A hydraulic cement for biomedical applications. The cement sets in-situ, hardening when exposed to water to produce nano-dispersed composite of calcium-silicate-hydrate gel mixed with hydroxyapatite. In comparison with prior cements, the composition provides high biocompatibility, high bioactivity and high biomechanical strength, due to the composite structure of the calcium silicate hydrate reinforced with co-precipitated particles of hydroxyapatite. Biocompatibility is also increased due to an absence of aluminum and magnesium in the composition. The cement is suitable for variety of applications, including dental implants, bone fixation, and bone repair.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention provides a new composition of hydraulic cement, and methods for making and using the composition for biomedical and dental applications. The new hydraulic cement has high mechanical strength, high bioactivity, and high biocompatibility. The cement is resistant to corrosion and is stable and durable in variety of environments, including biological environments. The cement sets at room or near-room temperatures and does not resorb (dissolve) in a biological environment.

The cement of the present invention is an aluminum-free and magnesium-free phospho-silicate hydraulic cement. The cement comprises oxides of calcium, phosphorous and silicon, and excludes magnesium and aluminum in any form. Although free of magnesium and aluminum compounds, the new cement rapidly gains strength through hydration-assisted setting at room temperature and pressure. As a result, it has high early strengths, high overall compressive strength, adjustable setting times, low hydration heat, and resistance to chemical degradation.

The cement compositions comprise at least one phosphate compound and at least one calcium silicate compound. The cement of present invention preferably uses synthetic (high purity) di- and tri-calcium silicates ([2CaO.SiO.sub.2], [3CaO.SiO.sub.2]), with no aluminum. The additive powders are preferably calcium phosphates, including dicalcium phosphate or monocalcium phosphate.

In a preferred embodiment, the first of the principal components of the biocement is calcium oxide (CaO), in the range of about 45%-80% by weight of cement in the composition, preferably in the range of about 50 wt %-70 wt %. The second of the main components is silica (SiO.sub.2), in the range of about 10%-35% by weight of cement in the composition, preferably in the range of about 15 wt %-30 wt %. The calcium oxide and silica are preferably provided in combined form, as di-calcium and/or tri-calcium silicates. The third of the main components is the phosphate (preferably in the form of P.sub.2O.sub.5 or as alternative ionic form), in range of about 1%-30% by weight of cement in the composition, preferably in the range of about 3 wt %-15 wt %.

Complex chemical and physical reactions and processes take place after the hydraulic cement powder components are mixed with water, which is preferably substantially pure water. These reactions involve hydration of calcium silicate compounds and dissolution of phosphate compounds, and the precipitation of calcium phosphates, including hydroxyapatite. These reactions proceed in an alkaline environment of pH>10. The dissolution of the phosphate compounds and precipitation of calcium phosphates take place during the hydration of the calcium silicate compounds, so that the by-products of the hydration of the calcium silicate compounds, particularly calcium hydroxide, are taken up and utilized to precipitate calcium phosphate compounds. More specifically the calcium silicate compounds (mainly di-calcium silicate (C2S) and tri-calcium silicate (C3S) react with water to produce calcium silicate hydro-gel and calcium hydroxide (CH). The inorganic chemical phosphate compound reacts in-situ with the calcium hydroxide to form a high strength hydroxyapatite precipitate, which is dispersed throughout the Calcium-Silicate-Hydrate (C--S--H) matrix, therefore simultaneously removing the CH (which as noted above, is ordinarily a structurally weak component in the body of set cement).

As a result, the biocement of the present invention has enhanced functionality, in particular enhanced strength and corrosion and dissolution resistance due to the absence of CH, combined with enhanced biocompatibility and bioactivity due to the presence of HAP and/or other phosphate inclusions. The HAP inclusions produced reactively in-situ also contribute substantially to the overall compressive strength of the set cement, both directly (through bonding to the C--S--H structure) and indirectly (through removal of the structurally weak CH inclusions). Additionally, HAP is much more resistant to environmental effects than CH, rendering the CPSC of the present invention more resistant to corrosion.

