Hydroxyapatite (

IMA IMA or Ima may refer to: Education * Indian Military Academy, Dehradun * Instituto Miguel Ángel, a school in Mexico City Galleries and museums * Indianapolis Museum of Art, Indiana, US * Institut du Monde Arabe, Paris, France * Islamic Mus ...

name: hydroxylapatite) (Hap, HAp, or HA) is a naturally occurring

mineral In geology and mineralogy, a mineral or mineral species is, broadly speaking, a solid substance with a fairly well-defined chemical composition and a specific crystal structure that occurs naturally in pure form.John P. Rafferty, ed. (2011): Mi ...

form of

calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...

apatite Apatite is a group of phosphate minerals, usually hydroxyapatite, fluorapatite and chlorapatite, with high concentrations of Hydroxide, OH−, Fluoride, F− and Chloride, Cl− ion, respectively, in the crystal. The formula of the admixture of ...

with the

formula In science, a formula is a concise way of expressing information symbolically, as in a mathematical formula or a ''chemical formula''. The informal use of the term ''formula'' in science refers to the general construct of a relationship betwe ...

, often written to denote that the crystal unit cell comprises two entities. It is the

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

endmember An endmember (also end-member or end member) in mineralogy is a mineral that is at the extreme end of a mineral series in terms of purity of its chemical composition. Minerals often can be described as solid solutions with varying compositions of ...

of the complex

apatite group Apatite is a group of phosphate minerals, usually hydroxyapatite, fluorapatite and chlorapatite, with high concentrations of OH−, F− and Cl− ion, respectively, in the crystal. The formula of the admixture of the three most common endm ...

. The

ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...

can be replaced by

fluoride Fluoride (). According to this source, is a possible pronunciation in British English. is an Inorganic chemistry, inorganic, Monatomic ion, monatomic Ion#Anions and cations, anion of fluorine, with the chemical formula (also written ), whose ...

chloride The term chloride refers to a compound or molecule that contains either a chlorine anion (), which is a negatively charged chlorine atom, or a non-charged chlorine atom covalently bonded to the rest of the molecule by a single bond (). The pr ...

, producing

fluorapatite Fluorapatite, often with the alternate spelling of fluoroapatite, is a phosphate mineral with the formula Ca5(PO4)3F (calcium fluorophosphate). Fluorapatite is a hard crystalline solid. Although samples can have various color (green, brown, blu ...

chlorapatite Apatite is a group of phosphate minerals, usually hydroxyapatite, fluorapatite and chlorapatite, with high concentrations of OH−, F− and Cl− ion, respectively, in the crystal. The formula of the admixture of the three most common end ...

. It crystallizes in the

hexagonal In geometry, a hexagon (from Greek , , meaning "six", and , , meaning "corner, angle") is a six-sided polygon. The total of the internal angles of any simple (non-self-intersecting) hexagon is 720°. Regular hexagon A regular hexagon is d ...

crystal system In crystallography, a crystal system is a set of point groups (a group of geometric symmetries with at least one fixed point). A lattice system is a set of Bravais lattices (an infinite array of discrete points). Space groups (symmetry groups ...

. Pure hydroxyapatite powder is white. Naturally occurring apatites can, however, also have brown, yellow, or green colorations, comparable to the discolorations of

dental fluorosis Dental fluorosis is a common disorder, characterized by Enamel hypocalcification, hypocalcification of tooth enamel caused by ingestion of excessive fluoride during enamel formation. Dental fluorosis appears as a range of visual changes in ename ...

. Up to 50% by volume and 70% by weight of

human bone The human skeleton is the internal framework of the human body. It is composed of around 270 bones at birth – this total decreases to around 206 bones by adulthood after some bones get fused together. The bone mass in the skeleton makes up ab ...

is a modified form of hydroxyapatite, known as

bone mineral A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, an ...

. Carbonated calcium-deficient hydroxyapatite is the main mineral of which

dental enamel Tooth enamel is one of the four major Tissue (biology), tissues that make up the tooth in humans and many animals, including some species of fish. It makes up the normally visible part of the tooth, covering the Crown (tooth), crown. The other ...

and

dentin Dentin ( ) (American English) or dentine ( or ) (British English) () is a calcified tissue (biology), tissue of the body and, along with tooth enamel, enamel, cementum, and pulp (tooth), pulp, is one of the four major components of teeth. It i ...

are composed. Hydroxyapatite crystals are also found in pathological calcifications such as those found in breast tumors, as well as calcifications within the

pineal gland The pineal gland (also known as the pineal body or epiphysis cerebri) is a small endocrine gland in the brain of most vertebrates. It produces melatonin, a serotonin-derived hormone, which modulates sleep, sleep patterns following the diurnal c ...

