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{{More footnotes needed|date=June 2021}}
{{chembox
{{Chembox
| verifiedrevid = 409522369
| Watchedfields = changed
| IUPACName = tetracalcium hydrogen phosphate diphosphate
| verifiedrevid = 428764453
| IUPACName = octacalcium dihydrogen hexakis(phosphate) pentahydrate
| OtherNames = Octacalcium Phosphate | OtherNames = Octacalcium Phosphate
| Section1 = {{Chembox Identifiers | Section1 = {{Chembox Identifiers
| CASNo_Ref = {{cascite|correct|??}}
| CASNo = 13767-12-9
| CASNo = 13767-12-9
| PubChem = 123896 | PubChem = 123896
}} }}
| Section2 = {{Chembox Properties | Section2 = {{Chembox Properties
| Formula = {{chem2|Ca8H2(PO4)6*5H2O}}
| Formula = Ca<sub>8</sub>H<sub>2</sub>(PO<sub>4</sub>)<sub>6</sub>.5H<sub>2</sub>O
| MolarMass = 446.234023 g/mol | MolarMass = 446.234023 g/mol
| Appearance = white powder | Appearance = white powder
| H-Bond Donor = 1
| H-Bond Acceptor = 12
}} }}
}} }}


'''Octacalcium phosphate''' (sometimes referred to as '''OCP''') is a form of calcium phosphate with formula {{chem2|Ca8H2(PO4)6*5H2O}}.<ref>{{cite journal |vauthors=LeGeros RZ |title=Preparation of octacalcium phosphate (OCP): a direct fast method |journal=Calcified Tissue International |volume=37 |issue=2 |pages=194–197 |date=March 1985 |pmid=3924374 |doi=10.1007/BF02554841 |s2cid=38990778}}</ref> OCP may be a precursor to ], ]e, and ]s. OCP is a precursor of ] (HA), an inorganic biomineral that is important in bone growth.<ref>{{cite journal |title=Crystallography of Octacalcium Phosphate |year=1957 |doi=10.1021/ja01576a068 |url=https://pubs.acs.org/doi/10.1021/ja01576a068 |vauthors=Brown WE, Lehr JR, Smith JP, Frazier AW |journal=Journal of the American Chemical Society |volume=79 |issue=19 |pages=5318–5319|bibcode=1957JAChS..79R5318B }}</ref> OCP has garnered lots of attention due to its inherent ]. While OCP exhibits good properties in terms of bone growth, very stringent synthesis requirements make it difficult for mass productions, but nevertheless has shown promise not only ], but also in ] clinical case studies.


== Background ==
'''Octacalcium phosphate''' (sometimes referred to as '''OCP''') is a ] ] with a formula Ca<sub>8</sub>H<sub>2</sub>(PO<sub>4</sub>)<sub>6</sub>.5H<sub>2</sub>O.<ref> Reacquel Z. LeGeros "Preparation of octacalcium phosphate (OCP): A direct fast method", Journal Calcified Tissue International, Volume 37, Number 2, March 1985, pp.194-197.</ref> OCP may be a precursor in creation of the ], ] and ]s in living organisms.
] was discovered by Johan Gottlieb in 1769, and since its discovery calcium phosphate has been widely researched and has been found to be one of the most important inorganic structures within ] of ]s.<ref name=Canillas_2017>{{cite journal |vauthors=Canillas M, Pena P, de Aza AH, Rodríguez MA |title=Calcium phosphates for biomedical applications |journal=Boletín de la Sociedad Española de Cerámica y Vidrio |volume=56 |issue=3 |date=May 2017 |pages=91–112 |issn=0366-3175 |doi=10.1016/j.bsecv.2017.05.001|hdl=10261/201422 |hdl-access=free }}</ref> Calcium phosphate has been used to treat various illnesses such as ], ], ], ]ations, and ], but its applications in ] and ] has been the main area of focus for many years.<ref name=Canillas_2017/> Prior to the utilization of calcium phosphates in orthopedics, ]s were widely utilized due to their bio inertness and advantageous mechanical properties, but despite the success of bioceramics, this material simply substituted broken bones, and did not provide a means of bone regrowth within the damaged tissue.<ref name=Canillas_2017/><ref name=Eliaz_2017>{{cite journal |vauthors=Eliaz N, Metoki N |title=Calcium Phosphate Bioceramics: A Review of Their History, Structure, Properties, Coating Technologies and Biomedical Applications |journal=Materials |volume=10 |issue=4 |date=March 2017 |pages=334 |pmid=28772697 |pmc=5506916 |bibcode=2017Mate...10..334E |doi=10.3390/ma10040334 |doi-access=free}}</ref>