Silicate nanoparticles may optionally be introduced into the cement composition of the present invention to improve mechanical, setting, and biological properties. The silicate nanoparticles may suitably be in a colloidal silica solution that is mixed with the biocement powder. Silicate nanoparticles can be mixed with the biocement powder by ball milling. The colloidal nanoparticle will speed up the hydration of calcium silicate compounds and increase mechanical strength. Also, the silicate can enhance biocompatibility and bioactivity of biocement.

Furthermore, for dental applications, radio-opaque materials may be added to the composition to enhance absorption of X-rays, for improved visibility of the cement under X-ray examination. Examples of radio-opaque materials suitable for dental applications include, but are not limited to, barium sulfate, zirconium oxide, bismuth oxide, tantalum oxide, and mixtures thereof. Radio-opacity is very desirable in the cases of dental fillings and sealings; for some applications, however, it is not necessary to have high radio-opacity, for instance, pulp capping or in many orthopedic applications.

The novel biocement of the present invention may also be used as a bioactive coating for medical devices and drug delivery vehicles. The cement coating can be deposited on the surface of a medical device at room temperature, which is advantageous by comparison with coating techniques that require elevated temperatures for deposition. Single or multiple drugs can be encapsulated into the biocement matrix using an in-situ process. A variety of coating deposition technologies, well known in the art, may be used for deposition of films of the biocement on substrates such as implants; the techniques may include, without limitation, dip-coating, spray-coating, electro-assisted coating, aerosol-coating, and combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION

a. Overview

The present invention provides novel cement compositions and methods of making them and using them in a variety of medical and dental applications. The hydraulic cement (called later BA) of the present invention has high mechanical strength, adjustable setting time, low hydration heat, resistance to degradation, high bioactivity and biocompatibility, and stability in corrosive environments.

The hydraulic cement of the present invention is obtained through a novel chemical process of in-situ formation of hydroxyapatite/calcium silicate hydrate gel composite, at room- or near-room-temperature and pressure, accompanied by the removal of CH during cement hydration, resulting in aluminum-free and magnesium-free hydraulic phosphor-silicate cement. This is accomplished by reacting the CH in-situ with phosphate ions to precipitate much stronger and chemically resistant calcium phosphate, in particular hydroxyapatite (HAP), intimately mixed with the C--S--H gel. The composite cement has high mechanical strength, as well as biocompatibility, bioactivity, and adjustable setting times. These properties do not require application of hydrothermal treatment, pressure-assisted forming, or high temperature sintering of the components. The setting time is adjusted through provision of micron-size particles of the hydrating powders, thus removing the need for early-hydration chemicals containing aluminum.

The major components of the biocement compositions, which make up approximately 60% by weight of cement in the cement composition, comprise at least one calcium silicate compound and at least one phosphate compound. Suitable calcium silicate compounds include, but are not limited to, dicalcium silicate C2S (2CaO.SiO.sub.2),tetracalcium silicate C4S (4CaO.SiO.sub.2, tricalcium silicate C3S (3CaO.SiO.sub.2) and mixtures thereof. Suitable phosphate compounds include, but are not limited to, calcium phosphates, with calcium phosphate monobasic generally being preferred. The phosphates may contain hydration water. More complex (pre-reacted) phosphates may also be used, such as many variants of the calcium phosphates. The at least one phosphate compound is preferably included in an amount sufficient to react a major portion of the calcium hydroxide that is produced by hydration of the calcium silicate compound or compounds. Other calcium compounds may be included in the cement composition, including but not limited to, calcium oxide, calcium carbonates, calcium hydroxides, and mixtures thereof. The at least one calcium silicate compound is suitably included in an amount in the range from about 30% to about 99% by weight of the cement composition, preferably in the range from about 40% to about 80%. The at least one phosphate compound is suitably included in an amount in the range from about 1% to about 70% by weight of the cement composition, preferably in the range from about 5% to about 30%. Where present, ancillary compounds are preferably included in a total amount less than about 30% by weight of the cement composition.

