Composition of substantially spherical granule for bone regeneration

Abstract

To provide a composition for bone regeneration.SOLUTION: A composition for bone regeneration includes substantially spherical granules. Each of the spherical granules include an outer shell including magnesium phosphate and nano-sized silica, and a bioactive core encapsulated by the outer shell. The granules include macro-pores and micro-pores. The macro-pores are intergranular spaces between adjacent granules, and the micro-pores are intragranular nanopores formed on the outer shell of each of the granules. A method of producing the substantially spherical granules includes providing a mixture of a biological active powder, magnesium phosphate, and an initiator with a colloidal silica solution; rotating the mixture with dual asymmetric centrifugation for a predetermined amount of time; and drying the resulting material.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Application No. 63 / 212,917, filed June 21, 2021. The entire disclosures of the above applications are incorporated herein by reference.

[0002] [Field] The present technology relates to compositions for bone regeneration, and in particular to compositions containing spherical granules for bone regeneration. The present invention relates to a composition comprising: [Background technology]

[0003] [Introduction] This section provides background information that is not necessarily prior art related to the present disclosure.

[0004] Synthetic bone graft substitutes are bone graft materials that consist solely of materials synthesized through chemical reactions. These grafts include cells, tissues, proteins, or tissues derived from humans or animals. This does not include calcium phosphates, which are used in synthetic bone graft products. This is the main type of material used.

[0005] Osteoinductive synthetic bone graft materials have fibroblasts or mesenchymal stem cells attached to their surface, followed by The cells must be able to grow, differentiate and perform other cellular activities. Where cells reside, bone formation occurs. Therefore, the physical characteristics of synthetic bone grafts are It must be properly designed so that it can remain in the desired location.

[0006] Generally, there are two different designs of synthetic bone graft surfaces, which have two different bone formation properties. The first design is a pore-free, limited strength bone graft. The mass is usually subjected to a certain mechanical force to strengthen the surrounding bone tissue. Although the bone may have substantial strength, new bone formation occurs only outside the mass, and Upon resorption / shrinkage of the bone graft, it slowly grows on the surface of the mass. It is made up of small pieces of bone graft packed together randomly, which form the condyle. The granules do not provide mechanical support to the bone tissue, but The random packing of the bone graft provides a much larger surface area. This inevitably leads to the formation of intergranular channels and pores between the cells, which allows This allows the cells to access the surface of the granules, followed by attachment and proliferation. When new bone forms around these structures, bone begins to grow from the area near the surface of the granules. New bone tissue is formed throughout the area that reaches the center of the packed granules. In the second design, the bone heals much faster.

[0007] Producing spherical granules is difficult, especially for biologically active ceramic materials. Usually, forming spherical ceramic granules involves a molding step. , heating, grinding, and / or milling The high temperature heating step (1000°C) is an almost unnecessary step in the process. This is avoided because it creates larger granules that are sufficient for application in bone graft products. The idea is to fuse many small ceramic particles, which are usually obtained as precursors from chemical reactions. This is because the process requires the metal to be melted or bonded together. The energy often changes the crystalline structure of the ceramic, causing a phase transition. High temperatures also bring about a lot of kinetic mobility for atoms and ions. This leads to particle fusion, and eventually the particle surface becomes smooth and the pores within the granules become smaller. These physical features are the result of rough and porous surfaces. The biological properties of such materials are disadvantageous for cells to attach and grow compared to those of other materials. Further measures need to be taken to increase activity.

[0008] Therefore, there remains a need for more efficient methods of producing spherical particles. Summary of the Invention [Problem to be solved by the invention]

[0009] [overview] Consistent with the present disclosure, a more efficient method for producing spherical particles has surprisingly been discovered. was discovered.

[0010] The spherical granules of the present disclosure can be advantageously produced at low temperatures (<150°C) using ceramic powders. Such compositions can be prepared with uniformly distributed intergranular pores, coarse grains, and It has a granule surface and nanometer micropores within each granule. [Means for solving the problem]

[0011] In one embodiment, the composition for bone regeneration comprises substantially spherical granules. Each of the granules has an outer shell containing magnesium phosphate and nano-sized silica, and and a biologically active core encapsulated by the outer shell. The macropores include macropores and micropores. The macro-pores are the intergranular spaces between adjacent granules, and the micro-pores are the intergranular spaces between adjacent granules. The o-pore is an intragranular nanopore formed on the outer shell of each of the granules. (nular nanopore).

[0012] In another embodiment, the method for producing substantially spherical granules comprises: A process for providing a mixture of magnesium phosphate and an initiator using colloidal silica solution. Step 5: rotating the mixture using a double asymmetric centrifuge for a predetermined period of time. and drying the resulting material.

[0013] Further areas of applicability will become apparent from the specification provided herein. The description and specific examples in the summary are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure. It is not intended to be limiting.

