EP2240211A2

EP2240211A2 - Bone cement mixture for producing a mrt-signaling bone cement

Info

Publication number: EP2240211A2
Application number: EP09710544A
Authority: EP
Inventors: Florian Wichlas; Hermann Josef Bail; Ulf TEICHGRÄBER; Jens Pinkernelle; René SCHILLING
Original assignee: Charite Universitaetsmedizin Berlin
Current assignee: Charite Universitaetsmedizin Berlin
Priority date: 2008-02-12
Filing date: 2009-02-12
Publication date: 2010-10-20
Also published as: WO2009100951A3; US20110098374A1; WO2009100951A2; DE102008013620A1

Abstract

The invention relates to a bone cement mixture for producing an MRT-signaling bone cement and an MRT-signaling bone cement which is obtained from the mixture. The bone cement mixture according to the invention contains: (a) at least one type of organic monomer which can be polymerized and optionally at least one polymer component which is already polymerized, (b) at least one MRT-signaling component having a magnetic susceptibility and a concentration in the cement mixture which are capable of generating a visible signal in at least one selected MRT sequence, and (c) at least 1 wt.-% water relative to the total mass of the bone cement mixture. The bone cement mixture according to the invention is characterized by good signals in the MRT in at least one measuring sequence, in particular in the T1 sequence.

Description

Bone cement mixture for producing an MRI signaling

bone cement

The invention relates to a bone cement mixture for producing an MRI-signaling bone cement as well as a polymer cement-based bone cement produced from the bone cement mixture.

For filling bone fractures or as a bone substitute, for example after surgical intervention in bone cancer, bone cements are known, which are introduced to the resulting defect site to harden there and replace the natural bone material. Other areas of application of bone cements include the anchoring of endoprostheses, of large joints, the support of implants (plates, nails, etc.) in osteoporotic fractures as composite osteosynthesis or the use as a placeholder in infected joints. A relatively new surgical technique in which bone cement is used is, for example, vertebroplasty, or kyphoplasty, in which a - for example due to osteoporosis - broken vertebral body is stabilized by injecting bone cement.

Conventional bone cements are based on inorganic materials, such as calcium phosphate, which cure after being mixed with water. More modern bone cements are based on organic polymers, wherein the bone cement mixture contains polymerizable monomers and an initiator and / or activator for initiating the polymerization, so that the solidification takes place by way of cold polymerization. A common organic bone cement is based, for example, on polymethyl methacrylate (PMMA), which is obtained by polymerization of the monomer methyl methacrylate (MMA). Commercial PMMA bone cements are offered as two-component systems to be mixed. The liquid component contains as its main constituent MMA and often an activator (eg N, N-dimethyl-p-toluidine) and / or a stabilizer / inhibitor (hydroquinone) to prevent polymerization during storage. The powder component consists mainly of particulate PMMA polymers, which often already a Initiator (eg benzoyl peroxide) to initiate the radical polymerization after mixing the two components is added. The powder component may further contain an X-ray contrast agent (eg, zirconia, barium sulfate) and / or an antibiotic and / or a dye. It is also known that not the pure polymers of MMA are used, but also copolymers with MMA and a comonomer or mixtures of PMMA and MMA copolymers. The powdery polymer component serves mainly to achieve a sufficiently high viscosity of the mixture for processing. An overview of bone cements based on PMMA can be found in Breusch & Kühn, Orthopäde 32 (2003), 41-50.

Magnetic Resonance Imaging (MRI) has been used over the past few decades to establish a diagnostic imaging method in medicine that can be used to create tissue structures in the form of sectional images at a defined tissue depth in the human body. Unlike computed tomography (CT), which mainly depicts solid, radiopaque structures, such as bone, the potential of MRI is essentially to depict hydrous tissue structures, making it particularly suitable for assessing organs. Since MRI uses magnetic fields and electromagnetic waves, one advantage is the lack of radiation exposure of the patient and medical staff. Recent developments are concerned with the above-mentioned imaging in the so-called "open MRI", in which a surgical intervention takes place under MRI observation.

