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  • 专利说明
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    • 专利摘要:
    The present invention relates to a mosaic implant (15) comprising a plurality of mosaic plates (17) connected by a wire or mesh that anchor the arrangement ( 9). Methods for forming such implants and methods for using said implants for the correction of bone and soft tissue defects are described.
    公开号:BR112012022686B1
    申请号:R112012022686-0
    申请日:2011-03-10
    公开日:2021-04-20
    发明作者:Hakan Engqvist；Thomas Engstrand；Jonas Aberg；Jan Bohlin
    申请人:Oss-Q Ab；
    IPC主号:
    专利说明:

    [0001] Field of invention
    [0002] The invention concerns mosaic implants, methods for manufacturing such implants and methods for correcting tissue defects.
    [0003] Fundamentals of the invention
    [0004] Bone tissue defects that cannot heal through tissue regeneration can be filled using autograft, allograft, or synthetic scaffolding materials. For large defects, eg skull or long bone defects, healing of the bone defect can be especially difficult. The framing strategies involve providing porous metallic meshes or ceramic materials that the new fabric can grow over and/or inside. Current strategies using wire mesh can give rise to problems with unhealed defects due to poor new bone formation or infections. Currently used ceramics are mechanically weak and brittle which lead to a high risk of frame failure due to low mechanical strength. Metal meshes can be formed in the operating room to intimately fit the defect, whereas ceramics cannot be formed after fabrication and therefore have to be made to order beforehand. To overcome the low bone ingrowth problem of Ti meshes, coating a Ti mesh with hydroxyapatite powder has been proposed for use in revision surgery in joint replacement. This method increases bone reconstitution, but limits the ability to form mesh in the operating room as bending the wires can cause the powder to fall out and the method has not been tested with metals other than Ti. There is an unmet need for to an implant system that facilitates bone reconstruction, has high mechanical strength and has the capacity to be formed in the operating room.
    [0005] Brief description of the invention
    [0006] The present invention describes a mosaic implant, which can be used as a biomedical implant and which combines a wire or mesh anchoring system (a wire anchoring system comprises a plurality of wires, preferably crossed wires, where none of the wires is joined together whereas a mesh comprises at least two crossed wires joined at some or all of their intersections) and a biomaterial mosaic element, which can be formed in the operating room and which provides combined and enhanced bone reconstitution better mechanical properties compared to prior art systems. The implant comprises a mosaic element which combines at least one flexible high strength wire or mesh with at least two molded solid mosaic plates. The invention can be used for the correction of soft tissue defects and hard tissue defects. The biomaterial system can be composed of resorbable biomaterials and/or stable biomaterials such as polymers, ceramics and metals. Preferably the implant is osteo-inductive (i.e., it can serve as a scaffold on which bone cells can attach, migrate, and grow and divide) or osteo-inductive (i.e., it can serve to induce new bone formation ), can be formed in the operating room (OR) and has high mechanical strength. This is satisfied by the use of a mosaic-shaped structured implant system that combines a system that anchors biomaterial (eg, a wire mesh) with a solid biomaterial system in a mosaic. This system has the beneficial effects of a mechanically strong wire mesh and an osteo-conductive and/or osteo-inductive solid part, which means that the implant system can be easily formed in the operating room by cutting the mesh to geometric shape. and desired size. Solid plates, which are molded at the intersections of the wires during implant fabrication, are composed of an osteo-conductive and/or osteo-inductive material that facilitates bone reconstitution in the implant system.
    [0007] Preferably the mesh is formed by the crossed wires to form a plane or dish shape. In one embodiment of the present invention the biomaterial mosaic tiles are fixed at the intersections of the wire or mesh with a gap between the edge surfaces of adjacent tiles. In this way a mosaic structure comprising gapped wire-supported plates is formed. In another embodiment of the present invention a shell having a thickness that is less than the thickness of the biomaterial mosaic tiles is formed between some or all of the mosaic tiles. The shell is preferably brittle, and may be provided with lines of brittleness, to allow selective breakage of it to form the mosaic implant. Non-limiting examples of wires include polymers, shape memory alloys, Ti, Ti alloys (eg Ti6A14V) and stainless steel. In the present application the word "wire" is intended to include filaments made from any such materials. Biomaterials are preferably moldable from the chemically bonded ceramic class of materials or a biopolymer, non-limiting examples include Ca salts such as: calcium sulfate, calcium phosphate, calcium silicate, calcium carbonate or combinations thereof. The materials are preferably cast onto the wires or mesh using a water miscible non-aqueous liquid or using a mixture of water and a water miscible non-aqueous liquid, allowed to harden to form a mosaic implant in a bath containing water and subsequently the implant mosaic is released from the mold. After packaging and sterilization the mosaic implant is ready to be used. The strength of the crossing wires and, where present, the intervals between the plates are chosen so that a surgeon is able to shape the mosaic implant during an operation to adapt its shape to the defect of the tissue being adjusted. The wider the gap between the plates, the more the surgeon is able to deform the implant and consequently produce a three-dimensional shape with complex curves. However wider gaps take longer to fill with bone tissue and in order to overcome this problem while still allowing complex three-dimensional shapes to form it is possible to provide an implant with different gap widths between plates - smaller gaps where the implant is intended be substantially flat and wider ranges where the implant is intended to be curved.
