giant, 2020, 3, 100022.
96. J. Saiz-Poseu, J. Mancebo-Aracil, F. Nador, F. Busqué and D. Ruiz-Molina, Angew. Chem., Int. Ed., 2019, 58, 696–714.
97. J. Yu, W. Wei, M. S. Menyo, A. Masic, J. H. Waite and J. N. Israelachvili, Biomacromolecules, 2013, 14, 1072–1077.
98. D. S. Hwang, M. J. Harrington, Q. Lu, A. Masic, H. Zeng and J. H. Waite, J. Mater. Chem., 2012, 22, 15530–15533.
99. Q. Lyu, N. Hsueh and C. L. L. Chai, ACS Biomater. Sci. Eng., 2019, 5, 2708–2724.
100. B. Cheng, J. Yu, T. Arisawa, K. Hayashi, J. J. Richardson, Y. Shibuta and H. Ejima, Nat. Commun., 2022, 13, 1892.
101. S. Geißler, A. Barrantes, P. Tengvall, P. B. Messersmith and H. Tiainen, Langmuir, 2016, 32, 8050–8060.
102. F. Reitzer, M. Allais, V. Ball and F. Meyer, Adv. Colloid Interface Sci., 2018, 257, 31–41.
103. H. Lee, S. M. Dellatore, W. M. Miller and P. B. Messersmith, Science, 2007, 318, 426–430.
104. S. Hong, Y. Wang, S. Y. Park and H. Lee, Sci. Adv., 2018, 4, 7457.
105. G. Sathishkumar, K. Gopinath, K. Zhang, E. T. Kang, L. Xu and Y. Yu, J. Mater. Chem. B, 2022, 10, 2296–2315.
106. W. Yan, M. Shi, C. Dong, L. Liu and C. Gao, Adv. Colloid Interface Sci., 2020, 284, 102267.
107. Z. Yang, H. Liu, J. Zhao, C. Wang, H. Li, X. Wang, Y. Yang, H. Wu, Z. Gu and Y. Li, Mater. Horiz., 2024, 11, 2438–2448.
108. S. H. Hong, S. Hong, M. H. Ryou, J. W. Choi, S. M. Kang and H. Lee, Adv. Mater. Interfaces, 2016, 3, 1500857.
109. F. Ponzio, J. Barthès, J. Bour, M. Michel, P. Bertani, J. Hemmerlé, M. d’Ischia and V. Ball, Chem. Mater., 2016, 28, 4697–4705.
110. Y. M. Li, Y. M. Li and Y. D. Bai, Chem. Eng. J., 2023, 465, 142967.
111. H. Wang, C. Lin, X. Zhang, K. Lin, X. Wang and S. G. Shen, ACS Appl. Mater. Interfaces, 2019, 11, 7615–7625.
112. S. Farshid, M. Kharaziha and M. Atapour, J. Magnesium Alloys, 2023, 11, 592–606.
113. J. Guo, Y. Ping, H. Ejima, K. Alt, M. Meissner, J. J. Richardson, Y. Yan, K. Peter, D. von Elverfeldt, C. E. Hagemeyer and F. Caruso, Angew. Chem., Int. Ed., 2014, 53, 5546–5551.
114. Y. Zhang, L. Shen, Q. Z. Zhong and J. Li, Colloids Surf., B, 2021, 205, 111851.
115. J. Wei, G. Wang, F. Chen, M. Bai, Y. Liang, H. Wang, D. Zhao and Y. Zhao, Angew. Chem., Int. Ed., 2018, 57, 9838–9843.
116. S. Lee, Y. Y. Chang, J. Lee, S. K. Madhurakkat Perikamana, E. M. Kim, Y. H. Jung, J. H. Yun and H. Shin, Biomater. Sci., 2020, 8, 3404–3417.