The measurement method of MRI is based on an alignment of nuclei of hydrogen, which possess a magnetic moment due to their spin (spin), in a strong static electromagnetic field. By applying a second, high-frequency alternating field (transverse field) at right angles to the first field, the cores are disturbed from their original position and begin a precession movement, whereby - in simplified view - their core axes of rotation are aligned in a direction tilted with respect to the static field. By choosing the strength of the static field and the frequency of the transverse field, it is determined which nuclei resonate. In MRI, these are basically the hydrogen nuclei of water. After switching off the transverse alternating field, the core precesses for a relaxation time further in the original plane defined by the alternating field until it recovers into its thermal equilibrium. This results in a transverse magnetism dependent on the tissue type. generated, which induces a current flow in a coil of the scanner, which represents the actual measured variable. Various measurement sequences are used in the MRI, which differ in the frequency of the transverse alternating field and / or the strength of the static magnetic field. In T1-based measurement frequencies, the spin-lattice relaxation (longitudinal relaxation) is measured and the representation of solids is emphasized. In contrast, T2-based measurement frequencies measure the spin-spin relaxation (lateral relaxation) and are particularly good at soft tissue. To simplify an overall assessment of all structures present in the body, the representation of an organ is therefore usually both T1- and T2- sequences.

A disadvantage of conventional bone cements is that they are not visible in magnetic resonance imaging (MRI), but can only be identified by a lack of signal. A differentiation from other non-signaling structures is therefore practically impossible, since the absence of the signal does not allow a safe conclusion on the presence of the cement. For the subsequent control of surgically introduced bone cement sites and for the assessment of surrounding structures on MRI, an MRI-signaling bone cement would be desirable. Especially for modern surgical techniques that are performed under MRI control ("open MRI"), for example in the above-mentioned vertebroplasty, or the filling of surgically evacuated tumor cavities with bone cement under MRI control, an MRI-visible bone cement is indispensable.

As already mentioned above, it is known to add an X-ray contrast agent to the PMMA cement, in particular the PMMA-containing powder component, in order to enable the representation of the bone cement in X-ray diagnostics or in computed tomography. US 2005/0287071 A1 discloses an inorganic calcium phosphate-based bone cement which is visible in the X-ray image by addition of a material which is impermeable to X-ray radiation.

US 6,585,755 B2 describes an endovascular implantable article, in particular a stent, of an organic polymeric material to which an MRI additive is added to render the stent remaining permanently in the body "MRI compatible", that is, the interactions caused by the stent with the magnetic field of the MRI too prevent or compensate. On the other hand, an immediate visibility of the stent on MRI in terms of active signaling is unlikely.

An MRI-visible bone cement is not yet known.

The invention is therefore based on the object to provide a bone cement mixture for the production of a bone cement based on organic polymers available that gives sufficient signal on MRI to be visible there.

This object is achieved by a bone cement mixture and by a bone cement made from this mixture with the features of the independent claims. The bone cement mixture according to the invention for producing an MRI-signaling bone cement contains

(a) at least one kind of polymerizable organic monomers and optionally at least one already polymerized polymer component,

(b) at least one MRI signaling component having a magnetic susceptibility and a concentration in the cement mixture capable of producing a visible signal at least in a selected MRI sequence, and (c) at least 1 wt% of water the total mass of the bone cement mixture.

It has been found that the bone cement according to the invention can be displayed well in the MRI by generating a well differentiable signal in the at least one MRI sequence. This result was surprising in that the hardened cement is a solid which is not per se visible on MRI, in which protons are basically made of water. Although conventional bone cement in the body is saturated to some degree with water, it is not sufficiently saturated to give a signal. It was particularly surprising that the combination of water and MRI-signaling component (hereinafter also referred to as MRI contrast agent) is essential in order to generate a signal in the brain in a synergistic manner in the MRT. With a suitable choice of the type and concentration of the signaling component and the water content, it can also succeed, even in different measurement sequences to produce differentiable signals of the cement to allow an overall assessment of the organ to be examined.

