Effects of different types of modifiers on structural variation of nano-hydroxyapatite for efficient application

Abstract

Hydroxyapatite (HAp) has emerged as a biomaterial of significant interest due to its intrinsic biocompatibility and structural similarity to natural bone minerals. While HAp is traditionally derived from natural sources, chemical synthesis via conventional methods, such as wet chemical precipitation and sol–gel processing, and newer techniques like microwave-assisted synthesis and hydrothermal methods have enabled greater control over its physicochemical properties. With the expansion of applications beyond conventional biomedical uses, recent research has concentrated on engineering nanohydroxyapatite with precisely tailored morphologies and structures. This review examines the influence of various organic modifiers on nano-HAp synthesis, highlighting how these agents modulate its crystal growth, crystallinity, surface topology, particle dimensions, and porosity. Potent chelating agents (e.g., citric acid and EDTA) have been shown to yield purer, more uniform nanoparticles, whereas cationic–anionic surfactants (e.g., CTAB and SDS) enhance the surface area. Modifiers such as Triton X-100, chitosan, and polyethylene glycol effectively adjust the pore size. Scientists are also investigating environmentally friendly and toxicant-free modifiers. Through summarization of insights from current literature, this review provides a comprehensive framework for selecting suitable modifiers to fabricate well-defined HAp nanomaterials for diverse applications in future studies.

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1. Introduction

In the current era of advanced materials research, hydroxyapatite (HAp) has become one of the most widely investigated biomaterials as it spans multiple disciplines, including medicine,¹ dentistry,² agriculture,³ industrial fields,⁴ environmental science,⁵etc. Different application fields of HAp are visualized (Fig. 1). HAp with the chemical formula Ca₁₀(PO)₆(OH)₂ closely resembles the inorganic component of bones and teeth.^6–9 Its exceptional properties, such as biocompatibility and reactivity, make it ideal for bone tissue engineering, drug delivery, and orthopedic applications.^10–12 The term “apatite” was first used by Werner in 1788 to refer to a family of compounds with similar hexagonal crystal structures and space groups despite varying compositions. After the development of X-ray diffraction, Dejong in 1926 confirmed that apatite is identical to the mineral component of bones and teeth.^13,14 Among the significant apatite groups, HAp has been extensively studied since the 1950s for its usage in medical disciplines.^15,16 Apart from medical usage, HAp also became worthwhile for industrial and technological applications such as a catalyst in chemical reactions,¹⁷ a host material for lasers,¹⁸ fluorescence materials,¹⁹ ion conductors,²⁰ and gas sensors.²¹ Furthermore, synthetic HAp is employed in protein and nucleic acid fractionation via column chromatography²² and water treatment²³ and soil remediation²⁴ for heavy metal contamination.²⁵ Hydroxyapatite (HAp) continues to be a focal point of scientific research. For instance, polycaprolactone/nano-hydroxyapatite (PCL/nano-HAp) nanocomposites have been utilized to fabricate drug-loaded implants through solution-extrusion 3D printing which have superior mechanical properties;²⁶ recently developed carboxymethylcellulose–Al(III)/HAp aerogel beads are capable of selectively removing fluoride from brick tea infusions without altering sensory properties, achieving adsorption capacities over 23 mg g⁻¹;²⁷ gold/hydroxyapatite nanocomposites functionalized with polydopamine nanocomposites modulate immune responses and facilitate vascularized bone regeneration;²⁸ collagen and κ-carrageenan fabricated with hydroxyapatite reinforced with lanthanum oxide nanoparticles, a biocomposite, has been shown to speed up the bone repair process.²⁹ These recent studies highlight that researchers are actively exploring new ways to improve hydroxyapatite.

Fig. 1 Application of HAp in different fields.

HAp has a Ca/P molar ratio of 1.67, which is the right balance with high stability of HAp and good mechanical properties.^30,31 Primarily, it exists in two nano-crystalline structures—hexagonal phase (P6₃/m or P6₃) and monoclinic phase (P2₁/b or P2₁).³² In hexagonal HAp, OH groups are aligned along the c-axis in two order variations: hexagonal disordered P6₃/m, where OH dipoles are randomly distributed over the whole crystal between the neighboring unit cells, and ordered P6₃ with a parallel orientation, a common phase found in synthetic hydroxyapatite. In monoclinic HAp, they also have the same variations as the hexagonal one but are less common.³³ The properties of hydroxyapatite mostly depend on its preparation method or origin. Studies showed that HAp from biological sources exhibits higher crystallinity (at 800 °C) than synthetic HAp, whereas the synthetic one has a larger surface area and porosity.³⁴ With the evolution of nanotechnology, nanosized HAp gained significant attention due to its improved qualities compared to normal HAp.³⁵ Superior biological responses such as bone regeneration, osteoblast adhesion, and proliferation made nano-HAp highly valuable.³⁶ Several research studies have been conducted to study the characteristics of the nanoparticles of HAp. Recent investigations revealed that nano-HAp has a complex surface structure, and the nanoparticles consist of a crystalline core that is elongated along the crystallographic c-axis.³⁷ Furthermore, it is assumed that the nanocrystals have a grain size of less than 100 nm in at least one direction, closely resembling the mineral found in hard tissues.³⁸ Conventional HAp cannot withstand high loads and is prone to brittle failure.³⁹ Nano-HAp follows the Hall–Petch relationship,⁴⁰ where the strength of the material increases with decreasing grain size.⁴¹ Furthermore, nano-HAp possesses higher dissolution rates⁴² because of the increased grain boundaries.⁴³ Among various morphologies of nano-HAp, needle-like and spherical shapes are the most common and applicable.⁴⁴ Owing to the exceptional physical and chemical properties of HAp, many synthesis methods have been developed by scientists to modify its morphologies, sizes, crystallinity, calcium–phosphate ratio, and other characteristics for specific applications.^45,46 These synthesis methods are significantly influenced by reaction conditions (reaction temperature, pH, calcination temperature, time, initial concentration, etc.).⁴⁷ For tailored applications, modifiers have received much recognition for the synthesis of nano-HAp with controlled properties, especially organic modifiers are extensively used such as citric acid-mediated F-doped mesoporous HAp, which has biocidal implant application,⁴⁸ surface-modified HAp with stearic acid (SA) is used as a coating agent for titanium dental implants.⁴⁹ Modifiers including urea, fatty acids, amino acids, citric acid,⁵⁰ carboxylic acids, cetyltrimethylammonium bromide (CTAB), sodium dodecyl sulfate (SDS),⁵¹ ethylenediaminetetraacetic acid (EDTA), Tween 20, trisodium citrate, and D-sorbitol⁵² are successfully used in different processes for controlled synthesis.^53,54

While many studies have explored how reaction conditions affect HAp's structure, there is still little research on how modifiers influence its properties, to the best of our knowledge. This review provides a comprehensive analysis of the existing literature on modifiers used for the structural variation of nano-hydroxyapatite (nano-HAp), aiming to facilitate future investigations to fill the knowledge gap. For this particular review paper, we will be discussing the effect of modifiers on the structural variation of nano-HAp synthesized by some of the most significant synthesis methods: the wet chemical technique, microwave-assisted method, sol–gel method, and hydrothermal method for efficient uses.

2. Synthesis methods

Several methods have been developed for synthesizing hydroxyapatite (HAp), and each of these methods results in unique characteristics of HAp.⁵⁵ These techniques can be classified into dry (e.g., solid-state synthesis and mechanochemical method), wet (e.g., wet precipitation and sol–gel), and high-temperature methods (e.g., combustion and pyrolysis).⁵⁶ Among these, the most commonly employed approaches, wet chemical, sol–gel, hydrothermal, and microwave-assisted methods, will be discussed here (Table 1).