    [0008] Brief description of the figures
    [0009] Figure 1 a) schematically shows a first embodiment of a mold for manufacturing a mosaic implant according to the present invention;
    [0010] Figure 1 b) schematically shows a cross section through section A-A of the mold in figure 1 a);
    [0011] Figure 2a) schematically shows the mold shown in figure 1 a) after a first step in a method for manufacturing mosaic implant according to the present invention;
    [0012] Figure 2b) schematically shows a cross section through section B-B of the mold in figure 2a);
    [0013] Figure 3a) schematically shows the mold shown in figures 1a) and 2a) after a second step in a method for manufacturing the mosaic implant according to the present invention;
    [0014] Figure 3b) schematically shows a cross section through section C-C of the mold in figure 2a);
    [0015] Figure 4a) schematically shows a mosaic implant formed when using the mold shown in figures 1 to 3 in a method for manufacturing the mosaic implant according to the present invention;
    [0016] Figure 4b) schematically shows a cross section through section D-D of the mosaic implant in figure 4a);
    [0017] Figure 5a) schematically shows a second embodiment of a mold for manufacturing a mosaic implant according to the present invention;
    [0018] Figure 5b) schematically shows a cross section through section V-V of the mold in figure 5 a);
    [0019] Figure 6a) schematically shows the mold shown in figure 5a) after a first step in a method for manufacturing the mosaic implant according to the present invention;
    [0020] Figure 6b) schematically shows a cross section through section VI-VI of the mold in figure 6a);
    [0021] Figure 7a) schematically shows the mold shown in figures 5a) and 5a) after a second step in a method for manufacturing the mosaic implant according to the present invention;
    [0022] Figure 7b) schematically shows a cross section through section VII-VII of the mold in figure 6a); and,
    [0023] Figure 8a) schematically shows a mosaic implant formed when using the mold shown in figures 5 to 7 in a method for manufacturing the mosaic implant according to the present invention;
    [0024] Figure 8b) schematically shows a cross section through section VIII-VIII of the mosaic implant in figure 8a);
    [0025] Figure 9a) schematically shows a third embodiment of a mold for manufacturing a mosaic implant according to the present invention;
    [0026] Figure 9b) schematically shows a cross section through section IX-IX of the mold in figure 9a);
    [0027] Figure 10a) schematically shows a mosaic implant formed when using the mold shown in figures 9a) to 9b) in a method for manufacturing the mosaic implant according to the present invention;
    [0028] Figure 10b) schematically shows a cross section through section X-X of the mosaic implant of figure 10a);
    [0029] Figure 11 schematically shows a cross section through another mold for manufacturing a mosaic implant according to the present invention;
    [0030] Figures 12a) to 12d) show axial CT scans (figures 12a) and 12c)) and CT scans formatted in 3D (figures 12b and 12d)) showing a mosaic implant covering the cranial bone defect in the patient no. 1 directly after surgery (figures 12a) and 12b)) and 3 months later (figures 12c) and 12d)); and,
    [0031] Figures 13a) to 13d) show axial CT scans (figures 13a) and 13c)) and 3D formatted CT scans (figures 13b and 13d)) showing a mosaic implant covering the cranial bone defect in the patient in the 2 directly after surgery (figures 13a) and 13b)) and 3 months later (figures 13c) and 13d)).
    [0032] Detailed description of the invention
    [0033] In an embodiment of a method of manufacturing a mosaic implant according to the present invention a mold 1 of depth D is used which, as shown in figures 1a) and 1b), comprises a plurality of cavities 3 of depth d, each of which is shaped like a mosaic board. The depth d of the cavities and the thickness of the resulting mosaic tile are less than the depth D of the mold. Each cavity 3 has a closed bottom end 3' which is closed by floor 4 of mold 1 and is open at the opposite open end 3" to allow filling of cavity 3.