[0014] The drawings described in this application are for the purpose of illustrating selected embodiments only and all It is not intended to illustrate possible implementations of the present invention, nor is it intended to limit the scope of the present disclosure. do not have. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 illustrates substantially spherical granules comprising magnesium phosphate, silica, and calcium phosphate. [Figure 2] Figure 2 illustrates a putty containing spherical granules and hydrated cellulose polymer. [Figure 3]FIG. 3 is a PXRD pattern collected from spherical granules containing magnesium phosphate, silica, and calcium phosphate. [Figure 4] 4a-4b include SEM images of (a) a spherical granule between 1 mm and 2 mm comprising magnesium phosphate, silica, and calcium phosphate, and (b) the surface of the granule (arrows pointing to pores on the surface). [Figure 5] 5a-5b include SEM images of the surfaces of mixtures of magnesium phosphate, silica, and calcium phosphate: (a) cauliflower-like globules, and (b) the globules containing many platelet particles. [Figure 6] FIG. 6 is a graph illustrating the attachment and proliferation of MC3T3-E1 cells in the presence of a mixture containing magnesium phosphate, silica, and calcium phosphate. [Figure 7] Figure 7 (a) and (b) are coronal micro-CT scan (500 μm thick) images of spherical granules containing magnesium phosphate, silica, and calcium phosphate. [Figure 8] Figures 8a-8b are representative low-magnification histological images of spherical granules containing magnesium phosphate, silica, and calcium in a rabbit distal femoral condyle, showing highly regular new bone infiltrating into the center of the spherical granules; arrow 3 indicates new bone tissue, while arrow 4 indicates graft material, arrow 5 indicates bone marrow, and the circle indicates the surgical defect. [Figure 9] 9a-9c contain high magnification histological images of the interface between new bone and spherical granules containing magnesium phosphate, silica, and calcium phosphate, showing that bone marrow (arrow 7) and new bone on the surface of the remaining particles (arrow 6) surround and infiltrate the spherical granules. [Figure 10]Figure 10 is a graph showing the release profiles of vancomycin (VCM) over 1, 4, 7, 14, or 30 days when mixed with spherical granules containing magnesium phosphate, calcium phosphate, silica, and various biopolymers, including sodium carboxymethyl cellulose with molecular weights of 90,000, 250,000, or 700,000 Da. DETAILED DESCRIPTION OF THE INVENTION

[0016] [Detailed explanation] The following technical description relates to the nature of the subject matter, making and using one or more inventions. For illustrative purposes only and without claiming priority to or in connection with this application. Any specific claims made in other applications that may be filed or in any patents resulting therefrom It is not intended to limit the scope, application, or uses of any of the inventions. With respect to the method, the order of steps presented is exemplary in nature and therefore may not be explicitly stated otherwise. Unless otherwise indicated, the steps described above are all the same, including cases where certain steps can be performed simultaneously. The order of steps may be different in various embodiments. "A" and "a" (indefinite article of a word) indicate "at least one" of the items. indicates the existence of "; if possible, there may be more than one such item. Unless expressly indicated otherwise, all numerical values ​​herein are "about" and all forms and The spatial descriptor is the broadest description of the technology, "substantial" (ly)" as applied to numerical values. In the case of "approximately," the term "approximately" means that the value may be slightly inaccurate due to calculation or measurement. indicates that the value is somewhat close to accurate; approximately or reasonably accurate. (approximately) to that value; (nearly). For any reason, "about" and / or "substantially" may be used. The imprecision provided by "" is understood by others in the art according to its ordinary meaning. If not understood, "about" and / or "substantially" as used herein shall not affect the accuracy of such parameters. The meter is not subject to variations that may arise from normal methods of measuring or using the At least show some movement.

[0017] All documents cited within this detailed description (e.g., patents, patent applications, and scientific literature) etc.) are incorporated by reference into this application unless expressly stated otherwise. There may be some inconsistencies or ambiguities between the included documentation and this detailed description. In such cases, the present detailed description will take precedence.

[0018] Non-limiting terms such as including, containing, or having The open-ended term "comprising" as a synonym for "comprising" is intended to include embodiments of the present technology. are used in this application to describe and claim the embodiments. , "consisting of" or "consisting essentially of" It may alternatively be described using more restrictive terms such as "partially of." For any given embodiment that lists materials, components, or process steps, ,The present technology also comprises such materials, components, or process steps. (consisting of) an embodiment consisting essentially of of) embodiments while excluding further materials, components, or process steps. and further embodiments that affect the important properties of the embodiment. Consisting essentially of (excluding) materials, components, or process steps sisting essentially of), in this application, such further materials, components, or Specifically includes process steps even if they are not explicitly listed. For example, elements A recitation of a composition or process that recites A, B, and C indicates that element D is excluded in this application. Excluding element D, which may be recited in the art even if not explicitly stated as such. An embodiment consisting of A, B, and C, and Embodiments consisting essentially of are specifically contemplated.