Table 1 Different synthesis methods for HAp⁵⁴

Dry method	• Solid-state synthesis
	• Mechanochemical method
Wet method	• Wet precipitation
	• Sol–gel
	• Hydrolysis
	• Hydrothermal
	• Emulsion
	• Sonochemical
High-temperature method	• Combustion
	• Pyrolysis

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2.1 Wet chemical method

In 1976, Jarcho and his colleagues first explored the wet-chemical precipitation method to produce a dense polycrystalline hydroxyapatite with high mechanical properties. Since then, many researchers have refined and expanded this technique.⁵⁷ Common sources of calcium for the wet chemical method are calcium hydroxide (Ca(OH)₂), calcium nitrate tetrahydrate (Ca(NO₃)₂·4H₂O), and calcium oxide (CaO) and sources of phosphorus are phosphoric acid (H₃PO₄) and diammonium hydrogen phosphate ((NH₄)₂HPO₄). For the synthesis, reactants are dissolved in water or a water–ethanol mixture, then stirred and aged at room temperature to 85 °C overnight, with the pH kept at 9–11. The filtered precipitate is dried using atmospheric drying, vacuum drying, or freeze drying and calcined at temperatures between 700 °C and 1250 °C.^58–61 Several characterization techniques, such as X-ray diffraction (XRD), Scanning Electron Microscopy (SEM), Fourier Transform Infrared (FTIR) spectroscopy, Transmission Electron Microscopy (TEM), Differential Thermal Analysis (DTA), and chemical analysis – Atomic Absorption Spectroscopy (AAS) or EDTA titration, demonstrated the purity (nearly pure) with a low level of impurity content.⁶² Other benefits, such as the minimal processing temperature and the ability to produce highly intricate nanomaterials and adapt according to specific applications, have drawn the attention of researchers.⁶³ Studies have shown that altering the critical processing parameters, such as temperature, pH, concentration of reactants, and aging time, can modify the physicochemical properties (morphology, particle size, and crystallinity), which have a significant influence on the biological response and clinical performance of nano-HAp.⁶⁴ For instance, spherical-shaped HAp nanoparticles with smaller particle sizes (21–78 nm) can be obtained under alkaline conditions (pH 11), while neutral to moderately basic pH conditions give particles shaped as beaded rods, nanorods, nanoflakes, or twisted boxes with large sizes (28–202 nm). The crystallite size ranging from 8 to 77 nm can be achieved at varying annealing temperatures from 300 °C to 900 °C (ref. 65) (Fig. 2).

Fig. 2 Synthesis of hydroxyapatite by the wet chemical method.

2.2 Microwave-assisted method

Microwave processing of materials is an innovative technology that provides a powerful approach for enhancing, improving, or altering the characteristics of existing materials.⁶⁶ It is an effective way to overcome the problems associated with traditional methods. Small-sized and highly pure nanoparticles with thermal stability can be achieved through this process.⁶⁷ The microwave synthesis method is fast and environmentally friendly. It is a time and energy-saving method, and almost 100% of the electromagnetic energy is converted into heat,⁶⁸ resulting in uniform volumetric heating of a sample.⁶⁹In vitro studies demonstrate the potential of microwave-synthesized HAp for osteoporotic bone regeneration⁷⁰ with cell viability of more than 80%, and its bio-compatibility nature was also proven.⁷¹ Over the past few decades, several attempts have been made to combine microwave irradiation with other techniques⁵⁶ (Fig. 3).

Fig. 3 Flow sheet of the main methods in MW-assisted preparation of nano-hydroxyapatite.⁶⁹

The first use of microwave (MW) irradiation to prepare pure hydroxyapatite (HAp) through precipitation from aqueous medium in under an hour was reported in 1991,⁷² where two sets of experiments were conducted in a microwave oven, one with ionic solutions to precipitate calcium phosphate species which was microwaved for 5 minutes and the other using a preformed wet solid.⁷³ In later experiments, the microwave irradiation period of the reaction mixture was prolonged to 20–25 minutes.⁷⁴ The resulting precipitate was filtered, then dried in an oven at 40 °C to 80 °C for 17–24 hours and calcined at 500–10 000 °C in most cases.^75–78 The MW-assisted nano-HAp precipitation method successfully produced a “biomimetic” amorphous carbonate nano-HAp structure using concentrated body fluids easily and rapidly with high purity and quantity.⁷⁹ In reflux-assisted MW synthesis, MW heating is combined with a reflux condenser to maintain the reaction temperature.⁸⁰ With modified process parameters,⁸¹ this method can produce highly crystalline nano-HAp powder with smaller particle size and mixed (lenticular and rod-shaped) morphologies. The MW-hydrothermal method uses a sealed MW device at high pressure & temperature, which accelerates crystal growth and phase purity.⁸² The MW-solvothermal method is similar to the hydrothermal method, but organic solvents are used instead of water.⁸³ For rapid synthesis, the MW-solid state method is preferable for being a one-step method.⁸⁴ Experiments show that spherical nano-HAp (calcium-deficient hydroxyapatite (CDHA), 50 nm, and Ca/P ∼ 1.5) was prepared within 4 min in a domestic MW by this process.⁸⁵ The MW-combustion system can be initiated by auto-ignition with a domestic MW oven.⁸⁶ This method has been used for doping nano-HAp with europium for bio-imaging applications with sufficient fluorescence emission intensity.⁸⁷ Combining ultrasonication and MW irradiation, the ultrasonic-assisted MW method enhances the surface area and mesoporosity⁸⁸ and fastens nucleation;⁸⁹ therefore, this process is a viable option for improving bioactivity & drug-loading efficiency. In subsequent studies, researchers have illustrated that various parameters such as aging time, microwave irradiation power, and time significantly impact HAp.⁹⁰

2.3 Sol–gel method

The sol–gel method (Fig. 4) is a prominent technology in the production of nanoparticles and is widely used in industries for exceptional purity and efficiency.⁹¹ This method involves the transformation of a sol into a gel, followed by subsequent drying and calcination steps to obtain the desired hydroxyapatite structure. The common source of Ca is calcium nitrate tetrahydrate [Ca(NO₃)₂·4H₂O] and that of P is phosphorus pentoxide (P₂O₅). Biocompatible sources, such as eggshell-derived calcium and trimethyl phosphate as a phosphorus source, have also been used. Water and ethanol are widely used solvents in the sol–gel method. Aging times vary from 1 hour (short process) up to 24 hours at room temperature; the drying temperature is typically kept at 80–100 °C, and calcination is done from 600 to 800 °C.^92–96 The sol–gel process offers the advantage of creating uniform and nanostructured materials at low processing temperatures.⁹⁷ Additionally, sol–gel coatings exhibit significant improvements in mechanical properties because of nanocrystalline grain structures.⁹⁸ Studies indicated that the grain structure morphology in sol–gel coatings contributes to superior biological and mechanical properties.⁹⁹ Besides, this method offers exceptional advantages, including precise control over particle size, morphology, versatility,¹⁰⁰ and the attainment of high purity and homogeneity.¹⁰¹ Some of the significant drawbacks of this method are that the precursors and solvents used in this process are costly,¹⁰² procedures such as aging and calcination are time-consuming,⁹³ and the possibility of the formation of a secondary phase of calcium oxide (CaO), which negatively impacts biocompatibility. The CaO content must be minimized through procedural adjustments or post-processing, such as washing with a dilute acid solution.¹⁰³

Fig. 4 Synthesis of hydroxyapatite by the sol–gel technique.

2.4 Hydrothermal method

Hydrothermal synthesis (Fig. 5) is a versatile, environmentally sustainable, and low-energy consumption method, which is used to create desired crystalline phases from slurries, solutions, or gels under mild reaction conditions.^104,105 Nanomaterials can be synthesized across a broad temperature range¹⁰⁶ with controlled size and morphology.¹⁰⁷ Various compounds, including simple and complex oxides, carbonates, silicates, chalcogenides, etc., are synthesized by this process. Furthermore, products with commercial value, including Be₃Al₂(SiO₃)₆ (beryl, emerald, and aquamarine), Al₂O₃ (corundum, ruby, and sapphire), BeAl₂O₄ (chrysoberyl and alexandrite), and ZnO (zincite) are grown by this method.¹⁰⁵ This process typically involves dissolving calcium- and phosphate-containing substances in distilled water to make a suspension, sealing the solution in an autoclave, and treating the precipitate at controlled temperature.^108,109 The reaction can be in a single or heterogeneous phase at pressures exceeding 100 kPa to initiate crystallization directly from solutions.¹¹⁰ The most common sources of starting material for hydrothermal synthesis of HAp include calcium nitrate tetrahydrate, Ca(NO₃)₂·4H₂O, and diammonium hydrogen phosphate, (NH₄)₂HPO₄. The synthesis temperature can be as low as 60 °C (minimum temperature for improved crystallinity) up to around 220 °C, the pH ranges from 3 to 11, a higher pH generally favoring the forward reaction for HAp formation, and synthesis time typically ranges from 24 to 72 hours.¹¹¹ Maintaining such conditions for extended periods increases energy consumption, making the process costly, which is one of the drawbacks of hydrothermal processes.¹¹²

Fig. 5 Synthesis of hydroxyapatite by the hydrothermal method.