In particular, the three components listed above (a), (b) and (c) at least 80 wt .-%, preferably at least 90 wt .-%, generally even at least 95 wt .-%, of the total mixture. Preferably, the cement mixture according to the invention consists essentially of these constituents. The remaining parts by weight may optionally be claimed by auxiliaries such as X-ray contrast agents, polymerization initiators, organic solvents for the monomers, etc.

In a preferred embodiment, the proportion of water is chosen so that the cement is visible in the at least one sequence. It should be noted on the one hand that a sufficient water saturation of the cement results, so that there is a sufficient signal of the MRI contrast agent, and on the other hand, the stability and processability of the cement is not disturbed as a result of excessive water content. Preferably, the maximum possible water content in terms of cement stability is selected. There are mass fractions of water from 1 to 60%, in particular from 5 to 45%, preferably from 14 to 23%, based on the total mass of the mixture have proven.

It is furthermore preferably provided to select the magnetic susceptibility and the concentration of the at least one MRI-signaling component in the cement mixture such that the cement generates a signal in the at least one sequence, in particular in the T1 sequence or a T1-based sequence , In this case, there is an interaction between susceptibility and the concentration such that with increasing susceptibility lower concentrations of the MRI contrast medium are sufficient and vice versa. The lower concentration limit is chosen so that it comes to a sufficient signal, while the upper concentration limit is such that no signal cancellation takes place. In this connection, it is familiar to the person skilled in the art to take materials of suitable magnetic susceptibility from the relevant tables and, if appropriate, to determine the suitable concentration experimentally by simple mixtures. It goes without saying that the selection of the MRI-signaling component and its concentration in the cement mixture must, of course, also be coordinated with the magnetic field strength of the MRI apparatus to be used, the susceptibility and / or concentration being greater the weaker the device is. Generally, today's MRI devices have magnetic field strengths of 1 Tesla or more.

Particularly suitable as MRI-signaling component are paramagnetic or ferromagnetic metals, which may be in metallic form, as a compound, salt and / or as a complex. Preferably, it is selected from the transition metals (especially the fourth period of scandium to zinc), the lanthanides and the alkaline earth metals (especially magnesium and calcium), as well as their compounds, salts and complexes. When selecting the contrast agent, it should be noted that it has the lowest possible toxicity and a low tendency to migrate and - in the case of a compound or a complex - a safe metabolic pathway. However, the aspect of toxicity plays a rather subordinate role due to the extremely low concentration of the contrast medium required. Particularly preferred MRI signaling components include manganese, iron, cobalt, nickel, copper, chromium, titanium, vanadium, scandium, zinc, gadolinium, dysprosium and calcium and magnesium, these elements being in the form of their metals or alloys, compounds, complexes or salts can be used. In principle, all transition metals or substances with ferromagnetic or paramagnetic properties can be used.

According to a further advantageous embodiment of the invention, a mixture of two or more MRI-signaling components is used, which generate signals in different measurement sequences.

The metal of the at least one MRI-signaling component is preferably present only in traces in the overall mixture. Typically, it has a concentration based on the total mass of the cement mixture of 0.05 to 5 μmol / g, in particular from 0.1 to

3 μmol / g, on. The lower concentration limit is chosen so that there is sufficient signal in the MRI, while the upper concentration limit is such that no signal cancellation takes place. Typical mass fractions are in the range of a few 10 ^'3 wt .-%, for example, 0.1 -10 ^"3 to 40-10 ^{" 3} wt .-%. All the above information refers to the pure metal, even if it is in the form of a

Compound or a complex is used. It is preferably provided that the MRT contrast agent is present in as homogeneous a distribution as possible in the cement mixture. For example, it can be present in the form of nano- or microparticles in homogeneous distribution in the cement, in particular in the case of metals or alloys. In the case of insoluble compounds or complexes, above all, a homogeneous dispersion and, in the case of soluble compounds or complexes, a homogeneous solution in the cement mixture comes into question.

