Current state of bioceramic bone repair materials in immune regulation: a review

Abstract

Extensive bone defects represent a significant clinical challenge, often leading to severe impairment of patients function and quality of life. Traditional treatments, such as autografts and allografts, are widely used but have notable limitations, including donor site morbidity and immunogenicity. As a result, tissue engineering has attracted increasing attention as a viable alternative. Bioceramic bone repair materials provide both mechanical support and bioactive functions in the treatment of bone defects. They modulate the immune microenvironment to promote cellular behaviors and signaling pathways conducive to bone regeneration. The immunoregulatory effects of these materials play a critical role throughout the bone repair process and are pivotal in determining the success of regeneration. For instance, hydroxyapatite can induce the polarization of macrophages towards the M2 phenotype, exerting anti-inflammatory effects that promote bone tissue repair. This review summarizes recent advancements in the research of bioceramics for bone tissue engineering, with a focus on the classification of bioceramic materials, their immunomodulatory mechanisms in bone regeneration, current fabrication techniques, and the status of clinical translation. We aim to provide insights that support future research and the development of improved strategies for bone defect repair.

Keywords

bioceramic / biomaterials / bone regeneration / bone immunoregulation / immune system

1 Introduction

Bone fractures represent a significant global public health concern. In 2019, an estimated 178 million new fractures were reported worldwide (95% UI: 162–196), reflecting a 33.4% increase since 1990 (95% UI: 30.1–37.0). The burden of disability-adjusted life years (DALYs) attributable to fractures reached 25.8 million (95% UI: 17.8–35.8), representing a 65.3% increase since 1990 (95% UI: 62.4–68.0) [1]. Among these fractures, bone defects remain a particularly challenging clinical issue. Bone defects can arise from both congenital and acquired factors. Congenital bone defects are relatively rare and primarily encompass three categories: deformity, deformation, and interruption. In contrast, acquired bone defects are more prevalent and commonly resulting from trauma, infection, tumors, or surgical procedures.

The use of bone repair materials is a well-established and viable strategy for the treatment of bone defects. Historical records indicate that as early as before the 18th century, natural materials such as willow branches, wood, hemp, and ivory were utilized for bone repair. In recent decades, the development of bone repair materials has advanced significantly, encompassing both natural and synthetic options. Natural bone grafts include allografts, xenografts, and demineralized bone matrix, while artificial materials comprise metals, inorganic non-metals, polymers, composites, and tissue-engineered constructs [2]. Among these, bioceramic materials have emerged as a key focus in bone tissue engineering due to their outstanding biocompatibility, mechanical strength, and osteoconductive properties.

Bioceramic materials not only provide robust structural support but also actively modulate the activity of osteoblasts and osteoclasts, thereby promoting bone tissue regeneration. They facilitate cell adhesion, proliferation, and differentiation, creating a favorable microenvironment for effective osteogenesis [3–5]. In addition, certain bioceramic materials exhibit notable immunomodulatory properties, enabling them to regulate the polarization states and cytokine secretion profiles of immune cells such as macrophages and T cells [6,7]. This regulation helps optimize the immune microenvironment at the site of bone defects by suppressing excessive inflammatory responses and reducing the release of pro-inflammatory and fibrosis-associated factors, thereby lowering the risk of fibrous tissue formation [8,9]. Moreover, bioceramics can promote reparative immune responses, activate osteogenesis-related signaling pathways, and enhance the function of bone-forming cells, thereby accelerating new bone formation and tissue reconstruction [10,11]. These immunoregulatory effects play a critical role in maintaining an environment conducive to successful bone repair (Fig. 1). Their physicochemical properties—such as porosity, surface morphology, and chemical composition—play a critical role in determining their in vivo performance [12]. By precisely regulating these parameters, the biological functionality of bioceramic materials can be significantly optimized, thereby improving their therapeutic efficacy in bone repair applications [13,14]. The physical, chemical, and biological properties of bioceramics are profoundly influenced by their fabrication processes, which in turn affect their performance in bone repair applications [15]. For example, electrospinning offers significant advantages in tissue engineering materials due to its extracellular matrix (ECM)-like structure, high specific surface area, and excellent drug-loading capacity [16,17]. However, its mechanical strength is relatively poor, limiting its ability to provide adequate structural support and protection for osteogenic cells [18]. Moreover, the incorporation of doping elements and the development of composite materials have further enhanced the functional properties of bioceramics, rendering them highly effective in the treatment of complex and large-scale bone defects [19,20].

We conducted literature searches in PubMed and Web of Science using Boolean operators to combine terms such as “Bioceramics” and related keywords, “Bone regeneration” and its related terms, and “immune regulation” and associated phrases. This resulted in 166 and 378 articles, respectively, published between 2020 and 2025. After removing duplicates to ensure the independence of the studies, we initially screened the articles based on their titles and abstracts to identify those relevant to the research topic. Subsequently, we performed a full-text review of the preliminary selections, further narrowing down to approximately 200 high-quality articles that were highly pertinent to the research focus.

In this review, we first provide an overview of the biological foundations of osteogenesis and the immune responses involved in bone formation. We then summarize the various types of bioceramic materials and their key biological and physicochemical properties. Next, we discuss the mechanisms through which bioceramic materials promote bone repair by modulating immune responses. We also examine how different fabrication techniques influence the performance of these materials. Furthermore, we introduce existing translational products and recent advancements in the field. Finally, based on a comprehensive analysis of the current literature, we explore future directions and potential challenges in the application of bioceramics for bone repair. This review aims to offer valuable insights for researchers and clinicians engaged in the development of bone tissue engineering strategies and clinical translation.