3. Importance of modifiers in nano-HAp synthesis

The characteristics and applications of nanomaterials are greatly influenced by their size, morphology, and surface chemistry. One of the most effective strategies to control these properties is through the application of modifiers during synthesis. While synthesis without modifiers can yield pure materials, they have limited control over the morphology, homogeneity, and dispersibility of nanostructures compared to modifier-assisted synthesis, which actively influences nucleation, crystal growth, and surface interactions of nanostructures.¹¹³ For example, in two sets of experiments on HAp synthesis by the precipitation method, one without a modifier resulted in irregular particle growth with a size range of 8.4–24 nm,¹¹⁴ while another with a modifier produced rod- and flake-shaped particles ranging from 19 to 143 nm (depending on the modifier used).¹¹⁵ This tunability is essential for optimizing nano-HAp for specific applications, such as enhanced bioactivity in bone regeneration, increased surface area for catalytic reactions, or improved dispersion in composite materials. For instance, stearic acid, as a surface modifier, prevents agglomeration, promotes better thermal stability, and improves cell viability, making the synthesized HAp highly biocompatible.¹¹⁶ Similarly, ionic surfactants CTAB or SDS were found to be highly effective in shaping the anisometric growth of nano-HAp particles, which makes them good candidates for tissue engineering applications and drug delivery systems.¹¹⁷ Exploring the specific effects of modifiers over different synthesis techniques will provide deeper insights into the importance of modifiers in nano-HAp synthesis for targeted applications.

3.1 Effect of modifiers on different synthesis methods

3.1.1 Wet chemical technique. HAp as a photocatalyst has been used for degrading toxic wastes and is still being explored.¹¹⁸ A study via the wet chemical method to enhance the photocatalytic activity of HAp indicated that modified HAp using urea, palmitic acid, and naphthalene exerted significant influence on their performance (e.g., maximum degradation capacity of 7 mg g⁻¹ for 100% ethanol-derived HAp). In general, these modifiers alter the crystallographic structure of HAp, creating more active surfaces for dye degradation and inducing microstrain within the crystal lattice, which affects the material's optical properties and photocatalytic efficiency. Experimental data demonstrated that urea-modified HAp showed the lowest photocatalytic activity, with only 69.63% degradation and 5.57% degradation capacity. The reason behind this poor performance could be the lowest degree of crystallinity and highest microstrain, resulting in poor photocatalytic performance.¹¹⁹ Stearic acid (SA), a surface modifier, is considered a good candidate for surface modification as it prevents particle agglomeration via hydrogen bond formation between the hydroxyl groups on the HAp surface and the carboxylic groups of SA. Hydrocarbon chains form a layer that stabilizes the particles, acting as a mechanical barrier limiting particle aggregation.¹²⁰ As the experiment was conducted using two concentrations of SA (7% & 15%), the result indicated that 7% SA-coated HAp showed the best dispersion and a homogeneous structure with reduced particle size (60–77 nm), offering good bioactive composite characteristics. Excessive concentration of SA (15%) leads to larger particle aggregates due to the formation of multiple SA layers or excess SA particles forming their phase, which decreases structural integrity.¹²¹ Organic modifiers such as citric acid, acetic acid, glutamic acid, and gallic acid are used to control the nucleation and crystallinity of particles. In the synthesis of carbonated hydroxyapatite (CHAp), citric acid produced the smallest CHAp particles with a rod shape (19–25 nm), and since it is a strong chelator, it binds three calcium ions per citrate ion (calcium–citrate complex), mobilizing calcium ions, which influence crystal growth.¹²² Citric acid can produce smaller sized hydroxyapatite than sodium dodecyl sulphate and sodium dodecylbenzene sulphonate.¹²³ Acetic acid resulted in flake-shaped particles but were larger in size as it chelated one calcium ion per acetate ion and limited calcium availability less effectively than citric acid. Glutamic acid also produced rod-shaped particles but with a slightly larger size compared to citric acid because it affected calcium availability moderately. Meanwhile, gallic acid led to the largest particles (127–143 nm) with a flake shape due to the π–π stacking interaction between CHA and GA units, promoting agglomeration. Here, temperature plays an important role; with increasing temperature, crystallinity increases.¹¹⁵ Cationic functionalized nano-HAp materials are highly promising for gene therapy. Study with the incorporation of arginine (Arg) or polyethylenimine (branched PEI – bPEI, or linear PEI – LPEI) as cationic modifiers and dispersing agents showed significant improvement in colloidal stability and DNA binding ability of HAp. Compared to Arg, the length and aspect ratio of the synthesized particle were lower in PEI with higher dispersibility due to the high content of NH₂ free groups in PE, while LPEI was evident as most suitable to generate plate-like morphology, similar to natural bone components.¹²⁴ As a part of an eco-friendly experiment, different concentrations (5 mg, 10 mg, and 20 mg) of caffeine, a nitrogen-containing heterocyclic compound¹²⁵ as a modifier, were used, which improved the shape and morphology of HAp. The findings suggest that, similar to EDTA or citric acid, caffeine prevents clumping of nanoparticles¹²⁶ and also acts as a stabilizing agent by capping the surface¹²⁷ of forming HAp nanoparticles, leading to smaller particle size (HAp size ∼ 35 nm). Concentration should be considered before using caffeine as a modifier. A low concentration of caffeine (5 mg) did not show significant differences compared to non-modified HAp. According to TEM images, increasing concentration (20 mg) exhibited the highest crystallinity with sharp XRD peaks and well-defined rod-like morphology.¹²⁸ Mesoporous hydroxyapatite nanoparticles were successfully synthesized using chitosan, a natural polymer. During calcination, when chitosan was separated, pores formed in the voids (average pore diameter ∼ 38 nm). Data showed that as the weight ratio of chitosan increases with varying pH, it produces larger and more interconnected pores. This tunable pore structure makes HAp highly suitable for drug delivery applications¹²⁹ (Fig. 6).

Fig. 6 (i) TEM microphotographs of the synthesized nano-HAp: (a) HApA-10, (b) HApbPEI-10, and (c) HApLPEI-5.¹²⁴ (ii) SEM image of HAp with different modifiers: (A) urea, (B) palmitic acid, and (C) naphthalene.¹¹⁹

An overview of the response to using various modifiers in the synthesis of nano-HAp by the wet chemical method is provided in Table 2. This table highlights the key characteristics and outcomes associated with each modifier, offering a clear comparison of their effects.

Table 2 An overview of the effects of modifiers in synthesizing nano-HAp by the wet chemical method^a

