INTRODUCTION
Accidents, surgical excision of benign or malignant lesions, congenital anomalies, periodontal inflammation, dental abscesses or extractions, and jaw atrophy due to age or systemic diseases are common causes of bone defects [1,2]. Alveolar bone defects can alter the shape and dimensions of the alveolar ridge, presenting challenges for patients seeking dental implants or removable prostheses, as well as resulting in aesthetic and masticatory issues [3]. Currently, various methods—including bone grafting—have been developed to address bone resorption and defects [1-3].
The ideal bone graft material should be biocompatible and possess characteristics similar to native bone. The choice of graft material—whether autogenous, allogenic, xenogenic, or synthetic—is crucial for achieving optimal outcomes and longterm success in bone regeneration [4,5]. Numerous bone substitute biomaterials are now available, each with unique properties. For example, synthetic grafts may utilize hydroxyapatite derived from marine coral [5]. Selection of the optimal graft depends on several factors, including material availability, size, shape, and volume of the graft, defect dimensions and biome-chanics, handling properties, cost, ethical considerations, biological behavior, and potential complications [5,6].
Structurally and chemically, hydroxyapatite is the principal mineral in human teeth and bones. It is notable for its biocompatibility, bioactivity, and its strong capacity to facilitate osseointegration with bone. The use of coral-derived hydroxyapatite continues to demonstrate significant potential in enhancing osteoconduction and osseointegration, making it a promising candidate for future regenerative medicine applications. Commercial synthetic hydroxyapatite powders can be produced from corals using a variety of methods, such as hydrothermal processing, solid-state reactions, sol-gel techniques, emulsions, microemulsions, and most commonly, chemical precipitation due to its simplicity and cost-effectiveness [7,8]. The aim of this paper was to review the potential application of coral-derived hydroxyapatite as a bone substitute.
METHODS
This study employed a systematic literature review to analyze and synthesize current scientific evidence regarding the potential of coral-derived hydroxyapatite as a bone replacement material. This approach was selected to provide a comprehensive overview of research advances in this field and to identify existing knowledge gaps. The literature search was guided by systematic review and meta-analysis reports following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [9]. Five electronic databases were utilized: PubMed, Embase, ScienceDirect, Web of Science, and Google Scholar. The publication period was restricted to the last 10 years (2014–2024) to ensure the relevance and novelty of the information. Keyword combinations included: “coral hydroxyapatite,” “bone substitute,” “bone tissue engineering,” “marine biomaterial,” “bone graft,” “osteoconductive,” “osteoinductive,” “bone regeneration,” and “sea coral.”
The inclusion criteria were as follows: (1) original research articles and reviews published in English or Indonesian; (2) studies specifically addressing coral-derived hydroxyapatite; (3) studies examining the application of coral hydroxyapatite as a bone replacement material; and (4) studies reporting on physicochemical properties, biocompatibility, or clinical performance of the material. Exclusion criteria included: (1) studies focusing solely on synthetic hydroxyapatite without any coral component; (2) single case reports; (3) articles that could not be fully accessed; and (4) non-scientific literature. Themes for this systematic review were organized using the PICO (Population, Intervention, Comparison, Outcome) framework, as shown in Table 1 [10].
The selection process was conducted in two stages. The first stage involved screening titles and abstracts to eliminate irrelevant articles. The second stage consisted of a full-text review to determine eligibility for inclusion. Article selection was performed independently by two researchers, and any disagreements were resolved through consensus discussion. Data extracted from each study included: (1) bibliographic information; (2) study characteristics; (3) hydroxyapatite synthesis methodology; (4) physicochemical properties of the material; (5) biocompatibility test results; (6) bone regeneration performance; and (7) potential clinical applications. The methodological quality of each study was evaluated using a risk of bias assessment tool appropriate to the study design. For laboratory experimental studies, modified SYRCLE criteria were applied, while for clinical trials, the Cochrane Risk of Bias Tool was used.