[0019] When referred to in this application, all compositional percentages are by weight of the total composition unless otherwise specified. Disclosure of ranges includes endpoints and all explicit values ​​unless otherwise specified. and any further subranges within that entire range. Thus, for example, "from A to B" Or, a range "from about A to about B" includes A and B. The disclosure of values ​​and ranges of values ​​for various components (weight percentages, etc.) is intended to provide a general understanding of other values ​​useful in this application. and ranges of values. Two or more specific examples may be given for a given parameter. The values ​​define the endpoints for a range of values ​​that can be asserted for the parameter. For example, in this application, a parameter X is illustrated to have a value A. and also exemplified as having a value Z, parameter X ranges from about A to about Z. Similarly, there may be more than one value for a parameter. Disclosing ranges (whether such ranges are nested, overlapping, or unclear) Claims made using the endpoints of the disclosed range (whether clearly distinct or not) It is intended to encompass all possible range combinations of possible values. For example, the parameter X may have a value within the range of 1-10, or 2-9, or 3-8. In the example shown, the parameter X is, for example, 1-9, 1-8, 1-3, 1-2, 2-10, 2-8, 2-3 It is also conceivable that it may have other ranges of values ​​such as 3-10, 3-9, etc.

[0020] An element or layer may be "on," "engaged to," or "on" another element or layer. When reference is made to "connected to" or "coupled to," It is directly on, involved in, connected to, or on top of another element or layer. In contrast, an element may be paired with another element or layer, or there may be an intervening element or layer. An element is "directly on" or "directly involved in" another element or layer. directly engaged to," "directly connected to," or "and When reference is made to "directly coupled to," the intervening element or layer Other terms used to describe relationships between elements are similar. (e.g., "between" and "directly between" "," "adjacent" and "directly adjacent," etc.). where applicable, the term "and / or" refers to any and all combinations of one or more of the associated listed items. Includes matching.

[0021] The terms first, second, third, fourth, fifth, sixth, sixth, eighth ... Second, third, etc. may be used in this application to refer to these elements, components, regions, layers, and and / or sections should not be limited by these terms. Distinguishing one element, component, region, layer or section from another region, layer or section Terms such as "first," "second," and other numbers may only be used to As used in this application, numerical terms do not refer to sequences or orders unless the context clearly indicates otherwise. Thus, the first element, component, region, layer or section discussed below does not imply any ordering. The invention may be modified to include a second element, component, region, or area without departing from the teachings of the example embodiments. These may be called regions, layers or sections.

[0022] Describes the relationship of one element or feature to another element or feature as shown in the drawings. To make it easier to write, the terms "inner," "outer," and "beneath" are used. ), "below," "lower," "above," "upper," and other spatially related terms. The above terms may be used in this application. Spatially related terms are those depicted in the drawings. It is intended to encompass various orientations of the device in use or operation in addition to the orientation shown. For example, if the device in this drawing were inverted, the element (which (elements described as "below" or "beneath" other elements or features) , will take a direction "above" said other element or feature. The term "below" may encompass both an orientation of above and below. The device may be placed in other orientations (rotated 90 degrees or in other directions). and spatially related descriptors used in this application should be interpreted accordingly.

[0023] A method and composition for bone tissue regeneration is disclosed. The composition comprises a substantially spherical The term "substantially spherical" is used in the context of this application. When used in a particle (which may be approximately or nearly spherical in shape, The purpose of this is to describe a radius (which may not have the same radius at all points, regardless of the radius). For example, substantially spherical particles may not be perfectly spherical. Granule embodiments are also disclosed.

[0024] The present disclosure contemplates compositions for bone regeneration, said compositions being described in more detail in this application. As such, they may be suitable for orthopedic implants to promote the bone healing process. Furthermore, the composition may be used in any further application known to those skilled in the art, such as for promoting bone growth. The composition may comprise substantially spherical granules. Each of the substantially spherical granules may comprise an outer shell and a biologically active core. The biologically active core is substantially or completely surrounded by the outer shell. May undergo encapsulation.

[0025] The outer shell may comprise magnesium phosphate and silica. Nano-silicon provided as an aqueous colloidal SiO2 solution or functioning in this composition may be any alternative silica compound or solution known to those skilled in the art. SiO2 nanoparticles increase the surface area of ​​the granules due to the high surface area to volume ratio of the nanoparticles. The high surface area to volume ratio of the nanoparticles allows for their additional It is beneficial to house cells as the surface area may encourage further cell growth. do.

[0026] Mg 2+ The presence of α-glucan is beneficial for new bone formation by enhancing cell accommodation and differentiation. Magnesium phosphate-based cements ( MPC)) has shown good biocompatibility when tested in vivo, and has been shown to suppress inflammatory responses, fibrotic tissue formation, and The dissolution rate of some magnesium phosphate compounds is higher than that of certain calcium-based cements. In the composition of the present invention, magnesium phosphate having excellent physical properties and biodegradability is used. It is preferably used.