Starting materials	Temp. (°C)	pH	Organic modifiers	Morphology	Particle size (nm)	Crystal size (nm)	Crystallinity	Ca/P	Pore size (nm)	Surface area (m^2 g^−1)	Application	Ref.
a All surface area and pore size measurements in this review paper were performed using the Brunauer–Emmett–Teller (BET) and the Barrett–Joyner–Halenda (BJH) methods, respectively, unless otherwise stated.
CaCl2·2H2O and 85% H3PO4	Room temp. (RT) to 80 °C	9	Citric acid	Rod-shaped	L: 19–25	—	28.6%	1.88	—	—	Dentistry, drug delivery system, and bone tissue engineering	115
					W: 13–20
			Acetic acid	Flake-shaped	L: 55–68		30%	1.66
					W: 22–50
			Glutamic acid	Rod-shaped	L: 33–43		27.7%	1.68
					W: 16–31
			Gallic acid	Flake-shaped	L: 127–143		25%	1.71
					W: 56–122
Ca(OH)2 and H3PO4	—	10–11	Naphthalene	Spherical	—	9.06	0.012	1.67	—	0.20	Photocatalysis	119
			Palmitic acid	Spherical		11.59	0.020			0.163
			Urea	Agglomeration		11.50	0.0038			0.165 (theoretical calculation)
Ca(NO3)2·4H2O and NH4NaHPO4·4H2O	RT	9	Arginine	Needle-like	L: 71.3	—	92.1%	1.56	—	—	Gene therapy	124
					W: 7.9
			Polyethylenimine branched (bPEI)	Plate-like	L: 45.9		92.2%	1.63
					W: 9.4
			Linear polyethylenimine (LPEI)		L: 32.2		94.6%	1.61
					W: 17.4
Ca(NO3)·2H2O and (NH4)2HPO4	RT	12	Caffeine, 5 mg	Nanorods clear in shape and size with increasing caffeine concentration	25–35	28	Improves with concentration	—	—	Larger	—	128
			10 mg			32
			20 mg			35
Ca(NO3)2·4H2O and NaH2PO4		8	Chitosan, 0 g	Spherical	—	38		1.36	28.5	21.3	Slow-release drug delivery and osteoporosis treatment	129
		9	0.1 g			34		1.48	29	36.5
		10	0.3 g			24		1.49	38.6	41.7
Calcium nitrate tetrahydrate and phosphoric acid (85%)	40 (post-treatment at 100 and 200 °C)	10	Citric acid	Rod-like	(At 100 °C) L: 15	—	Increases with increasing synthetic temp.	1.67	—	—	—	123
					W: 9
			Sodium dodecyl sulphate		L: 21			1.67
					W: 11
			Sodium dodecylbenzene sulphonate		L: 25			1.66
					W: 12
Calcium nitrate tetrahydrate and phosphoric acid (85%)	40 (post-treatment at 100 and 200 °C)	10	Polyethylene glycol (MW: 600)	Nanorod	(At 100 °C) L: 13	—	—	1.66	—	—	—	130
					W: 30
			Tween 20	Dendriform	L: 12			1.67
					W: 23
			Trisodium citrate	Nanorod	L: 10			1.65
					W: 17
			D-Sorbitol	Linear	L: 12			1.66
					W: 25
Ca(OH)2 and H3PO4	25	5	Lactic acid	Plate-like	∼19	—	—	1.05	—	—	Biomedical	131
		7		Spherical	∼111			1.32
		10			∼86			1.44
		12			∼48			1.55
Ca(NO3)2·4H2O and NH4HPO4	RT	3	PEG 600	Small agglomerates	50–60	—	—	—	0.18 cm^3 g^−1	23	Wastewater purification	132

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3.1.2 Microwave-assisted method. Organic modifiers such as EDTA, amino acids, CTAB, polyvinylpyrrolidone (PVP), and trisodium citrate showed significant influence on the morphology, crystallinity, and biocompatibility of HAp.¹³³ EDTA is a water-soluble polymer commonly used as a chelating agent and also as a complexing agent. It has been used as a capping agent for preparing various metal nanoparticles, including gold (Au), zinc (Zn), copper (Cu), and chromium (Cr).^134,135 Capping agents have clinical significance for modifying nanoparticles that are biocompatible¹³⁶ as surface capping enhances the biological properties and modifies the properties of colloidal suspensions.¹³⁴ EDTA⁴⁻, a complex reagent, is a member of the poly-amino carboxylic acid family. It acts as a hexadentate ligand while binding with Ca²⁺ ions, surrounding each Ca²⁺ ion with four oxygen atoms and two nitrogen atoms and forming several chelate rings in a stable Ca–EDTA complex.¹³⁷ Stable Ca–EDTA complexes control the crystal by modulating the availability of Ca²⁺.¹³⁸ One study using EDTA as a capping agent in the synthesis of hydroxyapatite (HAp) at varying pH^9,11,13 showed spectroscopic characteristics along with structural characteristics. The IR spectra of the samples indicated that EDTA-assisted samples are purer and uniform. The EDTA-assisted samples were structurally well-defined with smaller particle sizes (∼100 nm) and reduced carbonate contamination compared to the samples without EDTA.¹³⁹ Temperature plays a crucial role here with a higher sintering temperature of 1100 °C (pH 9), facilitating anisotropic growth, forming larger nanostrips.¹³⁸ Also, data indicated that at higher pH, the samples are more uniform and dispersed.¹³⁹ Similar to EDTA, oxalic acid, a chelating agent, forms calcium oxalate driven by the strong electrostatic attraction between the oxalate anions (C₂O₄²⁻) and calcium cations (Ca²⁺), which allows for controlled release of Ca²⁺ ions and prevents premature crystallization of HAp. In addition, oxalic acid increases the surface area and produces mesoporous HAp, which is highly preferable for drug delivery applications.^140,141 Cationic–anionic surfactants possess better adsorbent properties and are ideal for adsorption of dyes and metal ions. A study showed that the use of cationic–anionic surfactants (CTAB, sodium dodecylbenzene sulfonate (SDBS), and SDS) caused the surface area of HAp nanorods to increase (the surface area for individual anionic counterpart – 52 m² g⁻¹; for cationic – 48 m² g⁻¹; without surfactant – 19 m² g⁻¹; with a mixture of cationic–anionic surfactants, it was higher – 56 m² g⁻¹). They evaluated the adsorption capacity and found the maximum amount of dye adsorbed (methylene blue) was 833 mg g⁻¹.¹³⁷ CTAB has a potential ability to facilitate micelle formation. As the concentration increases, it reacts progressively to the PO₄³⁻ groups and creates an electrostatic barrier, effectively inhibiting longitudinal growth and yielding nanorods with smaller dimensions.^142,143 However, at much higher concentrations above the critical micelle concentration (CMC), flexible worm-like micelles form, providing elongated templates for particle growth.¹⁴⁴ Chitosan can generate well-dispersed nanoscale HA particles embedded in a polymeric matrix with a uniformly porous interconnected network. It is non-toxic to MG 63 osteoblasts with cell viability of up to 54.5%.¹⁴⁵ The modifiers typically used have exhibited some degree of toxicity, so researchers are shifting towards bio-friendly growth regulators, particularly those that naturally occur in the body, such as amino acids (glycine, serine, etc.). The electrostatic interaction between amino acids and the outer surface of nanocrystals of HAp leads to morphological changes. Adsorption of amino acids can occur on any specific crystallographic face, inhibiting growth in the perpendicular direction while allowing growth parallel to the face, which results in a larger surface area. They significantly reduce hydroxyapatite's aspect ratio and crystallinity, increasing the cytocompatibility.¹⁴⁶Moringa oleifera flower extract is another biofriendly option prepared by boiling dried moringa flowers and is rich in tannins and polyphenols. They act as chelating agents and enhance the structural and biological performance of synthesized HAp¹⁴⁷ (Fig. 7 and Table 3).

Fig. 7 (i) SEM image of citric-acid assisted HAp,¹⁵⁸ (ii) SEM image of Moringa oleifera flower extract capped hydroxyapatite,¹⁴⁷ and (iii) TEM images of HA powders prepared in the presence of (a) 15% alginic acid and (b) 15% sodium alginate.¹⁵⁰

Table 3 A summary of the effects of different types of modifiers in the structural variation of nano-hydroxyapatite synthesized by the microwave method

