Definition/Introduction

Reconstructing damaged hard tissue is essential for various reasons, including traumatic or nontraumatic events, congenital abnormalities, and disease. Such damage can significantly impact orthopedic, dental, and maxillofacial surgeries. Research on numerous biomaterials shows that calcium phosphates have been utilized in hard tissue reconstruction for over 6 decades, with hydroxyapatite being the primary material used in orthopedics and dentistry.

Hydroxyapatite is an inorganic mineral with a typical apatite lattice structure represented as (A10(BO4)6C2), where A, B, and C correspond to Ca, PO₄, and OH, respectively. Pure hydroxyapatite contains 39.68% calcium and 18% phosphorus by weight, resulting in a Ca/P molar ratio of 1.67. Commercial hydroxyapatite products have Ca/P ratios that can be higher or lower than 1.67. This variation in the Ca/P ratio indicates a phase shift between tricalcium phosphate (TCP) and calcium oxide (CaO). Hydroxyapatite with a Ca/P ratio greater than 1.67 contains more CaO than TCP, while those with a lower ratio contain more TCP.[1][2]

Hydroxyapatite crystals are naturally present in the human bones and teeth. Hydroxyapatite crystals, as a bioactive ceramic, account for 65% to 70% of its weight in human bone. Furthermore, the architecture of the bone comprises type-I collagen as the organic component and hydroxyapatite as an inorganic component. Together, these 2 components create a nanoscale composite structure, where nano-hydroxyapatite is interspersed within the collagen network. This composite forms mineralized collagen and serves as the precursor for biological mineralized tissues, ranging from tendons and skin to hard tissues such as bone and teeth. Moreover, in bones, hydroxyapatite crystals are plate- or needle-shaped, measuring approximately 40 to 60 nm in length, 20 nm in width, and 1.5 to 5 nm in thickness.[3] The varying sizes and shapes of hydroxyapatite crystals contribute to the structural stability, hardness, and function of these tissues.[4][5]

The dental role of hydroxyapatite is significant, as it constitutes 70% to 80% of the weight of dentin and enamel. Enamel, the hardest substance in the human body, is made up of relatively large hydroxyapatite crystals measuring 25 nm thick, 40 to 120 nm wide, and 160 to 1000 nm long.[6] Unlike bone, enamel lacks collagen; instead, amelogenins and enamelins provide a framework for mineralization. Hydroxyapatite is the primary component of enamel, helping to minimize diffuse reflectivity by filling surface pores, which contributes to the semitranslucent appearance of enamel.[4][7]

Overall, the focus in hard tissue repair is on hydroxyapatite due to its significant chemical composition, which constitutes the majority of challenging tissue, and its mechanical properties that support tissue integrity.[8] Hydroxyapatite is widely utilized as an implant material because of its excellent osteoconductive properties that facilitate osseointegration and osteogenesis. The raw materials and synthesis processes of hydroxyapatite influence the biological response to its implants, resulting in variations in product properties.

Issues of Concern

Hydroxyapatite has long been used in hard tissue engineering due to its chemical similarity to the mineral composition of hard tissues. The role of hydroxyapatite in regenerative science dates back to the 1950s when bioceramics were first used to fill bone defects. However, after more than 6 decades of scientific research and development, hydroxyapatite has transformed the traditional use of ceramics in medical science, leading to a broad range of applications in dentistry and drug delivery.

Hydroxyapatite applications in orthopedics range from bone defect repair and bone augmentation to coatings for metallic implants in the human body. Hydroxyapatite-based implants can feature an interlocked porous structure,[9][10] which serves as an extracellular matrix, promoting natural cellular development and tissue regeneration.[11] Furthermore, hydroxyapatite can enhance the osseointegration process by facilitating a strong connection between the implant and surrounding tissue while preventing fibrous tissue growth. Successful osseointegration ensures long-term bone anchorage, fully restoring functional ability.[12][13]

Another significant application of hydroxyapatite in dentistry dates back to 1979 when hydroxyapatite cylinders were used for tooth replacement. This application was followed in the early 1980s by the use of hydroxyapatite blocks and coatings to enhance bone fixation in restorative dental procedures. Hydroxyapatite is now used not only in dental cement and fillings but also in toothpaste, where it serves as a polisher to reduce the buildup of accretions on teeth.[14][7]

Hydroxyapatite is also utilized in drug delivery applications. Its naturally porous structure and high binding affinity create an ideal niche for drug loading, making it an effective drug carrier.[15] The low solubility of nano-hydroxyapatite in physiological conditions contributes to its prolonged degradation rate.[4] This characteristic makes it a valuable carrier for local drug delivery, whether through surgical placement or injection. Using hydroxyapatite for controlled drug delivery helps maintain consistent drug concentrations in the blood, thereby reducing toxicity to other organs.[4][15]