(and other structures of the brain) known as

corpora arenacea Corpora arenacea (''singular'': corpus arenaceum, also called brain sand or acervuli or psammoma bodies or pineal concretions) are calcified structures in the pineal gland and other areas of the brain such as the choroid plexus. Older organisms ...

or "brain sand".

Chemical synthesis

Hydroxyapatite can be synthesized via several methods, such as wet chemical deposition, biomimetic deposition, sol-gel route (wet-chemical precipitation) or electrodeposition. The hydroxyapatite nanocrystal suspension can be prepared by a wet chemical precipitation reaction following the reaction equation below: : The ability to synthetically replicate hydroxyapatite has invaluable clinical implications, especially in dentistry. Each technique yields hydroxyapatite crystals of varied characteristics, such as size and shape. These variations have a marked effect on the biological and mechanical properties of the compound, and therefore these hydroxyapatite products have different clinical uses.

Calcium-deficient hydroxyapatite

Calcium-deficient (non-stochiometric) hydroxyapatite, (where ''x'' is between 0 and 1) has a Ca/P ratio between 1.67 and 1.5. The Ca/P ratio is often used in the discussion of calcium phosphate phases. Stoichiometric apatite has a Ca/P ratio of 10:6 normally expressed as 1.67. The non-stoichiometric phases have the hydroxyapatite structure with cation vacancies () and anion () vacancies. The sites occupied solely by phosphate anions in stoichiometric hydroxyapatite, are occupied by phosphate or hydrogen phosphate, , anions. These calcium-deficient phases can be prepared by precipitation from a mixture of

calcium nitrate Calcium nitrate are inorganic compounds with the formula Ca(NO3)2(H2O)x. The anhydrous compound, which is rarely encountered, absorbs moisture from the air to give the tetrahydrate. Both anhydrous and hydrated forms are colourless salts. Hydrated ...

and

diammonium phosphate Diammonium phosphate (DAP; IUPAC name diammonium hydrogen phosphate; chemical formula (NH4)2(HPO4)) is one of a series of water- soluble ammonium phosphate salts that can be produced when ammonia reacts with phosphoric acid. Solid diammonium ph ...

with the desired Ca/P ratio, for example, to make a sample with a Ca/P ratio of 1.6: : Sintering these non-stoichiometric phases forms a solid phase which is an intimate mixture of tricalcium phosphate and hydroxyapatite, termed biphasic calcium phosphate: :

Biological function

Mammals (including humans)

Hydroxyapatite is present in

bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...

s and

teeth A tooth (: teeth) is a hard, calcified structure found in the jaws (or mouths) of many vertebrates and used to break down food. Some animals, particularly carnivores and omnivores, also use teeth to help with capturing or wounding prey, tear ...

; bone is made primarily of HA crystals interspersed in a

collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...

matrix—65 to 70% of the mass of bone is HA. Similarly HA is 70 to 80% of the mass of

and enamel in teeth. In enamel, the matrix for HA is formed by

amelogenin Amelogenins are a group of protein isoforms produced by alternative splicing or proteolysis from the '' AMELX'' gene, on the X chromosome, and also the '' AMELY'' gene in males, on the Y chromosome. They are involved in amelogenesis, the develo ...

s and

enamelin Enamelin is an enamel matrix protein (EMPs), that in humans is encoded by the ''ENAM'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA ...

s instead of collagen. Importantly, hydroxyapatite-coated orthopedic implants perform better in certain patients. For instance, for patients with steatotic liver disease hydroxyapatite-coated titanium has superior properties. Hence, the potential of hydroxyapatite in the engineering of biomaterials is considered substantial. Hydroxyapatite deposits in tendons around joints results in the medical condition

calcific tendinitis Calcific tendinitis is a common condition where deposits of calcium phosphate form in a tendon, sometimes causing pain at the affected site. Deposits can occur in several places in the body, but are by far most common in the rotator cuff of the s ...

. Hydroxyapatite is a constituent of calcium phosphate

kidney stones Kidney stone disease (known as nephrolithiasis, renal calculus disease, or urolithiasis) is a crystallopathy and occurs when there are too many minerals in the urine and not enough liquid or hydration. This imbalance causes tiny pieces of cr ...