Starting material	MW power (W)	MW time (min)	Sintering temp. (°C)	pH	Modifier	Morphology	Particle size (nm)	Crystal size (nm)	Surface area (m^2 g^−1)	Pore size (nm)	Yield (%)	Ca/P	Application	Ref.
Ca(NO3)2·4H2O and (NH4)2HPO4	800	45	1100	9	EDTA	Uniform nanostrips	L: 50–100	30–50	—	—	—	—	—	138
Calcium nitrate tetrahydrate and diammonium hydrogen phosphate	750	30	900	9	EDTA	Capsule-like	D: ∼10	—	—	—	—	—	Biomedical	139
				11		Scattered needle-like	L: ∼100
				13		Flower-like
CaNO3·4H2O and Na2HPO4	700	30	—	11	EDTA	Bow knot-like	W: 150	—	—	—	—	—	—	148
				13		Flower-like flakes	W: 150–200
Ca(NO3)2·4H2O and KH2PO4	700	20	—	13	Oxalic acid	Loosely agglomerated nanorods	L: 20–40	—	89	—	—	1.77	Biomedical	140
					SDS		L: 45–100		48			1.55
Ca(NO3)2·4H2O and NH4H2PO4	—	10	550	10	CTAB	Rod-shaped	L: varies from 80–120	—	48.8	—	—	—	Dye and heavy metal absorption	149
					SDS				52.8
					SDBS				50.4 (BET)
Ca(OH)2 and (NH4)2HPO4	800	300	—	11	Sodium alginate 5%	Aggregated nanocrystals	L: 50	25	—	—	—	—	Biomedical	150
					10%			24
					15%			22
					Alginic acid 5%			24
					10%			22
					19%			19
Ca(NO3)2·4H2O and (NH4)2HPO4	900	20	—	—	EDTA	Spherical	22	—	—	—	—	1.686	Electrochemical sensing of uric acid	151
Ca(NO3)2·4H2O and (NH4)2HPO4	300	20 s	—	—	Chitosan	Porous	50–70	65	—	112–343 μm (scaffold)	—	1.65	Bone tissue engineering	145
Ca(OH)2 and H2PO4	35	10	100	12	Moringa oleifera flower extract	Rod-like	41	18.6	—	—	—	1.81	Antimicrobial	147
Eggshells and NH2HPO4	900	—	900		EDTA	Flower-like	500 nm to 1.5 μm	—	—	—	At pH 13 19.6	1.37	Biomedical	152
				11	0.1
				12	0.2						50.4	1.51
				13	0.3						84.3	1.62
Ca(NO3)2·4H2O and (NH4)2HPO4	—	30	500	>10	Sodium lauryl ether sulfate (SLES)	Rod-like	L: 52	19.9	48	35.4	—	1.67	—	153
							W: 18
					Linear alkylbenzene sulfonate (LABS)		L: 80	19.2	60 (BET)	35.3 (BJH)
							W: 20
Eggshells and NH2HPO4	600	10 min	—	8	EDTA	Flower-like	L: 0.5–1 μm	—	—	—	—	1.65	Drug delivery	154
							W: 100–200 nm
Ca(NO3)2·4H2O and (NH4)2HPO4	400	45	—	6.1	Licorice root extract	Rod-like	L: 105	38	—	—	—	1.69	Biomedical	155
							W: 25
Ca(NO3)2·4H2O and (NH4)2HPO4	800	30	—	10	EDTA	Mixed	L: ∼71	23–34	20.63	2.29	—	—	—	156
					CTAB	Mixed	W: ∼16	26–33	22.65 (BET)	4.3
Black Chlamys varia seashell and K2HPO4	700	20	—	13	SDS	Rod-like	L: 300–600	—	49	2.46	—	1.42	Biomedical	157
							W: 10–15
Eggshells and potassium phosphate	700	30	—	13	Citric acid	Rod-like	L: 7–10	—	58.3 (BET)	7	—	1.86	Biocidal implant application	158
							W: 20–30
Ca(NO3)·4H2O and (NH4)2HPO4	—	30	—	10	CTAB	Rod-like	L: 242–136	51–47	—	—		1.69	Gas sensing and biomaterial applications	159
Ca(NO3)·4H2O and (NH4)2HPO4	—	30	—	9	(Amino acids) glycine	Irregular changes with concentration	Length 100–53	—	70–93	—	—	—	Scaffolds and drug delivery	146
					Serine		85–55		78–86

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3.1.3 Sol–gel method. For targeted applications, researchers started applying modifiers in the sol–gel method to fine-tune the characteristics of nano-hydroxyapatite. Organic modifiers such as trisodium citrate, citric acid, polyethylene glycol, Tween 20, D-sorbitol, ethylene glycol, and sodium dodecyl sulphate are widely used.¹⁶⁰ Mesoporous hydroxyapatite (MPHA) is highly biocompatible with a high surface–volume ratio and adsorption capability. To synthesize MPHA, stearic acid (SA), a surface modifier,¹⁶¹ resulted in high surface area, porosity, and pore size (5.84 nm – BET analysis), and excellent cytocompatibility with high cell viability (up to 83%). It was suggested that the carboxyl group in stearic acid likely adhered to the surface of the HAp during the process, creating small, uniformly distributed pores. Also, the strong interaction between SA and ethanol organized cylindrical structures (micelles), helping to create rod-like HAp. pH was a pivotal parameter here. Only pH 11 resulted in a well-defined structure, while pH 7 and 9 contained impurities like β-TCP (FESEM analysis) with a sponge-like structure.¹⁶² As a templating agent, CTAB can also produce porous HAp ranging from 6 to 10 nm with varying concentrations of CTAB.¹⁶³ Another templating agent, polyethylene glycol (MW 600), modifies the morphology of particles where nano-HAp appears to be agglomerated with sub-microscopic pores. Its flexibility allows its chains to interact with hydroxyapatite nanocrystals. The ether bonds (–O–) of polyethylene glycol interact with HAp nanocrystals, guiding them to grow in a specific direction. The flexibility is highly temperature sensitive in aqueous solution, which is a drawback of polyethylene glycol. At higher temperatures, it acts like a soft template, encouraging organized, oriented growth along certain axes and promoting the formation of flat, platelet-like HAp structures instead of random shapes, which is beneficial for biomedical use. A study using sintering temperatures of 400 °C, 750 °C, and 1100 °C showed that only at 1100 °C were the X-ray patterns aligned with ASTM data.¹⁶⁴ Citric acid is quite a common modifier used in the synthesis process of HAp.¹⁶⁵ When citric acid is used as a modifier, it forms a calcium–citrate complex. This chelating effect moderates the availability of free calcium ions in solution and limits the size of the HAp particles formed.¹⁶⁶ While synthesizing hydroxyapatite–calcite, data indicated that at 60 °C samples with citric acid modifiers produced smaller sized particles (55 nm) with lower crystallinity compared to samples without citric acid (particle size ∼ 84 nm), which is a good fit for biomedical applications. Temperature, pH, and concentration of citric acid are vital in these preparations (e.g., at room temperature, the particle size reduces to 51 nm from 55 nm (at 60 °C)).¹⁶⁰ Lemon extract, a natural source of citric acid, has also been used, and the resultant HAp showed well-defined characteristics with suitability for cancer treatment.¹⁶⁷ EDTA as a chelator can form mesoporous HAp with a surface area of up to 155 m² g⁻¹ with robust ion exchange capacity, making it an efficient absorbent for radioactive materials (55–63% uptake of U(VI) and Cs(I) within 10 minutes) with maximum adsorption capacities of 77.2 mg g⁻¹ for Cs(I) and 59.3 mg g⁻¹ for U(VI).¹⁶⁸ Latex and carbon fibers work as pore-forming templates and can generate HAp with micro-, meso-, and macropores (up to 100 nm) with a high surface area¹⁶⁹ (Fig. 8 and Table 4).

Fig. 8 SEM images of (i) modifier (0.1 M CTAB)-assisted HAp spheroidal particles¹⁶³ and (ii) stearic acid-assisted HAp at pH 7 (a and a2), pH 9 (b and b2), and pH 11 (c and c2), with uniform rod-like structures at 40k and 80k times magnification of the sample.¹⁷⁰

Table 4 An overview of the effects of modifiers in synthesizing nano-HAp by the sol–gel method

Starting material	Solvent	pH	Reaction temp. (°C)	Modifiers	Morphology	Ca/P	Particle size (nm)	Crystal size	Crystallinity	Specific surface area (m^2 g^−1)	Pore size (nm)	Application	Ref.
Ca(NO3)2·4H2O, 98%, (NH4)2HPO4, 99%	Deionized (DI) water	>10	Room temp.	Citric acid	Agglomerated (calcined at 400 °C)	—	51	—	3.61	—	—	Biomedical	160
			60				55		4.35
Ca(NO3)2·4H2O and (NH4)2HPO4	Ethanol	10	85	5% polyethylene glycol	Agglomerated (with sub-micrometric pores)	—	50–70	—	—	—	Sub-micrometric	Biomaterial in bone implantation	164
Ca(NO3)·4H2O and (NH4)2HPO4	Ethanol	7	—	Stearic acid	Rod-like (uniform)	1.602	—	11	(%) 1.749	∼7.7138	5.85	Drug delivery and bone tissue engineering	170
		9				1.55		11	1.757	∼10.519
		11				1.68		10	1.799	∼66.265
Ca(NO3)2·4H2O	Diluted water and ethanol	—	48	Polyethylene glycol	Needle-shaped	—	—	Avg 40–50	—	—	—	—	171
				Acetic acid	More agglomerated
				Together	Complex morphology
Ca(NO3)2·4H2O and H2PO4	Distilled water	9	50–120	Lemon extract	Spherical	1.59	25–35	—	—	—	—	Cancer treatment	167
Ca(NO3)2·4H2O and (NH4)2HPO4	Double distilled Millipore water	11	70	CTAB (0.1 M)	Spheroid	—	20–100	—	—	51.8	7.83	Drug delivery, antioxidant	163
CaCO3 and (NH4)2HPO4	Distilled water	11	80	Alginic acid	Agglomerated	—	50–100	—	—	—	—	Biomedical application	172
Ca(NO3)2·4H2O and H2PO4	Ethanol/DIW	7.9	70	EDTA	Irregular flaky-flower	—	—	—	—	155	4.2	Adsorbent for radioactive ion remediation	168
Ca(NO3)2·4H2O and P2O5	Alcoholic and aqueous solutions	3–9	60	CTAB	Spherical	—	50	—	—	—	2 density functional theory (DFT)	Coating material	173
CaCl2·2H2O, (NH4)2HPO4	Water		90	Siloxane-acrylate latex and carbon fibers	Needle-like	—	—	—	—	61.7	50–100	Bone tissue regeneration	169
Ca(NO3)2·4H2O and (NH4)2HPO4	Deionized water	—	150	Natural rubber latex	Plate-like	1.67	30–72	65–74 (calcination temp.: 600)	1.6–2.3	—	—	—	174