    [0034] Floor 4 does not have to be permanently attached to the mold, but, for example, it can be a surface that the mold is in contact during implant fabrication and that can be removed after molding to facilitate the release of the implant from the mold Preferably each cavity and thus each mosaic tile subsequently formed therein has a regular shape such as a triangle, a square, a rectangle, a pentagon, a hexagon (as shown in figures 1 to 4) etc with straight sides. Preferably all cavities have the same shape. In the event that the shapes of the cavities are not the same then the adjacent cavities are preferably given complementary shapes such that the cavities can be arranged in patterns with no overlap and if desired can have substantially equal gaps between adjacent edges. The maximum width of each cavity and thus each mosaic tile is w and preferably the maximum width w of each cavity is greater than its depth d. Preferably w is between 2 and 20 mm, more preferably between 3 and 15 mm and even more preferably between 4 and 10 mm. Preferably d is between 10% and 150% w, more preferably between 20% and 130% w and most preferably between 50% and 130% w. Each cavity is separated by a wall 5 of thickness t in the mold from its adjacent cavity/cavities. The wall thickness t in the mold leads to a nominal thickness gap t between adjacent plates in the implant, it is preferably less than 5 mm, more preferably less than 3 mm and most preferably less than 2 mm since the smaller the gap is easier then for the bone to grow and fill the gap between the mosaic plate. However the gap should not be too small so that it will prevent the proper movement of the mosaic tiles with respect to each other - a small gap means that after just a small deformation, the walls of the adjacent mosaic tiles will collide and prevent the shape. most desired implant. In other words, having a longer gap allows the implant to be deformed more before the adjacent plates make contact with each other, but the larger gaps between the plates also take a longer time to fill with bone tissue or indeed may be impossible for the bone cells to form a bridge. It is of course possible to have different size ranges between the wells if the implant is intended to have regions which although are substantially flat and other regions which will be formed into three-dimensional shapes. Each wall 5 between adjacent cavities 3 is pierced by at least one narrow channel, which retains wire 7, 7' of width ww. These wire-retaining channels 7 are intended to receive and retain during the molding process the wires of similar width ww used to form a wire arrangement or anchor mesh in the implant which holds the mosaic plates in relation to one another. An anchoring arrangement is preferably in the form of a cross wire mesh structure if the size of the implant is large enough to accommodate a mesh structure. It is conceivable that with narrow and elongated implants, the wires do not cross but are substantially parallel or that they cross only at a shallow angle and therefore may cross only in a portion of the wells. Preferably channels 7 that go in a first direction have a depth d1, while channels 7' go in another direction, for example an orthogonal direction that have a depth d2 and which is shallower at a distance that is the same as, or less than, the diameter of the wire (see below) used to form the mesh, ie, d1 > d2 > (d1-ww) so that the crossed wires are close to each other or in contact with each other . In this embodiment of the invention the wires are arranged in a grid where each wire is substantially parallel to its neighboring wire(s) in the same plane and is crossed by and in contact with at least one perpendicular wire in a different plan. Preferably the wires are spaced apart such that each cavity is crossed by two substantially parallel wires going in a first direction and two wires going in a non-parallel direction, for example the perpendicular direction. In another embodiment of the invention, not shown, each cavity is just crossed by a wire in the first direction and a wire in the perpendicular direction. This means that the subsequently formed implant can be lighter and more easily formed. It is also conceivable to have a plurality of wires which go substantially parallel in one direction across the cavity, but which are crossed by a smaller number of wires, for example a cavity may have two parallel wires crossed by a single perpendicular wire. Other arrangements such as three wires crossing at 120° are also conceivable.
    [0035] Although the cavities have been shown with vertical walls 5, it is of course possible to have sloping walls such that the width across any closed end section at the bottom of each cavity is less than the width of the corresponding open end section of the cavity so as to form release slopes that help release the molded product from the mold. Appropriately sloping walls also allow the implant to be deformed into deeper concave shapes without the edges of adjacent mosaic tiles coming into contact with each other than is otherwise possible with vertical walls.
    [0036] Figures 2a) and 2b) showed the mold 1 in a first step in a method for manufacturing a mosaic implant. In this step a wire mesh 11 is formed from overlapping wires 9, preferably of width or diameter ww so that they fit tightly into the wire retaining channels so as to hold them in place during fabrication and to reduce preventing leakage of cement around them. A wire is placed in place, and preferably extends from end to end of each of the channels. Preferably the channels 7 are arranged such that when the wires are arranged therein the central plane of the resulting wire mesh 11 resides in the central plane of the mold 1. This gives the advantage that when the mosaic implant is formed it is substantially symmetrical in around the center plane of the wire mesh which means it is equally easy to make concave and convex adjustments to its shape. However in the event that it is desired to have an implant that should be concave in only one direction, for example only convex then the wire mesh can be positioned further outside the center plane of the wells to allow for more curvature in the desired direction before adjacent plates get in touch with each other.
    [0037] Figures 3a) and 3b) show the following mold of a molding step in the method for manufacturing a mosaic implant. In this step the cavities 3 are filled with a non-aqueous, hydraulic cement composition 13 comprising a non-aqueous mixture of (a) a Ca salt precursor powder composition, and (b) a water-miscible non-aqueous liquid. This cementitious composition is cast onto wire mesh 11 and allowed to harden in a wet to wet environment. The water in the environment displaces the water-miscible non-aqueous liquid from the hydraulic cement and allows the cement to harden. Preferably the temperature and amount of water in the environment are adapted so that the hardening process takes at least 24 hours as this leads to a stronger product. Preferably before the cement has completely set, any excess cement composition 13 present in the wire retention channels 7, 7' is removed.
    [0038] Figure 4a) schematically shows a mosaic implant 15 formed when using the mold shown in figures 1 to 3 after it was released from the mold 1. The mosaic implant 15 comprises a plurality of mosaic plates 17 , each joined by wires 9 to adjacent mosaic sheets while being separated from them by a gap 10 of width t. Figure 4b) schematically shows a cross section through section DD of the mosaic implant in figure 4a).
