Patent Application
20120115981
The present invention relates to acrylic polymer-based bone cements capable of promoting osteointegration and simultaneously preventing the onset of post-operative infections.
In the clinical practice, cemented fixation of orthopaedic prostheses (hip, knee) implies the application of acrylic cements, typically comprising in situ-polymerised polymethylmethacrylates (PMMA).
PMMA cements are typically prepared from two components: a liquid and a powder. The liquid includes methylmethacrylate (MMA) monomers, an accelerator and/or inhibitor. The powder includes PMMA microspheres, a polymerisation initiator and/or radio-opacifying agent. These cements promote both the short-term and long-term prosthesis stability, through a mechanical anchorage, yet they do not become completely integrated with the bone tissue and exhibit poor mechanical properties. The PMMA-based cement is also used for making temporary prosthetic devices in case of revision.
A further use for this material is in spinal surgery in case of vertebral fractures, wherein PMMA is injected into the fractured vertebra for the consolidation thereof.
A significant problem in implant surgery is the possible development of infections. Indeed, the temporary prosthetic devices are often used during the infection treatment step by systemic or localised antibiotic administration.
In recent years, several expedients have been established in order to prevent the onset of periprosthetic infections; however, even though the infection rate has decreased, the problem is not completely solved. The possibility of introducing antibiotics directly into the bone cement used for fixing the prosthesis, so as to prevent the settlement of germs at the bone tissue-cement-prosthesis interface, has been known since the '70s. Since then, many investigations have been carried out to prove the effectiveness of such a method, by using different antibiotics and different bone cements.
Moreover, which way is the best way for introducing antibiotics into the cement is presently under discussion; in fact, the drug powder may be added manually during surgery to the polymer powder, or the blend may be accomplished directly during manufacture with industrial techniques.
In particular, the use of cements commercially-added with antibodies developed mainly in European countries; in contrast, in the United States it is preferred to introduce the required antibiotic manually during surgery.
In spite of the great numbers of data present in literature, very few studies actually compare commercially produced antibody-added cements and cements added in situ with antibodies. Even nowadays there is not a sufficient amount of extensive data that prove the effectiveness of cements added with antibiotics.
Also bio-active bone cements containing PMMA, a bio-active glass prepared from SiO2—CaO—P2O5 and antibiotics, are known. Bio-active glasses described by L. L. Hench in Bioceramics, J. Am. Ceram. Soc. 81 [7] (1998), 1705-1728 are characterised by the fact that they are able to induce an actual chemical bond with bone tissue, thanks to their ability of interacting with biological fluids, thereby forming a hydroxyapatite layer on the surface thereof.
Even though on one hand the use thereof can improve the osteointegration characteristics, the problem remains of conferring adequate and long-lasting antibacterial properties to the bone cement.
In these cements, the antibody active principle normally is mixed with the polymer phase and constitutes a third phase in the cement composition.
Furthermore, the use of PMMA bone cements containing antibacterial metal salts has been proposed; WO82/01990 describes a bone cement for cementing prostheses, which contains polymethylmethacrylate, a load of glass fibre or quartz particles and a material designed to release silver ions in the form of a colloidal silver salt. In this case, too, we are dealing with a three-phase composition, in which it is difficult to regulate a sustained release of the antibacterial metal ions. Moreover, the glass phase is not bioactive.
One object of the present invention is to provide a novel bone cement composition, particularly for use in the fixation of orthopaedic prostheses, in spinal surgery or in the production of temporary prostheses, made of acrylic polymers, which at the same time is suitable to promote binding to the tissue with which it comes into contact, and thus integration of the prosthetic device, and suitable to effect a sustained antibacterial action.
For such a purpose, object of the invention is a bone cement having the characteristics defined in the claims that follow.
In the bone cement object of the invention, the acrylic polymer typically is polymethylmethacrylate (PMMA), but it may also be made of a methylmethacrylate and methylacrylate copolimer, or by a bisphenol-a-glycidylmethacrylate (bis-GMA) polymer or mixtures thereof.
The glass/glass-ceramic component is introduced in the form of a powder into the polymer component of the bone cement. The mixture thus obtained is subsequently polymerised in situ by stirring with the liquid monomer and the activator. Typically, according to the conventional technique, the polymer component and glass/glass-ceramic component mixture preferably contains a powdered X ray opacifier, for example zirconium dioxide and/or barium sulphate.
