Definition/Introduction

There is a need to reconstruct damaged hard tissue for several reasons, including traumatic or nontraumatic events, congenital abnormalities, or disease. Damaged tissues stemming from these events can become significant in orthopedic, dental, and maxillofacial surgery. A study on numerous biomaterials revealed that calcium phosphates had been used in hard tissue reconstruction for more than 6 decades. Hydroxyapatite (HA) was the primary material used in orthopedics and dentistry.

HA is an inorganic mineral that has a typical apatite lattice structure as (A10(BO4)6C2), where A, B, and C are defined by Ca, PO4, and OH. Pure HA contains 39.68% by weight calcium and 18% by weight phosphorus, resulting in a Ca/P mole ratio of 1.67. There are commercial HA products with a Ca/P ratio bigger or smaller than 1.67. The variety in the Ca/P ratio indicates the phase shift between tricalcium phosphate (TCP) and calcium oxide (CaO). HA, with a Ca/P ratio bigger than 1.67, comprises more CaO than TCP and vice versa.[1][2].

HA crystals are present in the human body, inside bones and teeth. Regarding human bone, the HA crystals, as a bioactive ceramic, cover 65% to 70% of the weight of the bone. Furthermore, the architecture of the bone comprises type-I collagen as an organic component and the HA as an inorganic component. These 2 components form a composite structure at the nanoscale, in which nano-HA is interspersed in the collagen network. This composite forms mineralized collagen and is the precursor of biological mineralized tissue from tendons and skin to hard mineralized tissues such as bone and teeth. Moreover, in the bone, the HA crystals, in the shape of plates or needles, are about 40 to 60 nm long, 20 nm wide, and 1.5 to 5 nm thick.[3] Different HA crystalline sizes and shapes support this tissue's structural stability, hardness, and function.[4][5]

Concerning the dental role, HA crystal covers 70% to 80% by weight of dentin and enamel. Within the human body, the enamel is the hardest substance consisting of relatively large HA crystals (25 nm thick, 40 to 120 nm wide, 160 to 1000 nm long).[6] Different from bone, enamel does not contain collagen. Amelogenins and enamelins replace the function of collagen by providing a framework for mineralization. Besides, HA is the primary material of enamel that screens the diffuse reflectivity of light by covering the pores on the enamel surface, thus making the appearance of enamel semitranslucent.[4][7]

Overall, the pressure point in hard tissue reparation is on HA due to its chemical proportion that occupies the majority of challenging tissue composition and its mechanical properties that support tissue integrity.[8] HA is widely used as implant material due to its excellent osteoconductive property that supports osseointegration and osteogenesis processes. Its raw materials and synthesis process influence the biological response to HA implants, which makes product properties vary.

Issues of Concern

HA has been long used in hard tissue engineering due to its chemical similarity to the mineral of hard tissue. The era of HA in regenerative science dates back to the 1950s when bioceramics were used to fill bone defects. However, after more than 6 decades of scientific innovation through research and development, HA has restructured the traditional philosophy of using ceramics in medical sciences through the wide range of its applications in dentistry and drug delivery.

HA application in orthopedics can vary from bone defect repair and bone augmentation to coatings for human body metallic implants. The HA-based implant can provide an interlocked porous structure.[9][10] This structure can act as the extracellular matrix, promoting the natural process of cellular development and tissue regeneration[11]. Furthermore, HA can enhance the osseointegration process by promoting rigid anchorage between the implant and the surrounding tissue without fibrous tissue growth. Successful osseointegration retains the bone anchorage for a long period, restoring functional ability completely.[12][13]

Another significant application of HA has been seen in dentistry since 1979. HA cylinders have been used for tooth replacement. This application was followed by using HA blocks and coating to enhance bone fixation in a restorative dental procedure in the early 1980s. Now, HA is found not only in dental cement and fillings but also in toothpaste. HA in toothpaste acts as a polisher to decrease the deposition of accretions on teeth.[14][7]