    [0039] In another embodiment of a method of manufacturing an implant according to the present invention a mold 21 of depth D is used which, as shown in figures 5a) and 5b), comprises a plurality of cavities 23 of depth d, each of which is shaped like a mosaic board. The depth d of the cavities is less than the depth D of the mold. Each cavity 23 has a closed bottom end 23' which is closed by the floor 24 of the mold 21 and is open at the opposite open end 23" to allow filling of the cavity 23. Each wall 25 between adjacent cavities 23 is pierced by at least one narrow channel, retaining wire 27, 27' wide ww. In this embodiment the primary channels 27 going in a first direction join two opposite walls of the cavity at a depth d1 while the secondary channels 27' are aligned at an angle of 60° with respect to the primary channels at a depth d2 which it is shallower at a distance that is the same as, or less than, the diameter of the wire subsequently used to form the anchoring arrangement on the implant that holds the mosaic tiles in relation to each other. These secondary channels join two different opposite walls of each cavity. A third set of channels 27” is provided at an angle of 120° with respect to the first set of channels 27 and at a depth of d3, and these join the two remaining opposite walls of each hexagonal cavity. Thus in this embodiment of the invention the wires are arranged in a grid where each wire is parallel to its neighboring wire(s) and is crossed by at least two other wires which respectively make an angle of + 60° and - 60° with him. Preferably the wires are spaced such that each cavity wall is pierced by a pair of parallel wires. In another embodiment of the invention, not shown, each cavity wall is only pierced by a wire in the first direction and a wire in the perpendicular direction. This means that the subsequently formed implant can be lighter and more easily formed, but at the cost of reduced strength and stability.
    [0040] Figures 6a) and 6b) show the mold 21 in a first step in a method for manufacturing a mosaic implant. In this step a wire mesh 31 is formed from overlapping wires 29, preferably of width or diameter ww so that they fit tightly in the wire retention channels.
    [0041] Figures 7a) and 7b) show the following mold of a molding step in the method for manufacturing a mosaic implant. In this step the cavities 23 are filled with a non-aqueous, hydraulic cement composition 33. This cement composition is molded onto the wire mesh 31 and allowed to harden in a wet to wet environment. The water in the environment displaces the water-miscible non-aqueous liquid from the hydraulic cement and allows the cement to harden. Preferably the temperature and amount of water in the environment are adapted so that the hardening process takes at least 24 hours as this leads to a strong product. Preferably before the cement has fully set, any excess cement composition 33 present in the wire retention channels 27, 27', 27" is removed.
    [0042] Figure 8a) schematically shows a mosaic implant 35 formed when using the mold shown in figures 5 to 7 after it was released from the mold 21. The mosaic implant 35 comprises a plurality of mosaic plates 37 each joined by wires 29 to adjacent mosaic tiles. Figure 8b) schematically shows a cross section through section VIII-VIII of the mosaic implant in figure 8a).
    [0043] Figure 9a) and 9b) show an example of a mold 41 for use in another embodiment of a method for manufacturing a mosaic implant according to the present invention. In this embodiment of the invention it is desired to provide a bridged shell of material made of cement between adjacent mosaic slabs. This shell preferably has a thickness s which is less than the thickness of the mosaic tiles. Preferably it is greater than 0.5mm and less than 5mm in thickness and is intended to reinforce the mosaic implant between the mosaic plates. As such a shell would prevent the implant from being formed, the shell is preferably fabricated thin enough so that, if required, it can be broken or cut by a user in selected regions before being attached to a patient. Only by breaking or cutting the implant shell in the places necessary to allow the implant to be deformed is it possible to form the implant into the desired shape while maintaining most of the increased strength provided by the shell. The shell can be formed by sinking the tops of walls 45 between the cavities to a depth of the mold top surface 43 that is the same as the desired thickness of the shell. The tops of the walls can be provided with a protrusion 47, preferably in the shape of a point, which causes local thinning in the subsequently formed shell. Wire retaining channels are provided as needed and once the wires have been placed in the channels the mold is filled with cement and allowed to harden as before. In the event that the wires are positioned at a depth that is lower than the desired bottom surface of the shell, spacer material can be provided above the wires to prevent excess cement material from filling the gap between the wires and the bottom surface of the shell.
    [0044] Figure 10a) schematically shows the underside of a mosaic implant 55 formed when using the mold shown in figures 9a) and 9b) after it was released from the mold 41. The mosaic implant 55 comprises a the plurality of mosaic plates 57 each joined by wires 49 and shell 61 of thickness s to adjacent mosaic plates. Figure 10b) schematically shows a cross section through section X-X of the mosaic implant in figure 10a). The part of the shell 61 where the protrusions in the mold were placed is locally thinner, forming lines of weakness 63 which aid in fracture of the shell 61 when implant deformation is required.
    [0045] In another embodiment of the present invention a mosaic implant comprises a plurality of mosaic plates, some of which are joined to one or more neighboring mosaic plates by a shell and some of which are separated from one or more neighboring plates by a gap (shown by dashed lines 65 in Figure 10a).
