EP1869093A1

EP1869093A1 - Polymerized molded body

Info

Publication number: EP1869093A1
Application number: EP06721201A
Authority: EP
Inventors: Robert Liska; Monika Schuster; Jürgen STAMPFL; Heinrich Gruber; Franz Varga
Original assignee: Technische Universitaet Wien
Current assignee: Technische Universitaet Wien
Priority date: 2005-04-14
Filing date: 2006-04-10
Publication date: 2007-12-26
Also published as: JP2008535979A; WO2006108202A8; AT501700A1; WO2006108202A1; CA2604492A1; US20080287565A1; AT501700B1; US8022155B2

Abstract

The invention relates to polymerizable compositions which comprise 10-80 % by weight of a reactive diluent based on acrylic acid or methacrylic acid derivatives, and 10-50 % by weight of a monomer of the indicated chemical formula which is liquid or which can be dissolved in the formulation. The formula may contain amino acid residues or peptide sequences, especially such that are specific of the collagen. These structural elements allow the enzymatic degradation of the polymers of the inventive composition.

Description

Polymerized shaped body

The invention relates to radiation-curable, biocompatible and bioresorbable compositions and their use in molding processes for the production of polymeric bone replacement support materials.

For the healing of fractures for a long time metal implants in the form of screws, pins, nails or plates are used, with the disadvantage that a second operation to remove the fixation parts is necessary. Later, screws, pins and nails made of polyglycolic acid, polylactic acid and their copolymers were introduced for the fixation of fractures, on the one hand because of the mechanical properties that are close to those of bone, on the other hand, because these implants are degraded in the body and thus spare a second operation.

In the case of bone tumors that need to be removed, there often remains a major defect that needs to be filled. This requires a material that serves as a support for a short time as long as the organism needs to rebuild the bone. The material should therefore support the natural healing process and be completely absorbed by the body after a certain time. For this, the material must not only be biocompatible and biodegradable, but also be optimally suited for the attachment and proliferation of bone cells (osteoblasts). In addition, such a replacement material should have a similar structure as natural bones, so if possible be a porous, cellular composite material.

To create the porous structure of bones, there are two principal possibilities. On the one hand, in a liquid monomer formulation, a substance can be introduced, which generates pores during curing. This can be a foaming agent, or even a solid such as sodium chloride or sugar, which can be subsequently dissolved out.

For example, WO 98/20893 describes a process in which monomer mixtures are cured in the presence of sugar cubes in a silicone mold and the sugar is then dissolved out with water. The pore size and the Internal geometry can be controlled only within certain statistical limits in such methods and it is thus not possible to generate defined cellular structures.

More suitable for the production of implants is the rapid prototyping (RP) method, in which the desired cellular 3D structure "made to measure" can be fabricated by layerwise photopolymerization of a monomer formulation, not just randomly irregular shapes - as in the case of bone defects However, resolutions in the range of pore diameters of bone (100-500 μm) can be achieved, but conventional biopolymers which are already in medical use, such as poly (α-hydroxy acids), can not be prepared by means of RP Since they are not accessible from photopolymerizable monomers, photocrosslinkable formulations which result in biodegradable and biocompatible polymers are described occasionally in the literature.

WO 03/002490 A2 claims biomaterials based on poly (propylene fumarate) which are photocrosslinkable with diethyl fumarate. From these mixtures, prefabricated implants can either be prepared by means of molding techniques, or they are used as injectable formulations which are cured in vivo by photopolymerization.

Since these formulations always already contain a prefabricated polymer - namely poly (propylene fumarate) -, the adjustment of the appropriate viscosity is possible only over high levels of Diethylfumarat, but this leads to weakly crosslinked and thus mechanically not very stable moldings. Also, the targeted production of porous structures is not possible, also the temperature increase is problematic by the photopolymerization when used in vivo.

The system poly (propylene fumarate) / diethyl fumarate has also been used in a stereolithographic process. (M. Cooke, JP Fisher, D. Dean, C. Rimnac, A. Mikos, Journal of Biomedical Materials Research - Part B Applied Biomaterials, v. 64, n. 2, Feb. 15, 2003, p. 65-69). The production succeeded a prototype molding, which was not porous. Also, the mechanical stability of the moldings with a modulus of elasticity of about 200 MPa does not meet the mechanical material requirements for bone replacement materials, since a natural bone has a modulus of elasticity of about 2000 MPa. The authors also refer to the problem of the viscosity of the polymer / monomer mixture, which means that the shaped bodies obtained do not correspond exactly to the CAD model. High levels of Diethylfumarat reduce the viscosity, but inhibit the crosslinking, low proportions lead to strong cross-linking, but this again comes with a reduction in bioresorbability. Thus, with this system, a precise control of the outer and inner morphology of the implants is also possible only to a very limited extent by means of stereolithography. Another problem is the known low rate of polymerization of fumarates.

W. Matsuda et. al., (Matsuda, M. Mizutani, S. Arnold, Macromolecules 2000, 33, 795-800, M. Mizutani, T. Matsuda, Journal of Biomedical Materials Research, v. 61, No. 1, 2002, p. 53-60) themselves with photocurable biodegradable polymers based on poly (ε-caprolactone-co-trimethylene carbonate). In this case, branched aliphatic polyesters were prepared by ring-opening copolymerization of ε-caprolactone with trimethylene carbonate, in which then coumarin end groups were introduced. Upon irradiation with UV light, photodimerization of the end groups results in crosslinking of the polyesters. In addition to the problems with the viscosity adjustment which also occur here, crosslinking takes place only via the end groups. This not only leads to very low crosslinking rates, but only low crosslinking densities are obtained with these polymers, which has an unfavorable effect on the mechanical properties of the moldings, as shown by the low elastic moduli of not more than 40 MPa.