2 Osteogenesis

The process of bone formation is initiated by mesenchymal stem cells (MSCs), which possess tri-lineage differentiation potential and can differentiate into osteoblasts, chondrocytes, and adipocytes under specific conditions [21–23]. Among the key regulators of osteogenic differentiation are transcription factors such as Runx2 and Osterix. Runx2 promotes the expression of osteogenesis-related genes, including alkaline phosphatase (ALP), osteocalcin (OCN), collagen type I (COL1), bone sialoprotein (BSP), and osteopontin (OPN), while simultaneously inhibiting adipogenic differentiation of MSCs. Osterix, a downstream target of Runx2, is essential for osteoblast maturation; knockout studies have demonstrated that deletion of the Osterix gene leads to impaired development of both cortical and trabecular bone in mice [24–26]. Multiple signaling pathways are involved in regulating osteogenic differentiation, primarily through modulation of Runx2 and Osterix expression. The Wnt/β-catenin pathway plays a predominant role during the early stages of osteogenesis, whereas the bone morphogenetic protein (BMP)/Smad pathway becomes more influential in the later stages. In addition, the Hedgehog signaling pathway also contributes to the regulation of osteoblast differentiation [27–29].

Bone formation occurs through two primary processes: endochondral ossification and intramembranous ossification (Fig. 2). Endochondral ossification is primarily responsible for the formation of long bones, such as the femur and humerus, and is characterized by the gradual replacement of a cartilage model with bone tissue. Initially, MSCs accumulate in a designated area, differentiate into chondrocytes, and form a cartilage model by secreting collagen type II (COL2) and proteoglycans [30–32]. Subsequently, peripheral MSCs secrete collagen type X (COL10) and matrix metalloproteinases (MMPs), promoting the mineralization of the cartilage matrix. This process leads to the formation of bone tissue through intramembranous ossification and the establishment of a periosteal collar around the cartilage model [33,34]. In parallel, chondrocytes in the central region mature and hypertrophy, with the cartilage matrix gradually decreasing and calcifying. Blood vessels and MSCs then invade the calcified cartilage matrix, and MSCs differentiate into osteoblasts, forming the primary ossification center [35,36]. Osteoblasts secrete bone matrix on the surface of the mineralized cartilage matrix, leading to the formation of primitive trabeculae. Osteoclasts resorb mineralized cartilage and bone matrix to establish the bone marrow cavity [37,38]. Intramembranous ossification, on the other hand, occurs during the formation of flat bones, such as the skull and clavicle, and is characterized by the direct formation of bone tissue from mesenchymal tissue, bypassing the cartilage stage [39]. This process involves the aggregation and differentiation of MSCs into osteoblasts, which secrete COL1 and OCN to promote the formation of osteoid. The process culminates in the maturation and remodeling of the bone tissue [40,41].

During the process of bone formation, osteoblasts produce cortical bone on the outer surface of the bone shaft and cancellous bone at the ends and within the bone [42]. Cancellous bone consists of numerous needle-like or plate-like trabeculae that interconnect, forming a spongy structure. The orientation of these trabeculae aligns with the directions of compressive and tensile forces acting on the bone [43]. Cancellous bone has a lower bone density and softer texture compared to cortical bone. Its metabolic activity is higher, with the turnover rate of trabeculae approximately 8 times that of cortical bone [44]. Cortical bone, in contrast, is dense and composed of highly mineralized bone tissue with high bone density. It primarily consists of the Haversian system, which contains bone units and a central canal [45]. The bone lamellae are organized in concentric circles, forming these bone units. Cortical bone has high compressive strength and elastic modulus, serving primarily to provide mechanical strength and support, protect the internal structures, and resist external forces to prevent fractures [46]. Table 1 comprehensively illustrates the differential attributes between cortical and cancellous bone across various dimensions.

Fracture healing can be classified into primary and secondary bone healing. Primary bone healing occurs when the fracture ends are directly connected through the reconstruction of the Haversian system after fracture reduction and rigid internal fixation, without the formation of a soft callus [47,48]. In contrast, secondary bone healing, which is the most common process, typically occurs when the fracture ends are not fully reduced or when fixation is unstable. It involves four distinct phases: the inflammatory phase, the soft callus formation phase, the hard callus formation phase, and the remodeling phase [48,49]. During bone fracture healing, stem cells from the periosteum (e.g., Itm2a-positive cells) and MSCs serve as the primary sources of repair cells [50,51]. BMPs are critical regulatory factors in this process, as they promote the proliferation and differentiation of MSCs [52–54]. The inflammatory response plays an essential role in fracture healing, with inflammatory cells, such as macrophages, clearing necrotic tissue and releasing cytokines (e.g., TNF-α, IL-1) that regulate subsequent repair stages [55,56]. During bone regeneration, the immune system plays a pivotal role by orchestrating the repair and remodeling of bone tissue through a coordinated interplay of inflammatory responses, cytokine signaling, immune cell activation, and metabolic regulation [57,58].

When excessive damage occurs to bone tissue, natural fracture healing may be insufficient to restore bone integrity. In such cases, bone transplantation is the most traditional approach, which primarily includes autografts and allografts. Autografts offer the advantages of high osteogenic potential and a low risk of immune rejection; however, they are limited by the availability of donor sites and the risk of additional surgical trauma [59]. Allografts, on the other hand, provide an ample supply of bone tissue and avoid donor site-related complications but are associated with risks of immune rejection and disease transmission [60].

Tissue engineering is an emerging technology that aims to reconstruct damaged or degenerated tissues through the combination of cells, biomaterials, and growth factors [61]. The core of tissue engineering involves using biomaterials as scaffolds to guide cell growth, ultimately facilitating the formation of functional bone tissue [62]. Biomaterial scaffolds play a critical role by providing structural support and guidance for cells, making them a vital component of tissue engineering. Bioceramic materials, with their unique physical and chemical properties, hold significant potential for application in bone repair [63].