117. K. Xu, C. Mu, C. Zhang, S. Deng, S. Lin, L. Zheng, W. Chen and Q. Zhang, Biomaterials, 2023, 301, 122268.
118. M. He, H. Wang, Q. Han, X. Shi, S. He, J. Sun, Z. Zhu, X. Gan and Y. Deng, Biomaterials, 2023, 303, 122355.
119. H. Du, D. Zhang, K. Xue, L. Ma, R. Xu, J. Tan, F. Peng and X. Liu, J. Magnesium Alloys, 2024, 25, 41.
120. S. Benyahya, C. Aouf, S. Caillol, B. Boutevin, J. P. Pascault and H. Fulcrand, Ind. Crops Prod., 2014, 53, 296–307.
121. C. Wang, H. Sang, Y. Wang, F. Zhu, X. Hu, X. Wang, X. Wang, Y. Li and Y. Cheng, Nano Lett., 2018, 18, 7045–7051.
122. J. I. Clodt, V. Filiz, S. Rangou, K. Buhr, C. Abetz, D. Höche, J. Hahn, A. Jung and V. Abetz, Adv. Funct. Mater., 2013, 23, 731–738.
123. W. Z. Qiu, G. P. Wu and Z. K. Xu, ACS Appl. Mater. Interfaces, 2018, 10, 5902–5908.
124. M. Han, Z. Dong, J. Li, J. Luo, D. Yin, L. Sun, S. Tao, L. Zhen, J. Yang and J. Li, J. Mater. Chem. B, 2021, 9, 8501–8511.
125. Z. Wang, C. Li, J. Xu, K. Wang, X. Lu, H. Zhang, S. Qu, G. Zhen and F. Ren, Chem. Mater., 2015, 27, 848–856.
126. I. Zhuk, F. Jariwala, A. B. Attygalle, Y. Wu, M. R. Libera and S. A. Sukhishvili, ACS Nano, 2014, 8, 7733–7745.
127. X. Liu, W. Chen, B. Shao, X. Zhang, Y. Wang, S. Zhang and W. Wu, Biomaterials, 2021, 276, 120998.
128. Z. Xu, N. Wang, P. Liu, Y. Sun, Y. Wang, F. Fei, S. Zhang, J. Zheng and B. Han, Molecules, 2019, 24, 4397.
129. M. Shin, J. H. Ryu, J. P. Park, K. Kim, J. W. Yang and H. Lee, Adv. Funct. Mater., 2015, 25, 1270–1278.
130. Z. Dong, X. Ke, S. Tang, S. Wu, W. Wu, X. Chen, J. Yang, J. Xie, J. Luo and J. Li, Chem. Mater., 2021, 33, 7994–8006.
131. J. Ryu, S. H. Ku, H. Lee and C. B. Park, Adv. Funct. Mater., 2010, 20, 2132–2139.
132. B. Wang, F. Han, R. You, C. Chen and H. Xie, Int. J. Nanomed., 2023, 18, 1491–1505.
133. T. Chai, H. Zhang, X. L. Shen, H. B. Wang, X. P. Fan, B. B. Wang, D. Y. He and J. Su, Biosurf. Biotribol., 2023, 9, 129–141.
134. Z. B. Zhang, A. B. Liu, J. D. Fan, M. L. Wang, J. B. Dai, X. Jin, H. Z. Deng, X. Wang, Y. J. Liang, H. X. Li, Y. T. Zhao, P. Wen and Y. F. Li, Bioact. Mater., 2023, 27, 488–504.
135. J. Y. Lee, L. E. Aguilar, C. H. Park and C. S. Kim, Polymers, 2019, 11, 1200.
136. S. Du, Y. Luo, Z. Liao, W. Zhang, X. Li, T. Liang, F. Zuo and K. Ding, J. Colloid Interface Sci., 2018, 523, 27–34.
137. S. Kaabipour and S. Hemmati, Colloids Surf., A, 2022, 641, 128495.
138. D. Gan, W. Xing, L. Jiang, J. Fang, C. Zhao, F. Ren, L. Fang, K. Wang and X. Lu, Nat. Commun., 2019, 10, 1487.
139. S. J. Yang, L. Y. Zou, C. Liu, Q. Zhong, Z. Y. Ma, J. Yang, J. Ji, P. Müller-Buschbaum and Z. K. Xu, ACS Appl. Mater. Interfaces, 2020, 12, 54094–54103.