By introducing acrylate end groups into the same branched polyesters, the

Polymerization rate can be increased, but the other problems mentioned are not eliminated, (M. Mizutani, T. Matsuda, Journal of Biomedical Materials Research, 62, 2002, p. 387, T. Matsuda, M. Mizutani Journal of Biomedical Materials Research, 62, 2002, p. 395).

In US Pat. No. 6,083,524, acrylate-terminated macromonomers having a central polyethylene glycol segment extended by blocks of poly (lactic acid) or poly (glycolic acid) are claimed. From this, biodegradable hydrogels were prepared by photopolymerization. In addition to the low mechanical strength, in particular the poor cell adhesion is disadvantageous. This is attributed to the high proportion of polyethylene glycol with its known resistance to protein adsorption and cell adhesion (Sawhney, A.S., Pathak, CP .; Hubbell, J.A. Macromolecules, 1993; 26; 581-587). Similar macromonomers with a central diethylene glycol unit and blocks of oligo (lactic acid) or oligo (caprolactone) gave materials with somewhat better adhesion of osteoblasts (Davis, KA, Burdick, JA; Anseth, KS Biomaterials; 2003; 24; 2485-2495 ). In both cases, however, the high-viscosity or solid monomers can not be used for rapid prototyping processes.

A general disadvantage of these aliphatic polyesters based on glycolic acids or lactones is that the bonds are relatively hydrolysis-labile, i. that they are broken down relatively quickly in an aqueous environment. The degradation proceeds hydrolytically and is not controllable by the autocatalytic nature. Furthermore, the bone substitute disintegrates faster than new bone tissue can be formed. In addition, high acid concentrations can occur, creating a milieu, which can lead to uncontrolled cell death and thus to necrotic tissue changes. In contrast, purely enzymatic degradation would be preferable, i. With a biomaterial that promotes growth of bone cells (osteoconductive), and thus also enzymes are formed by these cells, which degrade the polymer. In this way, the body's cells can effectively control the degradation of the implanted plastic. Polymers which are built up over hydrolytically more stable amide bonds are generally better suited.

Thus, hydrogels based on gelatin and polyethylene glycol are known as biomaterials obtained by radical copolymerization of Jeffamin-bis-methacrylamides and methacrylamide-substituted gelatin (Zimmermann, J .; Bittner, K., Stark, B .; Mülhaupt, R. Biomaterials; 2002; 23; 2127-2134). These hydrogels are characterized by good cell adhesion and proliferation. Due to the polymeric building blocks used (eg Jeffamine bismethethyrylamides with Mn about 2000, gelatin with Mn about 3000), the mechanical strengths of these hydrogels are very low, the modules are in the range of 240 to 480 kPa, depending on the water content of the gels, are thus orders of magnitude smaller than required for bone replacement materials. In addition, these viscous formulations are only water soluble and not suitable for rapid prototyping.

Special hydrogel compositions are claimed in EP 1 142 596 A1 for the preparation of therapeutically active implants consisting of crosslinkable prepolymers (macromers) and biologically active peptides or proteins. Optional further additives include inorganic materials and / or vinyl monomers. Decisive for the application is the correct viscosity of the mixture, so that it can be deformed by hand, by means of hypodermic syringes or other surgical instruments. For this purpose, built-up of flexible aliphatic main chains prepolymers are used, which form after the polymerization far-meshed networks of prepolymers. After shaping, the pasty mass is introduced into the corresponding defect site and there in situ by means of

Redox initiators or photoinitiators at temperatures below 4O ⁰ C cured.

WO 1998/55161 A1 describes materials for wound dressings based on crosslinked methacryl-modified gelatin, or copolymers thereof, with methacryl-modified polysaccharides (for example dextran or xanthan). By definition, these hydrogel films are soft materials which must have good absorbency for aqueous media, as this is a prerequisite for wound dressings and dressings.

In US 2004/0110439 biocompatible protein fibers and crosslinked fibers or fabrics for medical applications described, which may optionally contain living cells. The fibers are produced on the basis of polymerizable derivatives of proteins, for example elastin, collagen or gelatin or polymerizable derivatives of peptide sequences which are characteristic of these proteins. The fibers are produced by electrospinning, with photochemical crosslinking subsequently taking place via the polymerizable groups with the aid of photoinitiators. Optionally, as in the case of spinning collagen, water-soluble polymers (polyethylene oxide) are added. By these measures, the mechanical stiffness of the fibers is increased, but only to a relatively small extent. For example, E moduli in the range of 8 to 12 MPa are given for collagen PEO fibers.

WO 1991/08242 A1 describes graft copolymers obtained by grafting mixtures of peptides, proteins, vinyl monomers and crosslinkers onto insoluble finished polymers, e.g. Cellophane or polyethylene terephthalate be prepared by gamma radiation. This procedure results in flexible films with a biocompatible surface, from which implants for the blood vessel replacement can be made.

Better mechanical properties were achieved with lysine-urethane dimethacrylate-based biomaterials obtained by photopolymerization in the presence of calcium hydroxyapatite (Müh, E., Zimmermann, J .; Kneser, U .; Marquardt, J .; Mülhaupt, R., Stark , B. Biomaterials; 2002; 23; 2849-2854). These materials have good cell compatibility and adhesion, but the monomer mixture is solid, can only be polymerized in the melt and therefore can not be used for rapid prototyping. The production of mechanically stable moldings, any geometric shapes and cellular structures is thus not possible.

