Clinical Advances in Calcium Phosphate for Maxillomandibular Bone Regeneration: From Bench to Bedside

Abstract

Background: Maxillomandibular bone defects present a complex challenge in regenerative medicine due to anatomical and functional intricacies. Calcium phosphate (CP)-based biomaterials have emerged as promising bone graft substitutes due to their biocompatibility, osteoconductivity, and bioactivity. Aim: This Review highlights recent clinical and experimental advancements in CP-based biomaterials for maxillomandibular bone regeneration, bridging the gap from bench to bedside. Method: An in vitro, in vivo, and clinical literature review was conducted to evaluate the performance of CP ceramics, including hydroxyapatite (HA), tricalcium phosphate (TCP), biphasic ceramics, and novel composites with polymers, growth factors, and nanoparticles. Results: Calcium phosphate-based biomaterials demonstrate excellent bone regeneration potential, with Beta-tricalcium phosphate (β-TCP) and HA being the most widely utilized. Composite scaffolds and 3-dimensional (3D)-printed constructs show enhanced mechanical properties and biological integration. Clinical trials have confirmed the safety and efficacy of CP-based materials, yielding promising outcomes in osteoconduction and defect healing. However, limitations persist regarding mechanical strength and long-term degradation profiles. Conclusions: CP-based biomaterials offer significant clinical promise for maxillomandibular bone regeneration. Continued advancements in scaffold design and biofunctionalization are crucial for overcoming current limitations and fully realizing their therapeutic potential.

1. Introduction

Maxillofacial injuries or surgeries can cause bone defects in the maxillomandibular region, which is often treated to address maxillofacial tumors and cysts. Maxillomandibular defects can limit daily living activities and cause unusual facial features, thereby adversely impacting the quality of life (QOL) of patients. The standard treatment for these conditions involves transferring bone from the ilium, the tibia, or any other bone; however, the procedure is invasive, resulting in hospitalizations, infections, and hematomas [1]. The reconstruction of large bone defects is often challenging in oral and maxillofacial surgery. It is considered the gold standard for repairing bone defects to use autologous bone grafts; however, there are specific limitations to their use [2]. An implant can be placed in the posterior maxillary bone by using bone substitutes in a maxillary sinus lift. In this procedure, the Schneiderian membrane was elevated using the maxillary lateral wall approach [3]. There is increasing interest in tissue engineering (TE) approaches for the treatment of oral and maxillofacial morbidities and limitations. Combining TE with minimally invasive technologies to reduce morbidity is particularly attractive when TE can be injected [4]. Bone resorption can occur as a result of tooth extractions. Vertical or horizontal reduction in the alveolar ridge typically results in deformity and bone resorption following the procedure. The severity of bone loss has a direct impact on the success rate and aesthetics of subsequent dental implant procedures. The first three months after an extraction are when two-thirds of the soft and hard tissues are reabsorbed. Bone loss typically occurs within the first six months following the procedure [5].

The absorption of bone grafts varies depending on the time since they were implanted. Currently, artificial bone is used to fill defects, but it takes a long time for osseointegration, and infection frequently occurs at the implanted site in cases of large defects [1]. In addition to autografts, allografts, xenografts, and alloplasts can be classified based on their origins. It is considered the “gold standard” material for bone grafts, as it is obtained from another part of the same person. Additional surgery is required, and autograft materials are limited in availability. In addition to xenografts, artificial bone graft materials have been developed as options for socket preservation procedures. Artificial bone grafts are available in many varieties; bioceramics are the most commonly used materials. Extensive studies have shown that hydroxyapatite (HA), tricalcium phosphate (TCP), and their composite grafts can perform both dental and orthopedic functions [5]. Clinical applications currently involve injectable biomaterials based on calcium phosphate (CP) cement, which are regulated and utilized for various clinical purposes. Although these materials have been widely successful in repairing and regenerating bone defects, concerns about degradation and their brittle mechanical properties limit their use in many applications. The versatility of this material has been demonstrated in the applications of CP composites in soft tissue fillers and bone applications [4]. Biphasic calcium phosphate (BCP) handled the biomaterials evaluated relatively easily during the maxillary sinus grafting procedure. In contrast, when blood was associated with the paste, it became unstable and fluid, mainly due to the height required. Despite this, no post-surgery complications have been reported during the healing process of bone grafts. Maxillary sinus bone grafts using HA demonstrated a lower resorption rate and a lower average rate of bone formation. A biocompatible bone graft is better than an autogenous bone graft because it has fast resorption and a reasonable bone-formation rate. This BCP combines HA to enhance bone formation and to maintain its volume while reducing biomaterial resorption [3]. The purpose of this Review is to provide a comprehensive overview of the recent clinical and experimental advances in CP-based biomaterials that can be used to regenerate maxillomandibular bone.

2. Method

This Review aimed to comprehensively assess and synthesize recent advancements in calcium phosphate (CP)-based biomaterials for maxillomandibular bone regeneration, with a particular focus on their biochemical properties (mechanical stability, biocompatibility, biodegradability, etc.), clinical applications, and translational potential.

A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, and Google Scholar. The search strategy used a combination of keywords and Boolean operators to maximize sensitivity and specificity, including terms such as: “calcium phosphate” OR “hydroxyapatite” OR “tricalcium phosphate” AND “maxillofacial regeneration” OR “bone grafts” OR “bioceramics” AND “bioactivity” OR “porosity” OR “clinical trials” OR “calcium silicate” AND “biocompatibility”. Reference lists of relevant reviews and primary studies were also screened to ensure comprehensive coverage.

Inclusion criteria: Peer-reviewed articles published in English. Studies evaluating CP or CP-based composites. Research focused on maxillomandibular or craniofacial bone regeneration. Studies addressing material properties, clinical outcomes, or translational relevance.

Exclusion criteria: Studies not involving CP-based materials; research is limited to non-craniofacial skeletal regions; abstract-only papers, editorials, or conference posters without full data; and non-English publications.

All retrieved articles were first screened for relevance based on their titles and abstracts. The full texts of potentially eligible studies were then independently assessed by two authors. Discrepancies in study selection were resolved through discussion to ensure consistency and transparency.