Although the invention is not limited thereto, an acrylate-based polymer is preferred as the base material of the cement. Accordingly, the at least one type of polymerizable organic monomer is selected from the group of acrylates, which comprises in particular methacrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, propyl acrylate, propyl methacrylate, butyl acrylate and butyl methacrylate, preferably methyl methacrylate (MMA), which by polymerization polymethyl methacrylate ( PMMA) or an MMA-containing copolymer. Similarly, as the already polymerized polymer component, an acrylate-based polymer or copolymer is preferable, especially based on acrylates comprising methacrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, propyl acrylate, propyl methacrylate, butyl acrylate and butyl methacrylate. The polymer component is particularly preferably PMMA or a copolymer of MMA and butyl methacrylate. In addition to the organic polymer cements, the principle according to the invention can in principle also be applied to any curable or settable material which offers an inclusion option for an MRI contrast agent and water. Thus, any conventional inorganic cement, especially calcium-based cements or hydroxy apatite, can be used in place of the organic polymer.

Although the polymerization can also be initiated by heat or radiation sources, for physiological and practical reasons, a (cold) polymerization is initiated, which is initiated by an initiator or radical initiator contained in the cement mixture and, after mixing together of the individual components of the polymerization in particular by Radical formation triggers. Accordingly, the cement mixture comprises at least one initiator and / or activator for initiating the polymerization of the monomers.

Of course, further, subordinate components may be present in the cement mixture, in particular stabilizer (s) for preventing the Polymerization during storage of the monomers, dye (s) for staining the cured cement, antibiotics for release from the cement and / or X-ray contrast agent for the preparation of the cement in the X-ray machine or in the CT.

Cement mixture in the sense of the present invention is understood to mean not only the composition of the already mixed components. Preferably, the cement mixture is in the form of a kit in separate components so that the user mixes them together immediately prior to use to initiate the polymerization. In this case, the kit comprises in particular at least one liquid phase which contains at least the monomers, and a solid phase which contains the particular powdery polymer component. According to a special embodiment, the kit comprises two liquid phases, wherein a first liquid phase (non-aqueous, hydrophilic phase) contains the monomers and a second liquid phase (aqueous phase) which contains at least one MRI-signaling component and the water. These are preferably first emulsified together before the emulsified mixture is mixed with the solid phase.

The MRI-signaling bone cement prepared from the bone cement mixture according to the invention is obtained by polymerization of the at least one kind of polymerizable organic monomers, so that the product contains no or only small amounts of unreacted monomers and instead the polymer of these.

A method for repairing bone defects accordingly comprises the steps of preparing the bone cement mixture according to the invention by intensive mixing of the individual components with each other, introduction of the bone cement mixture to the site of the defect and curing of the mixture by polymerization of the monomers. In this context, a bone defect is understood to mean any abnormality of a bone, in particular fractures and defects, for example by surgical intervention. The introduction of the bone cement mixture at the site of the defect is preferably carried out on the so-called open MRI, i. under direct MRI observation.

Further preferred embodiments of the invention will become apparent from the remaining, mentioned in the dependent claims characteristics. The invention will be explained below in embodiments with reference to the accompanying drawings. Show it:

FIG. 1 PMMA bone cement samples with variable concentration of a Gd complex (gadobenic acid meglumine) shown with different MRI

sequences;

FIG. 2 PMMA bone cement samples with variable concentration of a Gd complex (gadobenic acid dimeglumine salt) shown with different MRT sequences;

FIG. 3 PMMA bone cement samples with variable concentration of an Mn complex (mangafodipir trisodium) shown with different MRT sequences;

FIG. 4 PMMA bone cement samples with variable concentration of iron oxide nanoparticles shown with different MRT sequences;

Figure 5 PMMA bone cement samples with variable concentration of manganese (II) chloride tetrahydrate shown with different MRI sequences;

FIG. 6 PMMA bone cement samples with different MRI contrast agents, each with and without the addition of water;

FIG. 7 shows a transverse MRI image of a fracture of a bone vertebra filled with a conventional PMMA bone cement (left) and with a PMMA bone cement according to the invention with gadobenic acid meglumine as contrast agent (right); and

8 shows a sagittal MRI image of a spinal column in which vertebral bodies were filled with a conventional PMMA bone cement (arrows (a)) and with a PMMA bone cement according to the invention with gadobenic acid meglumine as contrast agent (arrows (b)). The principal preparation of the cement samples was by preparing the aqueous phase containing the MRI contrast agent and then mixing the aqueous phase with the liquid cement component containing the monomer (especially MMA). This liquid mixture was mixed with the powdered cement component containing already polymerized material (especially PMMA).