[0027] In certain embodiments, the magnesium phosphate may be present as a powder. The magnesium phosphate composition includes, but is not limited to, MgHPO4, MgHPO4·xH 2O, Mg3(PO4)2, Mg3(PO4)2·xH2O, or a combination thereof. Those skilled in the art can select other suitable magnesium phosphate compounds, if desired. .

[0028] The outer shell may also be made of any material known to those skilled in the art without departing from the spirit of the present invention. It may also contain fillers or other compatible compositions such as:

[0029] The biologically active core may comprise calcium phosphate, a biologically active glass, and Calcium phosphate (CaP) is a compound of calcium phosphate and calcium carbonate. A family of inorganic salts containing anions of phosphate, phosphate, phosphate- ... The calcium phosphate compound used in the composition is limited to Although not a complication, hydroxyapatite (HA), β-tricalcium phosphate (β-TCP), e.g. , Dicalcium phosphate anhydrous (DCPA), α-tricalcium phosphate, octacalcium phosphate, phosphorus dicalcium phosphate dihydrate, amorphous calcium phosphate, other calcium phosphates known to those skilled in the art. These calcium phosphate compounds include calcium phosphate compounds, ... It offers an improved healing response and a higher resorption rate than other HA-based materials. It is served.

[0030] Hydroxyapatite is the major component of human bone and enamel, as well as of human hard tissues. HA is a component of the endothelial cell membrane. It has biocompatibility and osseointegration properties. tive), osteoinductive activity, which makes HA an excellent candidate as a bone graft material. Tricalcium phosphate is much more soluble than HA (theoretical solubility is 100% higher than HA). It converts rapidly to HA under physiological conditions (approximately 100 times higher than HA).

[0031] Compositions containing both HA and β-TCP may be synergistic. - Due to the presence of TCP, it may be more biologically active and improve the stability of the implant. The quality is controlled by the presence of HA. The HA:β-TCP ratio is 60: The ratio may range from 10:40 to 10:90, depending on the specific use of the composition. Based on this, one skilled in the art may make adjustments.

[0032] Furthermore, unexpectedly, the incorporation of magnesium phosphate into calcium phosphate compositions Therefore, the in vivo degradation rate of the composition is approximately the same as the degradation rate of the calcium phosphate composition alone. It has been found that there are improvements compared to magnesium phosphate. The incorporation of an outer shell of calcium phosphate improves the decomposition rate of the calcium phosphate core. It can help you to improve.

[0033] The outer shell of the roughly spherical granules may have a textured surface. Surface roughness may be formed by the combination of multiple granules. Pores (macro-pores) may be present, which are the intergranular spaces between adjacent granules. There may also be micropores, which are an intragranular nanopore formed on the outer shell of each of the granules; The micro-pores may be of uniform or irregular shape. The micro-pores allow cells, fluids, or tissues to pass through. may be able to infiltrate into the core of the packed granules. This further promotes bone growth.

[0034] The biologically active glass for use in the core may be any biologically active glass. These compositions may contain silica-based compositions. Silica-based compounds with multiple metal / non-metal oxides that make them " Materials of this type may produce apatite on their surfaces when present in body fluids. This property allows the composition to bond directly to natural bone. This allows the composition to be "biologically active."

[0035] Biologically active glasses are prepared in the presence of magnesium phosphate and colloidal silica solutions. Advantageously, the biologically active glass may undergo encapsulation. The resulting composition may contain multiple particles of various compositions (the resulting composition Among the components, the biologically active glass has low decomposition rate, and other components contained therein (The composition may have higher degradability.) After implantation in the body, the more degradable parts is a biologically active substance that helps provide short-term healing but is only slowly degraded. The glass provides a stable scaffold for bone formation after the highly degradable part has completely degraded. Furthermore, magnesium phosphate and nano-sized silica are used to The encapsulation of the thermally active glass allows the chemical structure of each individual component, as well as its associated Any biological characteristics that may be present can be preserved.

[0036] Examples of biologically active glasses include, but are not limited to, 45S5 (46.1 mol % SiO2, 24.4 mol% Na2O, 26.9 mol% CaO and 2.6 mol% P2O5), S53P4 (53.8 mol% SiO2 , 21.8 mol% CaO, 22.7 mol% Na2O and 1.7 mol% P2O5), 13-93 (54.6% SiO2, 22.1% Ca 58S (60 mol% SiO2, 36 mol% Ca O, 4 mol% P2O5), 68S (70 mol% SiO2, 26 mol% CaO, 4 mol% P2O5), 63S (63 mol% SiO2 , 28 mol% CaO, 9 mol% P2O5), 77S (80 mol.% SiO2, 16 mol.% CaO, 4 mol.% P2O5), 80 S (80 mol% SiO2, 15 mol% CaO, 5 mol% P2O5), 35SM (35 mol% SiO2, 50 mol% CaO, 7 m ol% P2O5, 7 mol% MgO, 1 mol% CaF2), 85S (85 mol% SiO2, 10 mol% CaO, 5mol% P2O5), 70S30C (70 mol% SiO2, 30 mol% CaO), and combinations thereof.