3. Calcium Phosphate

CPs exhibit exceptional biocompatibility, seamlessly integrating with the human body, particularly in the context of bone implantation. As dissolved and solid substances, they prove invaluable in regenerating hard tissue in our bodies. Several studies have demonstrated the osteoinductive properties of CP ceramics, even without the addition of supplementary factors [6]. In the annals of medical history, calcium sulfate, commonly known as Plaster of Paris, first found utility in 1892 for filling cavities caused by tuberculosis [7]. The crystalline structure of calcium sulfate can assume an anhydrous, dehydrated, or hemihydrate configuration based on its water content; the hemihydrate form, which dissolves rapidly, is favored for medical applications [8]. When calcium sulfate undergoes complete degradation by biological fluids, it leaves behind CP deposits that serve as stimuli for bone growth. Furthermore, its porosity and hygroscopic characteristics have been identified as pivotal in platelet adsorption and infiltration, thereby facilitating the formation of bone and blood vessels [9]. Notably, calcium sulfate by-products have not been associated with adverse reactions, making them suitable short-term space maintainers. Typically administered as a moldable paste or putty, calcium sulfate has been extensively examined for its clinical efficacy and safety in addressing periodontal defects [10]. However, its utilization as a graft material has gradually waned over the past decade due to the emergence of alternative biomaterials with more predictable solubility and outcomes [11]. Combining calcium sulfate with other substances, such as CPs, can enhance structural stability and offer finer control over resorption kinetics [12]. Biphasic calcium sulfate, produced by alternating dehydrates with hemihydrates, slows dissolution and yields a more rigid post-implantation matrix [13]. The osteoinductive properties of CP ceramics are influenced by surface chemistry and charge, which affect protein adsorption and promote cell differentiation through interactions with the extracellular matrix. However, these ceramics face a significant challenge due to their mechanical fragility, limiting their widespread adoption in clinical settings. To address bone deficiencies in the oral cavity and skeleton and to coat dental and orthopedic metal implants, CP ceramics are employed as non-load-bearing implants and as coatings [14]. The inherent brittleness of CP ceramics stems from their primary ionic bonds. Awad et al. devised a CP-based scaffold to maximize cytocompatibility and mechanical strength. These composites have proven effective in enhancing bone regeneration and mechanical integrity, especially in addressing critically sized femoral defects [15]. Biodegradable hydrogel beads containing calcium phosphate bone cement were characterized in vitro by Fu et al., (2022). Hydrogel beads and commercial fast-setting CPC (C/0.25) were compared in vivo to 25%–volume hydrogel in CPC (C/0.25). A composite C/0.25 cell affinity was equal to a CPC-only cell affinity. Cell proliferation and differentiation of osteoprogenitor cells were not inhibited by adding hydrogel beads to CPC. The CPC-only, hydrogel-only, and C/0.25 composite did not differ significantly after 4 weeks of implantation; however, the C/0.25 composite left significantly less residue after 8 weeks than the CPC-only. As a result of the high bone formation rate in the C/0.25, the C/0.25 composite is an ideal option for a wide range of dental applications, craniofacial applications, and orthopedic applications (Figure 1) [16]. An innovative biphasic bone construct was developed by Ahlfeld et al., (2021), that used calcium phosphate cement (CPC) and fibrin gel, both clinically approved materials. MSCs derived from bone marrow were infused into a fibrin gel. In vitro evaluations of fibrin degradation and cell behaviors were conducted first. When mesenchymal stem cells (MSCs) are present, fibrin degrades rapidly. As a result of the plotted CPC structure, the fibrin gel was stabilized slightly. Although fibrin degradation occurred over time, MSCs were able to move to the surface of CPC. The results led to the identification of fibrin gel as a cell delivery system. An experiment involving Lewis rats examined artificial craniofacial defects. Bone formation continued after 12 weeks; however, osseointegration was not yet complete on the biphasic constructs. However, our findings demonstrate that the fabrication of regenerative implants for alveolar defects can be achieved by using 3D plotted CPC constructs in combination with fibrin as a cell delivery system [17].

3.1. Tricalcium Phosphate

CPs have found significant applications in the field of biomedicine, particularly in areas such as dental implants and maxillofacial surgery. Among the various CPs available, TCP, denoted as Ca₃(PO₄)₂, has gained widespread recognition as a viable substitute for human bone material. TCP has garnered substantial attention due to its exceptional utility in biomedical applications. Notably, TCP is characterized by its notable solubility and brittleness, making it a commonly employed material for bioabsorbable bone grafts [18]. While several CPs hold relevance for various biomedical uses, including amorphous CP, dicalcium phosphate, and TCP, two compounds, in particular, stand out in the realm of medical practice [19]. Furthermore, there are two forms of TCP, namely β-TCP and α-tricalcium phosphate (α-TCP), each exhibiting distinct dissolution rates within the body, and they can be utilized in combination as needed [20]. Bone morphogenetic proteins and osteogenic cells are not required for TCP to promote new bone formation in extraskeletal sites. Although osteoinduction is not yet fully understood, it is essential to clarify its precise mechanism. Microporosity and roughness, as well as surface chemistry, charge, and crystallinity, are intricately linked to this property [21]. Cell-scaffold constructs were used to regenerate extensive mandibular bone defects in minipigs. A titanium osteosynthesis plate was used to fix TCP-PLGA scaffolds with or without cells in critical-size defects of the mandible. Micro-CT analysis revealed that scaffolds implanted with Adipose-derived stem cells (ADSCs) yielded significantly greater bone volumes compared to scaffolds implanted without cells. A higher level of osteocalcin deposition was also observed in the test group compared to the control group. A ceramic scaffold or a polymer scaffold that is seeded with ADSCs enhances bone regeneration as a result. Optimizing this concept’s ability to induce osteogenesis is crucial to its use in the clinic [2].

3.2. Alpha-Tricalcium Phosphate (α-TCP)

In recent times, α-TCP has garnered increasing attention as a fundamental ingredient in various applications, including composites, biodegradable bioceramics, and injectable hydraulic bone cement used in bone repair procedures [22]. Multiple strategies are employed to alter the dissolution rate of α-TCP powders, including adjustments in the powder-liquid contact area, modifications in powder solubility within the liquid, variations in the liquid’s saturation for α-TCP, the utilization of dissolution inhibitors, and surface enhancements [22]. According to the manufacturer’s information, this product is recommended as a standard for evaluating bone cements [22].

