MONOLITHIC BODIES OF SINTERED CHEMICALLY BONDED CERAMIC (CBC) BIOMATERIAL PREPARED EX VIVO FOR IMPLANTATION, PREPARATION AND USE THEREOF

Abstract

The present invention generally relates to the use of pre-formed bodies of Chemically Bonded Ceramics (CBCs) biomaterial for implantation purposes wherein the bodies are prepared ex vivo allowing process parameters to be optimized for desired long term properties of the resulting CBC biomaterial. More particularly, the pre-formed CBC material bodies of the present invention are sintered. The pre-formed body of CBC material is machined to the desired geometry and then implanted using a CBC cementation paste for fixation of the body to tissue. The invention also relates to a method of preparing pre-formed bodies of CBC biomaterial for implantation purposes, methods of preparing an implant thereof having desired geometry, and a method of implantation of the implant, as well as a kit for use in the method of implantation.

Claims

1. A method of preparing ex vivo a monolithic sintered, hardened raw body of CBC biomaterial for implantation purposes comprising the following steps: A providing a CA-, CS- or CAS-system CBC powder; B compacting the CBC powder into a green body; S sintering ex vivo the green body, so as to obtain a sintered body; and D hydrating ex vivo the sintered body obtained in step S using an aqueous hydration liquid, so as to obtain a raw hardened, sintered body of CBC biomaterial.

2. The method of claim 1, wherein the CBC powder is a CAS-system CBC powder additionally containing phases of calcium phosphate.

3. The method of claim 1, wherein the CBC powder is a CA-system CBC powder.

4. The method of claim 1, wherein the CBC powder is a CA- or CAS-system CBC powder and the predominant Ca-aluminate phase is C.sub.3A.

5. A method of preparing ex vivo a sintered, monolithic CBC biomaterial implant comprising the following steps: A providing a CA-, CS or CAS-system CBC powder; B compacting the powder into a green body; S sintering ex vivo the green body, so as to obtain a sintered body; D hydrating ex vivo the sintered body obtained in step S using an aqueous hydration liquid, so as to obtain a hardened, sintered body of CBC biomaterial; E establishing a desired geometry of a desired implant; F machining to the desired geometry established in step E, e.g. using CAD/CAM or other chairside techniques, either: a) the compacted dry powder green body obtained in step B; b) the partly or fully hydrated body in step D; or c) the sintered body obtained in step S,  so as to obtain a monolithic CBC biomaterial implant.

6. The method of claim 5, wherein the CBC powder is a CAS-system CBC powder additionally containing phases of calcium phosphate.

7. The method of claim 5, wherein the CBC powder is a CA-system CBC powder.

8. The method of claim 5, wherein the CBC powder is a CA- or CAS-system CBC powder and the predominant Ca-aluminate phase is C.sub.3A.

9. A method of preparing ex vivo a monolithic, sintered CBC biomaterial implant, especially suited for chairside applications, comprising the steps of: A.sub.A-D providing a pre-formed hardened, sintered raw monolithic CBC material body for implantation purposes, obtainable by the method of claim 1; E establishing a desired geometry of a desired implant; and, F machining the pre-formed hardened, sintered raw monolithic CBC material body to the desired geometry established in step E, e.g. using CAD/CAM or other chairside techniques, so as to obtain a monolithic CBC biomaterial implant.

10. A pre-formed, hardened, sintered, raw monolithic CBC biomaterial body for implantation purposes having a reduced open porosity and improved mechanical strength obtainable by the method of claim 1, having a porosity within the interval of 2-8 vol-%.

11. A method of implanting a hardened, sintered, monolithic CBC biomaterial implant prepared ex vivo comprising the steps of: A.sub.A-F providing a machined monolithic, sintered, hardened CBC biomaterial implant, obtainable by the method of claim 5; G providing a CA-, CS- or CAS-system CBC powder; I mixing the CBC powder with an aqueous hydration liquid so as to obtain a cementation paste; J applying the paste obtained in step I to the implant; K inserting the implant with the paste applied thereupon obtained in step J into a site of implantation; and L allowing the cementation paste to harden at the site of implantation in vivo for fixation of the implant to the surrounding endogenous hard tissue.

12. A kit for use in the implantation method of claim 11, comprising a preformed hardened, sintered, raw monolithic CBC material body for implantation purposes obtainable by the method of claim 1; and a specified quantity of CA-, CS- or CAS-system CBC powder, and a corresponding quantity of aqueous hydration liquid forming a cementation paste with the CBC powder upon mixing therewith.