[0037] The outer shell of the substantially spherical granules may be used to encapsulate further substances. In other words, the outer shell may be used as a micro-encapsulating material. Some of the materials that can undergo encapsulation or microencapsulation are Some non-limiting examples include, but are not limited to, antibiotics, stem cells, and These substances may be used to support the bone healing capabilities of the composition. These materials may therefore be used to form substantially spherical granules of the bone graft composition. In certain embodiments, additional substances (e.g., peptides, In some cases, the substantially spherical granules may be micro-encapsulated with other substances (e.g., growth factors, antibiotics, etc.). Advantageously, this micro-encapsulation results in rapid degradation of the encapsulated material. This may prevent the problem from occurring.

[0038] In certain embodiments, the composition may be used to implant the composition. The carrier may be mixed with the ointment. Non-limiting examples of such carriers include water-soluble Examples of such biopolymers include, but are not limited to: Although not limited to, cellulose, chitosan, alginate, and other similar biomass known to those skilled in the art. These biopolymers can be hydrated to form hydrogels. The hydrogel may be made of, for example, biopolymers, proteins, or the like. It may contain one of the following: sugar, gum, carbohydrate, and cellulose. More particularly, the hydrogel may be prepared by mixing the following to form the hydrogel or putty: Biopolymers, proteins (e.g., gelatin, pectin), gums (e.g., agar, sodium alginate), carbohydrates (e.g., starch, chitosan), and cellulose (e.g., For example, carboxymethylcellulose, methylcellulose) and and using a granule-like material to encase substantially spherical granules of the composition to form a putty-like bone graft. The putty is also adhesive to bone tissue, so it stays in place and The putty can conform to the surface of the bone tissue on which it is placed. These nano-silica particles, which are essentially spherical granules, interact with the biopolymer molecules. This can further help maintain the biopolymer gel without degradation. When a more aqueous solution is used, the polymer gel forms a substantially spherical gel of the composition. Due to the lavage with the granules, they will not separate easily.

[0039] Surgery involving biomaterials, such as synthetic bone graft materials, can result in bacteria adhering to the biomaterial. Because of the presence of bacteria and the formation of biofilms from these bacterial strains, infections can occur. This can prevent infection and aid wound healing. Therefore, applying an antibiotic-loaded composition into the surgical site may address this issue. It is useful in addressing this issue.

[0040] In certain embodiments, the hydrogel further comprises at least one therapeutic component. Examples of such therapeutic components include, but are not limited to: antibiotic drugs, non-limiting examples of which include vancomycin, tobramycin, or gentamicin The antibiotic drug can be produced in a hydrophilic form, which They can be easily mixed with the biopolymer in its hydrophilic form. When drugs are mixed with the polymer gel, they are released at the molecular level, e.g., after implantation. The drug interacts with the polymer gel, and as the polymer gel degrades, the drug slowly Furthermore, microencapsulation of these antibiotics can improve their stability. This facilitates absorption and improves ease of handling, and provides controlled release of the drug. Furthermore, after the hydrogel decomposes, the spherical granules are able to induce osteoinductive healing. It can act as a scaffold for

[0041] The compositions are not limited to the hydrogel embodiments of the compositions disclosed above. It should be recognized that the present invention may be implemented in alternative forms. The composition may be provided in any suitable form. One example, but not limiting, is However, the substantially spherical granules are mixed with bone cement for use in treating osteomyelitis. The drug is then released upon degradation of the bone cement and / or Depending on the degradation, it may be released.

[0042] The compositions of the present disclosure also undergo micro-encapsulation, which can support bone healing. Micro-encapsulation is the process of encapsulating small particles with diameters ranging from 1 to 1000 μm. This refers to a technology that can produce small spherical particles. These are called natural or synthetic polymers. They may be made from polymeric or inorganic materials. s) Microcapsules may be obtained for specific intended uses. Microcapsules may contain a variety of materials based on the intended use. Materials for encapsulation include, but are not limited to, gelatin, polyvinyl alcohol, and the like. Nyl alcohol, ethyl cellulose, cellulose acetate phthalate and styrene maleic anhydride polymeric materials, such as carboxylic acids, or directly integral with the compositions claimed in this application. The various micro-encapsulation processes can be classified into chemical, physicochemical, and The processes are sometimes divided into electrostatic and mechanical processes. and in situ polymerization methods. The process includes coacervation phase separation, compound milk complex emulsion, meltable dispersion and powder bed method d), and mechanical processes include the air suspension method. on method, pan coating, and spray drying, spray coagulation Spray congealing method. Micro-encapsulated substances (e.g., antibiotics) substances, peptides, or stem cells) to prepare a mixture for transplantation. The encapsulated material may be mixed with bone graft composition granules containing the encapsulated material. When in contact with chemical fluids, it may dissolve and release the substances contained therein, and disperse These dissolution rates may vary depending on the specific encapsulation and implantation of the composition within the body. The nature of the biopolymer or other carrier used will depend on the nature of the specific material. When stem cells are mixed into the composition, nano-peptides are added to support the viability of the stem cells. It should be recognized that there may be cases where the