The object of the invention is to provide a radiation-curable composition which can be used by means of rapid prototyping for the production of any - especially cellular or porous - moldings with high mechanical strengths, similar to those of natural bones, and which are bioresorbable Support materials can be used for bone replacement. For this purpose, the compositions must be liquid, biocompatible, non-toxic, and highly reactive. In addition to biocompatibility, bioresorbability, sufficient mechanical stability, the polymer formed in the RP method must also contain structural elements which ensure good adhesion of osteoblasts, ie bone-forming cells. Furthermore, sufficient hydrolytic stability is required in order for the bone cell-induced enzymatic degradation to proceed preferentially.

It has now been found that this object can be achieved with the aid of a liquid, radiation-curable formulation which, in addition to reactive thinners, photoinitiators and fillers, also contains monomers with amino acid residues or peptide sequences, in particular also those which are specific for collagen. These structural elements, on the one hand, cause good adhesion of osteoblasts and, on the other hand, act as substrates for the enzymatic apparatus of the cells, whereby enzymes are increasingly formed which cleave the polymer. Thus, bioresorption preferably proceeds via an enzymatic degradation.

The invention relates to a composition curable by polymerization with a) 10-80% by weight of a reactive diluent based on acrylic acid or methacrylic acid derivatives, b) 10-50% by weight of a liquid or in the formulation ( the composition) of soluble monomer of the general formula

wherein n is an integer between 1 and 100, wherein X is hydrogen or R ³ or (C = O) -R ³ with R ³ is a linear or branched alkyl radical having 1-20 C atoms, which may be interrupted by one or more oxygen atoms or ester groups, or the rest

-

with R ² = H or -CH ₃ ,

wherein Zi is -O- (CH ₂ ) _X -CO-, -O- (CH ₂ -CH _2. -O) _X -CH ₂ -CO-, -O- (CH ₂ -CH ₂ .O) _x - CO-CH ₂ -CH ₂ -CO-, -O- (CH ₂ -CH _2. -O) _X -OC-CH = CH-CO- -O-CH ₂ -CH (OH) -CH ₂ -, or -O- (CH ₂ -CH ₂ -O) _X -CH ₂ -CH (OH) -CH ₂ - where x = 1-20,

the radicals Y independently of one another represent hydrogen, -CH ₃ , -CH ₂ -CH (CH ₃ ) ₂ ,

-CH (CHs) -CH ₂ -CH ₃ , -CH ₂ -COT, -CH ₂ -CH ₂ -COT, -CH ₂ -OX, - (CH ₂ ) ₄ -NHX - (CH ₂ ) ₃ -NH- C (= NH) -NH ₂ , -CH ₂ SX, -CH (OX) -CH ₃ , -CH ₂ -CH ₂ -S-CH ₃ , -CH ₂ -C ₆ H ₅ , -CH ₂ -C ₆ H ₄ -OX, -CH ₂ -CONH ₂ , -CH ₂ -CH ₂ -CONH ₂ ,

or

in which X has the above meaning,

R ^{1 is} hydrogen or R ³ or (C = O) -R ³ where R ^{3 has the} above meaning, or R ¹ together with Y represents the radical - (CH ₂ ) ₃ - or -CH ₂ -CH (OX) -CH ₂ - in which X has the above meaning,

T for the group -OH or OR ³ or the rest

with R ² = H or -CH ₃ , wherein Z _{2 is} -O- (CH ₂ ) _X -O-, -O- (CH ₂ -CH _2. -O) _x -, -O-CH ₂ -CH (OH) -CH ₂ -O-, or - 0-CH ₂ -CH (OH) -CH ₂ -O- (CH ₂ -CH ₂ -O) _X - where x = 1-20,

with the proviso that at least one of X, Y or T is the group

contains.

In a preferred embodiment, the composition is a UV or visible light curable (polymerizable) composition containing as component b) 10-50% by weight of a liquid or formulation-soluble monomer of the general formula

wherein n is an integer between 1 and 100,

where X is hydrogen, the rest

-

with R ² = H or -CH ₃ ,

wherein Z ₁ is -O- (CH ₂₎ _x -C0-, -0- (CH ₂ -CH ₂ -0.) _X is -CH ₂ -CO-, -0-CH ₂ -CH (OH) - CH ₂ - , or -O- (CH ₂ -CH ₂ -O) _X- CH ₂ -CH (OH) -CH ₂ - where x = 1-20,

the radicals Y independently of one another represent hydrogen, -CH ₃ , -CH ₂ -CH (CH ₃ ) ₂ , -CH (CH ₃ ) -CH ₂ -CH ₃ , -CH ₂ -COT, -CH ₂ -CH ₂ -COT, -CH ₂ -OX, - (CH ₂ ) ₄ -NHX - (CH ₂ ) ₃ -NH -C (= NH) -NH ₂ , -CH ₂ SX, -CH (OX) -CH ₃ , -CH ₂ -CH ₂ -S-CH ₃ , -CH ₂ -C ₆ H ₅ , -CH ₂ -C ₆ H ₄ -OX, -CH ₂ -CONH ₂ , -CH ₂ -CH ₂ -CONH ₂ ,

or

in which X has the above meaning,

R ^{1 is} hydrogen or R ¹ together with Y is the radical - (CH ₂ ) 3 or -CH ₂ -CH (OX) -CH ₂ -, in which X has the above meaning,

T for the group -OH or the rest

with R ² = H or -CH ₃ ,

wherein Z _{2 is} -0- (CH ₂ ) _x -O-, -O- (CH ₂ -CH _2. -O) _x -, -O-CH ₂ -CH (OH) -CH ₂ -O-, or - 0-CH ₂ -CH (OH) -CH ₂ -O- (CH ₂ -CH ₂ -O) _X - where x = 1-20,

with the proviso that at least one of X, Y or T is the group

contains.