Remineralisation of tooth enamel

Remineralisation In biogeochemistry, remineralisation (or remineralization) refers to the breakdown or transformation of organic matter (those molecules derived from a biological source) into its simplest inorganic forms. These transformations form a crucial link ...

of tooth enamel involves the reintroduction of mineral ions into demineralised enamel. Hydroxyapatite is the main mineral component of enamel in teeth. During demineralisation, calcium and phosphorus ions are drawn out from the hydroxyapatite. The mineral ions introduced during remineralisation restores the structure of the hydroxyapatite crystals. When

ions are present during the remineralisation process, either through

water fluoridation Water fluoridation is the controlled addition of fluoride to Public water supply, public water supplies to reduce tooth decay. Fluoridated water maintains fluoride levels effective for cavity prevention, achieved naturally or through supplem ...

or the use of fluoride-containing

toothpaste Toothpaste is a paste or gel dentifrice that is used with a toothbrush to clean and maintain the aesthetics of Human tooth, teeth. Toothpaste is used to promote oral hygiene: it is an abrasive that aids in removing dental plaque and food from th ...

, the stronger and more acid-resistant

crystals form instead of hydroxyapatite crystals.

Mantis shrimp

The clubbing appendages of the ''

Odontodactylus scyllarus ''Odontodactylus scyllarus'', commonly known as the peacock mantis shrimp, harlequin mantis shrimp, painted mantis shrimp, clown mantis shrimp, rainbow mantis shrimp, or simply mantis shrimp, is a large Stomatopod native to the epipelagic seabed ...

'' (peacock mantis shrimp) are made of an extremely dense form of the mineral which has a higher specific strength; this has led to its investigation for potential synthesis and engineering use. Their dactyl appendages have excellent

impact resistance In materials science and metallurgy, toughness is the ability of a material to absorb energy and plastically deform without fracturing.dentine hypersensitivity, preventing sensitivity after teeth bleaching procedures and cavity prevention. Avian eggshell hydroxyapatite can be a viable filler material in bone regeneration procedures in oral surgery.

Dentine sensitivity

Nano-hydroxyapatite possesses bioactive components which can prompt the mineralisation process of teeth, remedying hypersensitivity. Hypersensitivity of teeth is thought to be regulated by fluid within dentinal tubules. The movement of this fluid as a result of different stimuli is said to excite receptor cells in the pulp and trigger sensations of pain. The physical properties of the nano-hydroxyapatite can penetrate and seal the tubules, stopping the circulation of the fluid and therefore the sensations of pain from stimuli. Nano-hydroxyapatite would be preferred as it parallels the natural process of surface remineralisation. In comparison to alternative treatments for dentine hypersensitivity relief, nano-hydroxyapatite containing treatment has been shown to perform better clinically. Nano-hydroxyapatite was proven to be better than other treatments at reducing sensitivity against evaporative stimuli, such as an air blast, and tactile stimuli, such as tapping the tooth with a dental instrument. However, no difference was seen between nano-hydroxyapatite and other treatments for cold stimuli. Hydroxylapatite has shown significant medium and long-term desensitizing effects on dentine hypersensitivity using evaporative stimuli and the visual analogue scale (alongside potassium nitrate, arginine, glutaraldehyde with hydroxyethyl methacrylate, hydroxyapatite, adhesive systems, glass ionomer cements and laser).

Co-agent for bleaching

Teeth bleaching agents release reactive oxygen species which can degrade enamel. To prevent this, nano-hydroxyapatite can be added to the bleaching solution to reduce the impact of the bleaching agent by blocking pores within the enamel. This reduces sensitivity after the bleaching process.

Cavity prevention

Nano-hydroxyapatite possesses a remineralising effect on teeth and can be used to prevent damage from carious attacks. In the event of an acid attack by cariogenic bacteria, nano-hydroxyapatite particles can infiltrate pores on the tooth surface to form a protective layer. Furthermore, nano-hydroxyapatite may have the capacity to reverse damage from carious assaults by either directly replacing deteriorated surface minerals or acting as a binding agent for lost ions. In some toothpaste hydroxyapatite can be found in the form of nanocrystals (as these are easily dissolved). In recent years, hydroxyapatite nanocrystals (nHA) have been used in toothpaste to combat dental hypersensitivity. They aid in the repair and remineralisation of the enamel, thus helping to prevent tooth sensitivity. Tooth enamel can become demineralised due to various factors, including acidic erosion and dental

caries Tooth decay, also known as caries,The word 'caries' is a mass noun, and is not a plural of 'carie'.'' is the breakdown of teeth due to acids produced by bacteria. The resulting cavities may be a number of different colors, from yellow to black ...