3 Immune regulation in bone regeneration

Bone regeneration is a highly orchestrated, multicellular, and multifactorial process in which the immune system exerts a critical regulatory role [64]. In response to fractures or bone defects, injured tissues release damage-associated molecular patterns (DAMPs), including high-mobility group box 1 (HMGB1), S100 proteins, and adenosine triphosphate (ATP) [65–67]. These molecular signals activate resident and infiltrating immune cells, thereby initiating a coordinated inflammatory response [68]. Neutrophils are the first immune cells to be recruited to the injury site, guided by chemokines such as CXCL8 [69,70]. Upon arrival, neutrophils release a repertoire of antimicrobial effectors, including lysozyme and elastase, which function to eradicate invading pathogens and clear necrotic cellular debris [71]. Subsequently, macrophages are recruited and assume a central role in orchestrating the bone repair process through the secretion of pro-osteogenic cytokines and growth factors that regulate both osteogenesis and osteoclastogenesis [72,73].

In the initial phase of bone healing, macrophages predominantly exhibit an M1 pro-inflammatory phenotype, characterized by the secretion of cytokines such as TNF-α, IL-1, and IL-6 [74,75]. These mediators not only amplify local inflammation but also recruit additional immune cells and stimulate osteoblast proliferation [75]. As healing progresses, macrophages undergo phenotypic polarization toward the M2 anti-inflammatory state [76,77]. M2 macrophages secrete cytokines such as IL-10 and TGF-β, which attenuate inflammation and promote tissue regeneration [78]. In parallel, regulatory T cells (Tregs) contribute to the resolution of inflammation by secreting anti-inflammatory cytokines and maintaining the delicate equilibrium between pro- and anti-inflammatory signals [79]. This immunological balance is essential for effective bone regeneration, as sustained pro-inflammatory activity may result in chronic inflammation and impaired healing outcomes [80,81]. In summary, the early inflammatory phase of bone repair is predominantly mediated by classically activated M1 macrophages, which secrete pro-inflammatory cytokines and generate reactive oxygen species (ROS) to facilitate pathogen clearance and the removal of necrotic tissue [82]. Conversely, the subsequent resolution and regenerative phase is characterized by the predominance of alternatively activated M2 macrophages, which secrete anti-inflammatory cytokines and osteoinductive growth factors that support tissue repair and promote bone regeneration [83].

In recent years, growing evidence has reshaped the traditional understanding of macrophage polarization into the M1/M2 dichotomy [84]. It is now recognized that macrophages exhibit a high degree of plasticity, allowing them to adapt their phenotype and function in response to diverse microenvironmental signals [85]. This plasticity enables macrophages to participate in a broad spectrum of physiologic and pathological processes, and suggests that their polarization exists along a dynamic continuum rather than as two mutually exclusive states [86]. M1 and M2 phenotypes represent the two extremes of this spectrum, whereas most macrophages in vivo reside in intermediate or transitional states, exhibiting unique functional characteristics and marker expression profiles [87]. In certain microenvironments, macrophages may even adopt hybrid phenotypes, simultaneously expressing both pro-inflammatory (e.g., TNF-α) and anti-inflammatory (e.g., IL-10) markers [88]. In the context of bone repair, the shift from the early inflammation phase—predominantly mediated by M1 macrophages—to the subsequent tissue repair and remodeling phase—largely driven by M2 macrophages—represents a gradual and regulated phenotypic transition rather than a binary switch [89–91]. This dynamic transformation underscores the importance of understanding and modulating macrophage phenotypes as a continuum to optimize regenerative outcomes.

Immune cells play a pivotal role in regulating the balance between osteoclasts and osteoblasts. Foremost, the RANKL/RANK/OPG signaling axis is a key regulatory mechanism that maintains the dynamic equilibrium between bone formation and resorption [92]. Osteoprotegerin (OPG), a decoy receptor secreted by osteoblasts and immune cells, competes with RANK on osteoclast precursors to bind RANKL, thereby inhibiting osteoclastogenesis [92]. For osteoblasts, the Wnt/β-catenin signaling pathway is critical for regulating their activity by controlling the expression of osteogenic transcription factors such as RUNX2 and Osterix [93]. Additionally, several other signaling pathways are involved in bone homeostasis, including the NF-κB pathway (activated by TNF-α, IL-1β, and RANKL, promoting osteoclast activation), the STAT3 pathway (activated by IL-6 family cytokines, enhancing osteoclastogenesis), and the Smad pathway (activated by TGF-β, promoting osteoblast differentiation) [94–96]. Different immune cell subsets contribute to the regulation of osteogenesis and osteoclastogenesis by secreting distinct cytokines that engage these pathways [97]. M1 macrophages secrete IL-1β and TNF-α, which enhance RANKL expression, thereby promoting osteoclast differentiation [98]. In contrast, M2 macrophages secrete anti-inflammatory cytokines (e.g., TGF-β and IL-10), as well as osteoinductive growth factors (e.g., BMPs), collectively supporting osteoblast proliferation and differentiation [99]. Moreover, macrophages facilitate bone regeneration by phagocytosing apoptotic osteoblast debris and subsequently releasing pro-regenerative trophic factors that aid tissue remodeling [100]. Th17 cells produce IL-17A, which binds to receptors on osteoclast precursors, activating both the STAT3 and NF-κB pathways. This leads to upregulation of RANKL and suppression of OPG, disrupting the RANKL/OPG balance and promoting bone resorption [98]. In contrast, Tregs inhibit osteoclastogenesis and promote osteogenesis through the secretion of IL-10 and TGF-β [101]. Th1 cells produce IFN-γ, which suppresses osteoclast differentiation by inhibiting the NF-κB pathway, thereby functionally antagonizing Th17 cells [102]. Th2 cells secrete IL-4 and IL-13, which both block RANKL signaling to inhibit osteoclastogenesis and activate the STAT6 pathway in osteoblasts to promote bone formation [103]. Lastly, B cells contribute to bone homeostasis primarily through the secretion of antibodies and cytokines; although their role is relatively indirect, it is considered chronically stable and regulatory [104].