    [0046] Other molding methods can be used to form a mosaic implant in accordance with the present invention. For example, as shown schematically in Figure 11, an interconnecting mesh 101 (or at least one wire) is placed on the exposed surface 103 of a first mold half 105 comprising a plurality of cavities 107 of depth d1 separated by walls 109. The first mold half 105 is supported in a die 111. The first mold half 105 is provided with an excess amount of cement composition 113 (shown by the dashed lines) which not only fills the cavities 107 and covers the mesh (or wire(s)), but also extends outside the exposed surface of the first mold half 105. A second mold half 115, which preferably has cavities 108 of depth d2 arranged as a mirror image of the first mold half, is subsequently placed on top of the mesh and compressed towards the bottom of the mold to allow molding of mosaic tiles around the interconnecting mesh. The second mold half 113 can be supported on a backplate 117. The excess amount of cement composition must be sufficient to fill the cavities in the second mold half and must be positioned to be able to fill the second mold half. Excess cement is removed after the mold halves have been joined and preferably before the cement has hardened. Cement hardening can be achieved by adding moisture through holes 119, each hole being connected to each mold cavity within the mold. Holes 119 are also suitable for allowing excess cement to leave the mold.
    [0047] The depths of the cavities in each mold half do not have to be the same. If they are different then the mesh or wire(s) will not be disposed in the central plane of the resulting implant which, if desired, will allow the implant to be used with the exposed mesh or wires further away from the patient's skin and thus less likely to be damaged in the event of an accident.
    [0048] The minimum number of cavities in each mold is two and there is no limit to the minimum number of cavities. The minimum number of wires is one, but preferably the wires are at least provided as pairs of parallel wires to provide stability in the plane passing through the longitudinal axes of each pair of parallel wires.
    [0049] In all embodiments of the present invention, depending on the cement composition, cement hardening can be carried out at reduced, or normal or high temperature, and at ambient humidity. The mold can be of any dimensionally stable material that does not negatively react with cement or mesh/wires. If the mold material is permeable to water it can help to harden the cement.
    [0050] There are three preferred options with respect to cement molding: 1. Use (a) of a Ca salt precursor powder composition, and (b) water miscible non-aqueous liquid. In this case the hardening needs to be in a humid environment in order to start hardening. 2. Use (a) of a powdered Ca salt precursor composition, and (b) a mixture of water and a non-aqueous water-miscible liquid. Hardening will start automatically, but for final hardening a moist environment is required. 3. (a) a Ca salt precursor powder composition, and (b) a water-based liquid. Hardening is started in the mixture. It is not necessary to perform hardening in a wet environment, but hardening can be done in a wet environment.
    [0051] The calcium salt precursor composition may comprise one or more Ca salts selected from the group consisting of anhydrous calcium diphosphate, calcium diphosphate dihydrate, calcium octaphosphate, α-tricalcium phosphate, β-tricalcium phosphate, calcium phosphate amorphous calcium, calcium deficient hydroxyapatite, non-stoichiometric hydroxyapatite, calcium tetraphosphate and monocalcium phosphate monohydrate (MCPM), anhydrous monocalcium phosphate, phosphoric acid, pyrophosphoric acid, calcium sulfate (alpha or beta, preferably alpha) or calcium silicate (tricalcium silicate, dicalcium silicate or monocalcium silicate), calcium carbonate (aragonite, vaterite, calcite or amorphous) or combinations thereof.
    [0052] In a first embodiment of the invention a non-aqueous water miscible liquid can be used in the preparation of the pastes. Possible liquids include glycerol and related liquid compounds and derivatives (substances derived from non-aqueous water-miscible substances), substitutes (substances where part of the chemical structure has been replaced with another chemical structure), and the like. The purpose of the water miscible non-aqueous liquid is to give a longer working time during the molding of the mosaic, because if the material starts to harden then it is impossible to accurately obtain the mosaic shape.
    [0053] Certain alcohols may also be suitable for use as such a liquid. Preferably the liquid is selected from glycerol, propylene glycol, polypropylene glycol), poly(ethylene glycol) and combinations thereof. The composition may also include agents that facilitate rapid diffusion of water into the paste in situ, preferably nonionic surfactants such as Polysorbates. The amount of surfactant is preferably between 0.01 and 5% by weight of the powder composition, most preferably 0.1 to 1% by weight.
    [0054] In an alternative embodiment of the present invention the composition of the precursor powders is chosen to obtain a cure time above about 30 minutes and the liquid can then be water-based or water-containing. In this case the liquid can be pure water. In some formulations the salts can be dissolved in the liquid to obtain a quick or slower setting, eg citric acid, H3C6H5O7, Disodium pyrophosphate_Na2H2P2O7, sulfuric acid, H2SO4, phosphoric acid H3PO4. Hardening can then be carried out in a dry environment.