Data were analyzed narratively and thematically, based on the following aspects: (1) methods for synthesizing hydroxyapatite from coral; (2) structural and compositional characteristics; (3) osteoconductive and osteoinductive properties; (4) biocompatibility and biodegradability; (5) clinical applications and outcomes; and (6) comparisons with other bone substitute materials. This research did not involve human or animal subjects; however, attention was given to environmental sustainability by discussing approaches to the responsible use of corals as a biomaterial source.
RESULTS
The article identification process yielded 309 articles, from which a total of 15 articles met the inclusion and exclusion criteria following screening for eligibility (Fig. 1). Data and findings from each selected article are presented and organized in Table 2 [8,11-14].
A systematic review of the literature regarding the potential of coral hydroxyapatite as a bone substitute produced significant findings on the effectiveness, safety, and clinical prospects of this material. Analysis of recent scientific publications has en-abled the summary and evaluation of key data, providing a comprehensive understanding of this topic (Table 2).
Nandi et al. [11] investigated the effect of IGF-1 and BMP-2 impregnation on in vivo bone regeneration using hydrothermally converted coralline hydroxyapatite scaffolds in 24 rabbits. The results indicated that loading the converted coral scaffold with growth factors significantly accelerated early-stage bone formation, with IGF-1 found to be more effective than BMP-2. These findings enhance the potential application of converted hydroxyapatite coral for bone tissue engineering.
Siswanto et al. [8] concluded that the calcium hydroxide concentration producing the most optimal hydroxyapatite is 0.85 M. Based on the percentages of hydroxyapatite formation and crystallinity, samples with calcium hydroxide concentrations of 0.6 M and 0.85 M are promising candidates for bone replacement.
Karacan et al. [12] reported that scanning electron microscopy analysis of Millepora dichotoma coral, after conversion, revealed both large and small pores, encompassing micro-, nano-, and mesopores within its structure. The pore sizes were deemed suitable for osteoid growth, making the coral useful for bone graft applications. Importantly, the interconnected micropore structure of coralline hydroxyapatite is maintained, which may facilitate osteointegration after implantation. Additionally, this structure can function as a drug delivery system for surgery-related infections, as it enables the controlled release of gentamicin at the surgical site [12].
Mohan et al. [13] found that hydroxyapatite scaffolds prepared from calcium carbonate (calcite) precursors that mimic natural corals—using a hydrothermal exchange reaction in an alkaline ammonium phosphate solution—yielded porous bodies subsequently converted to hydroxyapatite under optimized conditions. The resulting material displayed a highly crystalline morphology with nacre-like, stacked hydroxyapatite crystals arranged to form micropores, providing the scaffold with a high surface area.
Fendi et al. [14] suggested that the use of three-dimensional printing technology represents an innovation in the fabrication of hydroxyapatite-based scaffolds, offering the advantage of personalized bone regeneration. Furthermore, natural hydroxyapatite was observed to possess superior scaffolding capacity compared to synthetic alternatives.
Physicochemical characteristics of hydroxyapatite from coral
Physicochemical evaluation of hydroxyapatite derived from coral demonstrated promising results. This material possesses both macroporous and microporous structures, closely resembling the architecture of human bone and making it highly suitable for bone regeneration applications. X-ray diffraction analysis confirmed that coral contains a very high concentration of calcium carbonate (97.69%), exceeding that of other natural calcium sources such as clam shells (87.12%), eggshells (89.98%), and snail shells (68.7%). The conversion of calcium carbonate to hydroxyapatite successfully retains the porous structure while enhancing mechanical stability and reducing the resorption rate. Microscopic analysis revealed that hydroxyapatite from coral has pore sizes in the range of 100–500 μm, which is ideal for vascularization and bone cell growth. This interconnected porosity supports nutrient flow and cell migration, both critical for effective bone regeneration [7,8,15].