Angiogenesis is one of the critical steps in the bone repair process [105]. Immune cells, such as macrophages and T lymphocytes, contribute to neovascularization by secreting pro-angiogenic factors, including vascular endothelial growth factor (VEGF) [106]. The formation of new blood vessels not only ensures the supply of oxygen and nutrients to immune cells but also facilitates their migration to the site of injury [107]. Moreover, endothelial cells themselves actively participate in the regulation of immune responses by releasing various cytokines [108]. Immune cells modulate angiogenesis through the secretion of cytokines such as TGF-β and IL-10, as well as chemokines like CXCL12 [109]. These signaling molecules promote the proliferation and migration of endothelial cells, thereby supporting the vascularization necessary for effective bone regeneration [110].

During the bone repair process, immune cells contribute to the remodeling of the ECM through the secretion of MMPs and tissue inhibitors of metalloproteinases (TIMPs) [111,112]. These enzymes facilitate ECM degradation and reorganization, thereby creating a favorable microenvironment for bone regeneration [113].

Additionally, the metabolic state of immune cells significantly influences the bone healing process. Classically activated M1 macrophages predominantly rely on glycolysis for energy production, whereas alternatively activated M2 macrophages utilize oxidative phosphorylation as their primary metabolic pathway [114]. This metabolic divergence underlies the functional heterogeneity of macrophage subtypes and directly impacts their roles in the regulation of inflammation and tissue regeneration during bone repair [115].

4 Classification of bioceramic bone repair materials

Bioceramics have emerged as ideal materials for bone repair due to their excellent biocompatibility, osteoinductivity, and biodegradability. They not only activate key signaling pathways to promote bone tissue regeneration but also modulate immune responses to create a microenvironment conducive to bone healing. The porous architecture of bioceramics facilitates cell adhesion and nutrient diffusion, while their mechanical properties provide essential structural support at the defect site [104]. Certain bioceramic compositions can actively influence the phenotype and function of immune cells, such as macrophages and T cells, thereby orchestrating an immunological milieu that favors osteogenesis and angiogenesis. For example, appropriately engineered bioceramics can induce a phenotypic shift from pro-inflammatory M1 macrophages to pro-regenerative M2 macrophages, thereby accelerating tissue repair and integration [116]. Moreover, the controlled release of bioactive ions—such as Ca²⁺, Si⁴⁺, and Zn²⁺—from bioceramics has been shown to regulate cytokine expression, enhance stem cell recruitment, and activate osteoimmunomodulatory pathways [117,118]. Their capacity for patient-specific customization further enables them to meet diverse anatomical requirements and significantly reduce the risk of complications associated with traditional bone grafting procedures. These attributes, combined with their structural support and drug delivery potential, position bioceramics as multifunctional platforms in bone tissue engineering, particularly for the treatment of complex or non-healing bone defects.

Bioceramic materials are typically classified into three categories: bioinert ceramics, bioactive ceramics, and biodegradable ceramics. Additionally, composite ceramic materials can be developed by combining bioceramics with other components, such as metals or biological factors. This section provides an overview of the primary types of bioceramic materials, along with their key biological and physicochemical properties (Fig. 3).

4.1 Bioinert ceramics

Bioinert ceramics are materials that exhibit minimal or no biological reactions within living organisms, such as Al₂O₃ (alumina) and ZrO₂ (zirconia). These ceramic materials exhibit excellent biocompatibility with human tissues, without inducing significant immune rejection or inflammatory responses. They demonstrate remarkable resistance to corrosion and degradation in physiologic environments, enabling long-term maintenance of their structural integrity and performance [119]. Moreover, they possess high strength, hardness, and wear resistance, and can withstand high-temperature sterilization processes, ensuring the sterility of implants [120]. However, bioinert materials lack bioactivity and fail to promote the attachment, proliferation, and differentiation of bone cells. The absence of chemical bonding with bone tissue results in poor osseointegration and reduced interfacial bonding strength between the implant and bone [121]. The elastic modulus of bioinert materials is typically higher than that of natural bone (e.g., the elastic modulus of alumina is approximately 380 GPa, compared to 10–30 GPa for natural bone), which may lead to stress shielding effects [122]. In such cases, the implant bears the majority of the load, while the surrounding bone tissue gradually atrophies due to insufficient stress stimulation [123]. Additionally, bioinert ceramics exhibit high brittleness and low impact resistance, making them susceptible to fracture under complex stress conditions.

Al₂O₃ ceramics possess a high melting point, hardness, chemical resistance, and elastic modulus [124]. They are highly stable in the human body, exhibiting minimal wear, and have low cytotoxicity, sensitization potential, and genotoxicity, making them highly biocompatible [125]. Al₂O₃ was the first bioinert ceramic material used in clinical applications. In 1972, Boutin replaced traditional metallic femoral heads in hip prostheses with Al₂O₃ [126]. It is commonly used in ball-and-cup bearings for artificial hip and knee joints. However, its brittleness and limited ability to withstand complex dynamic loads remain challenges [127].

ZrO₂ ceramics are known for their high fracture toughness, high fracture strength, and low elastic modulus [128]. The addition of yttrium oxide (Y₂O₃) to stabilize zirconia significantly enhances its stability [129]. ZrO₂ ceramics are widely used in spherical heads for artificial joints, dental implants, and other medical devices [130,131]. However, prolonged use can lead to low-temperature degradation, which compromises the material’s stability [132].