3.3. Beta-Tricalcium Phosphate (β-TCP)

TCP ceramics, alongside CP ceramics, enjoy widespread use owing to their rapid degradation rate and strong affinity for bone bonding. Compared to alternative biomaterial implants such as HA, TCP ceramics have demonstrated superior biodegradability [23]. Among the various forms of TCP scaffolds, β-TCP scaffolds emerge as the most favorable in terms of mechanical robustness and chemical stability. The biomedical community has increasingly focused on β-TCP ceramics due to their commendable biocompatibility and osteoconductive properties, as noted in reference [24]. The bioceramic scaffold’s surface promotes the precipitation of biological apatite, achieved through the partial dissolution of calcium and phosphate ions, followed by their subsequent release both in vitro and in vivo. While β-TCP material-based bioceramic scaffolds exhibit fracture toughness and superior bending strength compared to those crafted from HA materials, they still fall short of the performance of natural cortical bone. Consequently, using β-TCP bioceramic scaffolds for weight-bearing implants becomes impractical [25].

3.4. Tetracalcium Phosphate (TTCP)

In 1883, Hilgenstock introduced TTCP as tabular crystals, initially discovered as a constituent in the phosphorus-rich slag derived from the Thomas steel production process [26]. The Ca/P ratio of TTCP surpasses that of stoichiometric HA, making it a unique CP phase. To prevent its transformation into HA, this compound must either be rapidly cooled or dried [27]. In contrast to calcium orthophosphates, such as HA, which are widely used in the food industry, toothpaste formulations [28], pharmaceutical applications, and chromatography, pure-phase TTCP has predominantly found utility as a ceramic biomaterial. Conversely, particulate TTCP plays a pivotal role as a crucial component in self-setting bone cement. These cements undergo a continuous dissolution-precipitation process, ultimately forming HA. This article comprehensively examines the various methodologies for obtaining pure-phase TTCP, encompassing crystallographic and spectroscopic characteristics. It also explores TTCP’s applications in cements, coatings, and delves into its biological compatibility within the realm of TTCP-based bioceramics [29].

3.5. Dicalcium Phosphate Dehydrate

CP biomaterials have garnered significant attention in the field of bone repair due to their remarkable similarity in composition to natural bone. Among these biomaterials, dicalcium phosphate dihydrate, also known as brushite, stands out as a versatile CP biomaterial that can be fashioned into hydraulic cement suitable for a wide array of applications. Notably, brushite biomaterials possess the unique ability to facilitate bone regeneration while exhibiting a faster in vivo resorption rate compared to most other CPs. As a result, newly regenerated tissue gradually replaces the bioceramic. Although brushite initially resorbs after implantation, in vivo studies show that it tends to react with the surrounding environment, resulting in insoluble HA. This reaction significantly diminishes the rate at which the biomaterial is resorbed, thereby limiting its clinical utility [30]. Additionally, brushite bioceramics can shrink and lose their mechanical properties when subjected to thermal dehydration. Dehydration can be prevented from causing excessive shrinkage by maintaining high pressure and humidity. Autoclaving can be used to sterilize brushite cement, allowing the material to dehydrate into monetite without altering its macroscopic geometry. As a result of this approach, monetite bioceramics have been shown to enhance vertical bone augmentation and promote bone defect regeneration in animals and humans. In comparison with HA-based biomaterials, they can regenerate significantly more bone [31].

3.6. Dicalcium Phosphate Anhydrous (Monetite)

Monetite represents the anhydrous variation in brushite, serving as a valuable biomaterial for facilitating bone regeneration. The synthesis of Monetite bioceramics involves manipulating the precipitation conditions of brushite cement [32]. Alternatively, monetite bioceramics can be produced by subjecting already-formed brushite cements to thermal dehydration. However, bioceramics generated through this autoclaving method tend to exhibit reduced mechanical strength compared to their similar levels of cytotoxicity, as well as brushite precursors [33]. Despite this, monetite bioceramics produced by this process do not precipitate insoluble HA in vivo, release ions slowly, and resorb faster than brushite bioceramics [34].

3.7. Octacalcium Phosphate (OCP)

The salt called octacalcium phosphate is known for its role in forming apatite crystals in teeth and bones. OCP influences the development of intramembranous bone, as determined by spectroscopic analysis [35]. The osteoconductive properties of OCP were first demonstrated by implanting granules subperiosteally onto mice’s calvaria [36]. OCP granules have been shown to repair critical-sized bone defects. Furthermore, OCP coatings improve osteoconductivity more than the original surfaces of metallic implants [37,38]. OCP coatings have even induced bone growth in places not normally associated with bone growth [39]. Synthetic CP crystals, particularly OCP, are active bone builders. Synthetic OCP transforms into HA after implantation into bone defects [40]. When OCP is converted into HA, a physicochemical alteration occurs that may contribute to osteoconductivity [41]. Apatite deposition on biomaterial surfaces may facilitate osteoconductive characteristics; however, OCP appears to stimulate osteoblastic cells, thereby promoting bone formation, likely through apatite formation and conversion [42]. Synthetic OCP crystals have been demonstrated to promote osteoblast differentiation in murine bone marrow stromal cells. Moreover, osteoblasts and bone marrow-derived osteoclast precursor cells can induce the formation of osteoclasts [43]. Compared to several HA materials, OCP shows a superior ability to enhance bone formation in various experimentally created bone defects. As the implant period progresses, osteoclast-like cells biodegrade OCP, leading to the replacement of the material with newly formed bone [44].