Biocompatibility and osteogenic properties
Recent studies have demonstrated that hydroxyapatite derived from coral exhibits excellent biocompatibility with human bone tissue. In vitro cytotoxicity tests showed no significant toxic effects on osteoblasts or mesenchymal stem cells. On the contrary, the material promotes the attachment, proliferation, and differentiation of bone-forming cells. Regarding osteogenesis, coral hydroxyapatite shows outstanding osteoconductive properties, providing a scaffold for new bone growth. Notably, some studies have reported osteoinductive capabilities, with the material able to stimulate mesenchymal stem cells to differentiate into boneforming cells even in the absence of added growth factors [4,5].
Clinical data from recent research
Several recent clinical studies have evaluated the effectiveness of hydroxyapatite derived from coral in various bone reconstruction applications. The following summarizes data from two significant studies published between 2020 and 2025.
First research: application in craniofacial bone defect reconstruction
Hurley et al. [2] conducted a prospective study of 45 patients with craniofacial bone defects reconstructed using coral hydroxyapatite. Patients were followed for 24 months, with periodic radiographic and clinical evaluations. The data demonstrated a progressive increase in material integration and new bone formation throughout the observation period (Table 3). The low and decreasing complication rate indicated that the material achieved greater integration with host tissue over time. Gradual material resorption provided space for new bone growth, thereby achieving an optimal balance between material degradation and bone regeneration [2].
Second study: comparison with alternative bone replacement materials
Urban et al. [16] performed a controlled clinical trial comparing hydroxyapatite from coral with a standard bone substitute material in pre-implant alveolar bone augmentation procedures in 60 patients. The results demonstrated the superiority of coral hydroxyapatite in terms of increased bone thickness, new bone density, and implantation success rate. Additionally, the shorter healing time was a significant advantage, enabling faster patient rehabilitation. The minimal inflammatory response further demonstrated the superior biocompatibility of this material.
DISCUSSION
Bone healing mechanism
Bone defects can be congenital, developmental, acquired, traumatic, or surgical, often involving the oral cavity and its associated anatomical structures. Several reliable reconstructive techniques are available, and very few bone defects cannot be repaired. However, reconstruction remains an optional treatment and requires significant time, financial resources, and commitment from both the patient and the surgeon [17,18].
When the body cannot repair a fracture, the bones fail to unite. According to the Food and Drug Administration, a fracture nonunion is defined as a fracture that persists for 9 months without any signs of healing for three consecutive months. The type of nonunion that occurs determines the appropriate treatment approach. Excessive mobility at the fracture site can result in hypertrophic nonunion. In such cases, the bone retains its biological healing capacity, but excessive movement prevents bridging, and the fracture does not heal. Treatment for hypertrophic nonunion involves providing mechanical stability via internal fixation. Atrophic nonunion occurs when the biological environment is unfavorable for healing, such as insufficient blood flow or inadequate bone stability. Management of atrophic nonunion requires addressing both mechanical stability and bone biology [18,19].
Bone malunion occurs when a fracture heals in a misaligned position. It is characterized by bone shortening, angular deformity, or rotation greater than 5°. Depending on the clinical scenario, treatment of malunion may involve bone fixation, osteotomy, or bone grafting [19].
Types and sources of bone graft materials
Bone is a specialized mineralized tissue that provides structural support and contributes to calcium homeostasis. It is composed of inorganic minerals and organic matrix, and contains cells responsible for continuous bone formation and resorption as part of bone remodeling. Tumors—such as malignancies, cysts, or benign lesions—that lead to bone deficiency may also necessitate bone grafting [1,2].
Bone graft materials can be broadly classified according to their origin. Natural bone grafts and substitute materials include autografts, isografts, allografts, and xenografts. Autografts are harvested directly from the patient and have no antigenic properties because the donor and recipient are the same individual. Isografts are obtained from a genetically identical individual, such as a twin, and therefore share identical antigenic characteristics. Allografts are taken from another member of the same species, with their antigenic components removed or modified to reduce immune reactions. Xenografts, on the other hand, are derived from a different species. In addition to these natural sources, synthetic biomaterial substitutes have been developed to resemble native bone tissue and are widely used in clinical practice (Fig. 2) [1,5].