13. The kit of claim 12, wherein the composition of the cementation paste formed from the CBC powder and aqueous hydration liquid corresponds to the composition of the preformed hardened, sintered, raw monolithic CBC biomaterial body.

14. The kit of claim 12, wherein the CBC powder is a CAS- or CASP-system CBC powder, and wherein the aqueous hydration liquid and/or the CBC powder contains phosphate, so that the powder and liquid will form a CASPH-system paste upon mixing thereof.

15. A CBC powder comprising: 15-45% by weight of a ceramic cement binder system capable of being hydrated containing calcium aluminate (CaO—Al.sub.2O.sub.3); and 55-85% by weight of inert particles, said particles having an average particle size of <10 μm, characterized in that the calcium aluminate phase C3A constitutes at least 15% by weight of the CBC powder.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0033] The present invention is based on a unique utilization of a nanostructural chemically bonded ceramic system comprising both a pre-sintered material (the implant) with low porosity before hydration, e.g. as an inlay or onlay prepared to the final geometry by CAD/CAM or similar on-site (e.g. chairside) methods, and a cementation system for fixation of the preformed implant. The implant and the cementation paste may be based on similar chemistry to provide a complete biomaterial system with chemistry close to that of hard tissue (enamel, dentine and cortical bone). Such system is summarized as CaO—Al.sub.2O.sub.3—SiO.sub.2—P.sub.2O.sub.5—H.sub.2O (CASPH).

[0034] These findings in the first place relate to dental applications to allow for a low porosity, where geometry, similar chemistry contribute to avoidance of tension mechanically and thermally, as well as avoidance of post-operative problems are of great importance.

[0035] The present invention will allow for an improved translucency to be obtained in the CBC material, by virtue of being formed ex vivo, and especially by virtue of the inventive sintering step. Also, since higher pressure can be used for compaction, translucency can be obtained with less complex compositions, as compared to the compositions used for giving high translucency in materials from a paste.

[0036] The present invention also allows for the generally preferred calcium aluminate, not just the CaOxAl.sub.2O.sub.3 phase (CA), but also the 3CaOxAl.sub.2O.sub.3 phase (C.sub.3A) to be used, which is otherwise typically considered too reactive to be used in vivo. During hydration of the C.sub.3A-phase only the hydrated phase C.sub.3AH.sub.6 is formed, no complementary phase. Also, the reaction of heat associated with the use of C.sub.3A may often be limiting to its applicability. Other suitable phases in the calcium aluminate system are the 12CaOx7Al.sub.2O.sub.3 phase (C.sub.12A.sub.7) or mixtures of calcium aluminate phases, crystalline and/or in glass/amorphous state.

[0037] The inventive biomaterial system is based on chemically bonded ceramics, wherein the ceramic phase is based on Ca-aluminate and/or Ca-silicate.

[0038] The present invention is based on findings related to a specific chemical system based on materials produced from the CaO—Al.sub.2O.sub.3—SiO.sub.2—P.sub.2O.sub.5—H.sub.2O (CASPH)-system. The CASPH-system is close in chemistry to that of body hard tissues such as enamel, dentine and different bone structures. The complete system comprises 4 aspects which all are essential. These aspects relate to 1) a premade implant, 2) configuration of the implant, 3) in situ preparation of the final geometry in the clinical situation, and 4) cementation of the implant.

[0039] The premade implant is prepared outside the body to yield a high strength, low-porosity implant. The formation of the premade implant takes into account the following aspects; a) the possibility of using a temperature above body temperature for the hydration, b) the possibility of pressing of the original powder to a high density, c) possibility of hydrating the material using merely pure water as hydration liquid, d) possibility of using CBC powder composition of reduced complexity, e) inclusion of a sintering step, and f) achievement of an acid resistant material, as well as achievement of g) highly bioactive materials having improved translucency.

[0040] The invention generally relates to dental materials and implant materials used in hard tissue. The invention is aimed at producing biomaterials for dental applications with special reference to dental filling materials including underfillings and sealants, and general bone void filling.

[0041] A second binder system—a cross-linking organic binder system which provides for initial crosslinking of the freshly mixed paste—can be included in the cementation paste. Such systems are known in the art.

[0042] The invention is described in more detail below with special reference to development of the selected chemical system, the pre-formed CBC biomaterial body using presintering and methods to prepare the final geometry of the implant.

The Chemically Bonded Ceramic System of the Pre-Formed Sintered Body.

