Octacalcium phosphate (OCP) is a form of calcium phosphate with formula . OCP may be a precursor to tooth enamel, dentine, and bones. OCP is a precursor of hydroxyapatite (HA), an inorganic biomineral that is important in bone growth. OCP has garnered lots of attention due to its inherent biocompatibility. 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 in-vitro, but also in in-vivo clinical case studies.
Background Johan Gottlieb discovered calcium phosphate in 1769, and since its discovery calcium phosphate has been widely researched and been found to be one of the most important inorganic structures in hard tissue of vertebrates. Calcium phosphate has been used to treat various illnesses such as rickets, scrofula, diarrhea, ulcer, and inflammation, but its uses in orthopedics and dentistry have been the main area of focus for many years. Before the use of calcium phosphates in orthopedics, bioceramics 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.
By the 1900s scientists had started using calcium phosphate during surgeries as a means of applying simple bone grafts, and by 1950 the genesis of self-setting calcium phosphate in combination with bioceramics had been discovered. Between 1976 and 1981 calcium phosphates started to be used more prominently as coatings for orthopedic and dental implants in order to stimulate stronger osseointegration, 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 tissue engineering.
Octacalcium phosphate (OCP) was discovered in the 1950s, when scientists discovered that by varying the calcium phosphate ratio, various forms of calcium phosphates could be created. OCP has widely been seen as an inorganic precursor for hydroxyapatite which is similar to calcium phosphate in that it is an inorganic mineral found in bones and teeth that plays a major role in the overall structure, strength, and regeneration capabilities of bone. Along with this, compared to other forms of calcium phosphate OCP has been found to have greater levels of biocompatibility and increased rates of osteointegration. 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.
Type of ceramic–tissue interaction Ceramics can be categorized into four categories based on their interaction 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); the most stable/ideal ratio (Ca:P=10:6=1.67) results in hydroxyapatite (HA) which is often used in orthopedic settings due to the inherent biocompatibility and similarity to natural bone tissue. 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 sinter 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.
Material properties The table below displays various octacalcium phosphate material properties and descriptions of said properties. Octacalcium Phosphate PropertiesCrystal structure
(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 brushite.Stoichiometric composition
(bulk property) 33.3 mol% acidic phosphate to total phosphate found in either the hydrated or calcium deficient layer of the crystal structureChemical composition
(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.Thermal stability
(bulk property) Due to the large amount of water 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 collapseSolubility
(bulk property) Soluble at pH values of 7.4 Solubility at 25 °C = 0.0081 g/LBending strength
(bulk property) Spherule 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 MPaYoung's modulus
(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 GPaToughness (bulk property) Spherule crystals display Toughness values of 0.157 ± 0.02 mm GPa Plate crystals display Toughness values of 0.133 ± 0.03 mm MPa Ribbon-Like crystals display Toughness values of 0.28 ± 0.03 mm MPaSurface energy
(surface property) For (100) OCP crystal planes (apathetic layers) the surface energy is 1311 mJ/m2 in a vacuum and 462 mJ/m2 in water For (200) OCP crystal planes (hydrated Layers) the surface energy is 858 mJ/m2 in a vacuum and 189 mJ/m2 in water The three crystal types (spherule, ribbon like, and plate) all exhibit flexural behavior; some have brittle characteristics, others have ductile characteristics. Spherule- and ribbon-like crystals are brittle, similar to ceramics; deforming elastically up to a maximum stress, then immediately fracturing (irreversible deformation). 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 plastic deformation similar to metals and some polymers.
Synthesis
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 precipitation reactions, hydrolysis reactions, aging, and ion substitution. Previously stated methods have all been able to produce high-purity OCP; but, to upscale the production of OCP, it is imperative to control the reaction conditions as slight deviations in molarity, pH, or temperature can easily lead to different calcium phosphate variations such as dicalcium phosphate or hydroxyapatite.
Precipitation Precipitation involves mixing (calcium acetate) with a sodium phosphate solution usually consisting of a mixture of (disodium phosphate) and (sodium hydrogen phosphate). 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. pH ranged from 5.0 to 6.5; temperatures ranged from 37 – 90 °C.
Hydrolysis OCP is typically synthesized via hydrolysis of α-tricalcium phosphate (ɑ-TCP). To create OCP, ɑ-TCP along with calcium carbonate and brushite () 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 phosphoric acid at 25°C and a pH of 6. During hydrolysis, in order to prevent deviation from octacalcium phosphate, it is imperative to maintain a calcium phosphate (Ca/P) ratio of 1.33.
Aging Aging reactions are conducted similar to the precipitation reactions, but precipitation can occasionally produce poorly defined particles due to the fast precipitation process. So, upon finishing the precipitation reaction, the solution is mixed gently for times varying from 3 to 12 hours which results in well-defined OCP crystals which can then be extracted via filtration using membrane fillers.
Ion substitution Ion substitution reactions are conducted similar to precipitation reactions; but instead of calcium acetate, other variations are used, to result in more crystallized precipitates. Ions can include magnesium Mg, strontium Sr, or manganese Mn. Varying the form of acetate used during the precipitate reactions, can have varying effects depending on the element used and the concentration of element. Strontium has been found to improve the bioactive properties of OCP. In terms of thermal stability the addition of strontium or magnesium into the structure can result in reduced thermal stability and increases in the extent of collapsed OCP.
Octacalcium phosphate composites
Gelatin-OCP composites Gel sponges are typically used as bone integration scaffolds mainly due to their inherent porosity. The porous structure of the gel itself can aid in osteointegration when combined with CaP ceramic composites. Gel-OCP composites can be formed using various methods, but a common method is via coprecipitation and has been known to produce optimal Gel-OCP composites while still maintaining the inherent porosity that is useful for osteointegration. In-vivo pre-clinical studies comparing gel-OCP composites to pure gel control groups have found that the gel scaffold can regenerate substantial amounts of bone within months (~4 months) of implantation, indicating that the gel-OCP composites exhibit high osteoconductivity allowing for enhanced bone regeneration.
Collagen-OCP composites Collagen-OCP composites use collagen which is a matrix protein that accounts for 30% of total protein within most organisms. Collagen is unique in that it can be used in many applications, such as sponges or hydrogels, or even combined with other forms of calcium phosphate such as hydroxyapatite. Along with this, collagen-based composites exhibit similar properties and structure to natural bone tissue such as high osteoconductivity, and enhanced biointegration. Collagen-OCP composites, similar to gel-OCP composites, can be synthesized using many methods, but one common method is via molding mixtures of OCP and collagen solutions that have been extracted from animal skins. In-vivo preclinical studies evaluating the effects of collagen-OCP composites have shown that the composite by itself displays enhanced bone regeneration, osteoconductivity, and biodegradability compared to pure OCP or collagen control group as well as stimulated osteoblast and osteoclast activity during bone regrowth and remodeling indicating potential to be used for bone regrowth in clinical applications.
Alginate-OCP composites