[0043] The compositions of the present disclosure also contain compounds that support bone healing, such as peptides, stem cells, growth factors, antibiotics, etc. This may also include materials that have undergone macro-encapsulation, which allows for the Inside a stable shell that forms a capsule ranging in size from millimeters to centimeters to encapsulate pharmaceuticals in them so that they can be taken, for example, orally, or To allow surgical implantation or packing into a suitable cavity This refers to a set of techniques used to perform the bone transplant procedure claimed in this application. The explant composition may be encapsulated in a hard-shell capsule, which may be a dry, powdered These contain small pellets or liquids, which are made up of two parts. : A "body" with a smaller diameter that receives the filling and seals the body The larger diameter "cap" is used to make the capsule. or plant polysaccharides or their derivatives (carrageenan, modified starch, cellulose) The gelling agent may be an aqueous solution of gelling agents such as PEG, PEG-1, PEG-2, PEG-3, PEG-4, PEG-5, PEG-6, PEG-7, PEG-8, PEG-9, PEG-10, PEG-11, PEG-12, PEG-13, PEG-14, PEG-15, PEG-16, PEG-17, PEG-18, PEG-19, PEG-2 plasticizers such as glycerin or sorbitol, colorants, preservatives, disintegrants, and lubricants. Other ingredients may be added to the gelling agent solution.

[0044] The composition also includes a hard-shell capsule mixed with the substantially spherical granules. Pins or pegs on a metal plate of the desired shape and diameter are inserted into the The hard gelatin capsule shells are produced by dipping the capsules into a reservoir of gelatin mixture. The pegs are made of manganese bronze. The plate is lowered into the gelatin bath. By controlling the coating time, the pegs can be sunk to the desired depth. The plate and pegs can be removed from the gelatin bath to form a desired thickness. After the peg is lifted from the surface, the gel on the surface of the peg is removed by flowing temperature and humidity controlled air. Once dry, trim each capsule section to the appropriate length and Controlling the thickness of the gelatin wall is important for the capsule body and the cap. This is important because it affects the degree of adhesion between the capsule shells. , diameter, and capacity.

[0045] Thus, the composition comprises, in admixture with the substantially spherical granules, one of the following substances: , may include any or all of: micro-encapsulated material, macro-encapsulated and a therapeutic component, which are contained in a carrier together with substantially spherical granules. Those skilled in the art will be able to determine which components to use based on the specific application. You can specifically choose what you can do.

[0046] The composition may further comprise strontium phosphate and iron(II) phosphate. The composition also contains sodium phosphate dibasic (Na2HPO4) and sodium phosphate monobasic (N aH2PO4).

[0047] The present disclosure also contemplates a method for making a composition comprising substantially spherical granules, said method comprising: Generally, as explained in more detail above, bioactive powders, magnesium phosphate, and an initiator with a colloidal silica solution. The initiator may include one of MgO, CaO, and K2O.

[0048] Magnesium phosphate powder was mixed in a colloidal SiO2 aqueous solution and then subjected to double centrifugation. When the three components are mixed, they may not only form spherical granules, but also It should be appreciated that any powder within the granules will also undergo encapsulation and become part of the spherical granules. This method allows the preparation of biologically active spherical conjugates with various synergistic compositions. When subjected to asymmetric centrifugation, magnesium phosphate and silica are phase-separated. Interaction occurs, resulting in spherical granules ranging in size from about 0.25 mm to about 4 mm. Magnesium phosphate particles are formed in the range of several tens of microns and meters. These small particles are combined with silica nanoparticles, and then the surface of the spherical granules is The surface becomes very rough and has many grains with dimensions ranging from a few nanometers to a few hundred nanometers. Many of the micropores are filled (the advantages of this are described in this application).

[0049] The method comprises subjecting the mixture to dual asymmetric centrifugation (DAC). ) for a predetermined time. The DAC process , dynamic compaction, milling, and polishing processes, where DAC The rate of change is measured over a discrete period of time as the contents of the mixing vessel undergo an acid / base neutralization reaction. Independent input variables (e.g., reactant phase composition, % water of crystallization, step-by-step The interactions between the mixing rpm, number of mixing steps, time per step, total elapsed time, etc. This can affect output variables such as particle size and mechanical strength, thus affecting the desired properties. These may be used to controllably produce particles having Adjust these variables to achieve the specific granule size and composition needed for the intended use. may be created.

[0050] Using high rpm (>1000) mixes the reactants and forms particles / compaction This can be important during the early stages of DAC preparation to allow for the reaction to proceed smoothly. Both the instantaneous mixing of the particles and the resulting acid / base reaction simultaneously compact the particles. High rpm in the early stages of production (during the mixing and compaction steps) have significant mechanical properties (25 μm-3 mm) compared to particles produced using a lower rpm This results in a population of substantially spherical particles (weighted towards the upper limit).