Preferably, the composition contains 0-60% of a filler or solvent.

Preference is given to 0.01 to 5 wt .-% of at least one initiator, optionally 0 to 5 wt .-% of a coinitiator and / or 0-10% by weight of one or more additives such as stabilizers, UV absorbers, viscosity modifiers, solvents.

As reactive thinners, it is possible according to the invention to use all known mono-, di- but also polyfunctional acrylic or methacrylic esters and amides or mixtures thereof, for example acrylic acid, methacrylic acid, hydroxyethyl acrylate, hexanediol diacrylate, polyethylene glycol diacrylates, pentaerythritol triacrylate, dimethylacrylamide, diethylacrylamide, polylactic acid block polyethylene glycol block polylactic acid diacrylate.

Preference is given to liquid derivatives, such as N, N

Diisopropylacrylamide, 2- (butylcarbamoyloxy) ethyl acrylate, hydroxyethyl methacrylate, N, N-diisobutylacrylamide, 2- (2-ethoxy) ethoxy) acrylate, polyethylene glycol diacrylate, and trimethylolpropane triacrylate.

The monomers listed under b) are special (meth) acryloylated amino acids, peptides or proteins. These can be substituted according to the invention at one or both terminal groups and / or laterally on correspondingly reactive amino acid units, such as lysine, serine, tyrosine, aspartic acid or glutamic acid residues. Such monomers are known from the literature (E. Schacht, WO 98/55161, 1998) (Zimmermann, J .; Bittner, K., Stark, B .; Mülhaupt, R. Biomaterials; 2002; 23; 2127-2134)) but can also be prepared by reacting peptides with reactive (meth) acrylic acid derivatives, such as (meth) acryloyl chloride, anhydride or glycidyl ester. As peptides, mixtures which are obtained by hydrolysis of naturally occurring proteins, such as gelatin, keratin, fibrin or casein, but also peptide mixtures obtained from rice, soy, wheat, potato, hen's egg, meat or fish can be used for these reactions , Preference according to the invention is given to (meth) acryloylated peptides which contain collagen-specific amino acid building blocks (for example glycine, arginine, aspartic acid, glutamic acid, alanine, proline, hydroxylysine or hydroxyproline) and (meth) acryloylated gelatin hydrolysates having molecular weights of up to 10,000 , Particularly preferred according to the invention (meth) acryloylated peptides having sequences which have specific receptors for cell attachment (eg arginine-glycine aspartic acid, so-called RGD sequence, see Hern, DL; Hubbell, JA Journal of Biomedical Materials, Research Part A, 1998; 39; 266-276).

The polymerizable (meth) acryloyl radicals can also be bonded to the peptide via a spacer. Corresponding reaction reagents are: 12-Methacryloyloxydodekansäureanhydrid, mono (14-methyl-13-oxo-3,6,9, 12-tetraoxapentadek-14-en-l-yl) butane-1, 4-diacid esters (EP 324 455 A2 ) or commercially available acryloxy-polyethylene glycol-N-hydroxysuccinimides.

In addition to the classical thermal initiators, especially photoinitiators are preferred. Suitable photoinitiators are all radical-forming type I and type II initiators (compare "Photoinitiators for free radical polymerization" by J. Crivello and K. Dietliker, Wiley / SITA London). Examples of these are benzil ketals, benzoins, hydroxyalkylphenones, aminoalkylphenones, acylphosphine oxides, bisacylphosphine oxides, titanocenes. Type II initiators such as benzophenones, diketones, thioxanthones and ketocoumarins are used with suitable coinitiators. These are mostly tertiary amines such as 4-

Dimethylaminobenzoic acid ethyl ester (DMAB), triethanolamine or dimethylethanolamine.

Particularly suitable according to the invention are camphorquinone / DMAB, 2-hydroxy-1- [4- (2-hydroxyethoxy) phenyl] -2-methyl-1-propanone (Irgacure 2959) or phenylbis (2,4,6-trimethylbenzoyl) phosphine oxide ( Irgacure 819).

Fillers which can be used are all known biocompatible and bioinert organic polymers or inorganic materials. These may be soluble or dispersed in the liquid monomer mixture in the form of powders, fibers and the like. Examples of these are polyvinylpyrrolidone, polyvinyl alcohol, casein, keratin, gelatin, cellulose esters and ethers, chitosan, starch derivatives, hyaluronic acid derivatives, poly-α-hydroxy acid-based polyesters, poly-ε-caprolactone, polypropylene fumarates, polycarbonates, polyanhydrides, polyphosphazenes, aluminum oxide, Zirconia, or Ti, (Ta, Nb) Alloys. Especially preferred according to the invention are hydroxyapatite, tricalcium phosphate, bone meal, algipore, polyethylene glycol, polyesters based on lactic acid and glycolic acid, keratin fibers, and fibrin glue.

In a further aspect, the present invention relates to the use of the composition for the preparation of polymers or the process for the preparation of the polymers by polymerization of the composition. For polymerization, thermal or photoinitiators can be used.

The polymer is preferably a shaped body which is shaped in particular either by polymerization of the composition in a mold or by rapid prototyping (lithographic or stereolithographic rapid prototyping).

The constituents of the composition are preferably dissolved in organic solvents, with a water content of <10%, preferably <1%, most preferably <0.1% (in% by weight, and, possibly, a fluid constituent may also occur as solvent ).

