• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
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  • 优先权
    • 专利摘要:
    A mammalian body implantable composition, porous formed structure, substantially spherical bioactive glass particle and use of the composition The present invention is directed to implantable compositions comprising substantially active bioactive glass particles.
    公开号:BR112014009794B1
    申请号:R112014009794-1
    申请日:2012-10-24
    公开日:2019-10-15
    发明作者:Mark D. BORDEN
    申请人:Synergy Biomedical, Llc；
    IPC主号:
    专利说明:

    [001] The invention is directed to the use of substantially spherical bioactive glass particles in materials useful for bone healing.
    Prior art [002] Bioactive glasses are well-known surgical materials that have been used as bone graft material for over 24 years. The original 45S5 bioactive glass compositions were discovered by Hench and have the following composition: 45% SiO 2 , 24.5% Na 2 O, 24.5% CaO and 6% P2O 5 [Hench J. Biomed. Matter, Res. Symp. 117-141 (1971)]. As a bone graft material, bioactive glasses have a unique property of forming a layer of hydroxycarbon-apatite (HCA) on a glass surface when implanted in vivo. The formation of this layer is linked to the dissolution of glass, subsequent release of calcium (Ca) and phosphorus ions (P), and the formation of a layer rich in Ca-P on the glass surface. The layer eventually crystallizes in hydroxy-carbane-apatite and results in an interfacial bond between the bioactive glass and the bone that improves bone healing around the bioactive glass particles.
    [003] After Hench's original discovery of the 45S5 formula, the additional compositions were evaluated, but he noted that only a narrow range of the CaO-SiO2-Na2O ratio was bioactive with the 45S5 composition providing the best
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    2/36 results. Hench et al, “Life Chem Rep., 13: 187 (1996).
    [004] The work was also conducted in determining an optimal particle size. Initially, this was the focus on manual intraoperative improvement of wet glass during surgery. Low et al., (US Patent No. 4,851,046) examined the effect of the 45S5 bioactive glass particle size on intraoperative cohesion and glass manipulation. The test showed that a particle size 90-710 mm wide has the best intraoperative handling and, in vivo, bone formation in a primate periodontal defect.
    [005] Schepers and Ducheyne (US 5,204,106) also examined the particle size effects of bioactive glass 45S5. This was done to control the rate of disintegration and the rate of dissolution of the bioactive glass particles. It has been shown that the implantation of various particle sizes in the canine jaw bone has resulted in different biological responses to the glass. The results showed that the 280-425 pm size range provided the best response in bone formation at this skeletal site.
    [006] Despite the results from the study of the jaw bone observing the sub-optimal responses for smaller particles, this was attributed to the greater fluid flow and vascularity in the jaw. This led to a quick but resorption of the glass before sufficient bone growth could occur. The appendicular skeleton, however, has less vascularity and minimal fluid flow when compared to the mandible. After their original dental study, Scherpers and Ducheyne (US patent 5,658,332) observed that smaller particles (200-300 pm) of the bioactive glass implanted in the appendicular skeleton did not reabsorb at the rapid rate seen in the
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    3/36 jaw. They found that the smaller size range increased the rate of bone formation by providing a nucleus for bone tissue formation. The test conducted on a rabbit iliac crest defect showed that the 200-300 µm particle size supported bone growth on the surface of the particles (osteoconductor) and within the central area of the particles (excavation). In addition, in vivo testing of various glass compositions showed that 45S5 glass had the best bone formation.
    [007] Furthermore, Yang's work (US 6,228,386) addressed the cost related to the limited ranges of manufacture of bioactive glasses. Yang's work expanded the work of Schepers and Ducheyne from 200-300 um to 200-400 um in order to reduce the cost of making bioactive glass particles. This wide size range was tested on a rabbit iliac crest model in vivo and was compared against Schepers and Ducheyne in the 200-300 mm range and the original 90-710 μm range described by Low. Although the results are semi-quantitative and were based on 2 animals per group, the data showed that slightly wide bands 200-400 µm had the best performance.
    [008] The prior art showed that particle size had an effect on intraoperative handling, glass dissolution, function as a bone nucleation site, and manufacturing cost. After this initial work, it was discovered that a new characteristic of glass was the main contributor to the healing of bone by bioactive glass. In an Oonishi study, the 45S5 bioactive glass was directly compared to an amplitude using bone graft material (Hydroxyapatite) in a rabbit femur model in vivo
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    4/36 [Oonishi et al., Clin. Orthop. Rel. Res., 334: 316-325 (1997)]. The results showed that the bioactive glass resulted in a more robust and faster bone formation than hydroxyapatite. Oonishi hypothesized that bone formation increased with the 45S5 glass was attributed to the release of silica, calcium, and phosphorus ions that stimulated the colonization and proliferation of stem cells on the glass surface. This discovery was later confirmed by several studies that showed that ions released from bioactive glass increased bone formation through increased cell differentiation, proliferation and protein expression [Xynos et al., Biochem. Biophys Res. Commun., 276: 461-465 (2000); Bosetti et al. Biomaterials, 26: 3873-3879 (2005); Jell et al., J. Mater. Sci: Mater. Med., 17: 9971002 (2006)].
    [009] Despite the optimization data of the original bioactive glass evaluated the particle size of glass, all this work was based on the use of irregular glass particles and did not take into account recent data showing that the ion release has a significant impact about the ability of bioactive glass to provide bone healing. The irregularly shaped particles of the prior art were sieved for specific size bands and had a highly irregular and random shape, with rough and triangular edges. In addition, the insulation of the specific size bands has not been fully determined due to the oblong rice grain shape, which may or may not pass through the sieve during the separation process.
    [010] The prior art has also shown that bioactive glass which is very small can quickly dissolve and
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    5/36 lead to an explosive release of ions to the site that could have a detrimental effect on bone healing (US Patent 5,658,332). On the other hand, particles that are very large can release the ions very slowly, and the bioactive glass would not be beneficial from the short-lived ionic stimulation of local cells. In addition, the teachings of the prior art indicate that it is essential to use the irregular shape, rough-edged particles with micro-slits in order to achieve a beneficial bone healing response.
    [011] Further optimization of the shape and size of the bioactive glass particle to produce new materials is necessary to further improve the bone healing response.
    Summary [012] The invention is directed to compositions implantable in the mammalian body, comprising a physiologically acceptable vehicle and substantially spherical bioactive glass particles. Furthermore, within the scope of the invention are substantially spherical bioactive glass particles having a bimodal particle size distribution. Pre-reacted, mechanically stabilized particles are also within the scope of the invention. Substantially spherical particles of bioactive glass are also described.