A significant difference from prior art cements is that the hydraulic cement of the present invention is in its preferred embodiment both magnesium-free and aluminum free, or at least substantially free of such materials, and still maintains desirable setting and set cement characteristics. By contrast, as discussed above, all Portland cement derived hydraulic cements require fast hydrating aluminum compounds such as calcium aluminates, to achieve a sufficiently high rate for the initial hydration reaction and strength buildup of the setting cement, but with negative consequence for biocompatibility.

Minor compounds that may be included in the cement compositions in present invention include, but are not limited to, calcium oxide, silicon dioxide, iron oxide, other metal oxide compound, calcium sulfate, calcium sulfate dihydrate (CaSO.sub.4.2H.sub.2O), and mixtures thereof. The minor compounds will generally make up less than 10% by weight of cement in the composition and preferably no more than 30% by weight.

For some dental applications, radio-opacity materials may be added to the biocement composition for improving absorption of X-rays. Suitable radio opacity materials may be selected from heavy metals, oxides of heavy metals and salts of heavy metals, and may include, but are not limited to, gold, silver, barium bismuth, tantalum, barium sulfate, zirconium oxide, bismuth oxide, tantalum oxide, and mixtures thereof. The radio-opaque materials will generally constitute less than 70% by weight of cement in the composition; suitably, the radiopaque substance or substances may be included in an amount in the range from about 3% to about 50% by weight of the cement composition, preferably in the range from about 10% to about 40%.

When water is mixed with the novel cement, a complicated set of reactions is initiated. The phosphate and calcium compounds quickly dissolve in water and precipitate to produce new calcium phosphate compounds, especially hydroxyapatite, when pH is above 7.0. The reaction speed is adjustable in range from 20 min to 2 days to meet to the requirements of applications, through minor change in the system chemistry and precursor morphology.

Initially, the calcium silicates react with the water to produce a calcium silicate hydrate gel (CaO--SiO.sub.2--H.sub.2O gel); however, the rate of hydration reaction of calcium silicates is slower than that of the formation of hydroxyapatite and calcium phosphates. Consequently, in the process of co-precipitating nano-size particles of calcium silicate hydrate gel fill the voids among the precipitating hydroxyapatite particles.

A key aspect of the present invention is the in-situ formation of a hydroxyapatite/calcium silicate hydrate gel composite at room temperaturse, in ordinary prepared cement paste, without a need for elevate pressures or temperatures, and in particular without a need for thermal treatment of the setting cement paste, and without a need for Al or Mg ions participating in the reaction. The formation of the C--S--H/HAP composite is accompanied by a decrease of CH content in the set cement. The resulting composite biocement material, due to its decreased CH content, provides significantly increased mechanical strength, with the calcium phosphate and hydroxyapatite acting as a reinforcement phase and calcium silicate hydrate gel forming the matrix of the composite structure.

An important aspect of the current invention is its aluminum-free composition, which provides significantly improved biocompatibility, bioactivity and safety with as compound prior cements. As noted above, soluble aluminum is highly toxic to the osteoblast and inhibits mineralization of bone, may cause dialysis dementia, renal osteodystrophy and Alzheimer's disease.

By comparison with the cement disclosed by Wagh (as discussed above), the main components of the cement of the present invention are di-calcium and tri-calcium silicates and phosphate; the cement does not include magnesium oxide. Also, mono-calcium silicate (e.g. CaSiO.sub.3) powders are not necessary in the present invention, and it is not necessary to have any "sparsely soluble oxide" powder for the setting and hardening reactions. The liquid used to hydrate (set) the cement of the present invention is substantially neutral (pure) water, without any acidic pH modifying agents being needed for the cement setting and hardening reactions; to the contrary, the pH conditions during setting in present invention are alkaline, typically above pH=10. Moreover, the hydroxyapatite in present invention is produced through in-situ chemical reaction of the phosphate powder and the calcium hydroxide that is produced by the hydration of the calcium silicates, thus introducing nano-size HAP into the composition and thereby enhancing the mechanical properties and biocompatibility and bioactivity of the set cement; these reactions do not take place in Wagh's composition.