In a further aspect, the present invention relates to moldings consisting of the polymerized composition having an E-modulus greater than 500 MPa. Such a molded article is obtainable by the described method.

The shaped body preferably has an E-modulus greater than 500 MPa, preferably greater than 1000 MPa, in particular greater than 1500 MPa, especially preferably greater than 2000 MPa, most preferably greater than 5000 MPa or greater than 10000 MPa.

The modulus of elasticity (also: Young's modulus) is a material characteristic value from materials engineering that describes the relationship between stress and strain in the deformation of a solid body with linear elastic behavior. The modulus of elasticity is abbreviated to modulus of elasticity. The amount of elastic modulus is greater, the more resistance a material opposes to its deformation. Thus, a high modulus material is stiff, a low modulus material is compliant. The modulus of elasticity is defined as the slope of the graph in the stress-strain diagram at uniaxial loading within the linear elasticity range. Among other things, the composition is responsible for the hardness, which is preferably absorbed in anhydrous organic solvents - since there is no water-related swelling or shrinkage. In the polymerization of the selected components of the composition, it also does not water. (Moisture may be tolerated to a small extent depending on the hardness to be achieved.) In particular, the composition has <10%, preferably <1%, most preferably <0.1% of water (in% by weight). In particular, the components b) are not water-soluble (at most heterogeneously dispersible) but are soluble (homogeneously) in organic solvents.

With the formation of moldings for use as a bone substitute, it is possible to produce bodies that are surprisingly similar in their mechanical properties to bone materials. An modulus of elasticity of the molded article below 500 MPa is unfavorable because the body is too rubbery (relative to bone). Good values are between 1500 and 5000 MPa, preferably around 10000 MPa, which is the value of natural bone. Such a high value is preferably achieved by the additional use of fillers.

Macromolecular structures as described by Anseth (Biomaterials 2003: 2485) or published in EP 1 142 596 A1 achieve only a modulus of 500 MPa. Bismethacrylates of a polyorthoester have only a modulus of about 40 MPa (Kellomaki, M., Heller, J .; Tormala, P. Processing and properties of two different poly (ortho esters); Journal of Materials Science: Materials in Medicine (2000) 8-17 MPa (Cohn, D .; Hotovely-Salomon, A. Biodegradable multiblock PEO / PLA thermoplastic elastomers: molecular design and properties, polymer (II), 11 (6), 345-355), PEG-lactide bismethacrylate. 2005), 46 (7), 2068-2075). The present invention now provides compositions which polymerize to much cheaper moldings (see Examples, below).

Particularly preferably, the surface of the shaped body is modified. If the formulation contains, for example, methacrylic anhydride, the surface can easily be modified by means of aminolysis. Suitable substances that are thus accessible are added (from the composition) or alternatively, are peptides that improve the adhesion of osteoblasts or precursors of osteoblasts. These include peptides with RGD sequences, preferably collagen I or collagen IV-like peptides. The surface is preferably modified by covalently bonded proteins, peptides, amino acids or oligonucleotides.

Particularly preferably, the shaped body has a cellular or porous structure. Preferably, the cells have a wall thickness or pore size of 150-500 microns, in particular by 200 microns. 200 μm corresponds to the average striae diameter of trabecular bone. Pore diameters of between 150 μm to 500 μm, in particular 350 to 500 μm, are optimal for the attachment of osteoblasts. This can be effected by specific forms in which the composition is polymerized, in particular those forms which consist of soluble materials, after which, after dissolution in a suitable solvent, the molding remains (molding). On the other hand, such a structure can be constructed by means of the rapid prototyping method. In the rapid prototyping process, the solid shaped body is built up layer by layer from a solution or fluid composition of the starting materials (monomers), e.g. by slightly raising a lifting plate in a container with the starting composition from the bottom and light from below (a specific image of the respective layer to be polymerized) being radiated through the light (or UV) permeable bottom of the container, whereby at the illuminated areas the composition polymerizes. By further raising the plate and illuminating the next layer is built up, etc. The advantage of the rapid prototyping method is that a targeted geometry of the shaped article can be made which is precisely adapted to medical needs, e.g. For example, after the removal of a bone tumor, the bone hole can be precisely measured (tomography) and then an exactly matching shaped body can be produced by means of the imaging method.

Further procedural possibilities for obtaining cellular structures include (see Gibson LJ, Freyman ™, Yannas IV; Cellular Materials as porous scaffolds for tissue engineering. Progress in Materials Science 46 (2001), 273-282):

Salt leachincr: NaCl particles and polymer are mixed in solution. The solvent is evaporated, the polymer over

Melting point heated (better distribution of the particles), cooled, placed in water, the salt goes into solution. 20

93% porosity is achievable, with a pore size in the

Range of 30-120 μm.

Foaming: CO ₂ is pressurized (800psi, 25 ° C)

Polymer (composition) solved, the pressure is reduced, the

Gas expands and forms pores; typical: 93% porosity,

Pore size 100μm. Fiber Bonding: Polyglycolic acid (PGA) fibers are immersed in a solution of polylactic acid (PLA). The solvent is evaporated and the resulting network is heated above the melting point of PGA (network fused), PLA is dissolved and the

PGA network remains over.