Hydroxyapatite from corals: advantages and challenges
Mechanical properties of scaffolds intended for bone regeneration are critical, as the biomaterial must be sufficiently strong for in vivo mechanical functionality and manageable for surgical handling. Integration of the graft at the recipient site involves inflammation, revascularization, osteoinduction, osteoconduction, and remodeling [1].
Bone graft materials must meet specific criteria for optimal performance: (1) unlimited availability without donor site morbidity; (2) promotion of osteogenesis; (3) absence of host immune response; (4) rapid revascularization; (5) stimulation of osteoinduction; (6) enhancement of osteoconduction; and (7) complete replacement by new bone, matching the host tissue in quantity and quality [2].
Bone regeneration is a primary research focus for craniofacial and orthopedic surgeons. To promote bone regeneration, a bone graft should provide three key features: (1) osteoprogenitor mesenchymal cells, or even viable osteoblasts; (2) growth factors conducive to regeneration; (3) a scaffold capable of supporting mechanical cell adhesion, promoting growth and proliferation [1,7].
Over the past 50 years, extensive research has focused on biomaterials for bone grafts derived from mineralized marine organisms. Some marine creatures possess anatomical mineralized structures similar to human bone. Among these, corals are among the most widely investigated marine-derived biomaterials in bone tissue engineering. Corals possess an interconnected porous structure that permits vascularization, and their porosity range (100–500 μm) closely matches the morphology of human bone (Table 4) [12].
Types of corals as a source of hydroxyapatite for bone grafts
Coral reefs comprise a variety of genera with distinct structural characteristics, making some species more suitable than others as sources of hydroxyapatite for bone graft applications. Comprehensive analyses of porosity, structural connectivity, and mineral composition indicate that not all corals are equally effective for bone regeneration. Among the genera studied, Goniopora, Porites, and Acropora have emerged as the most promising candidates [19]. The genus Porites is particularly notable for its structural resemblance to human trabecular bone, displaying an interconnected porous architecture with pore diameters of 100–250 μm and a porosity of 60%–70%. This configuration significantly enhances cell migration, vascularization, and osteoconductivity. Microstructural studies have shown that Porites lutea and Porites lobata possess the most optimal pore distributions for osteoblast penetration and new bone tissue growth [20].
The Acropora genus, especially Acropora cervicornis and Acropora palmata, exhibits higher structural density, with porosity around 45% to 55%, making these species well-suited for applications requiring increased mechanical strength. Hydroxyapatite scaffolds produced from these corals achieve superior compressive resistance, ranging from 5 to 8 MPa after hydrothermal conversion, which is comparable to the values found in human cancellous bone. In contrast, Goniopora species are characterized by larger macropores (250–500 μm) with high interconnectivity, resulting in hydroxyapatite that is highly conducive to vascular network formation [14].
Differences in mineral composition among coral genera also significantly affect the quality of hydroxyapatite produced. Spectroscopic analysis has shown that Porites achieves a calcium-to-phosphorus ratio closer to that of human bone (1.67) after hydrothermal conversion, compared to other genera. Moreover, histological studies demonstrate that hydroxyapatite scaffolds from Porites induce more robust osteoblast responses, with faster extracellular matrix synthesis and more extensive mineralization [21].
The selection of coral species for hydroxyapatite production should also consider environmental conservation. Researchers have developed sustainable coral cultivation techniques that allow for the harvesting of coral skeletons without damaging natural reef ecosystems. In this regard, species such as Porites cylindrica and Acropora formosa exhibit relatively fast growth rates in controlled culture systems, providing a sustainable source of biomaterials. This strategy not only ensures raw material availability for hydroxyapatite production but also supports global marine biodiversity conservation [8,12,15].