The applications of hydroxyapatite in hard tissue restoration and drug delivery do not typically involve its pure form. Pure hydroxyapatite has relatively low mechanical properties and is brittle, making it unsuitable for load-bearing applications. Consequently, hydroxyapatite is often incorporated into composites or polymers to enhance its functionality.[11][16] In this case, the enhanced properties of hydroxyapatite result from the compressive strength of the hydroxyapatite ceramic phase, combined with the toughness and elasticity of the polymer or composite matrix. Generally, hydroxyapatite exhibits resistance to resorption in vivo at a rate of 1% to 2% per year, providing long-lasting structural support in the defect area.[8][12]

Several methods exist for producing hydroxyapatite from synthetic or natural sources. Synthetic hydroxyapatite is derived from raw materials such as calcium carbonate, calcium hydroxide, calcium nitrate, diammonium hydrogen phosphate, and ammonium hydroxide. The fabrication process of hydroxyapatite involves both wet methods and solid-state reactions, followed by calcination or sintering. These methods utilize chemical reactions that adjust the content of CaO and TCP to achieve the stoichiometric conditions necessary for hydroxyapatite formation.

The wet method produces nonstoichiometric hydroxyapatite powder that may contain impurities such as hydrogen phosphate, carbonate, chloride, and sodium ions. These impurities can lead to the formation of calcium-deficient hydroxyapatite.[1] Previous studies have identified these impurities as uncontrollable variables that can significantly alter the crystallographic arrangement and chemical properties of hydroxyapatite, ultimately affecting its dissolution process.

In contrast, the solid-state reaction yields a stoichiometric and well-defined crystalline structure of hydroxyapatite. However, this method requires high temperatures and extended heat treatment procedures. The raw materials used in the solid-state method should have a Ca/P ratio of 1.67 and must be ball-milled to ensure uniform particle size.[2] The solid-state reaction method solely depends on the solid diffusion of ions into the raw materials, thereby necessitating temperatures around 1250 ºC to initiate the reaction.[2] Moreover, prolonged heat treatment transforms singular crystalline particles into more blocky crystals, and the increase in crystalline size leads to a decrease in porosity, which is associated with the aging process.[6]

Hydroxyapatite from natural sources is commonly fabricated from materials such as fishbone, coral, bovine bone, eggshell, and seashells through a calcination process. Hydroxyapatite produced from these natural sources is often nonstoichiometric due to the presence of trace ions.[13][17] These traces of ions, which include cations such as Na⁺, K_⁺, Mg²⁺, Sr²⁺, Zn²⁺, and Al³⁺, as well as anions such as F^-, Cl^-, SO₄^2-, and CO₃^2-, are beneficial for promoting rapid bone regeneration.[18]

The mechanical properties of hydroxyapatite are influenced by factors such as phase composition, crystal size, and synthesis method. Pure hydroxyapatite typically has a bending strength of 38 to 250 MPa, compressive strength of 120 to 150 MPa, and tensile strength of 38 to 300 MPa. The Young modulus ranges from 35 to 120 GPa, depending on the presence of impurities.[19] Meanwhile, the Weibull modulus, ranging from 5 to 18, indicates hydroxyapatite is a brittle material. To enhance its mechanical properties, tough hydroxyapatite can be obtained by incorporating TCP, which increases its flexural strength. In contrast, the flexural strength reaches its minimum when hydroxyapatite contains calcium oxide CaO.[10][19] Furthermore, the sintering temperature also significantly alters the mechanical properties of hydroxyapatite. Higher sintering temperatures lead to increased density, compressive strength, grain size, and torsional strength.[1]

The phase composition and preparation method influence the chemical stability of hydroxyapatite. For instance, substituting apatite with magnesium, carbonate, or strontium increases solubility.[17] In contrast, substituting fluoride reduces solubility. Sintered hydroxyapatite has higher chemical stability than non-sintered forms, making it less soluble in vivo.[1]

Clinical Significance

Synthetic and natural hydroxyapatite have long been preferred for hard tissue repair over autografts and allografts. This preference arises from issues commonly associated with grafts, such as graft shortages, donor site morbidity, disease transmission, and the risk of graft rejection.