By the 1900s scientists had started utilizing ] during surgeries as a means of applying simple ], and by 1950 the genesis of self setting calcium phosphate in combination with bioceramics had been discovered.<ref name=Canillas_2017/><ref name=Eliaz_2017/> After that, between 1976 and 1981 calcium phosphates had started to be utilized more prominently as coatings for orthopedic and ]s in order to stimulate stronger ], and by the 1990s calcium phosphate had started to become utilized as an effective mode for drug transportation and had started to branch into other fields such as ].
OCP has been shown to be a precursor of ] (HAP), an inorganic biomineral that is very important in bone growth. Determinations of the crystal structures of OCP and acidic ] thus appear to be a pre-requisite to an understanding of the formation and chemical properties of ]. <ref> Brown, W. E., Lehr, J. R.. Smith, J. P., Frazier, A. W., J. Am. Chem. Soc., 1957, 79 (19), 5318. </ref> OCP could one day replace ] in ] and implants because of the similar apatite structure. OCP is an ] before the synthesis of ]. When mixed with boiling water the crystal structure morphs to one that is very similar to ] structure of ]. OCP has similar domains to ] and has an apatite crystal structure. This makes it ideal to fill in ] in teeth and bones.<ref> Brown, W.E., Eidelman, N., Tomazic, B., 1987. Adv. Dent. Res., 1; 306 </ref> The morphology of tooth and bone crystallites, as seen in their ], strongly indicates that OCP is involved in the formation of these tissues. There have been studies that have shown the advantages of using OCP in ] repair to stimulate the regrowth of the enamel because the crystal structure fits into the pores of ].<ref> Nelson, D.J.A., McLean, J.D., 1984. Calcif Tissue Int. 36, 219.</ref> Studies have been done with titanium plates and bone implants with a coating of OCP. The implants and plates with coatings of OCP were accepted and integrated more quickly and fully than those without OCP because of the apatite crystal structure of OCP that is similar to the crystal structure of bone.<ref> www.pubmed.gov Octacalcium phosphate: Osteoconductivity and crystal chemistry. Suzaki, O. Last accessed 4/09/10 </ref> OCP shows very promising signs of replacing HAP in bone and tooth repair and growth in grafts and implants and will likely be used more widespread in the healthcare fields.


Octacalcium phosphate (OCP) was first discovered in the 1950s when scientists discovered that by varying the calcium phosphate ratio various forms of calcium phosphates could be created.<ref name=Eliaz_2017/> OCP has widely been seen as an inorganic precursor for ] which is similar to calcium phosphate in that it is an inorganic mineral found in ]s and ] that plays a major role in the overall structure, strength, and regeneration capabilities of bone.<ref name=Teterina_2021>{{cite journal |vauthors=Teterina AY, Smirnov IV, Fadeeva IS, Fadeev RS, Smirnova PV, Minaychev VV, Kobyakova MI, Fedotov AY, Barinov SM, Komlev VS |display-authors=6 |title=Octacalcium Phosphate for Bone Tissue Engineering: Synthesis, Modification, and In Vitro Biocompatibility Assessment |journal=International Journal of Molecular Sciences |volume=22 |issue=23 |pages=12747 |date=November 2021 |pmid=34884557 |pmc=8657881 |doi=10.3390/ijms222312747 |doi-access=free}}</ref><ref>{{cite book |vauthors=Habibah TU, Amlani DV, Brizuela M |chapter=Hydroxyapatite Dental Material |date=2023 |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK513314/ |title=StatPearls |access-date=2023-04-30 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30020686}}</ref> Along with this, compared to other forms of calcium phosphate OCP has been found to have greater levels of ] and increased rates of ].<ref name=Teterina_2021/> The advantageous properties of OCP have made it a primary candidate for many orthopedic uses, and although mass production has been utilized, extremely strict chemical constraints make it difficult to mass-produce and fast paces.<ref name=O'Sullivan_2020>{{cite book |vauthors=O'Sullivan R, Kelly D |chapter=7 - Synthesis methodologies options for large-scale manufacturer of octacalcium phosphate |date=January 2020 |title=Octacalcium Phosphate Biomaterials |pages=147–176 |veditors=Suzuki O, Insley G |series=Woodhead Publishing Series in Biomaterials |publisher=Woodhead Publishing |isbn=978-0-08-102511-6}}</ref>
==Molecular and Crystal Structure==

] measurements on OCP gave the lattice a = 19.7 A., b = 9.59 A., c =6.87 A., α≅β = 90.7’ and γ = 71.8’. Corresponding ] constant 2a = 18.84 A., a’ = 9.42 A., c = 6.885 k., α = α’ = 90” and γ = 60”, resemble closely those of OCP in the values of b, c and a, which lie in the plane of the OCP plates. The final pattern was ], intermediate in sharpness between those of tooth enamel and bone. Boiling water decomposed OCP into an apatite approaching hydroxyapatite in composition, along with a variable amount of CaHP0<sub>4</sub>. Both thermal and hydrothermal treatments sometimes yielded apatitic single crystal ] after OCP, the c-axes being parallel to the c of the original OCP.<ref> Brown, W. E., Lehr, J. R.. Smith, J. P., Frazier, A. W., J. Am. Chem. Soc., 1957, 79 (19), 5318.</ref> Due to the small crystal structure of OCP it is often a twinned crystal structure. The average crystal size of OCP is 13.5 ± 0.2 nm <ref> M.J. Arellano-Jiméneza, M. J., García-Garcíaa, R., Reyes-Gasga, R. 2009. Journal of Physics and Chemistry of Solids 70, 390. </ref>
==Type of ceramic–tissue interaction==
Ceramics can be categorized into four categories based on their interactions with tissues. Type #1 (dense, nonporous, and inert) ceramics are strong, stiff, and attach to bone/tissue resulting in a cementing of the device into the tissue. Type #2 (porous and inert) ceramics exhibit a lower overall strength but are useful as coatings and result in biological fixation. Type #3 (dense and nonporous) ceramics exhibit biological fixation by chemically attaching directly to bone. Finally, type #4 (dense, nonporous, and resorbable) ceramics are slowly replaced with bone. The nature of octacalcium phosphate resembles that of type #4 ceramics.