    [0055] The compositions may also include porogens to give a macroporous end product to facilitate rapid resorption and tissue regeneration. Pores provide a good foundation for bone cells to grow. Porogen can include sugars and other rapidly resorbing agents. The amount of porogen is suitably between 5 and 30% by weight of the powder composition. This is independent of whether the composition chosen above is pre-mixed or not.
    [0056] The compositions may also include a non-toxic gelling agent to enhance cohesiveness and resistance to leaching. The gel forming agent can include collagen, gum, gelatin, alginate, cellulose, polyacrylic acid (eg PAA, PAMA), neutral polyacrylic acid (eg Na-PAA, Na-PAMA acid), HPMC, HMC and CMC and combinations thereof. The amount of gel-forming agent preferably represents between 0.1% by weight and 10% by weight of the powder composition, more preferably between 0.1% by weight and 2% by weight. This is independent of whether the composition chosen above is pre-mixed or not.
    [0057] In all cement compositions selected above the ratio of precursor powder to liquid should preferably be within the range of 1 and 10 as this gives optimal results. The average grain size of the precursor powder is preferably below 100 micrometers, and more preferably below 30 micrometers when measured in the volumetric grain size mode. Smaller grain sizes give higher mechanical strength than larger grain sizes. However for the embodiment of the invention which contains porous granules, the granule size may be larger, but preferably still below 500 micrometers. Usually the granules do not participate in the curing reaction of the paste. They are added as ballast to the material and the presence of pores gives a better biological response to the material. Preferably, at least some of the pores in a granule should be large enough for cells to enter the granule, usually over at least 10 microns. Inevitably there will also be smaller pores in the granules, but they are of lesser importance for cell integration.
    [0058] In another embodiment of a method of manufacturing an implant according to the present invention, in the step of molding a non-aqueous hydraulic cement composition comprising a non-aqueous mixture of (a) a powder composition of calcium phosphate forming Brushita or Monetita, and (b) non-aqueous water miscible liquid, is cast over the wire mesh and allowed to harden in a wet to wet environment.
    [0059] In another embodiment of a method of manufacturing an implant according to the present invention in the step of molding a non-aqueous hydraulic cement composition comprising a non-aqueous mixture of (a) a non-aqueous powder composition. hydrate which comprises porous β-tricalcium phosphate granules (β-TCP) and at least one additional calcium phosphate powder, and (b) non-aqueous water miscible liquid, is cast over the wire mesh and allowed to harden in an environment from wet to wet. An example of a wet environment is a water bath. An example of a humid environment is a chamber where the relative humidity is 100%. Optionally, the hardening of the cement material can be carried out at a reduced, or normal or elevated temperature, combined with a humidity, ie a relative humidity above 50%, ambient or wet environment.
    [0060] In an alternative embodiment, the powdered precursor composition is basic (apatitic) and comprises (a) a basic calcium phosphate component comprising porous β-TCP granules and tetra calcium phosphate (TTCP) and/ or amorphous calcium phosphate, and (b) an acidic phosphate, non-limiting examples of which include monocalcium phosphate monohydrate (MCPM), anhydrous monocalcium phosphate, phosphoric acid, pyrophosphoric acid or combinations thereof. The components of the apatitic precursor powder compositions are chosen such that (i) the pH of the cement paste during curing is higher than 6; and (ii) the end product of the curing reaction comprises hydrated amorphous calcium phosphate, hydroxyapatite, ion substituted hydroxyapatite, or combinations thereof.
    [0061] Once the cement has set, the cement and wire construction can be removed from the mold, any unwanted cement, for example cement that has become trapped in the wires between the hexagonal plates 15, is removed and the implant packaged and sterilized .
    [0062] Optionally the cement and wire construction of the implant system of the present invention can be exposed to pressure during hardening, for example by pressing in an inverse mold against the cement, in order to obtain a stronger end product.
    [0063] Optionally the implant system of the present invention can be combined with drugs to form a drug delivery system. Examples of medications are anti-inflammatory drugs, antibiotics, analgesics, anticarcinogens, bone growth promoting agents, fibroblast growth factors, and bisphosphonates. These drugs can be delivered by using porous components in the implant system, for example porous wires or porous cement or porous granules or a porous coating, and introducing the drugs into the pores of the porous component.
    [0064] The implant system can be attached to the host tissue by means of sutures and/or plates and screws and/or staples or any other means of fixation.
    [0065] The implant system can be used in tissue replacement (bone or soft tissue replacement) and in veterinary medicine. For soft tissue replacement the mosaic structure is preferably composed of polymeric materials, preferably resorbable polymers. For the hard fabric the mosaic system is preferably composed of metallic wires and ceramic solids, preferably of metallic wires and resorbable ceramics. In the event that the patient is still growing it is appropriate to use resorbable materials for the wires and/or mosaic tiles. Suitable resorbable polymers are Polydioxanone, poly L-lactic acid, and polyglycolic acid.
    [0066] The implant system optionally can also be combined with an injectable biomaterial or drug delivery vehicle that guides tissue regeneration within the gaps between plates in the system.