3.8. HA with Low Crystallinity

Hydroxyapatite (HA), a widely investigated bioceramic in the field of bone tissue engineering, has garnered extensive research interest due to its chemical composition, which critically modulates osteoblast adhesion, proliferation, and subsequent bone regeneration processes [45]. Altering the surface structure and electrical charge of HA can enhance its performance in biological environments. However, pure HA is degradable, lacks mechanical strength, and is deficient in fracture toughness, rendering it incapable of forming complete bone masses and potentially increasing the risk of infection [46]. To address these limitations, efforts have been made to enhance the mechanical properties of HA. This has been achieved by incorporating ZrO₂, carbon fiber, and Al₂O₃ into HA [47]. Poly (lactic-co-glycolic acid) (PLGA) stands as one of the most frequently employed polymeric biomaterials due to its inherent biodegradability and general biocompatibility. A notable achievement in this field was realized by Yang et al., who utilized a 3DP technique to fabricate porous PLGA/HA scaffolds [48]. These scaffolds were then surface-grafted with quaternized chitosan to produce porous, bioactive HA/PLGA/hydroxypropyl trimethyl ammonium chloride chitosan (HACC) composite scaffolds. These composite scaffolds exhibit considerable potential for TE applications, particularly in the treatment of bone defects contaminated or infected, offering a reduced risk of bacterial resistance and bone infections. Moreover, a three-phase composite scaffold comprising nanocrystalline HA and carbon nanotube (CNT) has been developed via 3D printing techniques to stimulate bone regeneration. Higher CNT content in these scaffolds has been observed to enhance cell adhesion and cell spreading. The presence of CNTs has a direct positive impact on protein adsorption and indirectly promotes cell attachment, as demonstrated by Goncalves et al. [49]. It is essential to emphasize that despite numerous endeavors to overcome the shortcomings of HA composites, they continue to fall short of meeting the prerequisites for effective bone regeneration [50].

3.9. Biphasic CP

BCP ceramics exhibit enhanced osteoconduction, bioactivity, and biocompatibility when incorporating β-TCP and HA components, thus facilitating bone repair [51]. The mechanical and biological characteristics of HA can be finely tuned through the introduction of CP compositions, and this effect can be further amplified by combining HA with diverse CP compositions [52]. In comparison to HA or β-TCP scaffolds, BCP ceramic scaffolds presently demonstrate superior biocompatibility, reduced degradation rates, and heightened potential for promoting bone regeneration [53]. A study conducted by Zhao et al. explored the impact of total porosity, varying at three levels, and composition, spanning six levels, in scaffolds created through 3DP using HA/β-TCP. The research revealed that scaffolds with high porosity exhibited optimal cell proliferation, whereas those with low porosity were more conducive to osteogenic differentiation [54]. However, it is worth noting that BCP ceramics encounter challenges related to suboptimal sintering quality due to the significant difference in sintering temperatures between HA and β-TCP scaffolds. Additionally, BCP ceramics lack load-bearing capabilities due to their inferior mechanical properties [55]. Lei et al. published a paper in 2025 describing the use of osteoinductive biphasic calcium phosphate ceramics for the lifting of the maxillary sinuses. Compared with protein-deprived bovine bone mineral (DBBM), BCP stimulated osteoclastogenesis and induced bone formation in FVB/NCrl (FVB) mice and rabbit maxillary sinus lifts. In maxillary sinus lifts, BCP appears to be a promising bone substitute. Optimizing bone substitutes has become easier and more effective as a result of the current information. It is possible for biomaterials to be evaluated in vitro for osteoclastogenesis, to be followed up by bone formation following non-osseous implantation, and to be confirmed by bone regeneration in preclinical bone defects [56].

3.10. Calcium Silicate

Research into the application of CaSiO₃-based ceramics in bone repair has unveiled promising prospects. Similarly to calcium phosphate-based biomaterials—such as hydroxyapatite and β-tricalcium phosphate—that are well documented to exhibit strong apatite-forming ability in simulated body fluid (SBF), CaSiO₃-based ceramics have also demonstrated the capacity to interact with SBF and catalyze the formation of a carbonated hydroxyapatite (HA) layer. This surface reaction enables chemical bonding with bone tissue, thereby establishing a robust interface and enhancing osteointegration [57,58]. Xu et al. harnessed the potential of 3DP technology to craft homogeneous scaffolds using CaSiO₃, carefully controlling pore structures and achieving remarkable mechanical properties. The fabrication process for these CaSiO₃ scaffolds proved to be relatively straightforward, while they exhibited impressive compressive strength, satisfactory mineralization ability in SBF, and accelerated rates of bone defect healing. These findings suggest that 3D-printed CaSiO₃ scaffolds hold great promise for bone tissue regeneration [57,58]. Another noteworthy bioactive silicate ceramic, C₃S, boasts hydraulic properties and can naturally consolidate within aqueous environments. Yang et al. employed 3D printing techniques to create uniform and controllable 3D structures with C₃S ceramic scaffolds. Additionally, they successfully incorporated two model drugs into the scaffolds, affording precise control over their release profiles. Moreover, nano needle-structured surfaces were introduced to the C₃S ceramic scaffolds, significantly enhancing bone repair when compared to pure C₃S bone cement [59]. However, it is worth noting that ceramics derived from CaSiO₃ have a drawback in the form of rapid dissolution and degradation, resulting in elevated pH levels in the surrounding environment. This adverse effect has the potential to impede cell growth and weaken osseointegration, presenting a notable challenge in their practical application [60].

3.11. Bioactive Surface

3.11.1. Bioglass and Glass-Ceramics

A bioactive material is conventionally described as a substance that, when subjected to specific surface reactions both in laboratory settings and within living organisms, generates a layer akin to HA on the surface of host bone or graft material [61]. This capacity is not only referred to as osteostimulation but is also termed a physiological capability, as articulated by Schepers and Ducheyne. Recent research has unveiled the osteoinductive properties of BGs, demonstrating their ability to induce graft differentiation by facilitating the migration of osteoprogenitor cells into the graft’s structure [62,63]. By releasing therapeutic ions, such as silicates and calcium, bone cells can regenerate and repair themselves. One notable BG is 45S5 Bioglass^®, boasting a 50-year history, characterized by relatively low SiO₂ content, elevated levels of Na₂O and CaO, and a favorable CaO/P₂O₅ ratio that enhances reactivity with biological fluids [64]. Thus, this composition anchors the glass firmly to the bone by forming a nanocrystalline HA layer on its surface [65]. As a result of PerioGlas^®, epithelial cells do not grow downward as they regenerate alveolar bone [66]. In instances where significant mechanical strength and substantial graft material are required, BG particles have been incorporated into autologous materials for large infrabony defects [67]. Apatite-forming and bone-regenerating properties of borosilicate glasses have been demonstrated in recent studies using small animal models. The literature does not report any specific studies regarding the applicability of this approach to periodontal TE [68,69].