Type #4 ceramics differ based on the ratio of calcium to phosphate (Ca:P), with the most stable/ideal ratio (Ca:P=10:6=1.67) resulting in ] (HA) which is often used in many orthopedic settings due to the inherent biocompatibility and similarity to natural bone tissue.<ref>{{cite book |vauthors=LeGeros RZ, LeGeros JP |chapter=Hydroxyapatite |veditors=Kokubo T |title=Bioceramics and their clinical applications |date=January 2008 |pages=367–394 |publisher=Woodhead Publishing |doi=10.1533/9781845694227.2.367 |isbn=9781845692049}}</ref> While HA has been widely used and established as an excellent candidate for orthopedic usage, OCP (Ca:P=1.33), while harder to synthesize and more difficult to ] and mold, has been proven to not only be more resorbable than HA, but also proven to result in greater overall bone formation than HA.<ref>{{cite journal |vauthors=Kamakura S, Sasano Y, Shimizu T, Hatori K, Suzuki O, Kagayama M, Motegi K |title=Implanted octacalcium phosphate is more resorbable than beta-tricalcium phosphate and hydroxyapatite |journal=Journal of Biomedical Materials Research |volume=59 |issue=1 |pages=29–34 |date=January 2002 |pmid=11745534 |doi=10.1002/jbm.1213}}</ref><ref>{{cite book |vauthors=Shiwaku Y, Suzuki O |chapter=Octacalcium phosphate effects on the systemic and local factors that regulate bone-cell activity. |veditors=Suzuki O, Insley G |title=Octacalcium Phosphate Biomaterials |date=January 2020 |pages=17–36 |publisher=Woodhead Publishing |doi=10.1016/B978-0-08-102511-6.00002-9 |isbn=9780081025116 |s2cid=213774945}}</ref><ref name=Suzuki_2013>{{cite journal |vauthors=Suzuki O |title=Octacalcium phosphate (OCP)-based bone substitute materials |journal=Japanese Dental Science Review |volume=49 |issue=2 |date=May 2013 |pages=58–71 |doi=10.1016/j.jdsr.2013.01.001|doi-access=free }}</ref>

==Material properties==
The table below displays various octacalcium phosphate material properties and descriptions of said properties.
{| class="wikitable"
| colspan="2" |'''Octacalcium Phosphate Properties'''<ref name=Suzuki_2013/><ref name=Suzuki_2020_2>{{cite journal |vauthors=Suzuki O, Shiwaku Y, Hamai R |title=Octacalcium phosphate bone substitute materials: Comparison between properties of biomaterials and other calcium phosphate materials |journal=Dental Materials Journal |volume=39 |issue=2 |pages=187–199 |date=March 2020 |pmid=32161239 |doi=10.4012/dmj.2020-001 |s2cid=212678939|doi-access=free }}</ref><ref name=Woodhead_Publishing_2019>{{cite book |veditors=Suzuki O, Insley G |title=Octacalcium Phosphate Biomaterials |publisher=Woodhead Publishing |year=2019 |isbn=9780081025123}}</ref><ref>{{cite journal |vauthors=Fan L, Zhang Y, Hu J, Fang Y, Hu R, Shi W, Ren B, Lin C, Tian ZQ |display-authors=6 |title=Surface Properties of Octacalcium Phosphate Nanocrystals Are Crucial for Their Bioactivities |journal=ACS Omega |volume=6 |issue=39 |pages=25372–25380 |date=October 2021 |pmid=34632195 |pmc=8495883 |doi=10.1021/acsomega.1c03278}}</ref>
|-
|''']'''

'''(bulk property)'''
|
* The structure of octacalcium phosphate has been determined to be triclinic with a space group P1.
* The lattice properties of the OCP unit cell: a = 19.692 Å, b = 9.523 Å, c = 6.835 Å, ɑ= 90.15°, β = 92.54°, and ɣ = 108.65°
** When collapsed at high enough temperatures: a = 18.86 Å, and ɣ = 114.65°
* The crystal structure itself consists of layers of calcium deficient apatite and a hydrated layer making the overall structure of OCP similar to that of ].
|-
|'''Stoichiometric composition'''

'''(bulk property)'''
|
* 33.3&nbsp;mol% acidic phosphate to total ] found in either the hydrated or calcium deficient layer of the crystal structure
|-
|''']'''

'''(bulk property)'''
|
* Ca/P ratio for OCP is 1.33
* Non stoichiometric ratios obtained via wet chemical synthesis result in a Ca/P value of 1.27.
|-
|''']'''

'''(bulk property)'''
|
* Due to the large amount of ] within OCP (caused by the hydrated layer) the thermal stability is relatively low, displaying complete decomposition at temperatures above 300°C
* Dehydration of the hydrated layer occurs at 170°C and resulting in contraction causing the OCP crystal structure to collapse
|-
|''']'''