In bone tissue engineering, the bioactivity of hydroxyapatite—characterized by its osteoconductive and osteoinductive properties—has been shown to support osseointegration. The osteoconductive property of hydroxyapatite provides a template to guide the new bone formation on its surface down to the pores of the implant body.[20] This property facilitates osteoblast attachment, proliferation, growth, and phenotype expression in direct contact with the implant, creating a solid tissue-implant interface. The effectiveness of osteoconductivity depends on the specific geometry and pore size of the hydroxyapatite structure.[17][21] 

On the other hand, the osteoinductive property of hydroxyapatite promotes tissue ingrowth, enabling neoformation of bone even in areas that typically do not form bone. Equally important, coating an implant with hydroxyapatite enhances initial mechanical stability post-implantation and reduces the risk of aseptic loosening. In this context, hydroxyapatite facilitates chemical bonding between the implant and surrounding tissue by absorbing proteins onto the implant surface.[10] Protein on the implant surface favors early healing at the tissue-implant interface, contributing to the high stability of the implant and making immediate loading more predictable. The chemical similarity of hydroxyapatite to bone minerals allows it to bond directly to bone tissue without forming an intervening fibrous layer.[11][17] Overall, the osteoinductive, osteoconductive, and osseointegration properties of hydroxyapatite are distinct yet complementary phenomena. All of these properties of hydroxyapatite indicate that its application as the cellular matrix is highly interesting.

Advancements in material fabrication have led to the development of nano-hydroxyapatite particles, which can accelerate dentin remineralization.[22] Nano-hydroxyapatite diffuses into the demineralized collagen matrix of dentin, transforming it into a suitable scaffold for remineralization and acting as a mineral precursor. Additionally, nano-hydroxyapatite serves as an excellent source of free calcium, promoting protection against dental erosion and caries.[14] This application of hydroxyapatite typically requires a high concentration of calcium hydroxide, indicated by an increased Ca/P ratio. Additionally, nano-hydroxyapatite in toothpaste can act as a filler, repairing holes and restoring the recessed enamel surface.[14] During this reparation process, nano-hydroxyapatite penetrates the enamel surface to replace lost phosphate and calcium ions, thereby remineralizing damaged enamel and rebuilding its structural integrity.[5][16] Moreover, nano-hydroxyapatite in toothpaste forms a protective coating over exposed dentinal tubules, providing a rapid and effective solution for tooth hypersensitivity.

The strong atomic bonds in hydroxyapatite prevent it from swelling or changing size across a wide range of pH and temperatures.[18] The low swelling ratio of hydroxyapatite prevents drug outbursts—a common issue in drug delivery systems. Hydroxyapatite is often used in bone cement as both a fixative material and a drug carrier.[15] Hydroxyapatite's capacity to facilitate controlled drug release is attributed to diffusion from the cement rather than the dissolution of the apatite material, as the cement exhibits lower in vitro solubility compared to standard block apatites.[23] Preferably, hydroxyapatite is better suited for delivering skeletal drugs directly to diseased bone rather than through the oral therapeutic system, as gastric acid can degrade its structure.

Several challenges exist regarding the application of hydroxyapatite in medicine. For instance, using hydroxyapatite as an implant presents inherent defects and fine porosity that can act as crack initiators. Following crack initiation, propagation can lead to catastrophic failure during use. Additionally, the application of bulk hydroxyapatite may result in a modulus mismatch between the bone and the implant, leading to disproportionate load sharing.[10] Conversely, hydroxyapatite, irrespective of its source, always contains trace elements such as fluoride ions (F^-) and hydroxyl ions (OH^-), which contribute to increased crystallite size and decreased solubility, thereby enhancing the strength of the apatite.[19] At the same time, elements such as phosphide ions (PO₃^3-) and chloride ions (Cl^-) have been shown to weaken the mechanical properties of hydroxyapatite by reducing crystallite size and increasing solubility.[10][12]

Another challenge in using hydroxyapatite for medical applications is fine-tuning its degradation rate. Poor mechanical properties of hydroxyapatite-based implants can result in rapid degradation, which may lead to implant failure and chronic inflammatory reactions.[11][24] For example, rapid degradation leads to the immediate release of the calcium content from hydroxyapatite into the surrounding environment, leading to increased local calcium concentrations.[9] Naturally, a high concentration of calcium is essential for bone regeneration. However, if degradation occurs too rapidly, it can lead to structural collapse of the implant and excessive graft resorption.[16][19] Therefore, managing hydroxyapatite degradation is crucial for the implant to induce tissue regeneration promptly. In this context, the controlled release of hydroxyapatite particles can be achieved by manipulating their size. Smaller particles have a wider surface area than larger particles of the same weight, thereby making them easier to detach from the implant body.[18]