3D - printincτ with porogen: PGA, PLA powder with NaCl, w.o., 95%

Porosity, 100μm pore size

The shaped body is preferably modified by bound proteins, peptides, amino acids or oligonucleotides. In particular, these are bone morphogenic proteins (BMP), cytokines, growth factors (e.g., TGF-β, PTH), cell differentiation factors, collagens or collagen fragments, preferably BMPs and collagens, especially type II collagen. Examples of BMPs are known from the literature, in particular BMP-I (US 5,108,922), BMP-2 and BMP-3 (US 5,116,738 and US 5,013,649), BMP-4 (US 5,013,649), BMP-5 (US 5,106,748), BMP-6 ( US 5,187,076) and BMP-7 (US 5,108,753). Examples of nucleic acids or oligonucleotides which promote bone growth are disclosed, for example, in EP 741 785. These proteins or oligonucleotides may also be administered separately in the medical application. Preferably, the surface is modified by hydroxyapatite coating.

In a further aspect, the present invention relates to moldings for medical use, in particular as a bone substitute or bone replacement part, in particular as an implant. This is especially for the treatment of Bone damage, such as tumor-related Knochenaushöhlungen, beneficial. In the body, the moldings are degradable after a certain time, which, without being limited to any particular theory, is caused by slow water penetration into the polymer.

In a related aspect, the invention also relates to the use of a shaped body according to the invention for the production of an implant for the treatment of bone damage.

In the following examples compositions of the invention are given which can be used by the rapid prototyping method for the production of mechanically stable bone substitute materials and compared with polymers of the prior art.

example 1

Preparation of Gela.txnehydrolysat-Methacxrylami.den GMl, GM2 and GM3:

I g (0.4 mmol) gelatin hydrolyzate (M <6000 g / mol, 0.63 mmol lysine / g) was dissolved in water with gentle heating (not above 50 ⁰ C). After the addition of 1 g (6.7 mmol)

Methacylic anhydride (MSA), the mixture was vigorously stirred for 0.25 h (GMl), 4 h (GM2) and 5 h (GM3), respectively, to obtain a different degree of substitution. Subsequently, excess methacrylic acid and methacrylic anhydride were removed in vacuo. The average degree of substitution (DS) of methacryloyl-substituted lysine units was determined by NMR:

GMl: 1.03 g yellow solid, DS = 5% GM2: 1.27 g yellow oil, DS = 47% GM3: 1.18 g yellow oil, DS = 52%

¹ H-NMR (DMSO δ (ppm): 7.19 (m, aromatics-H); 5.39 (s, HCE = C); 5.62 (s, HCH = C); 4.70-0.75 (m, aliphatic-H); 1.5 (s, CH ₃ )

Comparative Example 1 Preparation of methacrylate-terminated olxgo-butylgycol-lactic acid block copolymers

(E2-L20-M and E8-L20-M were prepared analogously to Davis Kelly A, et al, Biomaterials 2003, 24 (14), 2485-95).

E2-L20-M E8-L20-M

D, L-lactide 10.0 g (69 mmol) 10.0 g (69 mmol)

Diethylene glycol 0.74 g (7 mmol)

Polyethylengycol

400 2.78 g (7 mmol)

Sn Octoate 94 mg (0.2 mmol) 94 mg (0.2 mmol)

Triethylamine 2.11 g (21 mmol) 2.80 g (28 mmol

Methacrylic acid chloride 2.17 g [21 mmol] 2.90 g (28 mmol)

CH ₂ Cl ₂ abs. 70 ml 70 ml

Diethylene glycol or polyethylene glycol 400 were stirred overnight with CaCl ₂ and filtered off. Methacrylic acid chloride was freshly distilled before use.

D, L-lactide and the corresponding Etyhlenglykol were placed in a three-necked flask and heated to 130 ⁰ C. After the D, L-lactide had melted, the catalyst was added, vacuum applied and the mixture stirred at 13O ⁰ C for 6 h. After cooling, the oily solid was dissolved in anhydrous CH ₂ Cl ₂ and triethylamine was added under N ₂ atmosphere. The reaction mixture was cooled to 0 ⁰ C and slowly added dropwise with 30 ml of CH ₂ Cl ₂ diluted methacrylic acid chloride. The reaction mixture was further stirred at room temperature overnight.

Subsequently, the salts were filtered off and the solvent was removed on a rotary evaporator. The residue was taken up in toluene, filtered again and poured into cold PE. The product was reprecipitated a second time, then dissolved in CH ₂ Cl ₂ and washed several times with NaHCO ₃ solution and brine, dried with Na ₂ SO ₄ , filtered and evaporated.

E2-L20-M: 9.0 g sticky solid (66% of theory) ¹ H-NMR (DMSO): 6, 18 (s, 2H, HCH = C;) 5, 62 (s, -2H, HCH = C); 5, 13 (m, 20H, CH-CO); 4, 25 (m, 4H, CH ₂ -O); 3.65 (m, 4H, CH ₂ -O); 1, 94 (s, 6H, CH ₃ -C = C); 1, 58-1, 46 (m, 6 OH, CH ₃ -CO)

E8-L20-M: 4.5 g yellow solid (33% of theory) ¹ H-NMR (DMSO) 6.20 (s, 2H, HCH = C;) 5.60 (s, 2H, HCH = C) ; 5.13 (m, 20H, CH-CO); 4.25 (m, 4H, CH ₂ -O); 3.70-3.60 (m, 2QH, CH ₂ -O); 1.97 (s, 6H, CH ₃ -C = C); 1.60 to 1.48 (m, 6 OH, CH ₃ -CO)

Preparation of the specimens

To test the biocompatibility, specimens were prepared. Mixtures were each prepared as indicated in Table 1. Mixtures 1-4 were prepared analogously to the literature. The photoinitiator used in all cases was 1% of a 1: 1 molar mixture of camphor quinone and ethyl dimethylaminobenzoate.