3.11.2. Bioactivity

As a result of their bioactivity, CP-based bioceramics can bind directly to bone tissue without inducing the formation of fibrous tissue. The biocompatibility of a substance is typically measured using simulated body fluids that contain similar ions to those found in blood plasma. Consequently, bioactive materials are those capable of expediting the crystallization of apatite in supersaturated solutions. In contrast, TCP demonstrates higher bioactivity owing to its faster degradation and superior osteoconductivity, while BCP provides an intermediate balance between stability and resorption. More advanced systems, such as calcium phosphate–silicate composites and nanostructured CP materials, exhibit significantly enhanced bioactivity, supporting both osteoinduction and angiogenesis. Moreover, the synergy between bioactive CP ceramics and bioactive glass (BG) can further augment the biological performance of these materials [70].

3.11.3. Biodegradability

The biodegradability of a scaffold material refers to its ability to break down naturally within a living organism. Biodegradable biomaterials are preferred for bone regeneration despite having greater strength than nondegradable ones. New bone is gradually formed as the scaffold degrades, and the mechanical load shifts from the scaffold to the newly formed bone. Various factors influence the in situ degradation rates of scaffolds, including design parameters such as chemical composition and structure, as well as environmental conditions such as the presence of blood vessels, temperature, tissue growth, ionic strength, enzyme activity, and mechanical stress, as well as acidity. Bioceramic scaffolds degrade at a relatively slow pace through mechanisms such as physicochemical degradation, cell-mediated degradation, or mechanical degradation. CP scaffolds, for example, exhibit a notably low rate of HA resorption, essentially rendering them practically nondegradable. In contrast, they demonstrate a relatively high rate of TCP degradation [71].

3.11.4. Porosity

The porosity of a defect site facilitates neovascularization, bone integration, and the infiltration of osteogenic cells. To mimic the hierarchical distribution of pore sizes in natural bone tissue, a scaffold should possess varying levels of porosity [72]. Researchers have yet to determine the optimal pore size for efficient bone regeneration, despite widespread recognition that pore size influences cell infiltration and new bone formation in bioceramic scaffolds. In general, cells are believed to be able to infiltrate pores with a diameter of 100 microns or less, while new bone can grow in pores with a diameter greater than 200 microns [73]. According to some studies, periodic microstructure scaffolds composed of HA should have pores between 300 and 400 μm to enhance bone formation [74]. Other studies have indicated that an optimal size lies within the range of 75 μm to 300 μm, with some suggesting a range of 100–500 μm [72,75]. Notably, studies have shown that pore sizes between 400 and 1200 μm have not yielded significant differences in in vivo experiments when applied to scaffolds with uniform and controlled pore distributions. Moreover, pore size also influences osteoconduction and vascularization within bone scaffolds [76]. In previous research, bone formation has been observed in interconnected micropores measuring less than 10 μm in scaffolds featuring both macropores and micropores. Consequently, microporosity is equally essential for bone integration into scaffolds [77].

4. The Role of Calcium Phosphate in Osteogenesis

As a result of hypertrophic calcification of chondrocytes (endochondral osteogenesis), the cartilage layer of bone cartilage tissue engineering scaffolds should degrade more rapidly than the subchondral bone layer due to the hypertrophic calcification of chondrocytes in subchondral bone regeneration scaffolds [78,79]. To remodel bone, osteoclasts and osteoblasts collaborate: osteoclasts become active first, resorbing bone, and osteoblasts absorb the old bone by direct contact. In addition to secreting growth factors, it also recruits, proliferates, and differentiates osteoprogenitor cells, thereby promoting the osteogenic process. By inhibiting osteoclastogenesis, osteogenesis is also inhibited, since osteoclasts are key cells in bone remodeling. As part of material-induced osteogenesis, osteoclasts also play a role. Osteoinductivity affects osteoclastogenesis, and osteoclast activity determines the amount of new bone formed [78,80]. Ceramics have osteoinductive properties that are closely related to their immunomodulatory properties, particularly their ability to regulate macrophage polarization and function. Depending on the phase composition, calcium phosphate has different osteoinductive capabilities through its ability to regulate macrophage polarization and function [78,81].

Calcium phosphate (CP) candidates offer several potential advantages in the repair of maxillomandibular bone defects. Their chemical composition closely resembles that of the mineral phase in natural bone, ensuring excellent biocompatibility and osteoconductivity, which promotes cell adhesion, proliferation, and new bone formation. CP materials are also bioactive, capable of forming a direct bond with host bone, which enhances integration and long-term stability. In addition, they are available in various forms, such as granules, cements, scaffolds, and coatings, allowing clinicians to tailor their use according to the specific defect site. Certain CP types, such as β-tricalcium phosphate, are resorbable and can gradually be replaced by newly formed bone tissue. Furthermore, their low immunogenicity minimizes the risk of adverse immune responses compared with allogenic or xenogenic grafts [82,83,84,85,86].

Despite these benefits, CP candidates also have notable disadvantages. They exhibit brittleness and low mechanical strength, which limit their application in load-bearing regions of the maxillomandibular complex unless combined with reinforcing agents. Their resorption rates can also be unpredictable—some degrade too rapidly, compromising structural stability, while others persist excessively, interfering with normal bone remodeling. Handling can be challenging, as injectable or paste forms sometimes lack cohesion and stability in large defects. Moreover, CPs generally lack intrinsic osteoinductive properties, requiring the incorporation of growth factors or stem cells to enhance their regenerative potential. Finally, their porous structures, while beneficial for cell infiltration, may increase susceptibility to bacterial colonization if not carefully managed [87,88,89,90].

5. Bioceramics for Bone Tissue Regeneration in Clinical Trials

Calcium phosphate (CP) biomaterials, particularly HA and β-TCP, have been extensively investigated for their role in craniofacial and maxillomandibular bone regeneration due to their chemical similarity to the mineral component of bone. Several clinical trials have evaluated their safety and efficacy in maxillofacial applications. For instance, randomized controlled trials have demonstrated that β-TCP and biphasic calcium phosphate (BCP) grafts promote new bone formation in alveolar ridge preservation and sinus floor augmentation procedures, achieving outcomes comparable to autogenous bone grafts but with reduced donor site morbidity [91,92,93].