    Brief description of the drawings [013] Figure 1 represents an electron scanning micrographic image of the prior art 45S5 particles (32-710 pm);
    [014] Figure 2 shows a comparison of a sphere
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    6/36 uniform with an equal radius (D1-D2) versus an irregular state of the art particle with an unequal radius (D1 / D2);
    [015] Figure 3 shows an electron scanning micrographic image of substantially spherical 45S5 particles of the invention;
    [016] Figure 4 shows an electron scanning micrographic image of a bimodal particle size range of an embodiment of the invention - substantially spherical 45S5 bioactive glass;
    [017] Figure 5 shows the package of three spheres resulting in a pore with a triangular shape;
    [018] Figure 6 shows the dense packaging of irregular particles of the prior art indicating areas of blocked porosity and low porosity:
    [019] Figure 7 shows the formation of a layer of HCA on the surface of a bioactive glass particle followed by the outer coating with a mechanical stabilization layer;
    [020] Figure 8A represents the release profile of silica ions for various ranges of spherical unimodal size (90-180 pm; 180-355 pm; and 355-500 pm of substantially spherical particles) showing the benefits of certain embodiments of invention;
    [021] Figure 8B represents the release profile of the silica ion from the substantially spherical groups having a bimodal particle size distribution (90-
    180 / 355-500 pm; and 180-355 pm / 355-500 pm) and the group in irregular particle (32-710 pm) prior art; [022] Figure 9 show at microCT images of 6th to 12 species weeks of the study of rabbit femur starting
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    7/36 of the substantially spherical 45S5 particles of the invention and the prior art irregular particle group. The particles of the invention showed increased bone formation at the center of the defect;
    [023] Figure 10 represents the histological results of 6 and 12 weeks from a study of rabbit femur using the bimodal 45S5 particles of the invention; and [024] Figure 11 represents the histomorphometric analysis resulting from a study of rabbit femur comparing the particles of the invention to the groups of irregular particles of the prior art.
    Detailed description of the illustrative embodiments [025] Contrary to the prior art description that irregular shaped bioactive glass particles are necessary for bone healing, it has now been inexplicably discovered that the use of substantially spherical bioactive glass particles, in particular, 45S5 glass particles, significantly improves the rate of bone formation, bone fusion and bone healing. It has also been found that the use of substantially spherical bioactive glass particles, having a particular unimodal or bimodal particle size range, further improves the rate of bone formation, bone fusion, and bone healing. Said materials, and their use in biomaterials, for example, bone repair implants, are described here.
    [026] The materials of the invention can be used as implantable bone grafts in all areas of the skeleton including the long bones, spine, cranio-maxillofacial, dental, and periodontal bone. As used here,
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    8/36 implantable refers to the physiologically acceptable materials that can be placed within a mammalian body. Said physiologically acceptable materials will be sterile, non-pyrogenic, and non-immunogenic. Mammals intended for treatment using the compositions and methods of the invention include humans and domesticated animals such as dogs, cats, and horses.
    [027] The present invention is directed to bone grafts made of a bioactive glass material, such as 45S5 bioactive glass, borate glass, or any other appropriate bioactive glass material. Exemplary materials can comprise combinations of SiO2 and CaO; SiO2; CaO, and P2O5; or SiO2; Dog; P2O5; and Na2O. These materials, as well as other material not including the combinations mentioned, are well known in the art.
    [028] The materials of the invention comprise bioactive glass particles of a specific shape and size that result in greater biological activity and better bone formation than before the irregularly shaped bioactive glass particles. The substantially spherical particles of bioactive glass, having the particle size distribution described herein for use in the invention can be prepared according to methods known in the art and can be made to order by manufacturers, such as Mo-Sci Corporation (Rolla, Missouri).
    [029] One aspect of the present invention is the use of bioactive glass particles that have a more uniform ion release profile. The bioactive glass particles used within the scope of the invention include particles that are substantially spherical. As used here,
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    Substantially spherical 9/36 refers to particles having a substantially circular or oval cross section and appears as round or rounded particles at the microscope level, for example, in an electron scanning microscopic image. Particles that are flattened spheroidal, that is, particles that are rotationally symmetrical ellipsoids with a polar geometric axis shorter than the diameter of the equatorial circle whose plane divides it into two, are also within the scope of the substantially spherical particles of the invention.
    [030] Whether the particles are substantially spherical can be determined using methods known in the art. After the manufacture of the particles, they are microscopically inspected when the qualitative assessment, whether the particles are substantially spherical. The substantially spherical bioactive glass particles of the invention are shaped in contrast to typical bioactive glass particles having an irregular shape and rough surface that is based on the breaking or crushing of the glass followed by fusion formation (Figure 1). Particles that have a rough surface, are oblong spheres with tails, are broken spherical fragments, or are particles that are fused together are not considered to be substantially spherical within the scope of protection of the invention.
    [031] The substantially spherical bioactive glass particles of the invention preferably incorporate a unimodal or bimodal particle size distribution. As used here, the bimodal particle size distribution refers to the materials of the invention, where most particle sizes are within the scope of
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    10/36 distribution of two particle sizes. A preferred embodiment of a bimodal distribution of the invention will comprise a minority of small particles and a majority of large particles. The compositions of the invention comprise a bimodal particle size distribution can include a minority of particle sizes outside the scope of protection in both the specified particle distribution in two sizes. Preferably, at least 60-99% of the particles, by weight, are within the two specified particle size distributions. More preferably, at least 80-90%, for example, 85%, of the particles, by weight, are within two specified particle size distributions.
    [032] Multimodal particle size distributions are also foreseen. In said multimodal distributions, a majority of particle sizes fall within the scope of protection of three or more particle size distributions.
    [033] In preferred embodiments, the materials of the invention will include substantially spherical particles of bioactive glass having a first particle size distribution between 32 and 200 pm and a second particle size distribution between 300 and 800 pm. Preferably, between 5% and 50% of the particles, more preferably about 10% of the particles by weight, will have a particle size within 32 to 200 pm, more preferably within a range of 90 to 180 pm.
    [034] Also preferred are embodiments having between 50% and 95% of the particles, more preferably, about 90% of the particles, by weight, the particle sizes within
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    11/36 a range of 300 and 800 pm, preferably 355 to 500 pm.