140. Z. X. Wang, S. Q. Ji, F. He, M. Y. Cao, S. Q. Peng and Y. X. Li, J. Mater. Chem. A, 2018, 6, 3391–3396.
141. M. Xu, Q. Song, L. Gao, H. Liu, W. Feng, J. Huo, H. Jin, L. Huang, J. Chai, Y. Pei, X. Qu, P. Li and W. Huang, Chem. Eng. J., 2020, 396, 125240.
142. Y. Wang, X. He, Y. Cheng, L. Li, K. Zhang, E. T. Kang and L. Xu, Colloids Surf., B, 2022, 212, 112381.
143. S. Q. Xiao, J. W. Wei, S. E. Jin, X. Xia, L. Yuan, Q. Zou, Y. Zuo, J. D. Li and Y. B. Li, Adv. Funct. Mater., 2023, 33, 2208968.
144. G. Ge, W. Wang, Q. Wang, M. Wang, T. Wang, L. Yu, X. Zhang, C. Zhu, Y. Xu, H. Yang, J. Bai, G. Pan and D. Geng, Adv. Funct. Mater., 2024, 34, 2315849.
145. J. Zhou, Z. Lin, M. Penna, S. Pan, Y. Ju, S. Li, Y. Han, J. Chen, G. Lin, J. J. Richardson, I. Yarovsky and F. Caruso, Nat. Commun., 2020, 11, 4804.
146. Z. Du, F. Qiao, L. Tong, W. Zhang, X. Mou, X. Zhao, M. F. Maitz, H. Wang, N. Huang and Z. Yang, Innovation, 2024, 5, 100671.
147. J. Bolaños-Cardet, D. Ruiz-Molina, V. J. Yuste and S. Suárez-García, Chem. Eng. J., 2024, 481, 148674.
148. L. Long, Y. Fan, X. Yang, X. Ding, Y. Hu, G. Zhang and F. J. Xu, Chem. Eng. J., 2022, 444, 135426.
149. X. Lin, J. Qian, W. Zhang, P. Wang and G. Wan, Acta Metall. Sin., 2024, 60, 1545–1558.
150. C. C. Ho and S. J. Ding, J. Mater. Chem. B, 2015, 3, 2698–2707.
151. X. Zheng, M. Huang and C. Ding, Biomaterials, 2000, 21, 841–849.
152. S. Lešnik, M. Jukić and U. Bren, J. Cheminf., 2025, 17, 50.
153. S. Ding, H. Jiang and J. Fang, J. Immunol. Res., 2018, 2018, 1264074.
154. M. J. Xu, B. J. Liu, C. L. Wang, G. H. Wang, Y. Tian, S. H. Wang, J. Li, P. Y. Li, R. H. Zhang, D. Wei, S. F. Tian and T. Xu, Int. Immunopharmacol., 2017, 52, 24–33.
155. C. M. Klinge, K. A. Blankenship, K. E. Risinger, S. Bhatnagar, E. L. Noisin, W. K. Sumanasekera, L. Zhao, D. M. Brey and R. S. Keynton, J. Biol. Chem., 2005, 280, 7460–7468.
156. G. J. Wu, J. T. Chen, Y. G. Cherng, C. C. Chang, S. H. Liu and R. M. Chen, J. Agric. Food Chem., 2020, 68, 10639–10650.
157. X. G. Pang, Y. Cong, N. R. Bao, Y. G. Li and J. N. Zhao, BioMed Res. Int., 2018, 2018, 4178021.
158. H. Yang, Y. Xu, M. Zhu, Y. Gu, W. Zhang, H. Shao, Y. Wang, Z. Ping, X. Hu, L. Wang and D. Geng, Biomaterials, 2016, 80, 1–10.