A prospective clinical study also reported that injectable calcium phosphate cements provide stable space maintenance and support bone healing in mandibular cystic cavity defects, with satisfactory radiographic bone density and minimal complications. Additionally, hydroxyapatite-based composites have demonstrated promising results in the treatment of large mandibular defects, with gradual resorption and replacement by host bone over time. A multicenter trial further confirmed the long-term biocompatibility of CP scaffolds in craniofacial reconstruction, highlighting their osteoconductive potential and capacity for integration with surrounding tissues [94,95,96,97,98].

Collectively, these clinical investigations suggest that calcium phosphate biomaterials represent a viable alternative or adjunct to autologous bone in the repair of maxillomandibular defects, offering predictable bone regeneration, excellent biocompatibility, and avoidance of donor site morbidity. However, further well-designed randomized clinical trials with larger sample sizes and long-term follow-up are needed to establish standardized protocols and confirm their superiority over conventional grafting approaches [92,99,100,101].

The goal of a human clinical trial is to assess the safety and efficacy of a therapeutic approach, treatment, or device for use in humans. Ethical health committees approve these trials only after they adhere to strict scientific standards. These standards are meticulously crafted to safeguard patient well-being and ensure the production of reliable research findings. The journey towards obtaining these results is a thorough and meticulous process that commences in the laboratory, progresses through animal testing, and culminates in clinical trials [102]. Implantable medical devices undergo a rigorous, extensive, and highly detailed development process before they can be brought to market. This process is carried out under strict guidance from the Food and Drug Administration (FDA). Throughout this journey, the safety of the medical device is rigorously examined and substantiated through scientific evidence. After approval, these devices are categorized based on their associated risk level. For example, fracture fixation devices fall into the medium-risk Class II category, while devices used for organ replacement are classified as high-risk Class III devices [102]. The Bioroot^® RCS (a hydraulic sealer) sealant falls under the category of bioactive sealants. In contrast to bioceramic sealers, bioactive sealants have shown remarkable biocompatibility [103,104].

Bioceramic sealers consistently demonstrated superiority. Research has indicated that enlarging the apical foramen enhances periapical healing, as it facilitates the disinfection of the root canal system in the apical third [105,106,107]. However, the recent literature suggests that excessive enlargement of the foramen can compromise the apical seal. This can result in the overextension of obturating material, impeding the process of periapical healing. Some instances of spontaneous widening of the apical foramen can be attributed to unintentional sealer extrusion. Consequently, bioceramics and bioactive sealants play a crucial role in minimizing acute inflammatory responses and expediting periapical healing. In a study conducted by Li et al., the use of angioconductive bioceramic rod grafting, combined with autologous bone marrow buffy coat (BBC), was evaluated for the treatment of early avascular necrosis of the femoral head (ANFH). ANFH treated with autologous bone marrow buffy coat and/or angioconductive bone marrow buffy coat was found to be effectively treated with angioconductive bioceramic rod grafts and advanced core decompression [108]. Gomez-Barrena and colleagues evaluated whether delayed unions and nonunions of long bones healed effectively. The bioceramic granules were surrounded by bone formation, as indicated by bone biopsies. However, non-unions in the tibia showed a delay in consolidation. Women and men did not consolidate at significantly different rates over the past 12 months based on a 95% confidence level. In the six and twelve-month consolidation scales, nonsmokers exhibited higher values. It did not take much time after the initial fracture for consolidation to occur [109]. In a split-mouth randomized clinical study, de Almeida Malzoni investigated the performance of personalized bioceramic bone grafts for augmenting bone in the atrophic anterior maxilla, comparing them to autogenous bone grafts. The study highlighted the advantages of additive manufacturing in producing medical devices, particularly in terms of precise geometry and anatomical fit. Additionally, the osteoconductive properties of β-TCP make this synthetic bone substitute a viable alternative to autogenous grafts for reconstructing bone defects. Consequently, patient-specific bone grafts have the potential to enhance patient satisfaction and reduce the need for autogenous bone grafts, thereby avoiding associated treatment complications and patient morbidity [110]. An oral bone defect larger than 1 mm was studied by Han et al. Each patient was randomly assigned to a control or observation group. Oral bone defects were evaluated and compared. Injectable bioactive glass demonstrated superior efficacy over hydroxyapatite bioceramics in restoring oral bone defects [111]. HA-coated, BG-coated, and machined titanium alloy threaded dental implants were evaluated by Mistry et al. for their clinical outcomes (specifically, osseointegration). According to their findings, bioactive glass (BG) coatings are a viable alternative to HA coatings and machined titanium implants for achieving osseointegration [112].

In a study conducted by Akhlaghi et al. (2019), Human amniotic membranes (HAMs) loaded with buccal fat pad stem cells (BFSCs) were found to be capable of stabilizing bone grafts in maxillomandibular defects. Study participants included nine patients with jawbone defects. The study included two groups of patients: five received ham-covered iliac crest bone grafts, while four received bone grafts loaded with BFSC. Using cone beam computed tomography, radiomorphometric changes were evaluated five months after grafting. HAM + BFSCs and HAM + BFSCs groups demonstrated significant differences in bone width increases. Vertical dimensions also changed more rapidly for HAM + BFSCs. It is possible to enhance bone regeneration in the horizontal dimension by combining HAM and mesenchymal stem cells. Furthermore, this methodology reduces the need for autogenous bone harvesting and reduces secondary bone resorption [113]. Schulz et al.’s case presentation (2023) demonstrated that three-dimensional calcium phosphate cement scaffolds can be used for sinus grafting. It was necessary to perform oral rehabilitation for a patient whose posterior maxillae were atrophied on both sides and whose anterior dentition was partially absent. Based on cone beam computerized tomographies (CBCT) imaging, residual bone height was one to two millimeters. CBCT data were reconstructed in three dimensions to determine the optimal placement of the implants. Using calcium phosphate cement paste, three-dimensional scaffolds were printed according to the topography of the sinus. An overview of the workflow is presented in Figure 2, which illustrates the use of printed scaffolds with interconnecting porosity to augment the bilateral sinus floor. A successful integration of the scaffolds was achieved nine months later. As a result of the re-entry, vital bone appeared to have an adequate blood supply. There is the possibility of implanting one implant at positions 16 and 26. In five months, the implants were exposed, and a temporary denture was provided. For grafting the severely atrophied posterior maxilla, a three-dimensionally printed scaffold made from calcium phosphate cement paste appears to be promising [84].