[0043] The ceramic cement binder system of the chemically bonded ceramic system of the invention is based on calcium aluminate (e.g. CA, C.sub.3A) and/or calcium silicate (e.g. CS) phases, i.e. the ceramic cement binder system is a CA-, CS-, or CAS-system. The ceramic cement binder system is capable of being hydrated. In a preferred embodiment the ceramic cement binder system of the chemically bonded ceramic system of the invention is based on calcium aluminate (i.e. a CA-system), and the preferred phases are C.sub.3A and CA, especially C.sub.3A. The mean particle size of any particles present in the original powdered material should be below 10 μm, and the amounts of the chemically bonded Ca-aluminate phases should correspond to a c/w ratio close to complete conversion, the latter favoring general low porosity in the microstructure, comprising mainly of nanostructures including nanoporosity.

[0044] Lower contents of phases from the CaO—SiO.sub.2—H.sub.2O system and/or CaO—P.sub.2O.sub.5—H.sub.2O system are also preferred, especially from the CaO—P.sub.2O.sub.5—H.sub.2O system to facilitate formation of apatite phases.

[0045] Accordingly, in a preferred embodiment the ceramic cement binder system of the pre-formed implant is a CASPH-system, preferably based on calcium aluminate, the preferred phases of which are C.sub.3A and CA, especially C.sub.3A.

[0046] In a preferred embodiment the raw sintered monolithic body of CBC biomaterial, from which the inventive implant is formed, is prepared using a CA-, CS- or CAS-system CBC powder comprising the phase C.sub.3A.

[0047] The binder system preferably constitutes 15-45% by weight of the CBC powder.

[0048] An especially preferred CBC powder for preparing the monolithic sintered body comprises 15-45% by weight of the ceramic cement binder system wherein the calcium aluminate phase C.sub.3A constitutes at least 15% by weight of the CBC powder, and 55-85% by weight of inert particles having an average particle size of <10 μm. Other phases of calcium aluminate (CaO—Al.sub.2O.sub.3), and, optionally, any phases of calcium silicate (CaO—SiO.sub.2), may also be present in the CBC powder. Preferably the cement binder system is based on calcium aluminate, and more preferably the phase C.sub.3A. In a preferred embodiment C.sub.3A is the sole phase of the cement binder system.

Compaction of the CBC Powder

[0049] The powder is compacted using any traditional pressing techniques, including general pressing and isostatic pressing. The pressing technique is preferably selected so as to give the compacted material a high density. The total porosity is favorably below 45 vol-%, preferably in the interval 30-40% depending on the exact selected composition of the material. In order for the green body resulting from compaction of the powder to allow for machining thereof, the pressure used should be at least 25 MPa, e.g. within the interval of 50-350 MPa, preferably about 100 to about 300 MPa, typically from 100 MPa to 280 MPa.

Sintering of the Green Body

[0050] Sintering of the pre-compacted body is used as an additional compaction of the green body. The sintering provides the body, after sintering thereof, with a porosity in the interval of 10-25 vol-%. The prepressed green body is sintered at a temperature in the interval of from 1,200-1,500° C. for a time period in the interval of about 15 minutes to several hours. For C.sub.3A the preferred interval is 1,275-1,375° C. for a time period in the interval of 1-2 hours.

[0051] The subsequent hydration will further reduce the porosity of the sintered body to a porosity within the interval of 2-8 vol-%, preferably below 7 vol-%, and more preferably below 4 vol-%. The porosity, which after hydration will take the form of nanopores, remains open.

Forms and Sizes of the Pre-Formed Sintered Raw Body

[0052] Suitable dimensions of individual pre-formed sintered raw bodies are e.g. in the interval of 3-12 mm. A suitable shape is e.g. rods, tablets, or platelets. The preformed bodies can be provided with notches, or portions with otherwise markedly reduced cross-sectional area, so that individual bodies easily can be broken off from a larger body.

Hydration Temperature.

[0053] The premade implant is hydrated outside the body allowing hydration temperatures above body temperature. The preferred hydration temperature is within the interval of 50-90° C.

The Hydration Liquid

[0054] The bulk of the liquid used is water. For the pre-made implant pure water is preferred.

The Nanostructure.

[0055] The inventive requirements of the microstructure of Ca-aluminate and/or Ca-silicate based biomaterials allow the total biomaterial to be on the nanoscale level after hydration. This refers both to the premade biomaterial and the cementation paste by: [0056] a) the general nanostructure developed in the CASP-system; [0057] b) a nanoparticle/crystal size of hydrates in the interval 15-40 nm; [0058] c) a nanoporosity size of 1-4 nm; and, [0059] d) original particle size of the reacting chemically bonded ceramics of <10 μm.