b. Reactions and Materials

The precipitation reaction (A) of calcium phosphate apatite is as follows: 10Ca.sup.2++6PO.sub.4.sup.3-+2OH.sup.-.fwdarw.Ca.sub.10(PO.sub.4).sub.6(O- H).sub.2 (A) where the Ca/P ratio is between 1.2 and 2.0.

The hydration reactions (B, C) of calcium silicates can be approximated as follows: 2[3CaO.SiO.sub.2]+6H.sub.2O.fwdarw.3CaO.2SiO.sub.23H.sub.2O+3Ca(- OH).sub.2 (B) 2[2CaO.SiO.sub.2]+4H.sub.2O.3CaO.2SiO.sub.2.3H.sub.2O+Ca(OH).sub.2 (C) where the calcium hydroxide CH is the hydration product which contributes to the high alkalinity of the cement. The calcium silicate hydrate is not a well-defined compound and the formula of (3CaO.2SiO.sub.2.3H.sub.2O) is only an approximate description. The ratio of CaO/Si.sub.2O is in between 1.2 and 2.3, which depends on water contain, aging time and temperature, and other factors. The high pH (pH=10-13) during hydration, in the presence of phosphate ions (PO.sub.4.sup.3-) increases the precipitation rate of the calcium phosphate, particularly hydroxyapatite, according to the reaction (A), which in turn decreases the overall alkalinity of hydration. Consequently, a process is created which both (i) decreases the alkalinity and CH content in the setting cement; and (ii) provides a strong and bio-active HAP phase which reinforces the composite.

In order to further remove the calcium hydroxide CH during setting of the cement, and thus further enhance its mechanical strength, additional phosphate may be introduced into the cement composition, which will continue to react with calcium hydroxide to form hydroxyapatite. If the calcium phosphate compound is calcium phosphate monobasic, the following dynamic chemical reaction takes place: 3Ca(H.sub.2PO.sub.4).sub.2+7Ca(OH).sub.2.Ca.sub.10(PO.sub.4).sub.6(OH).su- b.2+12H.sub.2O (D)

The calcium hydroxide, produced during the hydration reaction of calcium silicates, reacts relatively rapidly with the phosphate compounds to produce the new compound, hydroxyapatite (HAP). Importantly, the same reaction (D) also provides water, which continues to react with the calcium silicates. The water supplied through reaction (D) is an important factor in controlling the hydration reaction speed, and thus setting time, hardening time, and the final mechanical strength of the composite biocement.

To further improve mechanical strength, silica nanoparticles may be introduced into the cement composition to react with remnant calcium hydroxide and thereby further decrease CH content and alkalinity of the cement.

The hydration rate of the calcium silicates (reactions B, C) increases as setting progresses, since the phosphate compounds in biocement react with calcium hydroxide to produce hydroxyapatite and water (reaction D), thus shifting the equilibrium. Therefore, the setting and hardening time of the biocement is shortened.

In the case of ordinary Portland cement (OPC) compositions, the hydration reactions of calcium silicates results in an increase of pH to over 12. In the cement composition of the present invention by contrast, the phosphate compounds react with the calcium hydroxide and thus neutralize the pH of the cement. The calcium hydroxide is therefore only the intermediate product of the hydration of calcium silicates in biocement of the present invention.