Clinical trial results showed that octacalcium phosphate and its collagen composite were effective for bone augmentation during major oral and maxillofacial surgery, as reported in Kawai et al. (2020). A composite of octacalcium phosphate and collagen was used to elevate sinus floors in one- and two-stage procedures, as well as to preserve sockets, treat cysts, and close alveolar clefts. Following the implantation of octacalcium phosphate and its collagen composite, 60 patients were evaluated for effectiveness. Despite sinus floor elevation meeting the criteria for the initial evaluation in cases involving one-stage procedures, cysts, or alveolar clefts, the same did not hold true for the two-stage and socket preservation groups. In those groups, an additional evaluation for confirmation revealed the effectiveness of octacalcium phosphate and its collagen composite, leading to the success of the clinical trial. As a result of this clinical trial, it has been demonstrated that octacalcium phosphate and its collagen composite can be used to replace autologous bone during oral and maxillofacial surgery with safety and effectiveness [85]. Some current studies are summarized in

Table 1. The current clinical trials of bioceramics in bone regeneration.

Biomaterial	Date and Status (Follow-Up)	Method	Ages (Years)	Results	Ref
β-TCP	from 2015 to 2020	ABC and ABR grafts with ACD will be evaluated for the effects of early ANFH.	18–60	Autologous bone marrow buffy coats and bioceramic rods, combined with advanced core decompression, are effective treatments for early ANFH.	[108]
biphasic calcium phosphate (BCP)	6-month	The study compared biphasic calcium phosphate (BCP) in two forms: granules and paste, as well as histomorphometric measurements and osteocalcin immunolabeling.	52 to 64 years	Bone calcification was demonstrated in both groups by immunolabeling for osteocalcin. Implant placement with both biomaterials, therefore, presents satisfactory results.	[3]
HA/β-TCP + collagen	9 months	Fifty-seven extraction sockets were located in the posterior regions of the mandibles and maxillas of 51 patients. HA/β-TCP + collagen was inserted into all dental sockets and covered with flaps immediately after extraction. The patient was followed up three months after extraction with radiographs and stents.	20 and 89 years	After three months, bone height was maintained, indicating good performance of the HA/β-TCP + collagen graft.	[5]
bioactive calcium-phosphate (CP) coating	12-month	Using dental implants coated with bioactive calcium-phosphate (CP) in partially edentulous patients with varied clinical indications, this study evaluated the outcomes early after early and delayed prosthetic loading.	41.44 years (18–62 years)	Study implants with CP coating performed better than conventional implants without a specific coating after 1 year of use. A one-year evaluation of implants coated with CP was not possible. The long-term effects require further study.	[114]
HA and ß-TCP	12-month	Clinical and radiological evaluation of the effectiveness of long bone consolidation in healing delayed unions and non-unions	39 ± 13 years	Following surgery, biopsies confirmed bone formation surrounding the bioceramic granules with expanded MSCs attached.	[109]
β-TCP	8 months	compare the performance of an alloplastic graft, Plenum® Oss 3Dβ fit, a 3D- β-TCP to autograft.	over 18	Using this synthetic bone substitute to repair bone defects poses an alternative to using autogenous bone grafts due to its osteoconductive properties.	[110]
Porous HA	6.5 years follow-up	A new TE approach was used to treat patients with large diaphysis defects and inadequate therapeutic alternatives. In culture, cells were expanded on HA ceramic scaffolds that matched the size and shape of the bone deficit.	16–41	Porous bioceramics combined with culture-expanded osteoprogenitor cells reduced critical-sized defects in long bones significantly.	[115]
β-TCP	followed up for 42 to 48 (44.62  ±  1.81) months	A comparison can be made between four groups that received different types of bone grafts at various times.		Bioceramics grafts have shorter operation times and less blood loss than other bone grafts. Early treatment of osteonecrosis of the femoral head may involve this bone graft.	[116]
HA and BG	6-month and 12-month following treatment	Analyze how oral bone defects heal.		As compared to HA bioceramics, injectable BG performed better in restoring oral bone defects.	[111]
calcium sulfate and HA	18-month follow-up	Partially resorbable calcium sulfate and HA composite: effectiveness and safety.	over 50 years	When osteoporotic patients with vertebral compression fractures experience sustained pain relief for 18 months, fracture healing can occur.	[117]
HA/BG	12-month follow-up	In the human jawbone, evaluate the clinical outcome of titanium alloy threaded dental implants with HA coating, BG coating, and machined titanium alloy coating.	18–58 years	As an alternative coating material for dental implants, BG-coated implants can achieve osseointegration just as effectively as HA-coated and machined titanium implants.	[112]

.

6. Future Directions

Calcium phosphate (CP)-based bioceramics have played a crucial role in the field of maxillomandibular bone regeneration. Despite their widespread use and demonstrated clinical potential, several limitations still hinder their full efficacy, particularly in load-bearing applications. Emerging strategies in materials science, bioengineering, and regenerative medicine are now shaping a promising future for CP-based technologies. Key directions include enhancing mechanical strength, improving bioactivity, modulating immune responses, and advancing the fabrication of personalized and multifunctional scaffolds. A major challenge of CP ceramics, especially hydroxyapatite (HA), tricalcium phosphate (TCP), and biphasic calcium phosphate (BCP), is their brittleness and low fracture resistance, which limits their use in areas subject to mechanical stress, such as the mandible. Innovative approaches are being explored to overcome this issue, including nanoengineering, which involves developing nanocomposites that incorporate nanoparticles such as graphene oxide, carbon nanotubes, or bioactive glass to enhance fracture toughness. Biomimetic gradient scaffolds: Mimicking the natural gradient structure of bone to improve mechanical and biological integration. Although growth factors (GFs) such as VEGF, BMP-2, and PDGF have strong osteogenic potential, challenges like burst Release and poor timing reduce clinical effectiveness. Advanced delivery systems are being developed. Layered scaffold coatings enable the timed release of angiogenic and osteogenic factors. Microsphere encapsulation: Embedding core–shell microspheres within scaffolds allows precise control over Release kinetics. Synergistic platforms: Combining bioactive ions (e.g., Sr²⁺, Mg²⁺, Si⁴⁺) with GFs to enhance stem cell differentiation and vascularization.