    [035] In particularly preferred embodiments, the materials of the invention will include substantially spherical particles of bioactive glass having a first particle size distribution between 90 and 180 pm and a second particle size distribution between 355 and 500 pm.
    [036] During this report, the term substantially spheroidal was used to define bioactive glass particles that are preferred for use in the invention when compared to particles that are not preferred. It should be understood that the substantially spherical defined term is a qualification and difficult to measure or determine by mechanical means. Consequently, the particles should be seen as being substantially spherical if they could be viewed via microscopy by a person skilled in the art because they are generally spherical in all three-dimensional form and have a predominantly smooth surface. It must be appreciated that few objects, both in nature and created by human hands, are truly, geometrically spherical. In addition, shape families that approach spherical geometry are considered to be spheres or substantially spherical. Thus, flattened spheroids, spheroids having one or more protuberances or protrusions, and spheroids that include one or more undulations or depressions can be seen to be totally spherical, being included in the set of substantially spherical particles.
    [037] Equally important, the total geometric shape is the smoothness of the particle's surface. In this sense, the particles preferred for use in the present invention are
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    12/36 distinguishable from those taught by the prior art for use in bioactive glass so that said earlier particles are at least predominantly rough and fractured, not smooth. Smoothness, again, is a qualitative property of the particles of the invention, whose property is determined by viewing under microscopy by a person skilled in the art. It will be understood that the prior art particles are rough or fractured, having multiple toothed angles or formations in them. On the contrary, the prior art is believed to have intentionally caused fracture and rough morphology in order to increase the surface area of the particle. The current particles in the set of substantially spherical particles of bioactive glass are not subjected to the forces which are also to result in said morphology, preferably, the smooth surface of the surfaces is desired.
    [038] Not all bioactive glass particles used in the practice of one or more embodiments of the present invention need to be substantially spherical. Within the scope of the invention, although higher percentages by the number of particles that are classified as substantially spherical are preferred, good results can be linked with the use of particles that are at least about 70% by the number of particles that are both within the ranges of preferred size and substantially spherical. Even more preferred, it is used for particles that are between 70% and about 90%, preferably about 80% or 85%, in number of particles that are both within the preferred size ranges and substantially spherical.
    [039] The bimodal particle size distribution of
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    13/36 substantially spherical bioactive glass particles can be created by mixing, for example, by mechanical means, two particle size distributions of the bioactive glass particles. The screening techniques known in the art can be used to separate the substantially spherical particles into different band sizes. Said techniques are more refined with the present invention because the particles have a more regular shape than those of the prior art. This allows bands of precise size to be isolated using the particles of the invention.
    [040] The screening process allows combinations of size ranges of two or more sizes to be created. Sifting is a technique well known in the art and these techniques are described in, for example, “NIST Recommended Practice guide, Special Publication 960-1 - Particle Size Characterization, January 2001. Using a combined size range, the release profile can be altered to provide optimum release from particles of various sizes. An example of a bimodal size strip containing two substantially spherical sizes is shown in figure 4. In this embodiment, a spherical mixture of bioactive glass is formed by combining a percentage, preferably a low percentage, of substantially spherical small particles of bioactive glass with a percentage, preferably a higher percentage, of larger, substantially spherical particles of bioactive glass.
    [041] In the materials of the invention, smaller particles provide an initial controlled release of ions to stimulate the healing process. Once the ion release to
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    14/36 Since these particles are moderated by the compositions described here, it can be controlled to prevent the harmful release of an excessive amount of bioactive glass ions. In addition, the presence of larger particles allows the particles to act as a support for continued bone formation. These particles have a slower dissolution and a rate of resorption and will be able to function as an osteoconductive surface during the healing process.
    [042] The bioactive glass particles of the invention use the shape having the greatest reproductive ion release and an optimal three-dimensional package. In examining various geometric shapes, the spherical shape was chosen due to the generally consistent distance from the center of the edge particle, the roundness, the generally uniform surface, and the ability to form a completely interconnected porosity due to its three-dimensional package (Figure 2). A substantially spherical bioactive glass particle provides a more consistent particle geometry and a controllable ion release profile.
    [043] An examination of substantially spherical 45S5 bioactive glass particles is shown in Figure 3. When implanted in vivo, exposure of the bioactive glass to body fluid initiates a dissolution process that releases ions out of the glass. Since the dissolution process is dependent on the shape of the particle, the use of a uniform spherical particle provides controlled ion release. By changing the particle size, the resulting ion release profile can also be changed. The dissolution test demonstrated that smaller particles provide rapid release
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    15/36 while larger particles provide slower release.
    [044] Another advantage of using spherical particles is that the package of particles in three-dimensional spaces is more conductive for growth (in-growth) in the bone than the porosity created from the package of irregular particles. The package of substantially spherical particles results in a porosity completely interconnected with open pores and without pore obstruction. Control of pore size is achieved by using particles of a specific diameter (larger spheres create larger pores).
    [045] Bone growth (ingrowth) within porous structures has previously been shown to be dependent on pore size [Hollis et al., Encyclopedic Handbook of Biomaterials and Bioengineering Mouth Rat: CRC Press pp. 806807 (1995)]. Pores that are too small will not allow bone growth (in-growth) within the porous structure while pores that are too large will slow down the bone formation process. An advantage for the sphere package is that the pore size can be controlled by the particle size. In addition, the rounded surface of the substantially spherical particles prevents the formation of porosity or an arrangement that results in very small pores for bone growth. In the sphere package, the smallest pores that can be created occur from the package of three particles together (Figure 5). By using a larger sphere, pores that are too small for bone growth can be avoided. As a result, the substantially spherical particles of the present invention can create a pore system that is
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    16/36 completely interconnected and allows bone growth in all porosity.
    [046] On the other hand, irregularly shaped particles can pack into dense arrangements with a% lower porosity, smaller pores, and blocked pore areas (blocked off). In particular, the flat surface and the smaller aspect ratio of the irregular particles allow the package to create areas of little to no porosity (as shown in Figure 6). This type of dense package would reduce the amount of bone that could form between the particles and within the implant site.
    [047] Furthermore, within the scope of the invention are methods to improve the bioactivity of the bioactive glass particles. This aspect of the invention can be applied to all forms of bioactive glass including, irregularly shaped particles, regular shaped particles, spherical particles, fibers, and porous supports. In this embodiment of the invention, the bioactive glass is incubated in an ionic solution such as simulated body fluid (SBF) during the manufacturing process to initiate the formation of a layer of hydroxycarbon-apatite (HCA) on the glass surface. When implanted in vivo, the presence of the HCA layer will provide a better surface for the attachment and formation of new bone. In addition, if the HCA layer is already present during the implantation period, the healing response would be accelerated by eliminating the time required to form the layer in vivo. This would allow for faster bone formation immediately after implantation.