. If left untreated this can lead to the exposure of dentin and subsequent exposure of the

dental pulp The pulp is the connective tissue, nerves, blood vessels, and odontoblasts that comprise the innermost layer of a tooth. The pulp's activity and signalling processes regulate its behaviour. Anatomy The pulp is the neurovascular bundle cen ...

. In various studies the use of nano hydroxyapatite in toothpaste showed positive results in aiding the remineralisation of dental enamel. In addition to remineralisation, in vitro studies have shown that toothpastes containing nano-hydroxyapatite have the potential to reduce

biofilm A biofilm is a Syntrophy, syntrophic Microbial consortium, community of microorganisms in which cell (biology), cells cell adhesion, stick to each other and often also to a surface. These adherent cells become embedded within a slimy ext ...

formation on both tooth enamel and

resin-based composite Dental composite resins (better referred to as "resin-based composites" or simply "filled resins") are dental cements made of synthetic resins. Synthetic resins evolved as restorative materials since they were insoluble, of good tooth-like appea ...

surfaces.

As a dental material

Hydroxyapatite is widely used within dentistry and

oral and maxillofacial surgery Oral and maxillofacial surgery (OMFS) is a surgical specialty focusing on reconstructive surgery of the face, facial trauma surgery, the Human mouth, mouth, Human head, head and neck, and jaws, as well as facial plastic surgery including clef ...

, due to its chemical similarity to hard tissue. In the future, there are possibilities for using nano-hydroxyapatite for tissue engineering and repair. The main and most advantageous feature of nano-hydroxyapatite is its biocompatibility. It is chemically similar to naturally occurring hydroxyapatite and can mimic the structure and biological function of the structures found in the resident extracellular matrix. Therefore, it can be used as a scaffold for engineering tissues such as bone and cementum. It may be used to restore cleft lips and palates and refine existing practices such as preservation of alveolar bone after extraction for better implant placement.

Safety concerns

The

European Commission The European Commission (EC) is the primary Executive (government), executive arm of the European Union (EU). It operates as a cabinet government, with a number of European Commissioner, members of the Commission (directorial system, informall ...

Scientific Committee on Consumer Safety The Scientific Committee on Consumer Safety (SCCS) is one of the independent scientific committees managed by the Directorate-General for Health and Consumer Protection of the European Commission, which provide scientific advice to the commission ...

(SCCS) issued an official opinion in 2021, where it considered whether the nanomaterial hydroxyapatite was safe when used in leave-on and rinse-off dermal and oral cosmetic products, taking into account reasonably foreseeable exposure conditions. It stated: The

(SCCS) reissued an updated opinion in 2023, where it cleared rod-shaped nano hydroxyapatite of concerns regarding genotoxicity, allowing consumer products to contain concentrations of nano hydroxyapatite as high as 10% for toothpastes and 0.465% for mouthwashes. However, it warns of needle-shaped nano hydroxyapatite and of inhalation in spray products. It stated:

Chromatography

Along with its medical applications, hydroxyapatite is also used in downstream applications under mixed-mode chromatography in polishing step. The ions present on the surface of hydroxyapatite make it an ideal candidate with unique selectivity, separation and purification of biomolecule mixtures. In mixed-mode chromatography, hydroxyapatite is used as the stationary phase in chromatography columns. The combined presence of calcium ions (C- sites) and phosphate sites (P-sites) provide metal affinity and ion exchange properties respectively. The C-sites on the surface of the resin undergo metal affinity interactions with phosphate or carboxyl groups present on the biomolecules. Concurrently, these positively charged C-sites tend to repel positively charged functional groups (e.g., amino groups) on biomolecules. P-sites undergo cationic exchange with positively charged functional groups on biomolecules. They exhibit electrostatic repulsion with negatively charged functional groups on biomolecules. For the elution of molecules buffer with high concentration of phosphate and sodium chloride is used. The nature of different charged ions on the surface of hydroxyapatite provides the framework for unique selectivity and binding of biomolecules, facilitating robust separation of biomolecules. Hydroxyapatite is available in different forms and in different sizes for the purpose of protein purification. The advantages of hydroxyapatite media are its high product stability and uniformity in various lots during its production. Generally, hydroxyapatite was used in the polishing step of monoclonal antibodies, isolation of endotoxin free plasmids, purification of enzymes and viral particles.