The liquid fraction contains the monomer, typically methylmethacrylate, in which a radical activator is dissolved such as for example N-N-dimethyl-p-toluidine. It is however understood that the invention is not restricted to the selection of specific initiators and/or radical activators.
The percentage of the glass/glass-ceramic component in the polymerised bone cement generally is lower than 80% by weight, referred to the total weight of the bone cement, and preferably is lower than 50% by weight, so as to allow for an excellent homogenisation with the acrylic polymer component. Percentages of the glass/glass-ceramic component from 10% to 50% by weight are preferred.
The granulometry of the glass powders, referred to as the largest granule size, typically is lower than 80 μm and preferably lower than 20 μm.
The bioactive glass/glass-ceramic component contains at least the following oxides: SiO2, CaO, Na2O, as well as at least one silver, zinc and/or copper oxide or mixtures thereof. Preferably, the glass/glass-ceramic component comprises:
Further oxides may be added, such as P2O5, K2O, MgO, Al2O3 e B2O3, individually or as mixtures of two or more of the mentioned oxides. By way of example, each of said oxides may be used in the glass composition in accordance with the following molar concentrations:
The glass/glass-ceramic component can be obtained by fusion of precursors of the above-mentioned oxides, typically carbonates. Alternatively, the glass/glass-ceramic component can be obtained by the sol-gel process.
The per se known sol-gel synthesis method is performed by stirring the metal alkoxides in solution, followed by hydrolysis, gelatinization and baking
The antibacterial element can be inserted into the composition in the form of an oxide during synthesis of the glass (or glass-ceramic) or preferably in an ion form, after synthesis, through ion exchange processes from solutions, for instance according to the method described in EP 1 819 372.
The ion exchange technique allows even high amounts of silver to be introduced into the glasses and glass-ceramics of suitable composition, which is difficult to achieve by the fusion and casting technique. Usually, the bio-glasses are synthesised by using refractory pots, therefore a high silver content may cause interactions between the silver and the pot, with formation of unwanted phases, and consequent non-uniform silver content in the different castings. Furthermore, the fusion and casting technique does not allow for an excellent silver dispersion and homogenisation within the material, with frequent formation of metal clusters (
EP 1 819 372 describes the bulk application of the ion exchange method to glass and/or glass-ceramic materials or on metal coatings. For application on powders, the process parameters need to be suitably modified and controlled; in fact, the same conditions applied for instance to bulks and powders give decidedly different results.
Particularly the ion exchange technique on powders must be carefully examined for each specific glass/glass-ceramic composition employed, even considering parameters, such as for example the pH value of the exchange solutions, which generally do not have effect during the process performed on bulks, coatings and scaffolds.
The high specific surface of powders makes them more reactive towards the surrounding environment and particularly during the ion exchange process in solution. For instance, glass powders (Example 1 composition), subjected to ion exchange under the same conditions of bulks and coatings with an identical composition, show precipitation of silver carbonate as a result of reaction between Ag+ ions and CO2 or the carbonates in the reaction environment (FIG. 2.a,
As previously anticipated, in order to obtain powders with an adequate dosage of silver ions without precipitation of other phases, not only the normal exchange parameters (time, temperature and concentration of the exchange solution) need to be varied and controlled, but also further parameters such as for example the pH of the exchange solutions.
In fact, precipitation of carbonates is favoured at highly basic pHs; instead, the maintenance of a pH between 5 and 8, preferably comprised between 7 (neutral) and 7.6, allows to favour maintenance of the antibacterial ions (e.g. silver) in solution, and thus a suitable diffusion thereof within the glass particles. Such a pH control could be carried out by adding a buffer to the exchange solutions; this solution however is not applicable to this specific case since it induces formation of other silver salt precipitates (chlorides, phosphates . . . ). In the application according to the invention it is preferable to use a glassy composition, the ion release of which does not make the solution highly basic (
Thus, a relevant and preferred feature of the bone cements object of the invention is that the antibacterial agent is only incorporated in the glass or glass-ceramic material and additional phases other than glass or glass-ceramic made of or enclosing the antibacterial agent are absent, such as for example inter-metal phases or metal clusters or precipitates including the antibacterial agent.
Therefore, the bone cement composition according to the invention is essentially a monophasic composition with regard to the phases that include the antibacterial agent.