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3.1.4 Hydrothermal method. Amino acids such as glutamine, alanine, and valine can tailor the morphology and crystallinity of HAp for efficient application.¹⁷⁵ A study using glutamine in the hydrothermal synthesis, which is simple and cost-effective, produced nano-rods of HAp with average lengths ranging from 50 to 100 nm. Being a biomolecule, glutamine is non-toxic and environmentally friendly. They can imitate biomineralization, a natural process (biomimetic method).¹⁷⁶ Another eco-friendly option is alginate, a naturally occurring linear polysaccharide commonly found in different brown seaweeds. As a modifier, they adsorb onto the surface of specific crystallographic planes of HAp nuclei, which blocks further ion attachment along the c-axis. Under hydrothermal conditions, alginate depolymerizes to oligosaccharides and monosaccharides. These anionic groups actively adsorb onto the surface.¹⁷⁷ In an experiment with three different concentrations of alginate (HA-0.4%, HA-0.8%, and HA-1.6%) and a sample without alginate, the effect of alginate on the morphology of HAp was evident. The XRD analysis revealed that with increasing concentration of alginate, the crystallinity decreases, and the particles become smaller and more aggregated. The SEM images showed that nanoparticles become more dispersed at higher alginate concentrations. If the goal is to get a well-defined rod-like structure, then glutamine is more suitable, as alginate gives less defined rod-like structures of HAp.¹⁷⁸ Saponin, a plant-derived surfactant, forms micelle-like structures that influence crystal nucleation and growth of the synthesized HAp. With increasing concentration of saponin, the nanorods become thinner and more acicular. It contributes antifungal and antibacterial properties and enhances the surface activity of HAp.¹⁷⁹ For mesoporous HAp under hydrothermal conditions, the use of Triton X-100 resulted in increased pore volume. Triton X-100 is a non-ionic surfactant that hinders clumping of HAp particles through van der Waals interactions, contributes to particle stability in suspension, leads to the formation of rod-like structures following oriented attachment of crystal growth (at high concentrations), and under hydrothermal conditions alters the pore structure (increases the pore volume). Although Triton X-100 has a similar hydrophilic side chain as polyethylene glycol (PEG), both show differences, while even at higher concentrations Triton X-100 does not have any impact on the crystallization process,¹⁸⁰ and PEG, on the other hand, influences crystal growth, which is mediated by temperature. With increasing temperature, crystallinity increases.^181,182 Different approaches of the hydrothermal method, including the use of novel techniques such as sono-chemical for biomedical applications along with organic surfactants like CTAB, can control the properties of particles. SEM analysis shows a well-defined rod-like structure with a diameter of 30–50 nm, which remained intact even after prolonged ultrasonic treatment. Residence time in the autoclave is an important parameter here; TEM images revealed that with increasing time (20 h), the diameter changes to 15–40 nm.¹⁸³ Furthermore, CTAB showed contradictory outcomes in the present study, where the former study encouraged that CTAB likely favors the growth of HAp crystals along the c-axis,⁵¹ and the study suggested that CTAB can block the growth along the c-axis. CTAB and PO₄³⁻ both have tetrahedral structures; this structural complementarity and the electrostatic effect sometimes lead to the adsorption of CTAB ions on the (001) planes of HAp, which may block the crystal growth along the c-axis, producing shorter nanorods rather than longer ones.¹⁸⁴ SDS is another surfactant that can be used instead of CTAB for its similar effect.¹⁸³ The EDTA-assisted hydrothermal process was used to synthesize a complex three-dimensional dandelion-like HAp, as EDTA controls agglomeration, growth, and is also cost-effective. Dandelion-like HAp possesses a high specific surface area and relevant properties for catalysts and molecular sieves.¹⁸⁵ The mechanism here can be described as involving the Ca–EDTA complex (mentioned in 2.2.1), which facilitates the radial self-assembly into dandelion-like HAp¹⁸⁶ (Fig. 9 and Table 5).

Fig. 9 SEM images of HAp synthesized with different modifiers: (i) PEG 400 assisted rod-like HAp,¹⁹⁴ (ii) EDTA assisted dandelion-like structure,¹⁸⁵ and (iii) aminotris assisted spherical nanoparticles of HAp.¹⁸⁸

Table 5 An overview of the effects of modifiers in synthesizing nano-HAp by the hydrothermal method

Starting materials	Modifiers	Temp. (°C)	Time (hour)	pH	Morphology	Particle size (nm)	Crystallinity	Pore size (nm)	Pore volume (cm^3 g^−1)	Ca/P	Application	Ref.
Ca(NO3)2·4H2O and (NH4)2HPO4	Triton X-100 (4% or 8%)	100	6	10.4	Nano-rods	31–90 (4%)	—	7.4–55	—	—	Catalysis	180
						33–159 (8%)
Ca(OH)2 and H3PO4	Urea	180	3	10–11	Small aggregates	38.745	0.154	—	—	1.67	Drug delivery	186
	Naphthalene				Controlled growth	53.236	0.308
	Palmitic acid				Excessive aggregated	50.798	0.027
Ca(NO3)2·4H2O and H3PO4	Trisodium citrate	100	8	10	Nano-rods	17.6	Increases with autoclaving temp	—	—	1.61	—	187
	Tween 20					23.0				1.65
	Polyethylene glycol (MW: 600)					30.2				1.66
CaCl2 and NaH2PO4·2H2O	Alginate 0.4%	200	5	12	Less-defined rod-like particles	44	Decreases with concentration		0.380 cm^3 g^−1	—	Tissue engineering	178
	0.8%					38			0.327 cm^3 g^−1
	1.6%					33			0.335 cm^3 g^−1
CaHPO4·2H2O	CTAB	150	2	—	Rod-like	50–30	Increases with concentration	—	—	1.67	Clinical application	183
Ca(NO3)2 and Na3PO4	CTAB and SDS	150	10	—	Nano rods	150	—	—	—	1.59	—	51
	PVA				Aggregates
CaCl2 and K2HPO4	EDTA	50	1.5	12	Dandelion-like	200 avg (individual nanorods)	Increases	—	—	—	Catalyst, molecular sieves, and biosensors	185
Ca(C2H3O2)2·H2O and H3PO4	Aminotris (methylene phosphonic acid) (ATMP)	140	6–24	9	Spherical shape	30–80	—	—	—	—	—	188
CaCl2 and H3PO4	CTAB	90	24	10–10.5	Rod-like	L: ∼75	—	—	—	—	Biomedical	189
	SDS				Thin rods	L: ∼137
	Triton X-100				Rods & spheres	L: ∼79
Hydroxyapatite	EDTA	70	6	6	Agglomerated rods	>100	—	—	—	—	Filler for dental restorative materials	190
	SDS			8	Smallest rods
	Apricot tree gum (ATG)			10	Largest rods
Ca(NO3)2·4H2O and (NH4)2HPO4	Polyvinylpyrrolidone (PVP)	120–180	12	—	Compact spheres (180 °C)	10 μm	—	—	—	—	Biomedical	191
Ca(NO3)2 and (NH4)2HPO4	Fruit extract mango	180	24	10–11	Rod-like	L: 265	60%		—	—	Manufacture of bone substitutes	192
	Grape					L: 148	65%
	Tamarind					L: 222	55%
Ca(NO3)2 and (NH4)2HPO4	Ceiba pentandra (KAPOK)	180	20	10	Tubular	10.32–45.5 (inner diameter)	—	—	—	—	Drug delivery	193
Ca(NO3)2·4H2O and (NH4)2HPO4	CTAB	90–150	22	7	Rod-like	50–80 (150 °C)	—	—	—	—	Biomaterial	194
	PEG 400
Ca(NO3)2·4H2O and (NH4)2HPO4	Saponin (0.5 to 5 g)	200	5	11	Rod like (0.5 g)	L: 72–150 (0.5 g)	2.23 (0.5 g)	—	—	1.59	Bone regeneration and antimicrobial coatings	179
					Needle like (5 g)		3.31 (5 g)
CaCl2 and K2HPO4·3H2O	CTAB	40	24	12	Ill-defined clusters	—	—	5.2	—	—	Biomedical	195
		80			Needle-like			2.1
		160			Rod-like			1.9 (not mentioned)
CaCl2 and K2HPO4·3H2O	CTAB	60–150	2	12	Rod-like	D: ∼20–15	—	—	—	—	—	196
						L: ∼60–150 (varies with temperature and time)				—
Ca(OH)2 and H3PO4	Succinic acid	180	3	10–11	Cluster-like	—	(16.1 ± 0.5) × 10^−3	—	—	—	Bone implants and drug delivery systems	249
	Ascorbic acid				Cloud-like	—	1.49 ± 0.05	—	—	—	Biomedical uses
	Stearic acid				Rod-like or needle-like	—	4.096 ± 0.1	—	—	—	Energy storage materials
CaCl2·2H2O and K2HPO4	EDTA	120	4	5	Plate-like	—	—	—	—	1.41	—	197
		140		7	Thin blade	5–10 μm				1.59
				9	Thin blade	1.5 μm in length				1.61