Use in archaeology

archaeology Archaeology or archeology is the study of human activity through the recovery and analysis of material culture. The archaeological record consists of Artifact (archaeology), artifacts, architecture, biofact (archaeology), biofacts or ecofacts, ...

, hydroxyapatite from human and animal remains can be analysed to reconstruct ancient

diets The Low Countries comprise the coastal Rhine–Meuse–Scheldt delta region in Western Europe, whose definition usually includes the modern countries of Luxembourg, Belgium, the Netherlands and parts of Northern France. Both Belgium and the ...

, migrations and

paleoclimate Paleoclimatology ( British spelling, palaeoclimatology) is the scientific study of climates predating the invention of meteorological instruments, when no direct measurement data were available. As instrumental records only span a tiny part of ...

. The mineral fractions of bone and teeth act as a reservoir of

trace elements __NOTOC__ A trace element is a chemical element of a minute quantity, a trace amount, especially used in referring to a micronutrient, but is also used to refer to minor elements in the composition of a rock, or other chemical substance. In nutri ...

, including

carbon Carbon () is a chemical element; it has chemical symbol, symbol C and atomic number 6. It is nonmetallic and tetravalence, tetravalent—meaning that its atoms are able to form up to four covalent bonds due to its valence shell exhibiting 4 ...

oxygen Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...

and

strontium Strontium is a chemical element; it has symbol Sr and atomic number 38. An alkaline earth metal, it is a soft silver-white yellowish metallic element that is highly chemically reactive. The metal forms a dark oxide layer when it is exposed to ...

. Stable isotope analysis of human and faunal hydroxyapatite can be used to indicate whether a diet was predominantly terrestrial or marine in nature (carbon, strontium); the geographical origin and migratory habits of an animal or human (oxygen, strontium) and to reconstruct past temperatures and climate shifts (oxygen). Post-depositional alteration of bone can contribute to the degradation of bone collagen, the protein required for stable isotope analysis.

Research

Due to its high

biocompatibility Biocompatibility is related to the behavior of biomaterials in various contexts. The term refers to the ability of a material to perform with an appropriate host response in a specific situation. The ambiguity of the term reflects the ongoin ...

bioactivity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...

, osteoconductive and/or osteoinductive capacity, nontoxicity, nonimmunogenic properties, and noninflammatory behavior, hydroxyapatite is available and used as a bone filler and as coatings on prostheses. Designing bone scaffolds with a higher capability of promoting bone regeneration is a topical research subject. Composite 3D scaffolds for bone tissue engineering based on nano-hydroxyapatite and poly-ε-caprolactone were designed. The 3D composite scaffolds showed good cytocompatibility and osteogenic potential, which is specifically recommended in applications when faster mineralization is needed, such as osteoporosis treatment.Codrea, C.I.; Lincu, D.; Ene, V.L.; Nicoară, A.I.; Stan, M.S.; Ficai, D.; Ficai, A. Three-Dimensional-Printed Composite Scaffolds Containing Poly-ε-Caprolactone and Strontium-Doped Hydroxyapatite for Osteoporotic Bone Restoration. Polymers 2024, 16, 1511. https://doi.org/10.3390/polym16111511

Defluoridation

Hydroxylapatite is a potential

adsorbent Adsorption is the adhesion of atoms, ions or molecules from a gas, liquid or dissolved solid to a surface. This process creates a film of the ''adsorbate'' on the surface of the ''adsorbent''. This process differs from absorption, in which a ...

for the

defluoridation Defluoridation is the downward adjustment of the level of fluoride in drinking water. Worldwide, fluoride is one of the most abundant anions present in groundwater. Fluoride is more present in groundwater than surface water mainly due to the leachin ...

drinking water Drinking water or potable water is water that is safe for ingestion, either when drunk directly in liquid form or consumed indirectly through food preparation. It is often (but not always) supplied through taps, in which case it is also calle ...

, as it forms

in a three step process. Hydroxylapatite removes from the water to replace forming fluorapatite. However, during the defluoridation process the hydroxyapatite dissolves and increases the pH and

phosphate Phosphates are the naturally occurring form of the element phosphorus. In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthop ...

ion concentration which makes the defluoridated water unfit for drinking. Recently, a ″calcium amended-hydroxyapatite″ defluoridation technique was suggested to overcome the phosphate leaching from hydroxyapatite. This technique can also affect fluorosis reversal by providing calcium-enriched alkaline drinking water to fluorosis affected areas.

References

External links

{{Authority control Calcium minerals Phosphate minerals Ceramic materials Biomaterials Hexagonal minerals Minerals in space group 176