    [048] Although a preformed HCA layer would be advantageous for bone healing, the layer formed using a process
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    17/36 in vitro is sensitive and easily detachable from the surface of the bioactive glass. Normal handling during manufacture and distribution would remove the pre-reacted HCA surface layer and the glass would lose this beneficial coating. To get around this issue, the HCA layer on the bioactive glass can be mechanically stabilized by adding an external coating (Figure 7). This outer coating can include water-soluble, bioresorbable materials such as hyaluronic acid, gelatin, alginate, chitosan, or other hydrogels, as well as mixtures thereof. In these embodiments, the bioactive glass is incubated in an ionic solution, such as SBF and the HCA layer is allowed to form. Once the surface is substantially coated with HCA, the bioactive glass can be immersed in a separate external coating solution that is allowed to dry on the glass surface. After this process, the outer coating will tend to stabilize the HCA layer, reduce its fragility, and prevent it from becoming detachable during normal handling and processing. When the particles of bioactive glass, coated with mechanically stabilized HCA are placed in a bone defect, the outer coating will dissolve and expose the HCA layer to the surrounding fluid and cells and allow bone healing to begin.
    [049] Furthermore, within the scope of the invention is the use of the substantially spherical particles of bioactive glass of the invention in bone grafting or cement materials. An exemplary embodiment of the present invention is a composition that is a fixed bone graft that comprises the substantially spherical bioactive glass particles of the
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    18/36 invention in combination with a physiologically acceptable vehicle to form bone graft fixation. As used here, a dough that is a composition having a soft, moldable, paste-like consistency. The bone graft mass can be made by mixing the bioactive glass particles of the invention into a moldable paste composition to create a mass.
    [050] Once the ion release is activated by an aqueous medium, aqueous based vehicles can be used. Preferably, the physiologically acceptable vehicles used here are non-aqueous compounds and are non-pyogenic, non-immunogenic, sterilizable, and have a very short reabsorption profile. Preferably, the vehicles used in the bone grafts of the invention will tend to dissolve in about 3-7 days both in vitro and in vitro.
    [051] Preferred vehicles for use in the masses of the invention include one or more phospholipid compounds, polyethers, or polyhydroxy. Preferably, the vehicles are a mixture of two or more components.
    [052] An advantage of a two- or multiple-component vehicle is that it allows the properties of the vehicles to be optimized for bone graft application. For example, wax-based polymers or phospholipids may not be appropriate on their own to create a moldable vehicle. By mixing them with a liquid that functions as a softening agent, however, a moldable vehicle can be created. In addition, the change in the concentration of the softener vehicle allows a variety of vehicle mass to be created. This includes a mass of
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    19/36 paste type to adhere to other bone graft material and to the implant site, an extrudable mass that can be released by a syringe or cannula, and a firm mass to be used as a bone graft alone (stand-alone).
    [053] Preferred vehicles for use in the dough of the invention include mixing phospholipids, for example, phosphatidylcholine, with triglycerides, monoglycerides, fatty acids, or combinations thereof. Such materials are known in the art per se, and are commercially available to suppliers such as Lipoid GmbH (Ludwigshafen, Germany) and American lecithin Company (Oxford, CT).
    [054] In an exemplary mass embodiment of the invention, the vehicle will comprise a mixture of a substantially pure solid form of phosphatidylcholine, for example, Phospholipon 90g (Lipoid GMbH) and a solubilized liquid form of phosphatidylcholine, for example, PHsal 53 MCT (Lipoid GmbH) to create a mixed moldable vehicle. The mixture contains 10% to 50%, preferably about 20% to about 40%, of the phosphatidylcholine solid form, by weight of the mixture, and 50% to 90%, preferably about 60% to about 80%, liquid phosphatidylcholine, by weight of the mixture. More preferably, the mixture contains about 35% of the solid phosphatidylcholine form, based on the weight of the mixture, and about 65% of the liquid phosphatidylcholine form, by weight of the mixture.
    [055] It may be desired, in certain uses of the dough of the invention, where the dough is soft and extrudable. The soft form can be used in minimally invasive surgery (MIS) and directly injected into the implant site. At
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    20/36 soft forms of the masses of the invention can be created by, for example, increasing the amount of the liquid form of the
    phosphatidylcholine gift at mixture. These mixtures may include fence in 25% of form solid of phosphatidylcholine, by weight gives mixing and about 75% the form
    phosphatidylcholine, by weight of the mixture.
    [056] The bioactive mass of the invention can then be formed by incorporating 60% to 90%, preferably 70% to 80%, of the substantially spherical bioactive glass particle of the invention, by weight of the mass composition, and 10% to 40%, preferably 15% to 35% or 15% to 25%, of the carrier mixture, by weight of the dough composition. Preferably, the mass composition contains about 80% of the bioactive glass particles, substantially spherical by weight of the mass composition, and about 20% of the carrier mixture, by weight of the mass composition. Another preferred embodiment includes mass compositions containing about 75% of the substantially active bioactive glass particles by weight of the mass composition, and about 25% of the carrier mixture, by weight of the mass composition.
    [057] The mass of the invention may include a unimodal, bimodal, or multimodal particle size distribution of the substantially spherical bioactive glass particles.
    [058] The dough compositions of the invention have excellent handling properties and are not affected by sterilization. They are moldable and retain their shape without adhering to surgical gloves. The vehicle mixtures used in the dough compositions have a short reabsorption period, do not interfere with bone growth, and are resistant to irrigation.
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    21/36 [059] Hard versions of the dough compositions of the invention can be made to create flexible dough strips. Said strips can be used, for example, in vertebral fusions. This is accompanied by an increase in the amount of the solid, substantially pure form of phosphatidylcholine in the vehicle mixture. Said vehicle mixtures can include 50% to 80%, preferably about 60% to about 70%, of the phosphatidylcholine solid form, by weight of the vehicle mixture, and 20% to 50%, preferably about 30% about 40% of the liquid form of phosphatidylcholine, by weight of the vehicle mixture. For example, flexible dough strips can be prepared using a mixture comprising about 60% of the solid phosphatidylcholine form, by weight of the mixture, and about 40% of the liquid phosphatidylcholine form, by weight of the mixture.