159. K. Hanami, K. Nakano, K. Saito, Y. Okada, K. Yamaoka, S. Kubo, M. Kondo and Y. Tanaka, Bone, 2013, 56, 1–8.
160. M. Wang, C. Wang, Y. Zhang and Y. Lin, Mater. Sci. Eng., 2021, 129, 112376.
161. Y. J. Chuah, Y. T. Koh, K. Lim, N. V. Menon, Y. Wu and Y. Kang, Sci. Rep., 2015, 5, 18162.
162. H. Omidian and R. L. Wilson, Materials, 2024, 17, 3916.
163. J. S. Lee, J. S. Lee, M. S. Lee, S. An, K. Yang, K. Lee, H. S. Yang, H. Lee and S. W. Cho, Chem. Mater., 2017, 29, 4375–4384.
164. A. Córdoba, M. Satué, M. Gómez-Florit, M. Hierro-Oliva, C. Petzold, S. P. Lyngstadaas, M. L. González-Martín, M. Monjo and J. M. Ramis, Adv. Healthcare Mater., 2015, 4, 540–549.
165. C. Stewart, B. Akhavan, S. G. Wise and M. M. M. Bilek, Prog. Mater. Sci., 2019, 106, 100588.
166. F. Weber, H. Q. Quach, M. Reiersen, S. Y. Sarraj, D. N. Bakir, V. A. Jankowski, P. H. Nilsson and H. Tiainen, J. Biomed. Mater. Res., Part A, 2022, 110, 1341–1355.
167. V. B. Damodaran and N. S. Murthy, Biomater. Res., 2016, 20, 18.
168. L. Li, Z. Cao, C. Zhang, L. Li, Q. Li, C. Liu, C. Qu, R. Luo, P. Fu and Y. Wang, Adv. Funct. Mater., 2024, 34, 2312243.
169. J. Y. Liu, Y. Hu, L. Li, C. Wang, J. Wang, Y. Li, D. Chen, X. Ding, C. Shen and F. J. Xu, Adv. Sci., 2020, 7, 2002243.
170. L. Xu, J. Fang, J. Pan, H. Qi, Y. Yin, Y. He, X. Gan, Y. Li, Y. Li and J. Guo, Bioact. Mater., 2024, 41, 564–576.
171. C. Xu, M. Sun, S. Lv, X. Liu, N. Zhao, Y. Li, S. Duan, F. J. Xu, W. Geng and Y. Sun, Adv. Funct. Mater., 2025, 35, 2423639.
172. S. Bai, X. Zhang, X. Lv, M. Zhang, X. Huang, Y. Shi, C. Lu, J. Song and H. Yang, Adv. Funct. Mater., 2020, 30, 1908381.
173. D. M. Vasconcelos, S. G. Santos, M. Lamghari and M. A. Barbosa, Biomaterials, 2016, 84, 262–275.
174. J. Liu, Y. Shi, Y. Zhao, Y. Liu, X. Yang, K. Li, W. Zhao, J. Han, J. Li and S. Ge, Adv. Sci., 2024, 11, 2307269.
175. D. Li, D. Wang, Y. Yang, P. Gao, W. Fan, X. Zhang, Y. Tang, W. Yang and K. Cai, Adv. Funct. Mater., 2023, 33, 2212016.
176. Q. He, S. Yuan, H. Tang, S. Wang, Z. Mu, D. Li, S. Wang, X. Jing, S. Hu, P. Ji and T. Chen, Adv. Funct. Mater., 2021, 31, 2101611.
177. Z. Lyu, Y. Zhao, S. Huo, F. Wang, X. Meng, Z. Yuan, T. Long and Y. Wang, Mater. Des., 2022, 222, 111069.
178. L. Liu, Y. Zhang, M. Li, M. Yang, L. Zhou, C. Zeng, H. Zhou, X. Zheng, P. Li, H. Wang and Y. Zheng, Colloids Surf., A, 2025, 726, 137760.