    [0067] Experimental Example 1
    [0068] A mosaic implant was fabricated using the fabrication method described above using pre-mixed acidic calcium phosphate cement cast over Ti wires. The clinical use of this example of a mosaic implant was for the restoration of a cranial defect great. Wires were placed in the mold which was then filled with the premixed acid calcium phosphate cement and allowed to harden in water for 48 hours at 20 degrees C.
    [0069] The premixed acid calcium phosphate cement consisted of beta-tricalcium phosphate, calcium monophosphate monohydrate and glycerol. Beta-tricalcium phosphate and calcium monophosphate monohydrate were mixed in a molar ratio of 1:1 and glycerol was added to the powder to obtain a powder:liquid ratio of 3.9:1 [g/ml]. The cement was carefully mixed until a homogeneous paste was formed.
    [0070] After hardening, the cement was found to consist mainly of the two phases brushite (CaHPO4-2H2O) and monetite (CaHPO4) - however some calcium pyrophosphate (Ca2O7P2) was also found.
    [0071] The mosaic implant was released from the mold, packaged and steam sterilized. The fabricated mosaic structure was clinically evaluated.
    [0072] Clinical Evaluation
    [0073] Patient #1: A 22-year-old patient with a cranial parietal bone defect measuring 40 x 40 mm was operated on. The defect was exposed through a local cranial skin flap. A sterilized mosaic implant with the original size of 100 x 100 mm was cut using a wire cutter and adjusted to a size of approximately 45 x 45 mm. The mosaic implant was fitted into the defect, which required cutting away small amounts of adjacent cranial bone to ensure a good fit. The periphery of the defect was formed to create an edge to support the implant and the implant was subsequently secured to the edge by titanium plates and screws. The patient did not demonstrate any local or systemic side effects and was able to leave the hospital the day after surgery. A postoperative CT scan (see Figures 12a) and 12b)) showed the implant in perfect position covering the original bone defect. Clinical and radiological follow-up 3 months after surgery revealed a well-tolerated implant with no signs of infection, inflammation or penetration through the skin. The implant was still intact without resorption at this initial time point as demonstrated by the CT scans shown in Figures 12c) and 12d)).
    [0074] Patient #2: A 53-year-old smoker had a large temporal cranial bone defect measuring 80 x 90 mm. The patient was previously operated extensively for complex craniofacial trauma and had previous implants that failed due to infections and penetration through the skin. The bone defect was exposed through a standard bi-coronary cranial skin flap. The soft tissue covering the defect was mostly fibrotic. An original size 100 x 100 mm sterilized mosaic implant was cut using wire cutters and adjusted to a size of approximately 85 x 95 mm. The mosaic implant was fitted into the defect by cutting the adjacent cranial bone to form supporting edges, and the implant was subsequently attached by fixing the implant between the edges and the titanium plates and screws. The patient demonstrated a mild local reaction at the operating site that eventually declined 3 to 4 days after surgery. A postoperative CT scan showed the implant in perfect position covering the original bone defect as can be seen in figures 13a) and 13b). Clinical and radiological follow-up 3 months after surgery showed a well-tolerated implant with no signs of infection, inflammation or penetration through the skin. The implant was still intact without resorption at this time point as demonstrated by the CT scans shown in Figures 13c) and 13d).
    [0075] Although the implant was ligated using staples in the examples above it is also possible to ligate it using sutures and a combination of staples and sutures.
    [0076] The invention is not limited to the embodiments shown, which can be freely varied within the working matrix of the following claims. In particular, the features of the various described embodiments and examples can be freely combined together in order to achieve additional embodiments, which are all considered to be part of the scope of the present application.
    权利要求:
    Claims (19)
    [0001]
    1. Implant, comprising a plurality of discrete biocompatible molded cement mosaic tiles (17; 37; 57) of thickness d characterized in that the mosaic tiles are connected by wire arms molded in and extending substantially laterally to starting from the mosaic slabs, where the neighboring tile slabs (17; 37) are separated by an empty space (10; 30) of width t.
    [0002]
    2. Implant according to claim 1, characterized in that at least two neighboring tiles of mosaic (57) are joined by a film (61) having a thickness s which is less than the thickness d.
    [0003]
    3. Implant according to claim 1, characterized in that each mosaic plate (17; 37; 57) has a maximum width w that is between 2 and 20 mm.
    [0004]
    4. Implant according to claim 3, characterized in that each mosaic plate (17; 37; 57) has a maximum width w between 3 and 15 mm.
    [0005]
    5. Implant according to claim 3, characterized in that each mosaic plate (17; 37; 57) has a maximum width w 4 and 10 mm.
    [0006]
    6. Implant according to claim 3, characterized in that the thickness d is between 10% and 150% of w.
    [0007]
    7. Implant according to claim 5, characterized in that the thickness d is between 20% and 130% of w.
    [0008]
    8. Implant according to claim 5, characterized in that the thickness d is between 50% and 130% of w.
    [0009]
    9. Implant according to claim 1, characterized in that the molded cement mosaic tiles comprise Monetite.
    [0010]
    10. Implant according to claim 9, characterized in that the mosaic tiles comprising Monetite are formed from an acidic cement composition comprising beta-tricalcium phosphate and monocalcium phosphate monohydrate.