The application of HA also can be found in drug delivery. The naturally porous structure with a high binding affinity of HA provides a niche for drug loading, thus making HA a good fit as a drug carrier[15]. The low solubility of nano-HA in physiological conditions contributes to its longer degradation rate.[4] This condition can be helpful as a carrier for local drug delivery, either by surgical placement or injection. This controlled drug delivery using HA can maintain drug concentration in the blood and, hence, reduce the toxicity to other organs.[4][15]

The applications of HA in hard tissue restoration and drug delivery do not use HA in pure form. The mechanical properties of pure HA are relatively low and brittle for load-bearing applications. Therefore, HA is usually incorporated in composite or polymer to increase its application.[11][16] In this case, the improvement properties of HA are a result of the compressive strength of the HA ceramic phase as well as the toughness and elasticity of the polymer or composite matrix. Generally, HA is resistant to resorption in vivo at a rate of 1% to 2% per year. Thus, this condition provides long structural support in the defect area.[8][12]

There are several methods to produce HA from synthetic or natural sources. Synthetic HA uses raw materials such as calcium carbonate, calcium hydroxide, calcium nitrate, diammonium hydrogen phosphate, and ammonium hydroxide. The fabrication process of HA is known as a wet method and solid-state reaction, followed by a calcination or sintering process. Both of these methods use chemical response by varying the content of CaO and TCP to reach HA stoichiometric conditions.

The wet method produces nonstoichiometric HA powder with impurities such as hydrogen phosphate, carbonate, chloride, and sodium ions. These impurities cause the formation of calcium-deficient HA.[1] Previous works have identified impurities as an uncontrollable variable that may promote significant changes in the crystallographic arrangement and chemical properties, which later affect the dissolution process of HA. On the other hand, the solid-state reaction produces a stoichiometric and well-defined crystalline shape of HA product. Yet, the solid-state reaction requires high temperatures and long heat treatment procedures. The raw materials of the solid method should have Ca/P = 1.67 and be ball-milled to ensure the product is uniform in size.[2] The solid method solely depends on the solid diffusion of ions into the raw materials, thereby needing a high temperature of around 1250ºC to start the reaction.[2] Moreover, prolonged heat treatment transforms the singular crystalline particle into more blocky crystals. Increasing crystalline size causes a decrease in porosity, which is associated with the aging process.[6]

HA from the natural source is commonly fabricated from fishbone, coral, bovine bone, eggshell, and seashells through calcination. HA produced from natural sources is non-stoichiometric due to trace ions found in the natural sources.[13][17][13] These trace of ions, which consist of cations such as Na+, K+, Mg2+, Sr2+, Zn2+, and Al3+, or anions like F-, Cl-, SO4 2-, and CO3 2-, are beneficial to promote rapid bone regeneration.[18]

The mechanical properties of HA depend on several variables, such as phase composition, crystal size, and the synthesis process. Pure HA has bending, compressive, and tensile strength in the range of 38 to 250 MPa, 120 to 150 MPa, and 38 to 300 MPa, respectively. Young modulus varies from 35 to 120 GPa, depending on the impurities.[19] Meanwhile, Weibull modulus, with a value of 5 to 18, exhibits that HA is a brittle material. To increase the mechanical properties of HA, for instance, tough HA is obtained when the composition containing tricalcium phosphate (TCP) makes HA have high flexural strength. Meanwhile, the flexural strength decreases to the minimum value if HA contains calcium oxide (CaO).[10][19][10] Furthermore, the sintering temperature also contributes to the change of HA mechanical properties. The rise of sintering temperature causes an increase in density, compressive strength, grain size, and torsional strength.[1] 

Phase composition and preparation method affect the chemical stability of HA. For example, exchanging magnesium, carbonate, or strontium with apatite promotes increased solubility.[17] In contrast, the exchange with fluoride causes a decrease in the solubility. Sintered HA has higher chemical stability than non-sintered HA, which causes sintered HA to be less soluble in vivo.[1]

Clinical Significance

Synthetic and natural HA have been long preferred as the material used in hard tissue repair over autografts and allografts. This is due to problems that the grafts are naturally associated with, including graft shortage, donor site morbidity, disease transmission, and graft rejection.