Table 1: Mixtures

No crosslinker comonomer filler solvent

1 99% PEGM ³ - - -

2 ¹ 6, 7 ^£ 5 PEGM ³ 10% PEO 82, 3% PBS ⁷

3 ² 99% E2-L20-M - - -

4 ² 99% E8-L20-M - - -

5 30% GMl * 50% AEEE ⁴ 19% HA-T ⁶ -

6 30% GM2 50% AEEE ⁴ 19% HA-T ⁶ -

7 30% GM2 50% DPA ⁵ 19% HA-T ⁶ -

8 30% GM 3 50% AEEE ⁴ 19% HA-T ⁶ -

9 30% GM3 50% DPA ⁵ 19% HA-T ⁶ -

¹ Dhariwala et al. Tissue Engineering, 10, 2004, 1316-1322

² Kristi S. Anseth et al, J. Polym. Be. A 39, 2001, 683-692

³ PEG 400 dimethacrylate,

⁴ acrylic acid (2- (2-ethoxy) ethoxy) ethyl ester (AEEE)

⁵ diisopropylacrylamide (DPA)

⁶ 1: 1 mixture of hydroxyapatite and tricalcium phosphate (HA-T) ⁷ PBS buffer: 10 mM sodium / potassium phosphate buffer pH 7.2, 0.8% NaCl and 0.02% KCl.

The mixtures were poured into a silicone mold and cured under nitrogen atmosphere on a UV system. The resulting test pieces were extracted to remove residual monomer with organic solvents and water in an ultrasonic bath. The extracted polymer forms were sterilized by irradiation with UV light.

Check for biocompatibility

For biocompatibility testing, osteoblast-like cells called MC3T3-E1 were used. The adherent cells were first detached from each other with pronase and from the bottom of the Petri dish. They were then mixed with freshly prepared nutrient medium and distributed evenly on the individual test specimens in the multiwell. The nutrient medium consisted of commercially available Dulbecco's Modified Eagle's Medium (DMEM, which originally contained 1000 mg / l glucose and was supplemented with further glucose up to a concentration of 4500 mg / l) supplemented with 10% FCS (fetal cow serum). , 30 μg / ml gentamycin (broad spectrum antibiotic), L-glutamine and ascorbic acid.

The multiwell with the cells was incubated at 37 ^° C. Using a microscope, it was possible to observe whether the cells can survive and adhere. If live cells were present after 2 weeks of culture, they were fixed with a solution of 4% paraformaldehyde and 0.5% Triton in PBS, washed several times with PBS buffer ⁷ and with a solution of 4, 6-diamidino-2-phenylindole (DAPI, 5 μg / ml) in PBS buffer ⁷ .

Biodegradability studies were performed at 37 ^° C. in PBS buffer at a pH of 7.0. The PBS buffer was changed every 12 hours in the first week, then every 3 days to keep the pH constant. Samples were taken after 1, 3, 7, 21 and 30 days. The mechanical stiffness of the materials was determined by determining the modulus of elasticity by means of dynamic mechanical Analysis determined. Corresponding values for the modulus of elasticity are given in the following table:

*) Mixture incompatible, **) specimens decay, +) living cells, ~) partially living cells, ++) many adherent cells, ~~) some adherent cells, -) no adherent cells

As can be seen from the table, formulations 6 to 9 according to the invention were able to achieve substantially higher and permanent stiffness values and, at the same time, excellent cell adhesion in comparison to known polymers 1-4 prepared according to the prior art.

Molds

For the production of cellular structures, the impression technique was used. On the one hand wax forms (Solidscape Modelmaker), on the other hand organolösliche polymer forms were used for these. The monomer formulations were mixed with 1% benzoyl peroxide and 0.07 to 0.2% 4- (dimethylamino) - mixed benzoate (DMAB) filled in the corresponding mold and cured at 45-75 ⁰ C for several hours. The wax form was removed by dissolving in ethanol, the organosoluble form was removed in a 1: 4 mixture of n-butylamine and tetrahydrofuran.

Claims

claims

Claims 1. A polymerization curable composition comprising

a) 10-80% by weight of a reactive diluent based on acrylic acid or methacrylic acid derivatives,

b) 10-50% by weight of a liquid or formulation-soluble monomer of the general formula

wherein n is an integer between 1 and 100,

wherein X is hydrogen or R ³ or (C = O) -R ³ with R ³ is a linear or branched alkyl radical having 1-20 C-Atorαen which may be interrupted by one or more oxygen atoms or ester groups or the rest

with «R2 ² _ = H or -CH ₃ ,

wherein Z ₁ is -O- (CHz) _x -CO-, -O- (CH ₂ -CH ₂ -O.) _X ~ CH ₂ -CO-, -0- _x (CH ₂ -CH ₂ -O.) - CO-CH ₂ -CH ₂ -CO-, -O- (CH ₂ -CH _2. -O) _X -OC-CH = CH-CO- -O-CH ₂ -CH (OH) -CH ₂ -, or -O- (CH ₂ -CH ₂ -O) _X -CH ₂ -CH (OH) -CH ₂ - where x = 1-20,

the radicals Y independently of one another represent hydrogen, -CH ₃ , -CH ₂ -CH (CHs) ₂ , -CH (CH ₃ ) -CH ₂ -CH ₃ , -CH ₂ -COT, -CH ₂ -CH ₂ -COT, -CH ₂ -OX, - (CH ₂ ) ₄ -NHX - (CH ₂ ) ₃ -NH -C (= NH) -NH ₂ , -CH ₂ SX, -CH (OX) -CH ₃ , -CH ₂ -CH ₂ -S-CH ₃ , -CH ₂ -C ₆ H ₅ , -CH ₂ -C ₆ H ₄ -OX, -CH ₂ -CONH ₂ , -CH ₂ -CH ₂ -CONH ₂ ,

or

in which X has the above meaning,

T for the group -OH or OR ³ or the rest

with R ² = H or -CH ₃ ,

with the proviso that at least one of X, Y or T is the group

contains.