    [0011]
    11. Implant according to claim 1, characterized in that each mosaic plate has a maximum width w of 2 to 20 millimeters and a thickness d between 50% and 130% w.
    [0012]
    12. Implant according to claim 1, characterized in that each mosaic plate has a top surface and a bottom surface, and at least one of the top and bottom surfaces is exposed.
    [0013]
    13. The implant according to claim 1, characterized in that the plurality of discrete biocompatible mosaic tiles are hexagonal molded cement mosaic tiles of maximum width w, where w is between 4 and 10mm, and thickness d, where d is between 50% to 130% w, connected by wire arms molded in and extending substantially laterally from the mosaic boards, wherein neighboring mosaic boards are separated by a void with width t, t and t is smaller than 3 mm, where each mosaic board has a top surface and a bottom surface, and at least one of the top and bottom surfaces is exposed, wherein the mosaic boards comprise Monetite.
    [0014]
    14. Method for the preparation of an implant as defined in any of claims 1 to 13, characterized in that the method comprises the steps of molding a cement composition around a wire or mesh, and subsequently allowing said cement composition is cured.
    [0015]
    15. Method according to claim 14, characterized in that the method comprises the steps of: a) producing a mold (1; 21; 41) with a plurality of cavities (3; 23; 53) of depth d, each of which is in the form of a mosaic plate, where each cavity has a closable bottom end (3', 23', 53') and is open at the opposite end to allow filling of the cavity, where each wall (5; 25; 45) between adjacent cavities is perforated by at least one narrow, wire-retaining channel or mesh with width ww; b) placing a wire or mesh in each wire or mesh retaining channel, c) filling said mold cavities with a cement composition (13;33;53) and d) allowing said cement to harden.
    [0016]
    16. Method according to claim 14, characterized in that it comprises the steps of: i) providing a first mold half (105) with a plurality of cavities (107) of depth d1, each of which is shaped like a mosaic plate, where each cavity has a closable bottom end and is open at the opposite end to allow filling of the cavity, ii) filling said first mold half with an excess of cement composition; iii) placing a wire or mesh (101) over the open ends of said cavities; iv) placing a second mold half (115) having cavities (108) of depth d2 mounted as a mirror image of the first mold half on top of the wire or mesh and compressing it towards the first mold half, and v ) allow said cement to harden.
    [0017]
    17. Method according to claim 14, characterized in that the step of allowing said cement to be hardened takes place in a wet environment.
    [0018]
    18. Method according to claim 14, characterized in that the step of allowing said cement to be hardened takes place in a humid environment.
    [0019]
    19. Use of an implant as defined in any one of claims 1 to 13, characterized in that it is to correct a defect in a tissue or bone of an individual.
    类似技术:
    公开号 | 公开日 | 专利标题
    BR112012022686B1|2021-04-20|mosaic implant, method for preparing an implant and using an implant
    ES2608873T3|2017-04-17|Implants for filling holes in bone tissue
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    US9220597B2|2015-12-29|Mosaic implants, kits and methods for correcting bone defects
    ES2784859T3|2020-10-01|Cement-forming compositions, monetite cements, implants and methods to correct bone defects
    US20110160322A1|2011-06-30|Porous bone cement
    US8883063B2|2014-11-11|Mould mat for producing bone cement pellets
    同族专利:
    公开号 | 公开日
    EP2544627A4|2014-08-13|
    RU2562596C2|2015-09-10|
    US9445900B2|2016-09-20|
    CN105125323A|2015-12-09|
    EP2544627A1|2013-01-16|
    RU2012143149A|2014-04-20|
    BR112012022686A2|2020-08-25|
    CN102883685B|2015-07-22|
    JP5871822B2|2016-03-01|
    CN105125323B|2017-04-12|
    HK1218505A1|2017-02-24|
    KR101901821B1|2018-09-27|
    KR20130020664A|2013-02-27|
    AU2011224893B2|2015-01-22|
    AU2011224893A2|2012-10-18|
    AU2011224893A1|2012-09-20|
    US20120330435A1|2012-12-27|
    JP2013521859A|2013-06-13|
    US20140324187A1|2014-10-30|
    CN102883685A|2013-01-16|
    EP2544627B1|2018-05-02|
    US8795377B2|2014-08-05|
    WO2011112145A1|2011-09-15|
    US20140195004A9|2014-07-10|
    ZA201207569B|2020-12-23|
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    法律状态:
    2020-09-08| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-09-15| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-02-02| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-04-20| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 10/03/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME MEDIDA CAUTELAR DE 07/04/2021 - ADI 5.529/DF |
    优先权:
    申请号 | 申请日 | 专利标题
    SE1000223|2010-03-10|
    SE1000223-6|2010-03-10|
    PCT/SE2011/050264|WO2011112145A1|2010-03-10|2011-03-10|Implants and methods for correcting tissue defects|
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