179. J. Yan, D. Xia, P. Xiong, Y. Li, W. Zhou, Q. Li, P. Wang, Y. Zheng and Y. Cheng, J. Mater. Sci. Technol., 2021, 71, 31–43.
180. X. Y. Wan, Z. R. Liu and L. L. Li, Adv. Funct. Mater., 2021, 31, 2010626.
181. Y. Kong, J. Z. Duan, F. Liu, L. Han, G. Li, C. H. Sun, Y. H. Sang, S. H. Wang, F. Yi and H. Liu, Chem. Soc. Rev., 2021, 50, 12828–12872.
182. S. Bauer, P. Schmuki, K. von der Mark and J. Park, Prog. Mater. Sci., 2013, 58, 261–326.
183. S. M. Latifi, R. Shankar and H. J. Donahue, Adv. Mater. Phys. Chem., 2020, 10, 339–349.
184. F. He, J. Li, Y. X. Wang, Z. P. Li, L. Wang, Y. C. Li, H. F. Chen, C. G. Wang, B. Liu, P. Ma, G. X. Dong and P. Zhou, ACS Biomater. Sci. Eng., 2022, 8, 4751–4763.
185. P. Xue, Q. Li, Y. Li, L. H. Sun, L. Zhang, Z. G. Xu and Y. J. Kang, ACS Appl. Mater. Interfaces, 2017, 9, 33632–33644.
186. Y. Hou, W. Y. Xie, L. X. Yu, L. C. Camacho, C. X. Nie, M. Zhang, R. Haag and Q. Wei, Small, 2020, 16, 1905422.
187. A. J. Steeves and F. Variola, J. Mater. Chem. B, 2020, 8, 199–215.
188. X. Chen, C. Cortez-Jugo, G. H. Choi, M. Björnmalm, Y. L. Dai, P. J. Yoo and F. Caruso, Bioconjugate Chem., 2017, 28, 75–80.
189. Y. X. Zhu, D. Z. Zhou, X. J. Zan, Q. S. Ye and S. R. Sheng, Colloids Surf., B, 2022, 212, 1123.19.
190. L. Chen, J. Y. Yang, Z. W. Cai, Y. R. Huang, P. C. Xiao, J. Wang, F. Wang, W. Huang, W. G. Cui and N. Hu, Adv. Funct. Mater., 2024, 34, 2314079.
191. J. J. Tian, R. Shi, Z. Liu, H. Ouyang, M. Yu, C. C. Zhao, Y. Zou, D. J. Jiang, J. S. Zhang and Z. Li, Nano Energy, 2019, 59, 705–714.
192. L. J. Mao, L. Bai, X. Q. Wang, X. L. Chen, D. Zhang, F. P. Chen and C. S. Liu, ACS Appl. Mater. Interfaces, 2022, 14, 44111–44124.
193. Y. H. Ding, Z. L. Yang, C. W. C. Bi, M. Yang, J. C. Zhang, S. L. Xu, X. Lu, N. Huang, P. B. Huang and Y. Leng, J. Mater. Chem. B, 2014, 2, 3819–3829.
194. G. X. Tan, Y. Liu, Y. X. Wu, K. Y. Ouyang, L. Zhou, P. Yu, J. W. Liao and C. Y. Ning, Electrochim. Acta, 2017, 228, 343–350.
195. M. Li, X. Chu, D. Wang, L. Jian, L. Liu, M. Yao, D. Zhang, Y. Zheng, X. Liu, Y. Zhang and F. Peng, Biomaterials, 2022, 282, 121408.