Silicon carbide (SiC) is a high-performance bioinert ceramic material known for its excellent mechanical properties, chemical stability, and biocompatibility, making it resistant to biodegradation [133]. The primary drawbacks of SiC is the complexity of its preparation process and its high production cost.

4.2 Bioactive ceramics

Bioactive ceramics are materials that induce specific biological reactions at the material-tissue interface and possess the ability to form a bond between tissues and materials. These materials can repair, replace, or regenerate body tissues. Bioactive ceramics typically contain hydroxyl groups, such as hydroxyapatite (HA), whose surface is composed of hydroxyapatite. Another category includes bioactive glass, which does not contain hydroxyapatite on its surface but can form a hydroxyapatite coating through chemical reactions in the physiological environment (Table 2).

Calcium phosphate ceramics, such as hydroxyapatite, exhibit good biocompatibility and bioactivity due to their similarity in composition and structure to human bone crystals [134]. These materials can be used as bone defect fillers, directly integrating with bone tissue to promote regeneration. Masanori Kikuchi demonstrated that HA can activate the osteogenic function of osteoblasts (MG63), promoting cell proliferation and expression of the ALP gene [135]. However, the relatively low mechanical strength of calcium phosphate ceramics limits their application in load-bearing regions.

Silicate bioactive ceramics can significantly enhance the proliferation and differentiation of bone cells by releasing silicon ions, accelerating bone tissue repair [136]. Compared to traditional calcium phosphate ceramics, silicate ceramics exhibit superior performance in promoting osteogenesis and angiogenesis [137]. Zhou et al. found that calcium silicate bioactive ceramics promote macrophage polarization, reduce inflammatory responses, and significantly enhance osteogenic differentiation of bone marrow MSCs via macrophage-derived oncostatin M [138]. However, further optimization of their degradation rate and mechanical properties is required to meet diverse clinical demands.

Bioactive glass is a material with both osteoconductivity and osteoinductivity, capable of tightly binding to host bone and promoting bone formation upon implantation. Depending on its composition, bioactive glass can be categorized into silicate bioactive glass, phosphate bioactive glass, and boron-containing glass [139]. Bioactive glass offers advantages such as good biocompatibility and a controllable degradation rate, though its low mechanical strength limits its application in high-load bone repair [140].

4.3 Biodegradable ceramics

Biodegradable ceramics are a unique subclass of bioactive ceramics. Due to their distinct degradability, they are categorized separately. These materials can gradually degrade within living organisms and be replaced by new bone tissue, making them ideal for use in bone repair and regeneration. Biodegradable ceramics provide temporary mechanical support while promoting the growth and healing of bone tissue.

Tricalcium phosphate (TCP) was first documented as a bone-repair material in 1920 by Albee, who showed that “triple calcium phosphate” powder could accelerate osteogenesis and promote fracture healing when implanted into rabbit radial defects” [141]. TCP exhibits excellent biocompatibility, osteoconductivity, and biodegradability. However, its mechanical properties and the challenge of matching its degradation rate with the rate of bone repair limit its application in certain clinical scenarios [142].

Calcium sulfate exists in two forms: anhydrous calcium sulfate and calcium sulfate dihydrate. Compared to TCP, calcium sulfate is easier to shape and handle, making it more convenient for surgical use. However, the sulfate ion produced during the degradation of calcium sulfate may not directly promote bone formation as effectively as the phosphate group in TCP. TCP is often used when osteoinduction and osteoconduction are required, while calcium sulfate may be more suitable as a temporary bone replacement material, particularly in cases where degradation rates need to be carefully controlled [143].

4.4 Composite ceramics

To meet the diverse needs of bioceramic materials, it is feasible to adjust their biological, physical, and chemical properties through material composites or by introducing additional components, such as metal ions, antibacterial agents, and drugs. Keppler et al. improved the biocompatibility and osteoconductivity of ceramic materials while maintaining mechanical strength by combining Al₂O₃ with calcium phosphate [144]. Losquadro et al. demonstrated that the incorporation of polylactide-co-glycolide (PLGA) fibers as a secondary phase enhanced the structural integrity and material strength of calcium phosphate bone cement [145]. The incorporation of various metal ions imparts distinct characteristics to bioceramic materials. For example, strontium promotes bone regeneration, magnesium supports both bone and cartilage regeneration, copper facilitates angiogenesis, iron exhibits chemotactic properties, lithium aids in vitamin B12 synthesis, and silver enhances antibacterial activity [146]. Bioceramic materials can also serve as drug delivery carriers, effectively controlling the release of drugs and growth factors to accelerate bone healing [147]. By combining alpha-calcium sulfate hemihydrate with platelet-rich plasma (PRP), Syam et al. demonstrated a significant enhancement in rabbit bone healing and regeneration [148].

5 The immune regulation of bioceramic bone repair materials

Bioceramic bone repair materials can modulate immune responses through multiple mechanisms, thereby creating a microenvironment conducive to bone regeneration [149]. Through a multifaceted synergistic approach, bioceramics effectively enhance osteogenesis and accelerate the repair of bone defects [150].