The cured cement samples were measured and evaluated with the following MRI sequences. It should be noted that the designations of the sequences are manufacturer-specific and thus deviate by name from the devices used (Philips Gyroscan, Philips Panorama, GE-MRT):

T1 (= T1 SE): spin echo in T1 with good resolution - assessment of

Solids (cement) and signal intensity

T1 FFE (= T1 FSPGR): fast sequence in T1 weighting T2 (= T2W): T2 - weighting liquids (water)

FIESTA (= bFTE balanced FFE): Fast gradient echo sequence.

Example 1: PMMA cements with different concentrations of Gd (gadobenic acid meglumine)

Chemicals: Dotarem® (Guerbet GmbH) 1 ml contains:

279.32 mg gadobenic acid meglumine water for injections

0.9 wt .-% NaCl in H ₂ O.

MMA BonOs® (AAP Implantate AG) 10 ml contains: 9.93 ml of methyl methacrylate 0.07 ml of N, N-dimethyl-p-toluidine 60 ppm of hydroquinone

PMMA BonOs® (AAP Implantate AG) 24 g cement powder contains:

10.95 g of polymethyl methacrylate 10.80 g of zirconium dioxide 0.50 g of benzoyl peroxide A variable amount of a 0.5 molar aqueous solution of gadobenic acid meglumine (Dotarem®, Guerbet GmbH) was first pipetted into 10 ml each of a 0.9% aqueous NaCl solution (mixture I). Of this mixture, I, 5 ml each of liquid 5 ml of methyl methacrylate were (MMA BonOs®, AAP Implants AG), already containing 7 vol .-% N ₁ N-dimethyl-p-toluidine as the activator and 60 ppm hydroquinone as an initiator, mixed (mixture II). The total amount (about 10 ml) of this mixture II was mixed with 12 g each of the solid cement component (PMMA BonOs®, AAP Implantate AG), ie 5.475 g PMMA, 5.40 g ZrO ₂ as X-ray contrast agent and 0.25 g benzoyl peroxide, mixed. Due to the lack of miscibility of the hydrophobic polymer component with the aqueous phase, the suspensions were prepared with permanent mixing and processed immediately. An overview of the mixture components is summarized in Table 1. The final samples contained between 0% by weight and 0 μmol / g (sample A) and 0.12% by weight and 7.4 μmol / g (sample N) of gadolinium (Gd) and about 22.7, respectively Wt.% H ₂ O.

Table 1 :

By filling in disposable syringes, cylindrical test specimens of cement samples were prepared and allowed to cure. Samples A to N were placed on a grid together with a contrast and anhydrous reference sample (sample Z) prepared and shipped according to the manufacturer's instructions and placed on MRI (Philips 1, 5 Tesla MRI (CVK), open MRI panorama 1, 0 Tesla (CCM) or GE 3 Tesla Signa (CVK)) using a head coil and using the above MRI sequences. The results are shown in FIG. It can be seen that the reference sample Z does not supply a signal in any of the sequences, ie is invisible in MRT. Also, the hydrous but Gd-free sample A shows only a very weak signal in the T1 sequences and a weak signal in the liquid-sensitive sequence T2 W and the mixed sequence bFFE. In T1 FSPGR and T1 SE samples D to H (0.34-2.23 μmol / g Gd) gave the strongest signals. For bFFE, the strongest signals were detected in samples E to K (0.57-4.37 μmol / g Gd). For T2 W, samples B and C (0.06-0.11 μmol / g Gd) gave the strongest signals. At even higher concentrations of Gd, there is a decrease in signal due to cancellation.