'''(bulk property)'''
|
* Soluble at pH values of 7.4
* Solubility at 25°C = 0.0081 g/L
|-
|''']'''

'''(bulk property)'''
|
* ] crystals display bending strengths of 7.633 ± 0.833 MPa
* Plate crystals display bending strengths of 7.07 ± 2.6 MPa
* Ribbon-Like display bending strengths of 16.2 ± 0.7 MPa
|-
|''']'''

'''(bulk property)'''
|
* Spherule crystals display Young's Modulus values of 4.8 ± 0.633 GPa
* Plate crystals display Young's Modulus values of 4.15 ± 0.62 GPa
* Ribbon-Like crystals display Young's Modulus values of 6.4 ± 0.7 GPa
|-
|
===Toughness===
'''(bulk property)'''
|
* Spherule crystals display ] values of 0.157 ± 0.02&nbsp;mm GPa
* Plate crystals display Toughness values of 0.133 ± 0.03&nbsp;mm MPa
* Ribbon-Like crystals display Toughness values of 0.28 ± 0.03&nbsp;mm MPa
|-
|''']'''

'''(surface property)'''
|
* For (100) OCP crystal planes (apathetic layers) the surface energy is 1311 mJ/m<sup>2</sup> in a vacuum and 462 mJ/m<sup>2</sup> in water
* For (200) OCP crystal planes (hydrated Layers) the surface energy is 858 mJ/m<sup>2</sup> in a vacuum and 189 mJ/m<sup>2</sup> in water
|}
The three crystal types (spherule, ribbon like, and plate) all exhibit flexural behavior with some displaying ] characteristics and others displaying ] characteristics. Spherule and Ribbon like crystals display brittle characteristics, similar to ]s, deforming elastically up to a maximum ] and then immediately fracturing (irreversible deformation).<ref name=Woodhead_Publishing_2019/> Plate crystals however displayed more ductile characteristics. Unlike spherule and ribbon like crystals, plate crystals deformed elastically up to the maximum stress, but did not fracture, instead transitioning into ] similar to ]s and some ]s.<ref name=Woodhead_Publishing_2019/>


==Synthesis== ==Synthesis==
Ca(CH<sub>3</sub>COO) + Na<sub>2</sub>HPO<sub>4</sub> + NaH<sub>2</sub>PO<sub>4</sub> → Ca<sub>4</sub>HO<sub>12</sub>P<sub>3</sub> at pH 5


<!--Overview-->
Dropwise addition of ] solution into a sodium acid phosphate solution at pH 5 or 6, maintained at 60°C for 3 to 4 hours.<ref>M.J. Arellano-Jiméneza, M. J., García-Garcíaa, R., Reyes-Gasga, R. 2009. Journal of Physics and Chemistry of Solids 70, 390.</ref>
Due to the multitude of implications of octacalcium phosphate (OCP), many synthesis methods have been developed as well as strides to upscale the overall production rate of octacalcium phosphate. Methods include ] reactions, ] reactions, aging, and ion substitution.<ref name=O'Sullivan_2020/> Previously stated methods have all been able to produce high-purity octacalcium phosphate, but in order to upscale the production of OCP, it is imperative to control the reaction conditions as slight deviations in ], ], or temperature can easily lead to different ] variations such as ] or ].<ref name=O'Sullivan_2020/>


===Precipitation===
Ca(C<sub>2</sub>H<sub>3</sub>O<sub>2</sub>)<sub>2</sub> + Na<sub>2</sub>H<sub>2</sub>P<sub>2</sub>O<sub>7</sub> → Ca<sub>4</sub>HO<sub>12</sub>P<sub>3</sub> pH 5 or 6
] involves mixing {{chem2|Ca(CH3COO)2}} (]) with a ] solution usually consisting of a mixture of {{chem2|Na2HPO4}} (]) and {{chem2|NaH2PO4}} (]).<ref name=Arellano-Jiménez_2009>{{cite journal |vauthors=Arellano-Jiménez MJ, García-García R, Reyes-Gasga J |title=Synthesis and hydrolysis of octacalcium phosphate and its characterization by electron microscopy and X-ray diffraction |journal=Journal of Physics and Chemistry of Solids |volume=70 |issue=2 |pages=390–395 |bibcode=2009JPCS...70..390A |issn=0022-3697 |doi=10.1016/j.jpcs.2008.11.001 |date=February 2009}}</ref><ref name=Komlev_2010>{{cite journal |vauthors=Komlev VS, Fadeeva IV, Fomin AS, Shvorneva LI, Ferro D, Barinov SM |title=Synthesis of octacalcium phosphate by precipitation from solution |journal=Doklady Chemistry |volume=432 |issue=2 |date=June 2010 |pages=178–182 |s2cid=95244316 |issn=0012-5008 |doi=10.1134/S0012500810060066}}</ref> The reaction constraints for precipitation reactions consisted of a calcium acetate molarity of 0.04 M, and sodium phosphate solution molarity of 0.04 M. Finally, pH levels ranged from 5.0 to 6.5 and temperature levels ranged from 37°C - 90°C.<ref name=Arellano-Jiménez_2009/><ref name=Komlev_2010/>