In bone tissue engineering, the bioactivity of HA, which is marked by osteoconductive and osteoinductive processes, has proved to support osseointegration. The osteoconductive property of HA provides a template to guide the new bone formation on its surface down to the pores of the implant body.[20] The HA osteoconductivity allows the osteoblast to attach, increase, grow, and express the phenotype in a direct contact manner, thus forming a tissue-implant solid interface. This osteoconductive property depends on HA's specific geometry and pore size.[17][21] On the other hand, the osteoinductive property of HA encourages tissue ingrowth that allows the neoformation of bone even in the non-bone-forming area. Equally important, the coating of an implant using HA enhances initial mechanical stability post-implantation, decreasing aseptic loosening. In this situation, HA facilitates the chemical bonding of the implant with surrounding tissue by absorbing protein into the implant surface.[10] Protein on the surface is favorable for an early healing event at the tissue-implant interface. The high stability of the implant makes immediate loading more predictable. The chemical resemblance of HA to bone minerals ensures its ability to bond directly to bone tissue without an intervening fibrous layer.[11][17][11] Overall, osteoinduction, osteoconduction, and osseointegration properties of HA are complementary, not the same, phenomena. All of these properties of HA serve as a fact that the application of HA as the cellular matrix is of great interest.

The materials fabrication process advances have led to the development of nano-HA particles, which can induce fast dentin remineralization.[22] Nano-HA diffuses into the demineralized collagen matrix of dentin, changing the environment into a suitable scaffold for remineralization and acting as the mineral precursor. Nano-HA provides a good source of free calcium and is essential to promote protection against dental erosion and caries.[14] This application of HA generally requires a high amount of calcium hydroxide marked by an increased Ca/P value. Furthermore, nano-HA in toothpaste can act as a filler to repair the holes and the recessed surface of enamel.[14] In this reparation process, nano-HA gets through the surface of the enamel to replace the phosphate and calcium ions that have dissolved, thereby remineralizing damaged enamel and reconstructing its structural integrity.[5][16] Moreover, nano-HA in toothpaste also provides a protective coating over dissolved dentinal tubules, offering a fast and potential remedy for tooth hypersensitivity.

Atomic bonds in HA are pretty strong, contributing to the fact that HA does not swell or change in size under the range of PH and temperature.[18] This low swelling ratio of HA forbids the outburst of drugs, a common problem in drug delivery. Bone cement usually has HA as a fixating material and drug carrier.[15] It is because of its capacity for controlled drug release via diffusion from the cement rather than via dissolution of the apatite material, as the cement has less in vitro solubility than typical block apatites.[23] Preferably, HA delivers the skeletal drug system in diseased bone rather than the oral therapeutic system, as the acid in the gastric environment can degrade its structure.

There are several problems regarding the application of HA in medicine. For instance, the use of HA as an implant has inherent defects/fine porosity that could act as a crack initiator. Following this event, the crack propagation can cause catastrophic deterioration during application. Furthermore, the application of bulk HA can sometimes cause a modulus mismatch between bone and the implant, which causes disproportionate load sharing.[10] On the other hand, regardless of their source, HA always contains traces of elements, such as fluoride ions (F-) and hydroxyl ions (OH-), which cause an increase in crystallite size and a decrease in solubility that can increase the apatite strength.[19] At the same time, elements such as phosphide ions (PO3 3-) and chloride ions (Cl-) have been known to decrease the HA mechanical properties by causing a reduction in crystallite size and an increase in solubility.[10][12]

Another issue that occurs by using HA in medical applications is how to fine-tune the degradation rate. Poor mechanical properties of the HA-based implant can induce not only fast degradation but also implant failure and chronic inflammatory reaction[11][24]. For example, rapid degradation leads to the immediate release of the calcium content of HA into the environment, raising the calcium concentration locally[9]. Naturally, high calcium concentration is essential for bone regeneration. Nonetheless, when the degradation is too fast, it may cause structural collapse of the implant and induce too much graft resorption.[16][19][16]. Controlling HA degradation is essential for the implant to induce tissue regeneration promptly.

Regarding this condition, the controlled release of HA particles can be controlled by manipulating particle size. Small-sized particles have a wider surface than larger-sized particles of the same weight. Thus, the smaller particle is more straightforward to detach from the implant body.[18]