2. The composition of claim 1 which is a UV or visible light curable composition containing as Component b) 10-50% by weight of a liquid or formulation-soluble monomer of the general formula

where n is an integer between 1 and 100,

where X is hydrogen, the rest

with τR> 2 ² _ = H or -CH ₃ ,

wherein Z ₁ is -O- (CH ₂₎ _x -CO-, -O- (CH ₂ -CH ₂ -O.) _X is -CH ₂ -CO-, -0-CH ₂ -CH (OH) - CH ₂ - , or -O- (CH ₂ -CH ₂ -O) _X- CH ₂ -CH (OH) -CH ₂ - where x = 1-20,

-CH (CH ₃ ) -CH ₂ -CH ₃ , -CH ₂ -COT, -CH ₂ -CH ₂ -COT, -CH ₂ -OX, - (CH ₂ J ₄ -NHX - (CH ₂ ) ₃ -NH -C (= NH) -NH ₂ , -CH ₂ SX, -CH (OX) -CH ₃ , -CH ₂ -CH ₂ -S-CH ₃ , -CH ₂ -C ₆ H ₅ , -CH ₂ -C ₆ H ₄ -OX, -CH ₂ -CONH ₂ , -CH ₂ -CH ₂ -CONH ₂ ,

or

in which X has the above meaning,

R ^{1 is} hydrogen or R ¹ together with Y is the radical - (CH ₂ ) ₃ - or -CH ₂ -CH (OX) -CH ₂ -, in which X has the above meaning, T for the group -OH or the rest

with R ² = H or -CH ₃ ,

wherein Z _{2 is} -O- (CH ₂ ) _X -O-, -O- (CH ₂ -CH _2. -O) _x -, -O-CH ₂ -CH (OH) -CH ₂ -O-, or - 0-CH ₂ -CH (OH) -CH ₂ -O- (CH ₂ -CH ₂ -O) _X - where x = 1-20,

with the proviso that at least one of X, Y or T is the group

contains.

3. Composition according to claim 1 or 2, characterized in that as component a) acrylic acid (2- (2-ethoxy) ethoxy) ethyl ester, diisopropylacrylamide,

Diisobutylacrylamide, acrylic acid 2- (butylcarbamoyloxy) ethyl ester, hydroxyethyl methacrylate, polyethylene glycol diacrylate, and trimethylolpropane triacrylate or one of their mixtures is used.

4. Composition according to one of claims 1 to 3, characterized in that the component b) comprises amino acids selected from glycine, arginine, aspartic acid, glutamic acid, alanine or proline.

5. The composition according to any one of claims 1 to 4, characterized in that the component b) comprises a methacryloylated gelatin hydrolyzate.

6. Composition according to one of claims 1 to 5, characterized in that the component b) comprises peptides having the sequence arginine-glycine-aspartic acid (RGD).

Composition according to any one of Claims 1 to 6, characterized in that the composition comprises 2-hydroxy-1- [4- (2-hydroxyethoxy) phenyl] -2-methyl-1-propanone or phenylbis (2, 4, 6 trimethylbenzoyl) phosphine oxide as initiator.

Composition according to any one of Claims 1 to 7, characterized in that the composition comprises camphorquinone as initiator and dimethyl-aminobenzoic acid, dimethylaniline, triethanolamine and / or methyldiethanolamine as coinitiator (s).

9. A composition according to any one of claims 1 to 8 comprising hydroxyapatite, tricalcium phosphate, bone meal or keratin fibers as a filler.

10. The composition according to any one of claims 1 to 9, characterized in that the components of the composition are dissolved in organic solvents with a water content of <10%, preferably <1%, most preferably <0.1%.

11. A process for producing a polymer comprising the polymerization of the composition according to any one of claims 1 to 10.

12. The method according to claim 11, characterized in that the polymer is a shaped body, which is preferably formed either by polymerization of the composition in a mold or by rapid prototyping.

13. Shaped body consisting of the polymerized composition according to any one of claims 1 to 10, wherein the shaped body has an E modulus greater than 500 MPa.

14. Shaped body according to claim 13, characterized in that the Forrαkörper an E modulus greater than 1000 MPa, preferably greater than 1500 MPa, in particular greater than 2000 MPa, more preferably greater than 5000 MPa, most preferably greater than 10000 MPa.

15. Shaped body according to claim 13 or 14, characterized in that the shaped body has a cellular structure with a pore diameter of between 150 microns and 500 microns.

16. Shaped body according to one of claims 13 to 15, characterized in that the surface of the shaped body is modified by hydroxyapatite coating.

17. Shaped body according to one of claims 13 to 15, characterized in that the surface of the shaped body is modified by covalently bonded proteins, peptides, amino acids or oligonucleotides.

18. Shaped body according to claim 17, characterized in that the proteins are bone morphogenetic proteins, cytokines, growth factors and cell differentiation factors, collagens or collagen fragments.

19. Shaped body according to one of claims 13 to 18 for medical use, in particular as a bone substitute.

20. Shaped body according to claim 19, characterized in that the medical application is a treatment of bone damage, in particular tumor-related Knochenaushöhlungen.

21. Use of a molding according to any one of claims 13 to 20 for the preparation of an implant for the treatment of bone damage.