[0051] Using a low rpm (<1000) allows for a faster and more efficient process for the DAC after the particles are formed. The particles formed by the process may be important for milling and polishing. DAC processing of the particles at low rpm reduces the particle size distribution, and The surface of the particle is polished to remove defects. Thus, in some embodiments, one or more A high rpm DAC step is followed by one or more low rpm DAC steps. In certain embodiments, the spinning step is centrifuged at 800-1900 revolutions per minute. The predetermined amount of time may be from about 20 seconds to about 2 minutes.

[0052] Suitable commercially available DAC systems include, but are not limited to, the Flacktek SpeedMixer s TM , which includes the DAC 150 series mixers, DAC 250 mixers, and DAC 400 mixers. Sir, DAC 600 Mixer, DAC 800 Mixer, DAC 1100 Mixer, DAC 3000 HP Mixer, and DAC 5000 HP Mixers. Commercially available DAC systems typically handle samples from 100 g to 10 kg. They are available in a range of sizes to process the various types of containers (e.g. Certain polypropylene jars (such as those listed) are designed for use with the DAC. and any additives are added to the reaction mixture prior to double asymmetric centrifugation. The total amount of contents in the DAC jar may be used to mix with other The size of the jar and the axis of rotation are important variables for optimal mixing. The center of mass of the jar contents must be properly calibrated to match the flow diagram. If the contents are at or above the center, they may deviate from the flow pattern (typically The paste will not disperse under the force of acceleration (relative to the lid of the container). The user can select the appropriate size jar to produce the appropriate granules.

[0053] In one particular embodiment, spheres of dicalcium phosphate (CaHPO), MgHPO·3H O, and SiO Without being bound by any particular theory, particles of this type may be produced using the DAC process. However, the interaction between MgHPO4·3H2O, MgO, and colloidal SiO2 liquid is not observed during the DAC process. It is believed that the solubility of the solubility of the solubility of the solubility of the

[0054] In one particular embodiment, biologically active glass / calcium phosphate, MgHPO4·3H SiO2 and MgO powders are mixed with colloidal SiO2 liquid in a closed plastic jar. Alternatively, the colloidal SiO2 solution can be dissolved in deionized water in a closed plastic jar. In either case, the mixture is then subjected to a series of DAC steps. The steps may start at high rpm (>1000 rpm) and then move to lower rpm ( <800 rpm) to obtain spherical granules.

[0055] In one particular embodiment, biologically active glass / calcium phosphate, MgHPO4·3H SiO2 and MgO powders are mixed with colloidal SiO2 liquid in a closed plastic jar. Alternatively, the colloidal SiO2 solution can be dissolved in deionized water in a closed plastic jar. In either case, the mixture is then subjected to a series of DAC steps. The step may start at low rpm (<800 rpm). The granulation is then carried out to form granules by a granulation process. This may be done by crushing the material into fine particles until the desired size is reached. It may also be automated using appropriate machinery such as a granulator.

[0056] In one particular embodiment, biologically active glass / calcium phosphate, MgHPO4·3H SiO2 and MgO powders may be mixed with colloidal SiO2 liquid in specially shaped molds. Alternatively, the colloidal SiO2 solution can be dissolved in deionized H2O in a closed plastic jar. In either case, the mixture may be diluted by heating under ambient or heating processes. In either setting, it may form a solid block.

[0057] In certain embodiments, biologically active glass / calcium phosphate, Na2B2O4·1 Powders of 0H2O, MgHPO4·3H2O and MgO are mixed with colloidal SiO2 liquid to form a paste. The paste can then be administered by injection through a narrow opening such as a needle or cannula. This paste can slowly turn into a hard block. In one embodiment, spherical granules made of MgHPO4·3H2O and nano-silica were sorted based on their diameter. These small granules can be selected to obtain small pellets between 0.1 mm and 0.5 mm. The paste can be easily mixed with bone defects under mechanical load. The paste is applied to the surface of the small granules to prevent leakage through the fine cracks inside. It may be held firmly.

[0058] The method includes drying the material resulting from the spinning step. The drying step may be carried out using ambient air, pressurized air, ambient inert gas, or the like. Evaporation process under an environment selected from gas, and pressurized flow of inert gas The drying process may include evaporation (for example, nitrogen, argon). The evaporation process under vacuum conditions is called the evaporation process. The drying step may include repeated drying with a solvent at low vapor pressure. and then washed by evaporation process. May contain (e.g., methanol, ethanol, acetone, propanol, hexane The drying step can be carried out in a conventional oven, a culture incubator, or a microwave oven. Evaporation process via a heating process using a heating device such as an oven (evaporation process), may be included.