One of the primary immunomodulatory mechanisms involves the regulation of macrophage polarization, particularly the transition from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype [151–153]. For instance, HA has been shown to induce macrophage polarization toward the M2 phenotype [154]. M2 macrophages secrete anti-inflammatory mediators such as arginase-1 (Arg1) and, while downregulating pro-inflammatory cytokines such as IL-1 and IL-6, thereby fostering an immunological milieu favorable for bone regeneration [155,156]. Bioactive glass also facilitates bone regeneration by modulating macrophage polarization [157]. For example, selenium-doped mesoporous bioactive glass (Se-MBG) enhances the expression of the antioxidant enzyme glutathione peroxidase 4 (GPX4) in macrophages, promoting the scavenging of excess ROS [158–160]. This modulation of redox homeostasis influences macrophage metabolism and mitochondrial function, ultimately promoting M2 polarization [161]. In addition to macrophages, bioceramic materials may affect the function of other immune cells. For example, β-TCP has been shown to activate dendritic cells (DCs) [162,163]. When incorporated into β-TCP scaffolds, these cells significantly upregulate osteogenic gene expression—including RUNX2, ALP, and OCN—thereby enhancing bone formation [164]. Bioceramics also modulate immune responses through the release of specific ions, such as Ca²⁺ and Zn²⁺, which participate in immune cell recruitment and regulation [165]. Calcium ions, for instance, activate various signaling pathways—such as MAPK, cAMP-PKA, and PI3K-AKT—thereby promoting osteoblast differentiation and M2 macrophage polarization [166–168]. Zinc ions possess both antibacterial and immunomodulatory properties, promoting osteoblast proliferation and differentiation while suppressing osteoclast activity [169,170]. Furthermore, bioceramic materials can release or adsorb various growth factors—such as BMP-2 and TGF-β—either through their inherent degradation or via surface modifications [171,172]. These growth factors directly enhance osteoblast differentiation and ECM deposition, thereby contributing to efficient bone regeneration [173].

Bioceramic materials can modulate immune cell behavior and responses by tailoring their physical properties [174]. Optimal pore size and porosity are critical in regulating osteogenic cell behavior, macrophage polarization, and immune responses [175,176]. For instance, bioceramics with a pore size of approximately 350 μm have been shown to promote both osteogenesis and angiogenesis, whereas smaller pores may exacerbate local inflammatory responses and hinder bone repair [177–179]. Although higher porosity enhances osteoblast adhesion and proliferation, it concurrently compromises the mechanical strength of the material, necessitating a balance between porosity and mechanical integrity [180,181]. Enhancing surface roughness can activate integrin–cytoskeletal complexes, thereby promoting M2 macrophage polarization and facilitating anti-inflammatory responses and bone regeneration [182,183]. For example, biphasic calcium phosphate ceramics with high surface roughness have been demonstrated to significantly downregulate inflammation-related gene expression and inhibit the TNF signaling pathway, ultimately promoting bone healing [184,185]. Moreover, engineering specific surface topographies—such as nanopits, nanopillars, and nanogrooves—on bioceramic materials can influence cellular adhesion, spreading, and proliferation, thereby regulating the bone regeneration process [186,187]. For example, HA scaffolds featuring defined surface grooves (25–30 μm) have been reported to improve the local inflammatory microenvironment by modulating macrophage activity and to enhance osteogenic differentiation through the downregulation of microRNA-214 [188].

Moreover, bioceramic materials can enhance angiogenesis by modulating immune responses, thereby ensuring an adequate supply of nutrients and oxygen essential for bone regeneration [189]. Angiogenesis is a critical component of the bone healing process, as it supports the formation and mineralization of new bone tissue. In addition, neovascularization facilitates the remodeling of the ECM, creating a microenvironment conducive to cellular adhesion, proliferation, and differentiation, ultimately promoting effective bone regeneration [3,189].

The immune response triggered by bioceramic implants is a dynamic and spatially organized process involving various immune cell types that coordinate tissue regeneration. During the early stage of implantation—namely, the acute inflammatory phase—macrophages respond rapidly by infiltrating the bioceramic surface and subsequently migrating into the internal pore structures. Initially, these macrophages exhibit a pro-inflammatory M1 phenotype, contributing to the clearance of pathogens and cellular debris [190]. As the response progresses into the subacute phase, a phenotypic transition toward the anti-inflammatory M2 subtype occurs, promoting angiogenesis and osteogenesis through the secretion of VEGF, BMPs, and cytokines such as IL-10 and TGF-β [191]. The accumulation of IL-10 and TGF-β in the local microenvironment facilitates the recruitment, proliferation, and differentiation of naive T cells into Tregs, which further secrete IL-10 and TGF-β to maintain immune tolerance and suppress excessive inflammation [79]. Concurrently, B cells are activated through antigen recognition via B cell receptors, and—with T cell help—differentiate into plasma cells or memory B cells. These activated B cells contribute to immune modulation by producing antibodies and secreting anti-inflammatory cytokines such as IL-10 [192].

Temporally, the immune response to bioceramic implants progresses from innate to adaptive immunity. Spatially, immune cell infiltration extends from the implant surface to its porous interior and the surrounding tissue interface. These spatiotemporal dynamics are essential for orchestrating the transition from inflammation to tissue regeneration. Understanding and manipulating these interactions through rational material design represents a promising strategy for enhancing the immunomodulatory properties of bioceramics and improving their regenerative efficacy.