===Hydrolysis===
Dropwise addition of ] solution into a sodium acid phosphate solution at pH 5 or 6, maintained at 60°C for 3 to 4 hours.
Synthesis of octacalcium phosphate is typically done via the ] of α-tricalcium phosphate (ɑ-TCP).<ref name=Bigi_2002>{{cite journal |vauthors=Bigi A, Boanini E, Botter R, Panzavolta S, Rubini K |title=Alpha-tricalcium phosphate hydrolysis to octacalcium phosphate: effect of sodium polyacrylate |journal=Biomaterials |volume=23 |issue=8 |pages=1849–1854 |date=April 2002 |pmid=11950055 |doi=10.1016/S0142-9612(01)00311-8}}</ref> In order to create OCP, ɑ-TCP along with ] and ] ({{chem2|CaHPO4*2H2O}}) are formed into a solid state in preparation for the hydrolysis. The hydrolysis reaction can then be performed by combining the previously prepared ɑ-TCP and 0.0016 M ] at 25&nbsp;°C and a pH of 6. During hydrolysis reactions, in order to prevent deviation from octacalcium phosphate, it is imperative to maintain an calcium phosphate (Ca/P) ratio of 1.33.<ref name=Bigi_2002/><ref name=Saengdet_2021>{{cite journal |vauthors=Saengdet PM, Ogawa M |title=Directional growth of octacalcium phosphate using micro-flow reactor mixing and subsequent aging |journal=RSC Advances |volume=11 |issue=26 |pages=15969–15976 |date=April 2021 |pmid=35481191 |pmc=9031023 |doi=10.1039/D1RA00827G |bibcode=2021RSCAd..1115969S}}</ref>
Dropwise addition of calcium into phosphate solution or vice versa at pH 4.5 at 70°C for 1 hour. The solutions were either stirred or unstirred during precipitation and during the subsequent digestion periods. The precipitates are filtered, washed several times with distilled water and air-dried. <ref>LeGeros, R. Z., 1985. Calcif Tissue Int 37:194</ref>


==Reactions== ===Aging===
Aging reactions are conducted similar to the ] reactions, but precipitation reactions can occasionally produce poorly defined particles due to the fast precipitation process.<ref name=Saengdet_2021/> So, upon finishing the precipitation reaction the solution is mixed gently for times varying from 3 to 12 hours which results in well defined octacalcium phosphate crystals which can then be extracted via ] using membrane fillers.
] of OCP easily creates ] <ref> M.J. Arellano-Jiméneza, M. J., García-Garcíaa, R., Reyes-Gasga, R. 2009. Journal of Physics and Chemistry of Solids 70, 390. </ref>


===Ion substitution===
==References==
Ion substitution reactions are conducted similar to precipitation reactions, but instead of ], other variations are utilized in order to result in more crystallized precipitates.<ref name=Boanini_2010>{{cite journal |vauthors=Boanini E, Gazzano M, Rubini K, Bigi A |title=Collapsed Octacalcium Phosphate Stabilized by Ionic Substitutions |journal=Crystal Growth & Design |volume=10 |issue=8 |date=2010-08-04 |pages=3612–3617 |issn=1528-7483 |doi=10.1021/cg100494f |url=https://pubs.acs.org/doi/10.1021/cg100494f}}</ref> Ions can include ] (Mg<sup>2+</sup>), ] (Sr<sup>2+</sup>), or ] (Mn<sup>2+</sup>). Varying the form of ] that is utilized during the precipitate reactions can have varying effects depending on the element used and the concentration of element.<ref name=Boanini_2010/> Specifically strontium has been found to improve the bioactive properties of OCP.<ref name=Teterina_2021/> In terms of ] the addition of strontium or magnesium into the structure can result in reduced thermal stability and increases in the extent of collapsed OCP.<ref name=Suzuki_2020_2/>
<references />


==Octacalcium phosphate composites==
== Sources ==

* Laurence C. Chow, Edward D. Eanes, "Octacalcium phosphate", Monograph in Oral Science, S. Karger AG, 2001, ISBN 978-3805572286.
===]-OCP composites===
* Brown, W. E., Lehr, J. R.. Smith, J. P., Frazier, A. W., J. Am. Chem. Soc., 1957, 79 (19), 5318.
Gel sponges are typically used as bone integration scaffolds mainly due to their inherent ]. The porous structure of the gel itself can aid in ] when combined with CaP ceramic composites.<ref name=Woodhead_Publishing_2019/> Gel-OCP composites can be formed using various methods, but a common method is via ] and has been known to produce optimal Gel-OCP composites while still maintaining the inherent porosity that is useful for osteointegration.<ref name=Woodhead_Publishing_2019/> ] pre-clinical Studies comparing Gel-OCP composites to pure gel control groups have found that the gel scaffold is capable of regenerating substantial amounts of bone within months (~4 months) of implantation, indicating that the gel-OCP composites exhibit high ] allowing for enhanced bone regeneration.<ref name=Woodhead_Publishing_2019/>
* M.J. Arellano-Jiméneza, M. J., García-Garcíaa, R., Reyes-Gasga, R. 2009. Journal of Physics and Chemistry of Solids 70, 390.