    [060] Said dough strips may include 60% to 90%, preferably 70% to 80% of the substantially spherical bioactive particles of the invention, by weight of the dough strip, and 10% to 40%, preferably 15% to 35% or 15% to 25%, or 20% to 30% of the vehicle mixture, by weight of the dough strip. Preferably, the dough strip contains about 80% of the substantially spherical bioactive glass particles, by weight of the dough strip, and about 20% of the carrier mixture, by weight of the dough strip. Another preferred embodiment includes strips of dough containing about 75% of the substantially spherical particles of bioactive glass, by weight of the dough strip, and about 25% of the vehicle mixture, by weight of the dough strip.
    [061] The dough strips of the invention can include a unimodal, bimodal, or
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    22/36 multimodal of substantially spherical particles of bioactive glass.
    [062] The pasta compositions and pasta strips of the invention can also be formed using the mechanically stabilized HCA coated bioactive glass particles described here.
    [063] In another embodiment of the invention, the vehicle may comprise resorbable or non-resorbable materials that are mixed in the period of surgery and harden into a rigid bone cement material. This includes, but is not limited to, resorbable cements including calcium sulfate, calcium phosphate, calcium carbonate, and non-resorbable cements such as methacrylate cements and glass ionomer cements. In this embodiment, the substantially spherical bioactive glass particles of the invention are pre-mixed with dry cement materials. During surgery, a cement consolidation solution is mixed into the dry material and the implant changes from a paste to a mass that eventually hardens into a rigid form. These bioactive cements can be used for surgical indications such as fracture repair, bone void filling, fusion, vertebroplasty, chifoplasty, bone reconstruction repair, and joint replacement.
    [064] In one example, the substantially spherical bioactive glass particles of the invention are mixed with an absorbable cement such as calcium sulfate hemihydrate, for example. The bioactive glass hemihydrate / calcium sulfate mixture is then mixed with sterile saline during surgery. As the sulfate hemihydrate of
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    23/36 calcium reacts with water to form calcium sulfate dihydrate, the cement thickens into a mass. The cement mass is then placed in the bone defect where it eventually hardens. The rigid implant resulting from calcium sulfate dihydrate and embedded in bioactive glass spheres provides mechanical stability for the bone graft site. Once implanted, the implant absorbs the body's fluid and the dissolution of the bioactive glass begins. In addition, calcium sulfate dihydrate also begins to reabsorb and slowly expose the bioactive glass spheres to the surface
    implant. During the process in resorption, the implant is substituted per one new bone. O use of bioactive glass substantially spherical in one resorbable cement is
    advantageous since the bioactive glass can diffuse out of the cement to stimulate healing on the implant surface.
    [065] In an exemplary embodiment of the invention cement, the bioactive cement will comprise a mixture of calcium sulfate hemihydrate (Sigma Aldrich, St. Louis, MO) and substantially spherical bioactive glass particles of the invention. The mixture contains 20% to 90%, preferably about 50% to about 80%, of calcium sulfate hemihydrate, by weight of the mixture and, 10 to 80%, preferably about 20% to about 50% of the substantially spherical bioactive glass particles by weight of the mixture. More preferably, the mixture contains about 70% calcium sulfate hemihydrate, based on the weight of the mixture and about 30% of the substantially spherical bioactive glass, by weight of the mixture.
    [066] The calcium sulphate / glass hemihydrate mixture
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    Bioactive 24/36 will be provided in a kit form with a separate container for the fixation solution. During the surgery, the fixation solution will be combined with the mixture of dry calcium sulfate hemihydrate / bioactive glass. The kit contains 1 cc of the fixing solution for each 2g to 6g, preferably 3g to 4g, of the dry cement material. Most preferably, the mixture contains 1 cc of the fixing solution per 3.5 g of dry cement. Fixation solutions are known in the art and can be selected from water, saline, or hydrogel solutions, such as gelatin, alginate, chitosan, hyaluronic acid.
    [067] Another exemplary embodiment of the present invention comprises compositions including the substantially spherical bioactive glass particles of the invention and a carrier which is a porous resorbable material. Porous materials, as used here, are materials with an interconnected pore system that connects the outer surface of the material to the interior. Said porous materials allow the growth of bone tissue in the structure. Resorbable materials are those that can be broken down and assimilated or excreted from the mammal's body. The resorbable materials used to create the porous bone grafts are known in the art and include, for example, type I collagen, chitosan, alginate, gelatin, hyaluronic acid, and resorbable polymers and copolymers such as poly (hydroxy acids) or a combination of themselves.
    [068] The particles of bioactive glass, substantially spherical can be incorporated into the proo, resorbable material to form a slide using methods known in the art. In those methods employing type I collagen,
    Petition 870190061131, of 7/1/2019, p. 33/59
    25/36 as the vehicle, standard collagen processing methods can be used to form the slides. For example, an acid wort of type I collagen fibers and bioactive glass particles of the invention can be melted into a slide form, neutralized, and freeze dried to remove all water and create a composition having an interconnected porosity. The resulting slide can be cross-linked using standard collagen cross-linking methods, such as dehydrothermal cross-linking. The slides of the invention will contain bioactive glass particles embedded in the invention in a porous collagen network. In addition to collagen, other porous materials can be used to create the blades, for example, and polymers or glass fibers, foams, or meshes.
    [069] In one embodiment, a blade of the invention will comprise 50-90% of the substantially spherical particles of bioactive glass of the invention, based on the weight of the blade, and 10% to 50% of the porous resorbable material, based on the weight of the blade. In other embodiments, the blades contain 80-90% of the substantially spherical bioactive glass particles of the invention, based on the weight of the blade, and 10% to 20% or the porous resorbable material, based on the weight of the blade. The slides of the invention can be manufactured with a range in density including those from 0.2 g / cc to 0.5 g / cc.
    [070] The slides of the invention can also be formed using the mechanically stabilized HCA coated bioactive glass particles described herein.
    [071] Another embodiment of the present invention includes porous shaped structures comprising substantially spherical particles of sintered bioactive glass. In
    Petition 870190061131, of 7/1/2019, p. 34/59
    In said embodiments, porous sintered bioactive glass implants can be created by losing leakage of substantially spherical particles in a mold and heating the mold to the sintering point of the bioactive glass. The unimodal, bimodal, and multimodal particle size distributions can be used within this embodiment of the invention.