6 Fabrication of bioceramic bone repair materials

The fabrication process of bioceramic materials significantly influences their properties and applications, including microstructure, porosity, mechanical properties, biological activity, and preparation cost. The microstructure encompasses the grain size, crystal phase composition, and pore structure of the bioceramics. Porosity and pore size are crucial factors that determine the bioactivity, degradation rate, and osteogenic potential of the material [193]. With regard to the bioactivity of bioceramic materials, porosity primarily affects the specific surface area and the penetration depth of body fluids. High porosity significantly increases the specific surface area of the material, thereby enlarging its contact area with physiologic fluids. This provides more surface sites for cell adhesion, biomolecular adsorption, and ion exchange, ultimately enhancing cellular attachment, proliferation, and differentiation [194]. For instance, porous HA exhibits a specific surface area 5–10 times greater than that of dense HA, enabling it to more rapidly achieve supersaturation of apatite in surrounding fluids and facilitating the deposition of a bone-like apatite layer [195]. However, excessively high porosity can result in a fragile and loosely connected structure prone to surface collapse, which compromises ion exchange stability and may even hinder the orderly formation of the apatite layer. Pore size influences bioactivity by regulating fluid infiltration efficiency and the local microenvironment for surface reactions. An appropriate pore size facilitates the formation of interconnected channels, allowing body fluids to penetrate deeply into the material. Simultaneously, it supports the infiltration and migration of endothelial and osteogenic cells, thereby promoting angiogenesis and new bone tissue formation [196,197]. The degradation of bioceramics primarily occurs through fluid-induced dissolution and cell-mediated resorption. Materials with high porosity and large pore sizes tend to have a more open internal structure, allowing body fluids and cells to quickly reach the core region and accelerate degradation [198]. However, excessive porosity or overly thin pore walls may significantly compromise the mechanical integrity of the material, limiting its clinical applicability. The porous architecture serves as a critical framework for osteoconduction, mimicking the structure of natural trabecular bone and creating a favorable three-dimensional microenvironment. This facilitates the colonization and osteogenic differentiation of MSCs by providing both spatial and mechanical support for bone tissue regeneration. Neither high porosity nor large pore size alone is sufficient to ensure optimal material performance. A balanced design that considers both the biological advantages of the porous structure and the mechanical stability of the material is essential to meet the demands of clinical applications [199]. Mechanical properties, such as density and strength, primarily govern the material's performance. Additionally, certain fabrication methods can enhance the bonding ability of materials to bone tissue by incorporating functional coatings (Table 5).

The traditional sintering method is one of the most commonly used techniques for bioceramic preparation. In this method, ceramic powder is mixed with an appropriate binder, pressed into a mold, and then sintered to produce a dense ceramic material. Its advantage lies in the ability to control the composition and microstructure of the ceramics, making it suitable for bioceramics that require high mechanical properties. However, high-temperature sintering may lead to the degradation of certain material properties, such as a reduction in biological activity [200].

The gas foaming method involves adding a foaming agent to ceramic slurry to create a porous structure, followed by sintering to produce porous ceramics [201]. This method is ideal for preparing bioceramic scaffolds with high porosity, which supports cell growth and tissue regeneration. However, it results in reduced mechanical properties, limiting its application in load-bearing areas. Additionally, the uniformity and distribution of pores must be precisely controlled [202].

The sol-gel method involves preparing a ceramic precursor sol through a chemical solution reaction, followed by gelation, drying, and sintering to form a uniform and delicate ceramic material. This approach allows for the preparation of high-purity and homogeneous materials at lower temperatures. The chemical composition can also be adjusted to impart specific biological activities, such as doping with ions [203]. Furthermore, nanoscale materials can be synthesized to enhance biological activity [204–206]. However, the process is complex, time-consuming, and costly, with limited production capacity, making it difficult to meet the demands of large-scale application.

Electrospinning is a technique in which a polymer solution or sol is ejected under high voltage to form nanometer- or micrometer-scale fibers, which can serve as scaffolds for bone tissue engineering to support cell growth [207]. This method can produce fibers with a large specific surface area, enhancing cell adhesion [208]. Moreover, it allows precise control over fiber diameter, shape, and alignment [209]. However, the preparation process is complex, and the mechanical properties of the material are often suboptimal.

Three-dimensional printing technology (additive manufacturing) has garnered widespread attention in bone tissue engineering in recent years [210]. This method involves creating complex bioceramic scaffold shapes by stacking layers, with precise control over internal pore structure and geometric accuracy, making it well-suited for producing personalized medical devices [211,212]. However, the preparation process is slow, the selection of materials is limited, and the properties of printed ceramics are significantly influenced by the printing process.

For coating formation, the plasma spraying method utilizes high-temperature plasma to melt ceramic powder and spray it onto the substrate surface [213]. Chemical vapor deposition (CVD) decomposes gaseous precursors and deposits them on the substrate surface at high temperature [174]. Electrophoretic deposition uses electric fields to deposit charged ceramic particles from a suspension onto the substrate surface, followed by sintering [214]. Surface coatings can enhance biocompatibility, improve mechanical properties, promote bone integration, reduce surface friction, and enable controlled release functions.

7 Translational products of bioceramic bone repair materials

There are various bioceramics available on the market for artificial bone products, primarily based on materials such as hydroxyapatite, calcium phosphate, alumina, and zirconia. Notable commercial products include Osferion in Japan, IngeniOs in the United States, and Cerasorb in Germany. While these bioceramics offer certain advantages over conventional bone repair products, they still fall short of fully meeting clinical demands (Table 6).

Clinical follow-up studies have demonstrated the favorable osteoconductive and biodegradable properties of Osferion. In a retrospective study of 15 patients who received Osferion for reconstruction of fibular donor-site defects after spinal fusion, the mean follow-up was 11 months. Radiographic analysis showed that the initial defect filling ratio decreased from 0.94  ±  0.14 postoperatively to 0.52  ±  0.27 at final follow-up, indicating progressive material resorption and new bone formation. Compared to the control group using Affinos, which showed a final ratio of 0.77  ±  0.14, Osferion demonstrated significantly faster biodegradation (P = 0.003) [215]. Another study involving 17 patients with fibular resections reported that among 34 assessed bone regions, 64.7% showed bone formation from the residual fibula, 35.7% from the preserved periosteum, and additional new bone formed within the β-TCP itself, confirming Osferion’s osteoconductive and limited osteoinductive potential [216]. These findings support Osferion as an effective material for bone defect reconstruction, promoting gradual resorption and reliable new bone regeneration within 6–12 months, with high radiological success rates and no major complications reported.