Example 2: PMMA cements with different concentrations of Gd (gadobenic acid dimeglumine) Chemicals: Multihance® 1 ml contains:

(Bracco Altana Pharma GmbH) 529 mg gadobenic acid as dimeglum salt (334 mg gadobenic acid) water for injections 0.9% by weight NaCl in H ₂ O MMA BonOs® (AAP Implantate AG) s. Example 1

PMMA BonOs® (AAP Implantate AG) s. Example 1

The preparation of the cement mixture and the samples was carried out analogously to Example 1 except that 0.5 molar gadobenic acid dimeglumine salt (Multihance®, Bracco Altana Pharma GmbH) was used as the contrast agent. An overview of the mixture components is summarized in Table 2. The finished samples contained between 0 wt .-% and 0 .mu.mol / g (sample A) and 0.12 10 ^'3 wt .-% and 7.4 .mu.mol / g (sample N) gadolinium (Gd) and each about 22.7% by weight H ₂ O. Table 2:

The results are shown in FIG. In T1 FSPGR and T1 SE samples D to H (0.34-2.23 μmol / g Gd) gave the strongest signals. For bFFE, the strongest signals were detected in samples E to K (0.57-4.37 μmol / g Gd). For T2 W, samples B and C (0.06-0.11 μmol / g Gd) gave the strongest signals.

Example 3: PMMA cements with different concentrations of Mn (mangafodipir trisodium)

Chemicals: Teslascan® 1 ml contains:

(GE Healthcare AS) 7.57 mg mangafodipir trisodium

(0.01 M) ascorbic acid NaCl / NaOH / HCl water for injections 0.9 wt .-% NaCl in H ₂ O.

MMA BonOs® (AAP Implantate AG) s. Example 1

PMMA BonOs® (AAP Implantate AG) s. Example 1

The preparation of the cement mixture and the samples was carried out analogously to Example 1 except that 0.01 molar mangafodipir trisodium solution (Teslascan®, GE Healthcare AS) was used as the contrast agent. An overview of the mixture components is summarized in Table 3. The final samples contained between 0% by weight and 0 mmol / g (sample A) and 0.82 × 10 ³ % by weight and 0.15 μmol / g (sample N) of manganese (Mn) and about 22, respectively , 7% by weight H ₂ O.

Table 3:

The results are shown in FIG. In T1 FSPGR and T1 SE, although a signal increase can be seen, good signal strengths are only achieved with samples M and N (0.13-0.15 μmol / g Mn). The one characterized by decreasing signal intensity Extinction range is not achieved at the concentrations tested. In bFFE, only weak and inhomogeneous signals of all samples were observed with only minor differences. With T2 W, signal rise occurs in the area of Samples B to F (up to 0.02 μmol / g Mn), followed by signal cancellation.

It can be stated that manganese in the form of the complex mangafodipir trisodium gives a visualization of the bone cement. Due to fluid and air inclusions in the cement an inhomogeneous appearance on MRI arises.

Example 4: PMMA cements with different concentrations of Fe (iron oxide nanoparticle)

Chemicals: Endorem® 8 ml contain:

(Guerbet GmbH) 126.5 mg superparamegnetische

Iron oxide nanoparticles (89.6 mg Fe)

Dextran, anhydrous citric acid,

D-mannitol

Water for injections

5% by weight of glucose in H ₂ O

MMA BonOs® (AAP Implantate AG) s. Example 1

PMMA BonOs® (AAP Implantate AG) s. Example 1

The cement mixture and the samples were prepared analogously to Example 1, except that a suspension of iron oxide nanoparticles (Endorem®, Guerbet GmbH) containing 0.2 mol / l of Fe was used as the contrast agent, and a glucose solution instead of the NaCl. An overview of the mixture components is summarized in Table 4. The finished samples contained between 0 wt .-% and 0 mmol / g (sample A) and 4.98 10 ^{~ 3} wt .-% and 0.89 .mu.mol / g (sample N) iron (Fe) and each about 22.7% by weight H ₂ O.