* LeGeros, R. Z., 1985. Calcif Tissue Int 37:194
===Collagen-OCP composites===
* http://pubchem.ncbi.nlm.nih.gov Summary octacalcium phosphate. Last accessed 4/9/10
Collagen-OCP composites utilize ] which is a matrix protein that accounts for 30% of total proteins within most ]s.<ref>{{cite web |title=Collagen: What it is, Types, Function & Benefits |website=Cleveland Clinic |url=https://my.clevelandclinic.org/health/articles/23089-collagen |access-date=2023-04-30}}</ref> Collagen is unique in that it can be used in many applications, such as sponges or ]s, or even combined with other forms of ] such as ].<ref name=Woodhead_Publishing_2019/> Along with this, collagen based composites exhibit similar properties and structure to natural bone tissue such as high osteoconductivity, and enhanced biointegration.<ref name=Woodhead_Publishing_2019/> Collagen-OCP composites, similar to gel-OCP composites, can be synthesized using numerous methods, but one common method is via molding mixtures of OCP and collagen solutions that have been extracted from animal skins.<ref name=Woodhead_Publishing_2019/> ] preclinical Studies evaluating the effects of collagen-OCP composites have shown that the composite by itself displays enhanced bone regeneration, osteoconductivity, and ] compared to pure OCP or collagen control group as well as stimulated ] and ] activity during bone regrowth and remodeling indicating potential to be used for bone regrowth in clinical applications.<ref name=Woodhead_Publishing_2019/><ref>{{cite journal |vauthors=Kawai T, Suzuki O, Matsui K, Tanuma Y, Takahashi T, Kamakura S |title=Octacalcium phosphate collagen composite facilitates bone regeneration of large mandibular bone defect in humans |journal=Journal of Tissue Engineering and Regenerative Medicine |volume=11 |issue=5 |pages=1641–1647 |date=May 2017 |pmid=26612731 |doi=10.1002/term.2110 |s2cid=3685228|doi-access=free }}</ref><ref name=Suzuki_2013/>
* www.pubmed.gov Octacalcium phosphate: Osteoconductivity and crystal chemistry. Suzaki, O. Last accessed 4/09/10

* Nelson, D.J.A., McLean, J.D., 1984. Calcif Tissue Int. 36, 219.
===Alginate-OCP composites===
* Brown, W.E., Eidelman, N., Tomazic, B., 1987. Adv. Dent. Res., 1; 306
] is a ] derived from a form of brown seaweed that has spiked interest due to its favorable ] and its ease of ].<ref name=Woodhead_Publishing_2019/><ref>{{cite journal |vauthors=Lee KY, Mooney DJ |title=Alginate: properties and biomedical applications |journal=Progress in Polymer Science |volume=37 |issue=1 |pages=106–126 |date=January 2012 |pmid=22125349 |pmc=3223967 |doi=10.1016/j.progpolymsci.2011.06.003}}</ref> Similar to the collagen and gel based OCP composites, both ] and mixing methods have been utilized to create alginate-OCP composites, both methods produce viable composites with favorable ] which can be further controlled by altering the alginate concentration or centrifugal speed during synthesis reactions,<ref name=Woodhead_Publishing_2019/> Alginate-OCP composites, similar to previously stated scaffolds, have also shown increased levels of osteointegreation and osteogenic interactions as well as the ability to stimulate ]s ], and the ability to aid in the conversion of OCP → ] in vivo.<ref name=Woodhead_Publishing_2019/>
* http://www.ccmr.cornell.edu/facilities/Winners06Sum/dattran.html Cornell Center for Materials Research. Dat T. Tran. Last Accessed 4/09/10

===Hyaluronic Acid-OCP composites===
] is a naturally occurring ] that is present in ], ]s, and ] as a component of the ] extracellular matrix.<ref name=Woodhead_Publishing_2019/> As a component of composites, hyaluronic acid acts as a delivery medium for OCP.<ref name=Woodhead_Publishing_2019/> Synthesis of Hyaluronic-OCP scaffolds is achieved by simply mixing OCP granules with hyaluronic acid at a controlled pH level and results in an injectable paste.<ref name=Woodhead_Publishing_2019/> In terms of bone regeneration hyaluronic acid-OCP composite pastes have shown enhanced osteoconductivity soon after injection, and exhibited biodegradation by osteoclasts.<ref name=Woodhead_Publishing_2019/>

==Applications==

===Orthopedics===
The structure of OCP is closely associated with HA structure, and has thus made it an attractive bone substitute for ] scientists and ].<ref name=Suzuki_2020_2/> A higher osteoconductivity was first observed in the bone tissue response in mouse where OCP was placed onto the calvaria in its granule form, showing it to have higher osteoconductivity than other Ca-P materials like anhydrous ] (DCP), ] (ACP), calcium deficient HA (CDHA), and stoichiometric HA.<ref name=Suzuki_2020_2/> OCP also tends to biodegrade in the bone.<ref name=Suzuki_2020_2/> OCP is an osteoconductive and biodegradable material capable of stimulating bone formation through ] differentiation and ] formation.<ref name=Suzuki_2020_2/> During thermodynamic conversion of OCP to HA it was found to strongly stimulate cell capacity via ] in '']'' environments.