Clinical applications of hydroxyapatite from coral
Located within the Coral Triangle, Indonesia’s waters contain an abundance of coral reefs and aquatic biodiversity. Compared to neighboring Southeast Asian nations, Indonesia offers the greatest diversity of marine life, accounting for 15.8% of the world’s coral reefs [20].
Corals are marine invertebrates belonging to the phylum Anthozoa, class Cnidaria. There are approximately 7,000 coral species, which are classified into two main groups: soft corals (lacking an inorganic skeleton) and hard or stony corals. Hard corals typically form dense colonies made up of numerous similar polyps. The polyps reside within a centripetal exoskeleton, and calcoblasts located in the outer coral layers—similar to osteoblasts in function—generate a rigid exoskeleton composed of calcium carbonate, providing structural strength and protection [12].
While coral exhibits similarities in composition and structure to normal bone, it cannot be used in its natural state due to the presence of harmful ions, insufficient bioactive hydroxyapatite, and excessive crystallinity. Coralline calcium carbonate-based materials generally display high solubility, limited lifespan, and instability. They are most often used to fill well-contained defects, relying on new bone growth for structural support. There is limited literature on the effectiveness of calcium carbonate grafts for fracture healing. For example, poor outcomes have been reported in cases such as nonunion scaphoid fractures treated with composites of coral calcium carbonate, collagen, and bone morphogenetic protein [11].
Comparison with other bone replacement materials
For effective vascularization and biological stability, the interconnectivity of porous structures is essential. Pore sizes between 100 and 150 μm are known to promote rapid fibrovascular network growth within scaffolds. Coralline-derived hydroxyapatite has been applied successfully to various clinical conditions, including distal radial fractures, periodontal augmentation, and maxillofacial injuries [11].
Hydroxyapatite is composed of inorganic mineral components and can be synthesized from various natural sources rich in calcium carbonate (CaCO₃). The composition of hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂), or HA, closely resembles the mineral fraction of bone, and has been widely documented for its osteoconductive properties. It promotes bone growth without causing local or systemic toxicity, inflammation, or immune reactions. X-ray diffraction studies have revealed that coral contains 97.69% CaCO₃, a much higher concentration compared to shells (87.12%), eggshells (89.98%), conch shells (68.7%), or mammalian bones (95.7%). This underscores the potential of corals as a raw material source for hydroxyapatite [4,14,21,22].
Due to its low toxicity and similarity to human bone, natural hydroxyapatite—derived from resources such as fish bone, cow bone, and shellfish—also represents an excellent bone filler and may become increasingly popular in the future. Commercial synthetic hydroxyapatite powders can be produced via hydrothermal methods, solid-state reactions, sol-gel processes, emulsions, microemulsions, and most commonly, chemical precipitation due to its simplicity and cost-effectiveness. However, the resulting substance may lack important ions, such as magnesium, sodium, potassium, silicon, strontium, and iron [21].
Hydroxyapatite has been shown to support bone growth and is considered a bioactive material. Its affinity for osteogenic and anti-resorptive molecules allows it to serve as a reservoir for growth factors, antibiotics, or drugs that inhibit osteoclasts, thereby facilitating direct attachment to bone. This property has been demonstrated in various investigations. Its osteoconductive qualities, which allow osteoblasts to adhere to and migrate across the material’s surface, are fundamental to its bioactivity [12].
CONCLUSION
The current review of hydroxyapatite makes some important contributions to biomedical applications. Hydroxyapatite from natural materials such as coral has faster and larger osteoblasts. Hydroxyapatite is used as a scaffold due to its characteristics that are highly comparable to bone and its high biodegradability. Hydroxyapatite can be considered as a bioactive material in bone grafts. Their osteoconductive quality, which allows osteoblasts to designate and migrate on the surface of the material, is related to their bioactivity. The findings obtained from this review provide insights for future research.
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