    [072] In these embodiments, once the glass is sintered and not molten, the heating will thermally connect the spheres together at their points of contact without inducing the structure to collapse. The resulting structure will have an interconnected porosity that is created by the 3-D package of the joined spheres. This method can be used to create a variety of porous shapes including, tampons, locks, chocks, rings, etc. These shapes can be used for feet and ankle fusion, facet fusion, intercorphon fusion, joint reconstruction, repair fracture, osteotomy, and other surgical procedures. In addition, the sintered implant can also be immersed in simulated body fluid to result in the formation of an HCA layer. Since the internal porosity is protected from the external surface, the coating may or may not need to be stabilized with an external coating, for example, gelatin or hyaluronic acid.
    EXAMPLE 1:
    [073] The mass compositions comprising 45S5 bioactive glass particles of the invention were prepared according to Table I and compared against a commercially available 45S5 bioactive glass mass having irregularly shaped particles.
    Petition 870190061131, of 7/1/2019, p. 35/59
    27/36
    Petition 870190061131, of 7/1/2019, p. 36/59
    28/36
    Table 1
    Group Particle size range Vehicle 1 90-180 pm Phospholipon 90G and PHosal 53 MCTPhospholipon 90G and PHosal 53 MCT 2 180-355 pm Phospholipon 90G and PHosal 53 MCT 3 355-500 pm Phospholipon 90G and PHosal 53 MCT 4 10% from 90-180 pm Phospholipon 90G and PHosal 53 MCT90% of 355-500 pm5 50% from 180-355 pm Phospholipon 90G and PHosal 53 MCT50% of 355-500 pm6 32-710 pm Polyethylene glycol and glycerol
    [074] In each group, the vehicle was removed from the masses to isolate the particles. The isolated particles were incubated in an SBF dissolution fluid at 37 ° c. The concentration and silica ion in the dissolution fluid were measured by inductively associated plasma optical emission spectroscopy.
    [075] The results of the dissolution study are shown in figures 8A and 8B. The silica release profile for the unimodal sphere sizes used in the study (90-180 pm; 180-355 pm; and 355-500 pm) are shown in figure 8A. The data show that the rate of silica release (and the resulting 45S5 dissolution) was dependent on the particle size. The 90-180 pm group demonstrated the fastest release, followed by the 180-355 pm group; and the 355-500 pm group.
    [076] The inclusion of the silica release profile from the bimodal spherical groups (spheres of 90-180 / 355-500 pm; and spheres of 180-355 pm / 355-500 pm) and the irregular particle group of 32 -710 pm from the prior art is shown in figure 8B. The data show that using a bimodal size distribution allowed the rate of
    Petition 870190061131, of 7/1/2019, p. 37/59
    29/36 release was controlled. In bimodal spherical groups, the addition of substantially spherical particles of 90-180 pm and 180-355 pm for substantially spherical particles of 355-500 pm increased the deliberate rate of particle silica from 355-500 pm alone. Both, the bimodal spherical groups had a release profile between the 180-355 pm group and the 355-500 pm spherical group.
    [077] The data also showed that the particle shape has a significant effect on dissolution as seen by the release profile of the 327190 pm irregular particle group in Figure 8B. Although this group has larger particles than the larger substantially spherical group (355-600 pm), the irregular particle group of 32-710 pm has a rapid release rate that was comparable to the substantially smaller spherical group (90-180 pm). Although I do not wish to be linked to any particular theory, this effect can be attributed to the rapid dissolution of the small irregular particles and the dissolution of the rough edges on the larger irregular particles.
    [078] EXAMPLE 2:
    [079] The sterile masses were manufactured with 90-180 pm and 355-500 pm from the substantially spherical glass particles of 45S5 bioactive glass, Fosfolipon 90G, and Phosal 53 MCT, and were tested to determine the properties of the mass. Vehicle dissolution was determined by incubating the mass in saline at 37 ° C for 7 days and measuring vehicle weight loss. In addition, mass handling and irrigation resistance were measured after exposure to extreme hot and cold temperatures for 2 weeks (60 ° C and -2 ° C). The data was compared to an ambient temperature
    Petition 870190061131, of 7/1/2019, p. 38/59
    30/36 control. This was done for extreme imitable conditions that can be encountered during product distribution.
    [080] The results of the vehicle dissolution study showed that the vehicle was effectively removed through an aqueous dissolution process. This was represented by a linear decrease in weight during the study. With a total dissolution time of ~ 5 days, the vehicle will be quickly removed from the site and will not interfere with the bone healing process.
    [081] The temperature study showed that the handling of the masses exposed to various storage conditions was identical and there were no differences in moldability, cohesion, or viscosity. All masses were easily moldable,
    keeping your shapes, and no crumble or adhere to gloves surgical. In the study gives irrigation, the masses were completely submerged in salt pans and the dissolution was
    qualitatively assessed for 60 minutes. During the course of the study, the mass showed negligent dissolution and remained completely intact with no particles within the mass specimen. This was seen by all three storage conditions. The mass's ability to resist initial dissolution from irrigation is a beneficial property of the vehicle to minimize graft migration due to excessive irrigation. Based on the observations, the consistency of the mass and the resistance to irrigation will assist the surgeon in locating the bioactive particles and will allow the graft to remain in place.
    EXAMPLE 3:
    [082] Masses containing bioactive glass (5 implants per group) were placed in a critical size defect of
    Petition 870190061131, of 7/1/2019, p. 39/59
    31/36
    6x10mm in the distal femur of New Zealand white rabbits. At 6 and 12 weeks, the femurs were harvested, and visualized using an x-ray and microcomputer tomography (micro-CT) images. The femur was then soaked in polymethylmethacrylate and serial sections were taken. The histological sections were stained with methylene blue and fuchsin to visualize the implant and the bone. The histological slides were qualitatively evaluated to examine the response of the local tissue to the implant and the bioactivity of the bioactive glass particles. Histomorphometric analysis was conducted to quantify the amount of bone in each group. Using image analysis software to identify and quantify the amount of bone at the defect site, bone formation values for each group were calculated. [083] The results showed that the masses using the substantially spherical bioactive glass particles of the invention had better healing and showed a considerable improvement in bone formation, when compared to irregular 45S5 particles. A representative image of 6 and 12 weeks of micro-CT for each of the groups is shown in Figure 9. At 6 weeks, images of the 32-710 pm irregular particle size group showed bone growth from the periphery the defect towards the center. At the edge of the defect, the bone was seen growing on the surface of the particles in a space between the particles. Bone healing does not extend through the entire defect, however, and a void filled with the intact bioactive glass granules was seen at the center of the defect. By comparison, the 6-week images of the substantially spherical particles of the invention showed
    Petition 870190061131, of 7/1/2019, p. 40/59
    32/36 substantially more bone growth at the defect site. The best bone formation was seen in the 180-355 pm group, the 355-500 pm group, and bimodal groups. These groups showed extensive bone formation across the implant area with the entire defect filled with bone. The 90-180 pm size range of the invention, however, had no bone at all in the defect. Although there is more bone than the 32-710 pm irregular particle group there is still a small void in the center of the defect.