Table 4:

The results are shown in FIG. In T1 FFE and T1 SE good signals can be seen in samples F to I (0.045-0.226 μmol / g Fe). By contrast, in the bFFE and T2 weighting only the samples give a good signal containing negligible concentrations of the contrast agent, therefore it is to be assumed that the iron oxide leads to a signal reduction while the cement can be visualized by the introduced aqueous glucose solution.

It is noted that iron oxide nanoparticles can be used to produce an MRI-visible cement. However, liquid and air pockets in the cement cause an inhomogeneous appearance in the MRI.

Example 5: PMMA cements with different concentrations of Mn (manganese (II) chloride tetrahydrate (MnCl ₂ .4H ₂ O))

Chemicals: Contrast medium solution 1 ml contains:

10 mg of manganese (II) chloride 4-hydrate

(0.05M) in H ₂ O

0.9 wt .-% NaCl in H ₂ O.

MMA BonOs® (AAP Implantate AG) s. Example 1

PMMA BonOs® (AAP Implantate AG) s. Example 1 The preparation of the cement mixture and the samples was carried out analogously to Example 1, except that a self-prepared aqueous 0.05 molar MnCl ₂ -4H ₂ O-l_ösung was used as a contrast agent. An overview of the mixture components is summarized in Table 5. The finished samples contained between 0.03 10 ³ wt .-% and 0.01 mol / g (sample A) and 4.1 10 ^'3 wt .-% and 0.74 .mu.mol / g (sample M) manganese (Mn) and each about 22.7 wt% H ₂ O.

Table 5:

The results are shown in FIG. In T1 FFE, T1 W SE pre and T1 W TSE samples D to H (0.03 to 0.22 μmol / g Mn) showed good signal strength, while in T2 FSE samples B and C (0.01 μmol / g Mn) show a good signal intensity, which already drops again at higher contrast agent concentrations. It should be noted that with manganese in the form of the chloride salt, an MRI-visible bone cement can be produced. In addition, the cement samples allowed to mix well and were relatively homogeneous even in the cured state.

Example 6 Comparison of PMMA Cements with Different MRI Contrast Agents Each With and Without Addition of Water

In order to investigate the influence of water on the visibility of bone cements in MRI, PMMA cements to which only one MRI signaling component was added and PMMA cements according to the present invention, which in addition to the MRI signaling component, were also prepared was added. In particular, bone cements according to the invention according to the compositions of Example 1, sample F (PMMA cement with about 1 .mu.mol / g Gd (Dotarem®) and 23 wt .-% H ₂ O), Example 2, sample F (PMMA cement with about 1 μmol / g Gd (Multihance®) and 23% by weight H ₂ O) and Example 5, sample E (PMMA cement with about 1 μmol / g Mn (MnCl ₂ -4H ₂ O) and 23 wt .-% H ₂ O). For each of these samples in each case a comparative sample (Comp. -Bsp. 1 F, 2F, 5E) was prepared with the same composition but without water. Thus, the comparative samples contained only the water introduced by the aqueous contrast medium solution, which showed a negligible effect. As in the previous examples, cylindrical test specimens of cement samples were prepared by filling in disposable syringes. The test specimens of the samples (Examples 1 F, 2F, 5E) were prepared together with the comparative samples (Comp. -Bsp. 1 F, 2F, 5E) as well as with a contrast medium and anhydrous reference sample (Sample Z), which were prepared according to the manufacturer and was carried along, arranged on a grid, which is shown in the lower part of Figure 6. The samples thus arranged were placed in a water bath and measured in an open MRI (Philips Panorama 1, 0 Tesla) with the sequence T1 W SE. The results are shown in the upper part of FIG. It can be seen that the samples according to the invention each show a clear signal (middle line), whereas the anhydrous comparative samples (bottom line), as well as the water and contrast agent-free reference sample Z (top) give no signal, but only by a missing signal identifiable are. This finding demonstrates that, in addition to the MRI signaling component, the presence of water is an indispensable prerequisite for producing an MRI-signaling cement. Application example: Verteroplasty with Gd-containing PMMA cement with different concentrations of Gd (gadobenic acid meglumine)

There was a cement according to Example 1, i. prepared with gadobenic acid meglumine (Dotarem® Guerbet GmbH) as MRI contrast agent. Human cadaver spines were drilled and the wells were filled with conventional cement prepared according to the manufacturer's instructions or with the Gd-containing cement according to the invention. The measurements were carried out in a 1.5 Tesla Gyro Scan MRI (Philips Medical Systems) using different sequences.