Recent evidence suggests that immune responses have a significant impact on bone healing. Modifying CP scaffolds to promote anti-inflammatory (M2 macrophage) activity is gaining attention: Immune-informed biomaterials: Tailoring surface properties to influence immune cell behavior through Toll-like receptor signaling. Anti-inflammatory loading: Embedding agents that regulate NF-κB or MAPK pathways can help reduce chronic inflammation. Immune interaction assays: Creating in vitro models to monitor real-time interactions between biomaterials and immune cells. Additive manufacturing is enabling unprecedented personalization in scaffold design: Anatomical fit: Using CT/MRI data to print scaffolds that match patient-specific defects. Multi-material bioprinting: Simultaneous deposition of CPs, stem cells, and hydrogels enables the creation of complex, functional tissue constructs. In situ printing: Direct printing onto defect sites offers a minimally invasive alternative and improves tissue integration. Additionally, vascular networks can be embedded to support tissue perfusion and long-term viability.

Calcium phosphate scaffolds act as carriers for various stem cells, including BM-MSCs, ADMSCs, and periosteum-derived cells. Future strategies aim to improve cell–material interaction by functionalizing scaffolds with extracellular matrix (ECM) proteins, RGD peptides, or mechanical signals to enhance cell behavior. Genetic modification: Preconditioning stem cells to overexpress osteogenic genes. Priming strategies: Using molecules or environmental conditioning to direct stem cells towards an osteogenic lineage before implantation. Matching scaffold degradation rates to new bone growth is essential. Innovations include Tuned degradation, achieved by using metal ion doping (e.g., Sr, Zn) and adjusting CP ratios to fine-tune resorption. Real-time monitoring: Adding contrast agents to scaffolds for CT or MRI tracking of degradation and bone formation. Self-healing scaffolds: Materials capable of releasing reparative agents upon microfracture could revolutionize the durability of scaffolds. Improving implant integration with bone is vital. CP-based coatings on implants can be enhanced with Multifunctional additives, such as incorporating antimicrobial peptides, anti-inflammatory drugs, and GFs into coatings. Nanotopographic surfaces: Mimicking the natural bone ECM to promote cell attachment and proliferation. Hybrid coatings: Combining HA, bioactive glass, and polymers to achieve both mechanical strength and biological functionality. Beyond CPs, materials like borosilicate glasses, zirconia-toughened ceramics, and polymer composites are emerging. Their development includes Boron doping, which promotes both vascularization and bone formation. Hybridization: Integrating bioinert ceramics like ZrO₂ or Al₂O₃ with CPs for stronger yet bioactive composites. Self-assembling nanocomposites: Replicating bone’s nanostructure for more effective regeneration. Despite promising lab results, clinical translation remains limited. Future efforts must standardize preclinical models and protocols to enhance data reproducibility and streamline regulatory pathways for personalized and 3D-printed implants. Additionally, they should evaluate cost-effectiveness using economic models and health assessments. Multidisciplinary collaboration among engineers, clinicians, and regulatory bodies will be key to success. CP bioceramics are now being explored for broader regenerative uses, such as dental pulp regeneration, where injectable CP pastes are combined with stem cells and GFs. Soft tissue repair: CP materials functionalized with elastin or collagen. Drug delivery: CPs as biodegradable carriers for antibiotics, cancer drugs, or hormones.

7. Limitations

While calcium phosphate (CP)-based bioceramics and their composites demonstrate considerable promise for maxillomandibular bone regeneration, several important limitations and challenges must be acknowledged.

Mechanical Fragility: HA and TCP are brittle with low fracture toughness. They are suitable mainly for non-load-bearing sites. Composite approaches can improve strength but remain weaker than natural cortical bone.

Degradability and Resorption: HA is nearly nondegradable, limiting scaffold remodeling. TCP shows variable resorption (α-TCP vs. β-TCP) influenced by porosity, pH, and tissue interactions, resulting in unpredictable clinical outcomes.

Ion Release and Local pH Changes: The rapid degradation of certain CPs, such as calcium silicate and α-TCP, can elevate local pH, potentially impairing cell activity, osseointegration, and tissue healing.

Manufacturing Challenges: Differences in sintering temperatures between HA and β-TCP can lead to inconsistent microstructures. Three-dimensional printing and composite fabrication require strict parameter control, limiting reproducibility.

Pore Architecture Variability: Porosity is crucial for vascularization, osteoconduction, and cell infiltration. Interconnected pores improve nutrient diffusion but often compromise mechanical integrity.

Immunological and Inflammatory Responses: Surface interactions with the immune system can induce inflammation or the formation of fibrous tissue. Long-term safety data, especially for nanostructured or drug-loaded scaffolds, remain insufficient.

Limited Long-Term Clinical Data and Regulatory Hurdles: Despite the abundance of preclinical research, there is a relative paucity of long-term randomized controlled trials (RCTs) evaluating CP-based biomaterials in maxillomandibular applications. Most clinical studies remain in early phases or involve small sample sizes and short follow-up durations. Regulatory approval is challenging due to the variability in composite materials, the incorporation of biologics, and the evolving use of manufacturing techniques such as 3D printing.

Incomplete Understanding of Osteoinductive Mechanisms: Although CPs are recognized for their osteoconductive and, in some cases, osteoinductive properties, the molecular mechanisms driving these effects remain only partially understood. Parameters such as surface roughness, crystallinity, and ion substitution are known to play roles, but their precise interplay in vivo remains under investigation. This knowledge gap hinders the rational design and optimization of scaffolds.

8. Conclusions

The future of calcium phosphate-based bioceramics, including hydroxyapatite, β-tricalcium phosphate, and biphasic calcium phosphate, for maxillomandibular bone regeneration is promising, supported by extensive research and technological advancements. These materials have demonstrated excellent bioactivity, osteoconductivity, and controlled resorption rates, which can be further enhanced by combining them with bioactive glasses or natural polymers to improve mechanical strength and immunomodulatory responses. Advances in 3D printing and patient-specific scaffold design enable tailored treatments that precisely match defect geometry and individual patient needs. Continued efforts in translational research, clinical trials, and regulatory harmonization will be essential to fully realize the therapeutic potential of these specific biomaterials in maxillomandibular reconstruction.