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3.1.5 Special class of modification. Doping hydroxyapatite (HAp) with foreign ions has gained much recognition in recent times for effectively altering properties such as size, morphology, surface charge, porosity, and topology, compared to other structural modifications.¹⁹⁸ Different dopants such as Zn, Cu,¹⁹⁹ Mg,²⁰⁰ Sr,²⁰¹ Ag,²⁰² Mn,²⁰³ Se, and F²⁰⁴ are used for biomedical applications, coating materials,²⁰⁵ anti-microbial effect,²⁰⁶ human hepatoma cells,²⁰⁷ catalytic activities,²⁰⁸ and so on. The choice of dopant depends on its functionality, structural compatibility, solubility, mechanical enhancement, and application. More than half of the elements in the periodic table can be incorporated into the HAp structure. Considering the potential toxicity and radioactivity of certain elements, some have not been tested yet. 72 out of 118 elements have been successfully incorporated into HAp, representing 61% of the periodic table.²⁰⁹ They can be introduced as single elements or binary and multiple.²¹⁰ Single incorporation is done for altering specific properties, such as Mg to improve cellular behavior.²¹¹ Binary or multi-ions enhance multi-functionalities, for example, Sr–Zn doping maintains a higher HAp phase percentage (>93%) and crystallinity higher than the value of 71%,²¹² and Mg, Si, and CO₃ together enhanced the solubility rate of HAp with ion release for a longer period.²¹³ The synthesis process of single ion doping in the HAp structure is easier and less complex than that using binary or multiple ions (Table 6).

Table 6 An overview of the effects of dopants on nano-HAp

Starting material	Method	Dopant	Additive	pH	Reaction temperature (°C)	Morphology	Particle size (nm)	Crystallinity	Crystal size (nm)	Surface area (m^2 g^−1)	Application	Ref.
Ca(NO3)2·4H2O and (NH4)2HPO4	Chemical co-precipitation	Mg	—	11	80	Spherical nanoparticles with a uniform distribution	∼93.3	Reduced	—	—	Antimicrobial activity	214
CaCl2·2H2O and H3PO4	Modified sol–gel technique	Europium (Eu)	Triethylamine (TEA) and dimethyl sulfoxide (DMSO)	10	Room temp.	Short rod-shaped	∼48 (length)	—	4.29 (1% Eu)	—	Bioimaging	215
		Samarium (Sm)				Mixed	∼74 for long, ∼28 for short		4.78 (1% Sm)
Ca(NO3)2·4H2O and (NH4)2HPO4	Reflux method	Fe 0.05 M	—	10	70	Spherical-shaped with slight agglomeration (0.05 and 0.1 M) and needle-like (0.2 M)	—	Decreases with increasing Fe concentration	6.63	—	Anti-bacterial	216
		0.1 M							4.5
		0.2 M							3.53
Ca(NO3)2·4H2O and (NH4)2HPO4	Sol–gel synthesis	Ce	—	—	40	Ellipsoidal	∼10 to 25 nm	—	9.4 ± 0.5 nm	—	Antifungal	217
CaCl2·2H2O and (NH4)2HPO4	Co-precipitation	Zn	Casein	—	30	Rod-like	27 (1%)	Reduced	—	138–182	Antimicrobial	218
							26 (2%)
Ca(OH)2 and H3PO4	Wet-chemical	Cu	—	10–11	25	Rod-like	—	∼2–6.7	∼65–43	—	Dye degradation	219
Ca(NO3)2 and (NH4)2HPO4	Wet chemical	Pd	—	9.4–9.5	Room temp.	Highly agglomerated	58.2	—	Larger crystal	—	Electrocatalytic detection of hydrazine	220
Ca(NO3)2 and (NH4)2HPO4	Combustion method	Ag–F	Urea	—	600	Rod-like	8 to 63	—	—	—	Biomedical	221
Ca(OH)2 and H3PO4	Wet precipitation	Zn (5%)	—	11	Room temp.	Needle-like	10–20	0.330	23	—	Drug delivery	222
Ca(OH)2 and H3PO4	Chemical precipitation	Ag	Trisodium citrate and urea	12.5	100	—	58	87%	—	—	Orthopedic and body implantation	223
HAp	Ion-exchanged method combined with calcination	Co	—	—	Ambient temp	—	150	—	—	45–52	Catalyst	224
Calcium nitrate tetrahydrate and potassium dihydrogen phosphate	Surfactant-mediated approach	Co	Triton X-100 and nitric acid	—	—	Needle-shaped	30–60	—	52–16	—	Implant and reconstructive surgery applications	225
Ca(NO3)2·4H2O and (NH4)2HPO4	Sol–gel	Ni	—	10	—	Spherical	40–50	—	39.91	—	Orthopedic and surgical procedures	226
Ca(NO3)2·4H2O and (NH4)2HPO4	Wet-chemical	Ni	CTAB	10–12	80	Spheroid shape	15–25	22–42%	111.7–83	—	Bone tissue engineering	227
Cow's cortical bone	Ball-milling	Li	Stearic acid	—	—	Cauliflower-shaped	60–120	95%	89–59	—	Bone scaffold application	228
Ca(NO3)2·4H2O and (NH4)2HPO4	Sol–gel	Sr	—	10–11	50	—	200	—	—	115.7	Adsorbent for Cd(II) removal from wastewater	229
Ca(NO3)2·6H2O and (NH4)2HPO4	Chemical co-precipitation	Zn	—	11	—	Round	—	—	60–41	—	Bone tissue engineering	230
Ca(OH)2 and H3PO4	Wet-chemical precipitation	Eu	—	8	80	Rod-like	100	—	18–13	—	Drug/gene carrier	231
		Fe
Ca(OH)2 and H3PO4	Hydrothermal	Si	—	—	—	Spherical	—	—	Decrease	—	Biomedical	232
Ca(OH)2 and H3PO4	Microwave-assisted co-precipitation	Al	—	—	Room temp.	Spherical and plate-shaped	61–90	—	35–77	—	Orthopedic application	233

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4. Discussion

4.1 Synthesis methods

As stated before, there are several synthesis methods for HAp, and each of these methods has its advantages and drawbacks, which make them suitable for specific applications. To ensure the large-scale production and practical application of HAp nanoparticles, a simple, environmentally sustainable synthesis method with high-quality nanoparticle yield in significant quantities is essential (Table 7).

Table 7 Comparison of synthesis techniques

Methods	Advantages	Limitations	Best application	Ref.
Wet chemical	Simple and low-temperature processing	Lower crystallinity	Photocatalysis	119
Microwave-assisted	Rapid synthesis, energy-efficient, and higher crystallinity	Requires specialized equipment	Drug delivery and rapid HAp production	234
Sol–gel	High purity, homogeneity, and controlled morphology	Long processing time, requires organic solvents	Biomedical application and composite materials	170
Hydrothermal	Lesser energy requirement, high crystallinity, uniform morphology, and tunable porosity	Requires high pressure and long reaction times	Bone tissue engineering and bioactive coatings	235

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Hydrothermal synthesis became widely recognized in the 20th century.²³⁵ Its ability to create high-purity end products, improved morphological control,²³⁶ and compatibility with large-capacity equipment revived commercial interest.²³⁷ Similarly, microwave-assisted synthesis is another promising technique because of its uniform heating, faster reaction rates, and pollution-free operation, which result in narrower size distributions, improved crystallinity, and smaller particle sizes.²³⁸ Also, it is affordable, which increases the appropriateness for production on a wide scale.