Biodegradable ]s (Ca-P's) like OCP can promote bone regeneration through ], which involves both ] by ]s and ] by osteoblasts.<ref name=Suzuki_2020_2/> One study showed that osteoclast formation of OCP was almost the same as that of 𝛽-] (𝛽-TCP) and that OCP and OCP/HA mixtures had higher expression of ] coupling factor compared to 𝛽-TCP when cultured with mouse marrow ]s.<ref name=Suzuki_2020_2/>

Activation of the bone cellular responses and stimulation of bone remodeling processes, has been shown in studies where OCP granules were implanted in mouse ] defects.<ref name=Suzuki_2020_2/> Composite scaffolds with OCP and ] have also been shown to induce bone regeneration in line bones in rabbits and at faster rates than 𝛽-TCP alternatives.<ref name=Suzuki_2020_2/>

===Dentistry===
Though OCP has not been established in the dental field, bioactive properties of OCP have attracted the attention of oral surgeons and researchers.<ref name=Suzuki_2020_2/> For example, OCP coatings on ] oral implants have the potential to improve osseointegration of already existing ] implants due to their high osteoconductive attributes and drug delivery capabilities.<ref name=Stefanic_2012>{{cite journal |vauthors=Stefanic M, Krnel K, Pribosic I, Kosmac T |date=March 2012 |title=Rapid biomimetic deposition of octacalcium phosphate coatings on zirconia ceramics (Y-TZP) for dental implant applications |journal=Applied Surface Science |volume=258 |issue=10 |pages=4649–4656 |doi=10.1016/j.apsusc.2012.01.048|bibcode=2012ApSS..258.4649S}}</ref> This coating allowed for reproductibility, quick synthesis, simplicity, and good tensile ] strength. Under certain conditions, synthesis of OCP coatings may allow for incorporation of biologically active molecules in the coating, providing potential for drug delivery applications.<ref name=Stefanic_2012/> Studies have also indicated potential for OCP-based cement as a potentially promising pulp-capping agent demonstrated in rats, concluding that OCP-based cement allowed for the occurrence of favorable healing processes in the ].<ref>{{cite journal |vauthors=Sena M, Yamashita Y, Nakano Y, Ohgaki M, Nakamura S, Yamashita K, Takagi Y |title=Octacalcium phosphate-based cement as a pulp-capping agent in rats |journal=Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics |volume=97 |issue=6 |pages=749–755 |date=June 2004 |pmid=15184859 |doi=10.1016/j.tripleo.2003.10.029}}</ref>

===Drug delivery===
The functionalization of therapeutic agents for drug-delivery systems for the treatment of bone pathologies has focused mainly on Ca-P ]s, HA nanocrystals, and apathetic cements, coatings and porous scaffolds, but literature on the use of OCP in these applications is limited.<ref name=Woodhead_Publishing_2019/> Most of this research includes functionalization of OCP with ]s (BPs), which are commonly used as antiresorptive agents.<ref name=Woodhead_Publishing_2019/> ], a commonly used BP, has been combined with OCP in some studies, demonstrating inhibited ]ogenesis and osteoclast differentiations but enhanced ] proliferation and activity.<ref name=Woodhead_Publishing_2019/> Alendronate-loaded OCP also showed enhancement of osteoblast differentiation markers compared to HA-loaded alendronate.<ref name=Woodhead_Publishing_2019/> In-vitro tests carried out on osteoblast, osteoclast, and ] biomimetic environments showed that BPs imbue functionalized OCP with antresorptive and antitumor properties.<ref name=Woodhead_Publishing_2019/>

==Safety==
Octacalcium phosphate has been shown to be safe in various preclinical studies. One study conducted a safety assessment after OCP collagen composites were implanted in cases of ] defects, indicating that all participants completed the trial without major problems in condition.<ref name=Kawai_2016>{{cite journal |vauthors=Kawai T, Tanuma Y, Matsui K, Suzuki O, Takahashi T, Kamakura S |title=Clinical safety and efficacy of implantation of octacalcium phosphate collagen composites in tooth extraction sockets and cyst holes |journal=Journal of Tissue Engineering |volume=7 |pages=2041731416670770 |date=2016-01-01 |pmid=27757220 |pmc=5051665 |doi=10.1177/2041731416670770}}</ref> No serious ], ] dysfunction, ], or abnormal ] results were shown, and a healthy immune response was noted.<ref name=Kawai_2016/> The border between the original bone and OCP composite implant became indistinguishable, indicating a safe and effective integration.<ref name=Kawai_2016/>

==Case studies==

===Case #1===
Case study #1 involved 60 male and female patients from nine hospitals ranging in age from 20 to 70 years old. All participants consisted of patients undergoing either sinus floor elevation, ], ] of the jaw, or ] at the ] in preparation for a dental implant. The study itself focused on testing the efficacy of bone regrowth for OCP/Col composites.<ref>{{cite journal |vauthors=Kawai T, Kamakura S, Matsui K, Fukuda M, Takano H, Iino M, Ishikawa S, Kawana H, Soma T, Imamura E, Kizu H, Michibata A, Asahina I, Miura K, Nakamura N, Kibe T, Suzuki O, Takahashi T |display-authors=6 |title=Clinical study of octacalcium phosphate and collagen composite in oral and maxillofacial surgery |journal=Journal of Tissue Engineering |volume=11 |pages=2041731419896449 |date=January 2020 |pmid=32030119 |pmc=6978823 |doi=10.1177/2041731419896449}}</ref>

For sinus floor elevation cases the procedures were separated into either one stage or two stage cases depending on the length between the alveolar crest and sinus floor (2 stage=< 5&nbsp;mm and 1 stage=≥ 5&nbsp;mm). For the one stage treatment the OCP/col composite was implanted into the alveolar space via sinus membrane elevation and the dental implants were then placed at the missing tooth region. Six months later the ] were implanted into the one stage patients. For the two stage treatment the OCP/col composite implantation and the dental implantation were spaced apart by six months. Then six months after the dental implant procedure the prosthetics were loaded into the previously placed implants. Implants for sinus floor elevation patients were made of ] and were not coated in any bioactive materials.