    [084] For 12 weeks, micro-CT results showed continued bone formation within the defect in all groups. The 32-710 pm irregular particle group showed spots through the outer cortex, however, there are still some particles without bone growth present in the center of the defect. The 90-180 pm group showed filling in the internal defect with a small interval close to the external cortex. Similar to the 6-week results, the 180-355 pm group, the 355-500 pm group, and two bimodal groups showed more bone formation with bone extension through the entire defect.
    [085] Histological analysis of the species showed that all groups supported by bone growth on the surface and within the bioactive glass particles. Additionally, histology showed that all groups were bioactive with the formation and an HCA layer on the surface of the particle. Qualitatively, the histological analysis combined the micro-CT data with more bone seen in the 180 pm -355 pm group, the 355 pm - 500 pm group, and the two bimodal groups, when compared to the 32-710 pm and irregular particle group. o 90-180 pm of the substantially spherical group.
    Petition 870190061131, of 7/1/2019, p. 41/59
    33/36 [086] A representative example of histology is shown in figure 10. This image shows the bone growth on the surface of the spheres from the 90-180 / 355-500 pm group at 6 and 12 weeks. As seen from the images, the vascularized bone is visible completely around the substantially spherical particles. In addition, the characteristic HCA region is shown as a white layer on the outer surface of the particles. In 12 weeks, bone formation increased and the thickness of the HCA layer was increased with some of the smaller particles showing the entire conversion.
    [087] Using the histological image, the amount of bone within the defect in each group was quantified using histomorphometry. The results of the histomorphometric analysis combined with the qualitative observations from the micro-CT and histological analysis, and are shown in figure 11. The data showed that the 180-355 pm, 355-500 pm group, and bimodal groups resulted in an increase substantial for the average amount of% bone found at the site at both 6 weeks and 12 weeks. The only training data was used to calculate the change in bone formation compared to the 32-710 pm irregular particle group. A summary of the data on the increase in bone formation is shown in Table II.
    Table II
    Spherical particle group Particle distribution type Increase in6 weeks (decrease) of increase in 12 weeks 90-180 pm Unimodal 41% -16% 180-344 pm Unimodal 84% 5% 355-500 pm Unimodal 45% 27% 90-180 / 355-500 pm Bimodal 66% 29% 180-355 / 355-500 pm bimodal 31% 10%
    Petition 870190061131, of 7/1/2019, p. 42/59
    34/36 [088] The data showed that all substantially spherical groups (with the exception of 90-189 pm) showed increased bone formation at both time points. It was evident from the results that the shape of the bioactive glass particle improved resulting in faster and more robust bone healing during the study. The data also demonstrated that the healing response was also dependent on the particle size. The comparison within the substantially spherical groups showed that the bimodal group with 10% of the substantially spherical particles of 90-180 pm and 90% of substantially spherical particles of 355-500 pm had the best results combined in 6 and 12 weeks.
    [089] Conversely, the 90-180 pm group had the least bone formation response within the substantially spherical particle groups. This group had an ion release profile (from example 1) similar to the group of
    irregular particle in 32-710 pm, 90-180 pm. In total, the data showed that O control over release in ion through the shape and of size of particle can Tue an
    improvement on bone healing. Contrary to the state of the art, this effect was not dependent on the irregular shape of the particle with a rough, but very smooth surface, the substantially spherical particle providing an optimal porosity and ion release profile.
    EXAMPLE 4:
    [090] The substantially spherical 45S5 particles of the invention, or irregularly shaped particles known in the art, can be pretreated with simulated body fluid to form an HCA coating on the surface. The fluid
    Petition 870190061131, of 7/1/2019, p. 43/59
    35/36 simulated body (SBF) is an artificial solution containing ions similar to human extracellular fluid. SBF solutions are well known to those skilled in the art and can have a variety of different compositions. In one embodiment, the bioactive glass is incubated at 37 ° C in the solution described by Kukubo [Kokubo et al., “J. Biomed. Mater. Res., 24: 721-734 (1990)] for 7 days. After the formation of the HCA layer, the glass is gently removed from the SBF solution and washed.
    [091] The resulting HCA-coated particles can then be coated by immersion using, for example, a 3% hyaluronic acid solution. Gelatin can also be used as an external coating. The externally coated bioactive glass is then allowed to dry to create a mechanically stabilized pre-coated bioactive glass form.
    [092] Despite the exemplary embodiments described above, several other modifications and additions will be apparent to those skilled in the art.
    References
    - U.S. 4,851,046;
    - U.S. 5,204, 106;
    - U.S. 5,658,332;
    - U.S. 6,228,386;
    - Hench et al. Bonding mechanism at the Interface of Ceramic Prosthetic materials. J. Biomed. Mater. Res. Symp. 117-
    141 (1971);
    - Oonishi et al. Particulate 45 S5 compared with hydroxyapatite as a bone graft substitute. Clin. Orthop. Rel. Res. 334: 316-325 (1997);
    - Xynos et al. lonic products of bioactive glass dissolution
    Petition 870190061131, of 7/1/2019, p. 44/59
    36/36 increase proliferation of human osteoblasts and induce insulin-like growth factor II mRNA expression and protein synthesis. Biochem. Biophys. Commun. 276: 461-465 (2000);
    - Bosetti et al. The effect of bioactive glasses on bone marrow stromal cell differentiation. Biomaterials 26: 38733879 (2005);
    - Jell et al. Gene activation by bioactive glasses. J. Mater. Sci: Mater. Med. 17: 997-1002 (2006);
    - Hollis et al. Factors affecting bone in-growth. In Wise et al. Encyclopedic Handbook of Biomaterials and Bioengineering Vol 1. Boca Raton: CRC Press. Pp. 806-807 (1995);
    - Kokubo et al. Solutions able to reproduce in vivo surfacestructure changes in bioactive glass- ceramic A-W. J. Biomed. Mater. Res. 24: 721-734 (1990).