In addition, a recent retrospective study involving 43 patients with benign or low-grade malignant bone tumors further confirmed the clinical reliability of Cerasorb. Following intralesional curettage and bone defect filling with Cerasorb, patients were followed up for an average of 14.6 months, with scheduled radiographic assessments at 6 weeks, 3 months, 6 months, and 1 year. The results demonstrated that all patients achieved radiological consolidation. However, only 16.3% of cases showed complete graft resorption within the follow-up period, while 83.7% remained partially resorbed. Although 4 patients (9.3%) experienced pathological fractures within 6 weeks postoperatively, these occurred primarily in weight-bearing or mechanically stressed regions such as the distal femur and humeral shaft. The study concluded that Cerasorb exhibits reliable osteoconductivity, predictable biocompatibility, and low complication rates, though its resorption process tends to be relatively slow in certain anatomical sites [217].

Overall, the available long-term clinical follow-up studies on these bioceramic materials remain limited. Most existing studies are single-center, small-sample, retrospective analyses with relatively short follow-up periods, typically ranging from 6 months to 1 year. Moreover, the majority of these studies lack standardized radiological evaluation criteria and objective functional outcome measures. These limitations contribute to considerable uncertainty when comparing the clinical performance of different products. Therefore, large-scale, multicenter, prospective clinical trials with long-term follow-up are urgently needed. Such studies should incorporate standardized evaluation systems to more robustly verify the clinical efficacy, safety, and long-term bone regeneration outcomes of various bioceramic materials in clinical applications.

Researchers have devoted substantial efforts to advancing breakthroughs and innovations across various aspects. For instance, material structure plays a critical role in tissue regeneration. Dorozhki highlighted that the internal connections within a material are pivotal for cell growth and osteogenesis [218]. Inadequate connectivity can hinder cell migration, slow vascular growth, and ultimately reduce the efficacy of bone repair [219]. Fan et al. introduced the concept of the “minimum functional unit” for bone repair, adjusting the unit template by controlling factors such as solvent concentration, processing time, bonding temperature, and loading pressure through spherical cell microhole stacking technology. This innovation enabled the precise fabrication of porous ceramics for the first time, strengthening the internal connections [220]. The resulting porous ceramics demonstrated 65% porosity, a pore size of 500–600 μm, and an inner connection diameter of 120 μm, all of which facilitated optimal cell migration, adhesion, vascularization, and bone formation.

Moreover, a balance between mechanical properties and osteoinductivity remains a challenge. Porous ceramics often lack the necessary mechanical strength, while dense ceramics alone do not foster bone formation, and combining both materials has proven difficult, particularly in load-bearing bone repair. Hammer et al. incorporated bone conduction additives such as HA and β-TCP into organic-inorganic hybrid coatings, which increased the nanoscale roughness of the coatings and consequently enhanced their surface free energy. These modifications promoted protein adsorption, thereby facilitating osteoblast adhesion and functionality on the coating surface. Their findings indicate that HA- and β-TCP-modified hybrid coatings play a positive role in improving the biocompatibility and corrosion resistance of Ti6Al4V alloys [221]. Huang et al. developed a mechanical matching calculation method to elucidate the relationship between material mechanical properties and load-bearing capacity, providing a theoretical foundation for reinforced manufacturing. By incorporating stem cells and utilizing dynamic culture technologies, the team improved cell growth and tissue regeneration capabilities, significantly enhancing the repair potential of porous ceramics [222]. This breakthrough addressed the issues of weak strength and poor interface connection by introducing micron-sized yarn and collagen.

8 Final remarks and future perspectives

In summary, bioceramic materials hold significant promise in the field of bone tissue repair, with increasing attention being directed toward their role in modulating the immune microenvironment. However, achieving effective immunomodulation remains a major challenge. Although notable progress has been made in optimizing the mechanical strength, biocompatibility, biodegradability, and osteoinductive properties of these materials, the immune response during bone regeneration is highly complex and dynamic. Excessive inflammation can inhibit osteogenesis, whereas immunosuppression may elevate the risk of infection and compromise healing outcomes. Therefore, the rational design of bioceramics—encompassing compositional engineering, surface modification, and functionalization strategies—must aim to precisely regulate immune cell phenotypes (e.g., macrophage M1/M2 polarization), inflammatory cytokine expression, and the intricate immune–bone crosstalk. These remain critical scientific challenges in the development of next-generation biomaterials.

Moreover, considerable inter-individual variability in immune responses further complicates the clinical translation of bioceramics, as patients may exhibit divergent biological reactions to the same material. Consequently, future research should prioritize the development of bioceramics with adaptive or programmable immunomodulatory capabilities. Leveraging tools such as bioinformatics, high-throughput screening platforms, and advanced manufacturing technologies—such as 3D printing and computer-aided design (CAD)—will be essential for constructing personalized bone repair solutions.

We propose that future research should focus on three key breakthrough areas: First, personalized bioceramic design, which optimizes parameters using artificial intelligence (AI) technology based on the patient’s immune phenotype and bone defect structure to achieve customized and precise repair. Second, the deep integration of multifunctional bioceramics with advanced manufacturing technologies. This would involve incorporating antibacterial, immunomodulatory, and osteoinductive functions into a single material system, further enhanced through 4D printing of deformable microstructures or microfluidic chip-organ models to better serve clinical applications. Third, a systematic study of immune regulation mechanisms, which would involve developing multi-cell interaction models, analyzing signaling pathways, and creating smart materials capable of precisely intervening in immune-metabolic reprogramming. Based on a comprehensive understanding of immunoregulatory mechanisms, the design of multifunctional bioceramic materials that integrate osteogenic, angiogenic, and immunomodulatory functions may enable a paradigm shift from structural substitution to functional regeneration in bone tissue engineering. Such innovations are expected to provide more precise and effective therapeutic strategies for the repair of complex and large-volume bone defects.

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