In ordinary Portland cement (OPC), the main strength providing compound is calcium silicate hydrate (C--S--H). C--S--H is an amorphous or poorly crystalline material which forms very small particles of submicron (less than 1 um) size. The calcium hydroxide CH, on the other hand, is a well-crystallized material with a definite stoichiometry, which occupies about 20-25% of the volume of OPC cement paste. The calcium hydroxide precipitates wherever free space is available and may completely engulf the cement grains. However, as noted above, calcium hydroxide is mechanically weak and it therefore greatly reduces the mechanical strength of the cement. In present invention, the calcium hydroxide is only an intermediate product, as it reacts with the phosphate compounds to produce the hydroxyapatite and water, according to reactions A and D.

In the set biocement of the present invention, the calcium silicate hydrate (C--S--H) interlocks with the hydroxyapatite, leading to in situ formation of a composite-like structure interspersed at a nanoscale level. The hydroxyapatite thus provides a reinforcement phase while the C--S--H forms the matrix of the composite structure. As a result, both phases contribute mechanical strength to the composite. By comparison with mineral trioxide aggregate (MTA) which, as noted above, is derived from ordinary Portland Cement, the mechanical strength and corrosion resistance of the material are significantly improved, because the weak phase calcium hydroxide of the former is replaced with high strength, chemically stable hydroxyapatite (HAP). The HAP has a compressive strength (>60 MPa) which is much higher than that of calcium hydroxide (<1 MPa). Moreover, hydroxyapatite (Ca.sub.10(PO.sub.4).sub.6(OH).sub.2) is one of the most biocompatible and bioactive ceramics because it is similar to the mineral constituents of natural human bone and teeth. Consequently, due to the relatively large content of HAP, the presently disclosed biocement of the present invention is not only bioactive and biocompatible, but also is osteoinductive and osteogenic (i.e., it encourages bone in-growth).

As a result, the cement of the present invention is especially suited for use in medical materials and devices, such as prostheses, implants, coatings, and other surgical procedures. The biocement is self-setting, injectable, and develops high strength cement, allowing it to be used for both weight and non-weight bearing applications. The cement can be deposited in a selected location in a patient's body and then allowed to cure to a solid therein. The cement resists disintegrative washout upon contact with blood, and injection into the wound is less stressful to the surrounding tissue because of being completely biocompatible with the physiological environment. Therefore examples of bio-medical applications for biocement of the present invention include, but not are limited to, orthopedic surgery, bone repair, bone reconstruction bone filling, bone fixation and combinations thereof, such as. for example, human and veterinary percutaneous vertebroplasty, craniomaxillofacial surgery, ridge augmentation, spinal fusion cage/implant, treatment of radial fractures, treatment of temporal mandibular, joint disorders, plastic surgery and cosmetic augmentation, bone graft substitution, scaffolding, drug delivery, and variations thereof. The biocement can also be used for dental applications, such as, for example, root canal filling, root canal sealing, root perforation repair, root resorption repair, root-end filling, retrofilling materials, pulp capping, apexification, and combinations thereof. The cement may also be used as a coating on devices, in particular medical implants. Another example includes use of the cement with drugs or proteins to address the specific medical problems, e.g.,. microspheres of biocement may be designed for targeted delivery of drugs, proteins, DNA, or other medically active species to areas of interest in the body.

The cement of the present invention can also be used make composite materials including specific secondary reinforcement phases, such as fibers, aggregates, bioglasses, bioceramics, polymers, and metals, in variety of morphological forms such as particles, fibers and loops for example.
 

Claim 1 of 18 Claims

1. A bio-active and biocompatible hydraulic cement composition for medical and dental applications that reacts with water at a substantially neutral pH, said hydraulic cement composition comprising: at least one calcium silicate compound that produces calcium silicate hydrate-gel and calcium hydroxide during hydration when water is added to said composition at near neutral pH, said at least one calcium silicate compound being selected from the group consisting of: di-calcium silicate; tri-calcium silicate; tetra-calcium silicate; and combinations thereof; and calcium phosphate monobasic that reacts with said calcium hydroxide that is produced by hydration of said at least one calcium silicate compound to produce hydroxyapatite in-situ during setting of said composition; said hydraulic cement composition being substantially free of both aluminum and magnesium.

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