FIG. 7 shows the transversal representation of a bone vertebral body with a filling with the conventional PMMA bone cement (left) and with the PMMA bone cement according to the invention (right). While the conventional cement gives no signal (arrow a), the cement according to the invention in the illustrated T1 sequence can be recognized by a positive signal (arrow b). The same result can be seen from the sagittal representation in T2 sequence in Figure 8, left side. The positive effect in the T1 sequence can be seen even more clearly (FIG. 7, right-hand side), where the cement according to the invention stands out against a otherwise dark background by means of a bright signal, while the conventional cement is at most identifiable by a missing signal.

Claims

A bone cement mixture for preparing an MRI-signaling bone cement containing

(b) at least one MRI signaling component having a magnetic susceptibility and a concentration in the cement mixture capable of producing a visible signal at least in a selected MRI sequence, and

(c) at least 1% by weight of water.

2. MR cement mixture according to claim 1, characterized in that the water with a mass fraction of 1 to 60 wt .-%, in particular from 5 to

45 wt .-%, preferably from 14 to 23 wt .-%, based on the total mass of

Mixture is included.

3. MRI-cement mixture according to one of the preceding claims, characterized in that the concentration of the at least one MRI-signaling component is dimensioned so that the cement is visible at least in a T1 sequence or a T1-based sequence.

4. MRI-cement mixture according to one of the preceding claims, characterized in that the at least one MRI-signaling component comprises a paramagnetic or ferromagnetic metal, which is present in metallic form, as a compound, salt and / or as a complex.

5. MR cement mixture according to one of the preceding claims, characterized in that the at least one MRI-signaling component in particular selected from the transition metals, lanthanides and alkaline earth metals, and their compounds, salts and complexes.

6. An MRI-cement mixture according to claim 5, characterized in that the at least one MRI-signaling component is selected from the group comprising manganese, iron, cobalt, nickel, copper, chromium, titanium, vanadium, zinc, scandium, gadolinium, dysprosium, Magnesium and calcium, in the form of their metals or alloys, compounds, complexes or salts.

7. MRI-cement mixture according to one of claims 5 or 6, characterized in that the metal of the at least one MRI-signaling component has a concentration based on the total mass of the cement mixture of 0.05 to 5 .mu.mol / g, in particular from 0.1 to 3 μmol / g.

8. MRI-cement mixture according to one of the preceding claims, characterized in that the at least one MRI-signaling component in the form of particles or as

Dispersion or solution is present in the cement mixture.

9. MRI-cement mixture according to one of the preceding claims, characterized in that the at least one type of polymerizable organic monomers from the group of

Acrylates is selected, in particular comprising methacrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, propyl acrylate, propyl methacrylate, butyl acrylate and butyl methacrylate.

10. An MRI-cement mixture according to any one of the preceding claims, characterized in that the at least one already polymerized polymer component is an acrylate-based polymer or copolymer, in particular based on acrylates comprising meth- acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, propyl acrylate, propyl methacrylate, butyl acrylate and butyl methacrylate.

11. MRI-cement mixture according to one of the preceding claims, characterized in that the cement mixture contains at least one initiator and / or activator for triggering the polymerization of the monomers.

12. An MRI cement mixture according to any one of the preceding claims, characterized in that the cement mixture is in the form of a kit in separate components, in particular in at least one liquid phase containing the monomers, and a solid phase containing the polymer component.

13. An MRI-cement mixture according to claim 12, characterized in that the kit comprises two liquid phases, wherein a first liquid phase containing the monomers and a second liquid phase containing at least one MRI-signaling component and the water.

14. MRI-signaling bone cement prepared from a bone cement mixture according to any one of claims 1 to 13.