Such a feature allows to obtain a controlled release of the antibacterial ions when the bone cement is applied in situ in contact with physiological fluids.
To that end, it is thus preferable to prepare the bone cement by using glass or glass-ceramic material powder subjected to ion exchange in an aqueous solution containing antibacterial metal ions; the ion exchange process is carried out at temperatures below 100° C., preferably from 37 to 100° C., for periods of from 15 to 240 minutes, at a pH comprised between 5 and 8, by using a powdered glass or glass-ceramic material that includes metal ions (e.g. alkaline or alkaline earth materials) liable to exchange with the antibacterial ions (particularly silver).
In particular, a bioactive powdered glass or glass-ceramic material is used, the oxide composition of which is such that, when the material is kept in water, the release of chemical species from such a material is not capable of bringing the pH to values higher than 8, under balance conditions or for periods of up to 240 minutes.
Examples of compositions suitable for maintaining a neutral pH:
Further advantages and features of the bone cement according to the invention will be apparent from the following examples.
In the appended drawings:
A bioactive glass having the following composition was prepared:
The glass was prepared by using SiO2, CaCO3, Na2CO3, Al2O3 as the oxide precursors.
The fusion process was performed at a temperature of about 1400° C.-1550° C. and the molten was poured out into water to obtain powders.
The powder thus obtained was milled and sieved to a size smaller than 20 μm. The powders were added with silver ions by replacement of sodium ions through ion exchange in aqueous silver nitrate solutions, thereby obtaining a final glass composition of:
The synthesis was carried out as in Example 1, by including though directly the silver oxide in the form of Ag2CO3 within the precursors, thereby obtaining a glass having the following molar composition:
A bioactive glass having the following composition was prepared:
The glass was prepared as in Example 1 and silver ions were added by replacement of sodium ions through ion exchange in aqueous silver nitrate solutions, as in Example 1.
The powder obtained as in Example 1 was mixed with a polymeric polymethylmethacrylate component according to the following ratios:
The powder obtained as in Example 2 was mixed with a polymeric polymethylmethacrylate component according to the following ratios:
EXAMPLE 5a
The tests performed demonstrated that the bioactive glasses/glass-ceramics, even when included in the polymeric acrylic composition, are capable of promoting the formation of a hydroxyapatite layer on their surface subsequent to reaction with mock physiological fluids.
The powder obtained as in Example 3 was mixed with a polymeric polymethylmethacrylate component according to the following ratios:
The presence of a bioactive phase that becomes exposed on the cement surface causes this structure to promote the binding in vivo to the tissue with which it comes into contact, and thus integration of the prosthesis thus cemented. The presence of the glass/glass-ceramic component also has the advantage of decreasing the local temperature rise due to the exothermic character of the polymerisation reaction, with undisputed advantages for the bone directly in contact with the cement.
Moreover, adding the second glass/glass-ceramic phase does not alter the material's processing and hardening properties
In addition, the presence of the inorganic phase in the bone cement contributes to enhancing the cement's mechanical properties.
By suitably varying the glass composition and the parameters for the introduction of the antibacterial oxide, it is possible to modulate the bioactivity degree of the cement, the release kinetics of the metal ions and the mechanical properties of the composite material, depending on the particular application requirements.
The antibacterial tests on the bone cement were carried out by using each of the cement types mentioned in Examples 4, 5, 6.
The antibacterial effect of the composite cements was assessed by the inhibition halo test according to the NCCLS (National Committee for Clinical Laboratory) standards. Such a trial contemplates preparing a solution of known bacterial concentration and diffusing an aliquot of such a solution onto Mueller Hinton plates, which allow the bacteria to grow rapidly. The samples are placed on the plates containing the bacteria and incubated at 35° C. for 24 hours. At the end of the incubation the area where the bacteria did not grow is examined and measured.
The antibacterial tests were carried out by using a standard Staphylococcus Aureus strain, one of the bacterial strains most involved in the development of infections.
The test results further demonstrate that the bone cement according to the invention allows to obtain a sustained release of antibacterial metal ions with an activity that lasts for periods of from about 7 days to more than a month and therefore results advantageous compared to the restricted antibacterial activity periods of bone cements loaded with antibiotics.
| Number | Date | Country | Kind |
|---|---|---|---|
| TO2009A000518 | Jul 2009 | IT | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IB10/53181 | 7/12/2010 | WO | 00 | 1/9/2012 |