[0060] The use of a premade sintered implant according to the described conditions will guarantee that the nanostructure also will: [0061] a) be free of large pores from handling aspects; and [0062] b) exhibit a low content of nanopores, preferably below 7 vol-%, most preferably below 4% upon hydration thereof.

The Inert Filler Particles in the Premade Implant

[0063] A complementary inert filler material in the premade implant is preferably used to enable complete hydration of the ceramic cement binder system. The inert filler material can be a hydrated CBC biomaterial, e.g. having same composition as the inventive CBC biomaterial, or e.g. a glass. A preferred inert filler is a glass with a refractive index close to that of the hydrated phases, i.e. a refractive index in the interval 1.58-1.67. The resulting reduced porosity of the sintered body will allow for accommodation of less water into the system for hydration of the binder phase. To compensate for the lower amount of water available for hydration of the binder phase, the content of the inert filler system is preferably increased, and is preferably in the range of 55-85 w/o, more preferably 70-80 w/o, of the CBC powder to provide conditions for complete hydration of the ceramic cement binder system.

The Cementation Paste

[0064] The cementation cement or paste is preferably based on the system CaO—Al.sub.2O.sub.3—SiO.sub.2—P.sub.2O.sub.5—H.sub.2O (CASPH). The ceramic cement binder system of the cementation paste will thereby exhibit a chemistry close to both the chemistry of the premade implant, e.g. the CAH system, and the chemistry of hard tissue, which is mainly a Ca-phosphate system. For optimum rheological and handling aspects a glass ionomer system may be added. The CBC powder used for preparing the cementation paste is preferably based upon mono-phase CA. A suitable amount of the glass ionomer when used is for example about 15% by weight of the CBC powder.

The Clinical and the In-Situ Preparation

[0065] The premade implant is given its final geometry using in the clinic present CAD/CAM equipment or similar equipment on-site (e.g. chairside), or at general dental laboratory CAD/CAM equipment or similar equipment. The final cementation (the paste) is prepared in minutes just before treatment and the bond between the final implant and the tissue is established in minutes after treatment.

[0066] Machining the preformed CBC biomaterial body to the desired geometry can be made on the green body of dry powder as obtained after pressing of the powder, which body after machining thereof is sintered and hydrated to a hardened, sintered CBC biomaterial implant, on the sintered body as obtained after sintering, or on the pre-formed, sintered CBC biomaterial body which is in the process of being hydrated, i.e. on a partly hydrated pre-formed CBC biomaterial body, or on the fully hydrated, and thus hardened, pre-formed CBC biomaterial body. Machining the green body of dry powder, or the partly hydrated pre-formed body will allow for greater ease of machining. However, for clinical chairside applications the premade implant will typically be provided in a sintered and hydrated form, which will merely be machined at the clinic to the appropriate geometry.

[0067] The present invention is preferably used as inlays, tooth fillings including underfillings, and fissure sealings. Other application fields according to the present invention are within orthopedics, and as a carrier for drug delivery.

The Kit

[0068] The present invention also relates to a kit for use in the implantation method comprising a preformed hardened, sintered, raw monolithic CBC material body for implantation purposes; and a specified quantity of CBC powder, and a corresponding quantity of hydration liquid for forming a cementation paste thereof.

[0069] In preferred embodiments of the inventive implantation method and kit, the CBC powder and aqueous hydration liquid will be selected so as to form a cementation paste belonging to the CASPH-system.

[0070] The kit is preferably in the form of a capsule or syringe mixing system containing the CBC powder and the aqueous hydration liquid in separate capsules or syringes, respectively.

EXAMPLES

Description of Raw Materials and Preparation

[0071] 1. The calcium aluminate (C.sub.3A=3(CaO)(Al.sub.2O.sub.3)) used was synthesised and treated according to the description below.
2. Deionised water.
3. Inert glass of the composition SiO.sub.2—BaO—B.sub.2O.sub.3—Al.sub.2O.sub.3 in wt % 50-30-10-10 average particle size 0.4 μm, d(99)≦3 μm.
4. LiCl as an accelerator for the cement paste hydration was used as a pre-prepared standard solution, p.a. quality.