    权利要求:
    Claims (14)
    [1]
    1. Implantable composition in a mammalian body, characterized by the fact that it comprises a physiologically acceptable vehicle and a substantially spherical bioactive glass particle having a circular or oval cross section, with the bioactive glass particle package forming a completely interconnected porosity, being that the vehicle is a mixture of at least two phospholipids comprising a solid form of phosphatidylcholine and a liquid form of phosphatidylcholine, or the vehicle is a porous resorbent material; and with the spherical bioactive glass particles having at least one particle size distribution selected from the group consisting of:
    a) a distribution in size in particle unimodal; being that distribution in size in particle unimodal includes particles between 180 and 500 One; preferably, being that size distribution of unimodal particle includes particles between 180 a and 355 One or particles between 355 um and 500 One; andb) a distribution in size in particle bimodal; being that distribution in size in particle bimodal includes
    particles between 32 and 200 μm and particles between 300 and 800 μm; preferably, the bimodal distribution includes particles including sizes between 90 µm and 180 µm and particles between 355 µm and 500 µm.
    [2]
    2. Composition according to claim 1, characterized in that the vehicle is a mixture of at least two phospholipids comprising a solid form of phosphatidylcholine and a liquid form of phosphatidylcholine and the composition comprising 60% -90% of the particles
    Petition 870190061131, of 7/1/2019, p. 46/59
    2/5 substantially spherical bioactive glass, by weight of the composition, preferably 70% -80% of the substantially spherical bioactive glass particles, by weight of the composition; or the vehicle being a porous reabsorbent material and the composition comprises 50% -90% of the substantially spherical bioactive glass particles, by weight of the composition, preferably 80% -90% of the substantially spherical bioactive glass particles, in weight of the composition.
    [3]
    3. Composition according to any of the claims
    1 or 2, characterized by the fact that the porous reabsorbent material comprises collagen, hyaluronic acid or a combination thereof.
    [4]
    4. Composition according to any of the claims
    1 or 2, characterized in that the vehicle is a mixture of at least two non-aqueous compounds, preferably the compounds are phospholipids, polyhydroxy compounds, polyethers, or a mixture thereof, more preferably, the mixture comprises a solid form of phosphatidylcholine and a liquid form of phosphatidylcholine; and the composition preferably comprising 60% -90% of the substantially spherical bioactive glass particles, by weight of the composition, more preferably, 70% -80% of the substantially spherical bioactive glass particles, by weight of the composition.
    [5]
    5. Composition according to any of the claims
    1 or 2, characterized by the fact that the vehicle is a porous resorbent material; preferably, the porous resorbent material being a physiologically acceptable polymer, a physiologically acceptable hydrogel, collagen,
    Petition 870190061131, of 7/1/2019, p. 47/59
    3/5 preferably type I collagen, or hyaluronic acid; and the composition preferably comprising 50% -90% of substantially spherical bioactive glass particles, by weight of the composition, more preferably 80% -90% of the substantially spherical bioactive glass particles, by weight of the composition.
    [6]
    6. Composition according to any of the claims
    1 or 2, characterized by the fact that the vehicle is a reabsorbent or non-reabsorbent cement, preferably with the cement comprising methacrylate, glass ionomer, or a mixture thereof.
    [7]
    7. Composition according to any one of claims 1 to 3, and 4 to 6, characterized in that the bioactive glass is 45S5 glass and / or the bioactive glass particles are coated or partially coated with a layer of hydroxy-carbane-apatite; preferably, the hydroxy-carbane-apatite layer is further coated or partially coated with an outer coating which preferably comprises gelatin, alginate, chitosan, hyaluronic acid, or other hydrogels, as well as mixtures thereof.
    [8]
    8. Composition according to any one of claims 1 to 3, and 4 to 7, characterized in that it further comprises 10% to 30% by weight of the composition, of substantially non-spherical bioactive glass particles.
    [9]
    9. Composition according to any one of claims 1 to 3, and 4 to 8, characterized by the fact that it has the characteristic of a bone graft mass, a bone graft paste, a bone graft cement, a gel, or a flexible blade.
    Petition 870190061131, of 7/1/2019, p. 48/59
    4/5
    [10]
    10. Porous formed structure, characterized by the fact that it comprises substantially spherical sintered bioactive glass particles having a circular or oval cross section, the bioactive glass particle package forming a completely interconnected porosity, and the bioactive glass is preferably , the 45S5 glass.
    [11]
    11. Substantially spherical bioactive glass particle, characterized by the fact that it has a circular or oval cross section, the bioactive glass particle package forming a completely interconnected porosity, and a bimodal particle size distribution including particles between 33 pm and 200 pm and particles between 300 pm and 800 pm, 10% to 50% of the particles by weight, are in the range between 32 pm and 200 pm; and preferably, the bioactive glass is 45S5 glass.
    [12]
    Particle, according to claim 11, characterized in that the bimodal particle size distribution includes particles between 90 pm and 180 pm and particles between 355 pm and 500 pm, preferably, the particle size distribution includes particles between 90 pm and 180 pm and particles between 350 pm and 500 pm, and / or 10% of the particles by weight are between 90 pm and 180 pm.
    [13]
    13. Particle according to any one of claims 10 to 12, characterized in that the bioactive glass particles are coated or partially coated with a layer of hydroxy-carbane-apatite, preferably with the layer of hydroxy-carbane -apatite is additionally coated or partially coated with an outer coating which preferably comprises gelatin,
    Petition 870190061131, of 7/1/2019, p. 49/59
    5/5 alginate, chitosan, hyaluronic acid, or other hydrogels, as well as mixtures thereof.
    [14]
    14. Structure formed porous to repair or heal bone, characterized by the fact that it comprises the composition as defined in any one of claims 1 to 3, 4 to 10.
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    法律状态:
    2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-04-02| B07A| Technical examination (opinion): publication of technical examination (opinion) [chapter 7.1 patent gazette]|
    2019-08-20| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2019-10-15| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 24/10/2012, OBSERVADAS AS CONDICOES LEGAIS. (CO) 20 (VINTE) ANOS CONTADOS A PARTIR DE 24/10/2012, OBSERVADAS AS CONDICOES LEGAIS |
    2020-02-11| B16C| Correction of notification of the grant|Free format text: REF. RPI 2545 DE 15/10/2019 QUANTO A PRIORIDADE UNIONISTA. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201161550706P| true| 2011-10-24|2011-10-24|
    US61/550,706|2011-10-24|
    PCT/US2012/061574|WO2013063033A1|2011-10-24|2012-10-24|Compositions and their use in bone healing|
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