4.2 Suitable modifier for specific applications

Selection of the optimal combination of synthesis route and modifiers mainly depends on the target application. For photocatalytic activity, the wet chemical method with the organic modifier naphthalene is preferable as it increases the surface area and results in a higher degradation percentage and capacity.¹¹⁹ In bone tissue engineering, citric acid is a good option for its ability to control nucleation and crystallinity, and it also produces smaller, rod-shaped particles.¹¹⁵ However, the sol–gel method with stearic acid (SA) works better, as mesoporous hydroxyapatite (MPHA) offers high biocompatibility, an increased surface-to-volume ratio, and improved adsorption capability. Stearic acid also contributes to high surface area and porosity, with a pore size of 5.84 nm (BET analysis) and exceptional cytocompatibility, achieving cell viability of up to 83%.¹⁷⁰

For gene therapy, LPEI is the most suitable modifier, as it improves the strength of biocomposites and produces plate-like morphology, making it a preferred choice.¹²⁴ In drug delivery applications, some modifiers work very well, such as oxalic acid (with a surface area of 89 m² g⁻¹), which enhances the porosity and mesoporous structure, making it highly effective.¹⁴⁰ A non-toxic alternative is serine with the microwave-assisted method, which has a stronger electrostatic effect on the surface of the crystal, resulting in a great impact on crystallization characteristics, which enhances biocompatibility and is promising for drug delivery applications.¹⁴⁶ Chitosan as a modifier increases pore size (average pore diameter ∼ 38 nm), which makes it particularly useful for slow drug release applications, especially for osteoporosis treatment.¹²⁹ Under hydrothermal conditions, Triton X-100 increases the pore volume and effectively produces a combination of meso- and macropores suitable for catalysis and drug delivery.¹⁸⁰ For eco-friendly synthesis, caffeine can be considered as it prevents agglomeration of nanoparticles similar to citric acid, and it promotes the formation of well-defined nanorods, with improved shape and size as the concentration increases.¹²⁸ EDTA is beneficial for electrochemical sensing of uric acid and biosensor applications.^146,186 EDTA is also preferred for synthesizing hydroxyapatite (HAp) with high surface area, uniform microporosity, and strong ion-exchange capacity, and is promising for environmental remediation and nuclear wastewater treatment applications.¹⁶⁸ In adsorption applications, a combination of cationic–anionic surfactants (CTAB, SDBS, and SDS) increases the surface area, leading to better dye adsorption capacity.¹⁴⁹

5. Challenges and limitations

While modifiers play a crucial role in controlling the morphology, porosity, and surface area of HAp nanomaterials,¹⁵³ their use also presents certain limitations and challenges. One of the primary concerns is the cost associated with modifiers. They can significantly increase the overall expense of the synthesis process. Studies suggested that phase-pure HAp nanorods can be synthesized through simpler, cost-effective routes without the need for hard templates or surfactants,¹⁴² thereby raising doubt about the necessity of modifiers in certain applications. Some modifiers work better at higher temperatures, for instance, glutamic acid shows lower solubility at room temperature, and solubility increases with higher temperature.²³⁹ Experimental data showed that the solubility of gallic acid increases from ∼0.72 to ∼29 g per 100 g water for 273 K to 373 K temperature.²⁴⁰ Achieving higher temperatures is another cost-intensive factor for a process. Concentration control of modifiers is another significant obstacle. As mentioned before, with increasing concentration, caffeine produces nano-HAp with well-defined characteristics, but higher concentrations can lead to excessive particle growth and secondary agglomeration if not controlled properly.¹²⁸ It emphasizes the importance of optimization to avoid structural inconsistencies and material loss. Some modifiers possess environmental risk due to their potential toxicity. The toxicity of common surfactants like Tergitol NP-10, Triton X-100, and Tween 40 was evaluated using the Microtox® acute toxicity test. According to the findings, all of these surfactants had EC₅₀ values less than 100 mg L⁻¹, suggesting that they are somewhat toxic and could be dangerous for aquatic life.²⁴¹ Use of surfactants is estimated at over 15 million tonnes per year, and reports indicate that up to 60% (by weight) may be discharged into water bodies. Synthetic surfactants tend to persist in ecosystems due to their low biodegradability, where they can disrupt biological processes, promote eutrophication, and cause foaming in water bodies. Furthermore, their degradation byproducts may exhibit higher toxicity than the original compounds, and they can facilitate the mobilization of other contaminants, such as heavy metals.²⁴² Some surfactants, such as SDS, cocamidopropyl betaine (CAPB), have been shown to cause significant cytotoxicity in uncalcined hydroxyapatite (HAp), with cell viability dropping below 70%, compromising biocompatibility.²⁴³ Therefore, the implementation of modifiers must be evaluated against cost, processing complexity, environmental concerns, and scalability to ensure workable and effective synthesis methodologies for biomedical and industrial use.

6. Future recommendations

From the identified limitations, it is clear that we need to explore more eco-friendly substituts to improve the sustainability and versatility of HAp synthesis. One promising approach is using inexpensive, natural modifiers such as tea polyphenols, which can improve the mechanical strength, osteoconductivity, and biocompatibility with necessary porosity and crystallinity for biomedical applications.²⁴⁴ Researchers should explore other natural compounds with similar benefits. Another environment-friendly way is the synthesis of HAp from biogenic sources, such as eggshells, fish bones, and mussels,^245,246 which can minimize waste, cut production costs, and preserve high material purity along with modifiers.²⁴⁷ Expanding research on these biogenic HAp syntheses can help with environmental cleanup and sustainable biomedical applications, and it can be a good substitute for traditional synthetic techniques. On top of that, advanced modeling techniques, such as numerical analysis for scaffold fabrication, offer a powerful tool for optimizing sintering temperatures, compaction loads, and microstructural integrity.²⁴⁸ These computational approaches can improve the mechanical performance of HAp scaffolds, which may ensure their suitability for clinical applications where structural reliability is vital, and subsequent studies can improve potential weaknesses and optimize system efficiency.

7. Conclusion

HAp can be synthesized through various methods; among them, four methods are mostly common: the wet chemical technique, microwave-assisted method, sol–gel method, and hydrothermal method. As the diversity of HAp applications expanded, modifiers such as CTAB, EDTA, amino acids, urea, fatty acids, Triton X-100, polyethylene glycol, citric acid, SDS, etc., were considered by researchers to synthesize HAp particles with a uniform shape, size, and properties. In general, these modifiers control the crystallization process and promote growth in a particular direction. Strong chelating agents such as citric acid and EDTA produce uniform particles as they limit calcium availability effectively. Chelating agents, surfactants, and natural polymers such as chitosan can produce larger and interconnected pores, making nano-HAp highly suitable for biomedical applications, particularly for drug delivery. Currently, researchers are prioritizing eco-friendly modifiers such as caffeine or amino acids. Caffeine works as a stabilizing agent by interacting with the surface of nanoparticles. Amino acids, on the other hand, promote growth in a particular direction by adsorbing on the outer surface of nanocrystals. Notably, the fundamental mechanisms of these modifiers that influence HAp synthesis remain consistent across different synthesis methods. Instead, it is the variation in the concentration of these modifiers and the reaction conditions—such as temperature, pH, and synthesis duration—that primarily drive differences in the resulting HAp structure and morphology. Despite the benefits of modifiers in customizing the morphology of nano-HAp, their use in the synthesis process is relatively unexplored. This is mainly due to the complexity of synthesis, cost, application-specific limitations, and environmental concerns. However, future researchers can focus on eco-friendly, biocompatible modifiers in nano-HAp synthesis to expand applications while addressing cost, versatility, and safety.

Data availability

Data will be made available on request.

Author contributions

Nahida Sultana Bristy contributed to conceptualization, methodology, analysis, writing – original draft, and writing – review and editing. Md. Kawsar contributed to conceptualization, writing – review and editing, and validation. Md. Sahadat Hossain contributed to supervision, writing – review and editing, and validation.

Conflicts of interest

The authors have no conflicts to declare.

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