Example 1—Preparation of the Powder and Pressed Rods/Tablets

[0072] The calcium aluminate used for this material was synthesized using high purity Al.sub.2O.sub.3 and CaCO.sub.3. The appropriate amounts of the raw materials are weighed in to a suitable container (1:3 molar ratio). The powders are intimately mixed by tumbling in excess isopropanol. Thereafter, the isopropanol is removed, such as by evaporation of the solvent using an evaporator combining vacuum and heat and finally heating in oven. The next step is filling high purity Al.sub.2O.sub.3 crucibles with the powder mix and heat treating it at a temperature of 1,340° C. for 4 h. After heat treatment the material is crushed using a high energy crusher, in this case a roller crusher with alumina rollers. After crushing the calcium aluminate is milled using an air jet mill (Hosokawa Alpine) to the specified particle size distribution with a d(99)v of <8 μm and an average particle size of 3 μm.

[0073] The final powder formulation is obtained in the following way: All powder components are weighed in with high accuracy according to the composition in Table 1.

TABLE-US-00001 TABLE 1 Composition of the final powder formulation for the implant. Raw material Wt % Calcium aluminate 22.00 C.sub.3A phase Glass, inert 78.00 Ps < 0.5 μm

[0074] The components are weighed into a glass beaker, and the beaker is thereafter placed in a dry mixer and the components are mixed for 3 hours. The next step after mixing is sieving through a 125 μm sieve in order to homogenize the powder and remove large agglomerates. After sieving, the powder is transferred to a suitable container, which is then sealed and stored dry. The powder is pressed into rods (diameter 8 mm and length 8 mm.).

[0075] The powder was pressed into rods using cold isostatic pressing. The cold isostatic pressing was performed at 100 MPa.

Example 2—Sintering of the Pressed Rods

[0076] The rods prepared in Example 1 above were thereafter sintered at a temperature of 1,280° C. for different time periods (15 min to 12 hrs), yielding a further compaction of the bodies, corresponding to a total porosity prior to hydration of maximum 25 vol-%, as set out in the Table below.

Example 3—Machining into Desired Geometry

[0077] The final geometry was accomplished by means of machining the sintered body obtained in Example 2 using CAD/CAM.

Example 4—Hydration of the Sintered Bodies

[0078] The liquid for hydration was prepared as follows. The Ca.sub.3(PO.sub.4).sub.2 is added to pure, deionized water in an amount of 2% by weight. The liquid is now ready for use as a hydration liquid for hydrating the preformed sintered body.

[0079] Using the above hydration liquid the sintered bodies obtained in Example 3 above were hydrated in a closed chamber at 60° C. for 4 hours. The humidity in the chamber was close to 100%.

[0080] The hydrated, sintered bodies having a final geometry are now ready to be implanted using the below described cementation paste as a glue for fixation thereof to tissue. See Example 5 below.

Example 5—Preparation of the Cementation Paste

[0081] The CBC powder used in this Example is based on the mono-phase CaO Al.sub.2O.sub.3 (CA) and comprises 15% by weight of a glass ionomer. The powder is mixed by hand with a sufficient amount (about 45 vol-% of the total paste thus formed) of the hydration liquid described in Example 4 to form a paste. The paste may in a next step be used to glue the pre-prepared sintered hydrated body to tissue.

Example 6—Description of Tests and Results Obtained

[0082] The premade sintered and hydrated implants prepared above were evaluated chemically, mechanically and biologically according to the table below. Each test comprised 12 samples. The tests were conducted using standard ISO testing, which comprises the following sections: Cytotoxicity (ISO10993-5), Sensitization (ISO10993-10), Irritation/Intracutaneous reactivity (ISO10993-10), Systemic toxicity (ISO10993-11), Sub-acute, sub-chronic and chronic toxicity (ISO10993-11), Genotoxicity (ISO10993-3), and Implantation (ISO10993-6).

[0083] The porosity of the sintered bodies was calculated by use of the density of compounds of the body and the volume of the sintered body. The porosity of the sintered and hydrated bodies were measured by weighing the material before and after hydration, respectively, and by measuring the reduction of weight after drying the hydrated bodies at a temperature of 125° C. for 2 hrs.

TABLE-US-00002 Duration Porosity Porosity Compres- Bio- Bio- Trans- of sin- after sin- after hy- sion compat- activ- lucen- tering tering dration strength ibility ity cy % 15 min 25% 7%  250 ± 12 OK OK 30 ± 2 4 hrs 17% 4% 380 ± 8 OK OK 38 ± 3 12 hrs 14% 3% 390 ± 8 OK OK 42 ± 3