For Socket Preservation cases OCP/col composites were placed into the tooth removal site and then ] closed. Six months post OCP/col implantation the dental implants were placed at the missing tooth site and six months later the prosthetics were loaded into the implants.

For ] cases, after the ] and ] were ablated, surrounding bone was removed, jaw cysts were extirpated and the missing bone was filled in with the OCP/col composite; finally the gingiva and periosteum were repositioned and ] closed. Finally for alveolar cleft cases, OCP/col was placed into the alveolar bone defect and the defect was covered in gingiva and periosteum and sutured closed.

For analysis ] and ] analysis results were deemed "good" if newly formed bone was recognized and there was no histological abnormalities and if implant treatment passed six out of six inspections, whereas if the newly formed bone was minimal, unrecognizable, or the histological analysis was abnormal and implants received four or less points on the implant inspection, results were deemed as "poor". Histological analysis of sinus floor elevation for a patient within the two stage group showed newly formed bone at the site of OCP/Col implantation and no scar or inflammation cells were found. Table #1 displays the quantitative Bone width results for the four different groups within the clinical study.

'''Table #1:''' Average vertical Bone Widths Before & 24 weeks Post OCP/Co Treatment
{| class="wikitable"
| rowspan="2" |'''Surgery'''
| colspan="2" |'''Average vertical Bone Width'''
|-
|'''Pre. OCP/Co Implantation (mm)'''
|'''24 Weeks Post OCP/Co Implantation (mm)'''
|-
|'''Sinus Floor Elevation (1-Stage)'''
|4.4 ± 1.3
|12.4 ± 2.1
|-
|'''Sinus Floor Elevation (2-Stage)'''
|2.4 ± 1.3
|13.0 ± 3.8
|-
|'''Socket Preservation'''
|11.0 ± 7.2
|18.9 ± 8.6
|}

===Case #2===
Case study #2 involved three male patients, ages 63 to 77, who had previously undergone sinus or ] augmentation with at least one year of functional loading. The three surgeries were performed by a single periodontist and each participant underwent a different surgery. Patient #1 underwent a bone augmentation of peri-implant defects, Patient #2 underwent a vertical ridge augmentation, and patient #3 underwent a sinus and ridge augmentation.<ref>{{cite journal |vauthors=Kim JS, Jang TS, Kim SY, Lee WP |date=2021-08-27 |title=Octacalcium Phosphate Bone Substitute (Bontree): From Basic Research to Clinical Case Study |journal=Applied Sciences |volume=11 |issue=17 |pages=7921 |issn=2076-3417 |doi=10.3390/app11177921 |doi-access=free}}</ref>

Patient #1 underwent a three part implantations in the 44, 45, and 46 regions (1st ], 2nd bicuspid, and 1st molar of ] region). Upon having the implants inserted a guided bone regeneration procedure was performed over the peri-implant ] defect utilizing a mix of commercialized OCP synthetic bone substituent (bontree) and whole blood. Four months post implantation, sufficient levels of horizontal bone were observed partially counteracting the initial loss of bone tissue from the ] that the patient experienced prior to the study.<ref>{{cite web |title=Peri-Implant Diseases |website=American Academy of Periodontology |url=https://www.perio.org/for-patients/periodontal-treatments-and-procedures/dental-implant-procedures/peri-implant-diseases/ |access-date=2023-04-30}}</ref>

Patient #2 also underwent three implantations in the 24, 26, and 27 regions. Prior to implantation vertical ridge augmentation was performed using bontree mixed with whole blood and a titanium mesh covering. Six months after ridge augmentation the first stage of the implant was placed, and an additional four months after the first implantation the second implant was placed. Finally, six months after the second implantation the prosthetic was loaded.

Patient #3 underwent a three part implantation procedure. Firstly, sinus augmentation and vertical ridge augmentation were performed using bontree, whole blood, and a ] d-PTFE membrane for the vertical ridge augmentation. Six months after the augmentations the first and second implantation was performed in the 16-17 regions following a single stage implant surgery. Four months after the first implantation surgery a modified ] fenestration was performed due to the loss of attached ] bucally. Finally, six months post the second implant operation the ] was inserted. ] tests showed the deposition of newly formed bone around the bone grafts and good incorporation of the newly formed bone with the synthetic bone graft. Also, no ]s or ] problems were detected.

Radiological tests performed after the dental implants for all three patients showed no immediate post operative problems with the implants, and four months post operation showed implant stability levels greater than 60 for all implants. One year post implantation showed integration of the implants with newly regenerated alveolar bone and no apparent bone loss.

==References==
{{Reflist}}


{{Phosphates}}


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