196. S. Kim, L. K. Jang, H. S. Park and J. Y. Lee, Sci. Rep., 2016, 6, 30475.
197. S. Kim, L. K. Jang, M. Jang, S. Lee, J. G. Hardy and J. Y. Lee, ACS Appl. Mater. Interfaces, 2018, 10, 33032–33042.
198. X. L. Chen, Y. J. Wu, V. D. Ranjan and Y. L. Zhang, Carbon, 2018, 134, 174–182.
199. C. M. Xie, P. F. Li, L. Han, Z. M. Wang, T. Zhou, W. L. Deng, K. F. Wang and X. Lu, NPG Asia Mater., 2017, 9, 358.
200. L. Zhou, L. Fan, X. Yi, Z. N. Zhou, C. Liu, R. M. Fu, C. Dai, Z. G. Wang, X. X. Chen, P. Yu, D. F. Chen, G. X. Tan, Q. Y. Wang and C. Y. Ning, ACS Nano, 2018, 12, 10957–10967.
201. Y. F. Ma, M. Lin, G. Y. Huang, Y. H. Li, S. Q. Wang, G. Q. Bai, T. J. Lu and F. Xu, Adv. Mater., 2018, 30, 1705911.
202. J. G. Zhang, C. Cheng, J. L. Cuellar-Camacho, M. J. Li, Y. Xia, W. Z. Li and R. Haag, Adv. Funct. Mater., 2018, 28, 1804773.
203. K. Ye, L. P. Cao, S. Y. Li, L. Yu and J. D. Ding, ACS Appl. Mater. Interfaces, 2016, 8, 21903–21913.
204. F. Zan, Q. Wei, L. M. Fang, M. Y. Xian, Y. Ke and G. Wu, ACS Biomater. Sci. Eng., 2020, 6, 912–922.
205. J. Chen, Z. Cai, Q. Wei, D. Wang, J. Wu, Y. Tan, J. Lua and H. Ai, J. Mater. Chem. B, 2020, 8, 316–331.
206. S. Yang, A. Y. P. Leung, Z. Wang, C. K. Y. Yiu and W. L. Dissanayaka, Int. Endod. J., 2024, 57, 1639–1654.
207. S. S. Yang, Y. Wang, S. Luo, C. J. Shan, Y. B. Geng, T. H. Zhang, S. R. Sheng and X. J. Zan, Colloids Surf., B, 2019, 181, 549–560.
208. X. Li, S. Liu, S. Han, Q. Sun, J. Yang, Y. Zhang, Y. Jiang, X. Wang, Q. Li and J. Wang, Adv. Healthcare Mater., 2023, 12, 2300326.
209. S. Park and T. G. Jung, Bioengineering, 2024, 11, 343.
210. S. Cometta, B. C. Donose, A. Juárez-Saldivar, A. Ravichandran, Y. Xu, N. Bock, T. R. Dargaville, A. D. Rakić and D. W. Hutmacher, Bioact. Mater., 2024, 42, 68–84.
211. X. Chen, M. Sun, L. Zhang, Y. Hu, Z. Yang, S. Duan, F. J. Xu and J. Jing, Chem. Eng. J., 2024, 490, 151792.
212. D. Fan, H. Liu, Z. Zhang, M. Su, Z. Yuan, Y. Lin, S. Yang, W. Li and X. Zhang, Front. Pharmacol., 2021, 12, 618724.
213. S. J. T. Jackson and R. C. Venema, J. Nutr., 2006, 136, 1178–1184.
214. X. He, W. Liu, Y. Liu, K. Zhang, Y. Sun, P. Lei and Y. Hu, Mater. Today Bio., 2022, 16, 100348.
215. W. Liu, Q. Wang, H. Liu, S. He, H. Wang, C. Xu, C. Jin, N. Li and L. Li, J. Orthop. Transl., 2025, 52, 150–166.
216. S. Cheng, D. Wang, J. Ke, L. Ma, J. Zhou, H. Shao, H. Zhu, L. Liu, Y. Zhang, F. Peng and X. Liu, Colloids Surf., B, 2020, 194, 111176.

---