[0059] Various examples of the present application involve formulations with Ca and Mg phosphate phases as the main components. Although described, other alkaline earth metals such as strontium (Sr) and iron (Fe) can be used in the present invention. For example, the composition may contain phosphate phosphates. It may contain one of the following: trontium and iron(II) phosphate.

[0060] Compositions containing substantially spherical particles can be delivered via kits containing one or more key components. may be made available to practitioners (e.g., surgeons, veterinarians, or dentists) A non-limiting example of such a kit is a dry (e.g., substantially spherical) and a liquid component in separate containers, wherein the containers contain Many other kits may or may not be present in a combination of kits that include, for example, a premixed putty instead of a powder and setting liquid; a syringe or a combination of syringes for injecting the bone cement composition formed from the components of the kit; and a kit including a number of syringes. The kit typically includes a kit for carrying out the method of the present invention. and instructions for using the components of the kit to carry out the method of the present invention. The instructions for practicing the methods are generally recorded on a suitable recording medium. The instructions may be included in the kit as a package insert or on the kit or its components. In another embodiment, the instructions may be present in a suitable container label. Electronically stored data residing on computer-readable storage media (e.g., flash drives, etc.) In another embodiment, the instructions are present in the kit as a data file. Although not physically present, the instructions may be obtained from a remote source, such as via the Internet. An example of this embodiment is a device that allows the user to view the instructions and / or or a kit including a web address from which the instructions can be downloaded. As with the instructions, this means for obtaining the instructions is recorded on a suitable substrate. . [Example]

[0061] Exemplary embodiments of the present technology are provided with reference to several drawings attached to this application. do.

[0062] [Example 1] Dry powder components: 10.4 g of Ca(OH)2 and 27.6 g of Mg(OH)2 were mixed in a mixer. In the bath, the liquid component H3PO4 (156 ml) diluted with 204 ml of H2O and 24 g of sodium bicarbonate The resulting slurry was dehydrated using an oven to form a dry cake. The cake was then milled to produce a fine powder, which was then placed in a stainless steel The dried, fine CaP + MgP powder (Monetite) was collected using a 1000 cc (1000 cc) mesh sieve. A mixture of sapphire and newberyite was added to an empty plastic jar. 8.75 g of magnesium oxide (MgO) powder was added to the beaker and the resulting dry powder mixture was The product (containing CaP, MgP, and MgO) was homogenized. A solution containing ethanol and water was prepared in a separate plastic jar. The dry powder mixture was added to the granules or substantially A centrifugation process was carried out which led to the formation of spherical beads. The beads were dehydrated using a polymeric carrier (sodium CMC). Upon hydration, the carrier swells and forms a putty, as seen in Figure 2. Complete.

[0063] Figure 3 shows the PXRD patterns obtained from these SiMN granules, which show two different crystalline phases. Monetite is indicated by * and newberyite is indicated by +. The granules had a porous surface, as seen in the SEM images in Figures 4-5. Figure 4a shows the typical morphology of SiMN granules. The diameter of these granules ranged from 1 mm to 2 mm. Higher magnification reveals that the granule surfaces are highly rough. Numerous micropores can be observed throughout the rock (arrows in 4b). The bond between the rheolite and silica particles creates a rough surface.

[0064] The granules are biologically active as can be seen from Figure 5. As shown in Figure 5a, Ta After immersion in s-simulated body fluid (t-SBF) for 2 days, the surface of the granules An additional layer was observed in the cauliflower-like layer, with an average size of about 5 μm. At higher magnification, the crystals forming the spherules were shaped like plates. The negative control, polyethylene glycol phosphate, was detected as platelets (Fig. 5b). No additional particles were observed in the solution, which indicates that on the surface of a given substrate, the solution As shown in Figure 6, the positive control represents the total amount of cells seeded in the medium, and approximately 25% of the cells were attached to the HA control after 24 hours. After 72 hours, 75% of the seeded cells were attached to the cells, and increased to 50% after 72 hours. After 72 hours of culture, the amount of cells attached to the disclosed compositions was , showing a 4-fold increase and remaining at 75% of the total amount.

[0065] At 6 or 12 weeks, radiographs of the adjacent host bone in the defect showed: There was no evidence of infection or adverse effects on the implanted material, and all μCT images showed no significant changes in the defect area. A representative μCT image was taken at a coronal plane with a 500 μm The thickness is shown in Figure 7.

[0066] In μCT images taken at 6 weeks, new bone formation was observed between the spherical granules. The new bone completely penetrated the packed granules and formed a large area around the center and periphery of the defect. The spherical shape of the granules observed at 6 weeks remained unchanged by 12 weeks. However, this was eventually lost with graft remodeling, along with loss of edge detail (Fig. 7a and 7b, arrow 2). New bone formation in the defect area was observed between 6 and 12 weeks, with remodeling occurring. The dense and thin trabecular structure (Fig. 8a, arrow 3) observed at 6 weeks was well organized. They had matured into thicker trabeculae (Fig. 8b, arrow 3).

[0067] No adverse reactions related to inflammatory cell responses were observed at 6 weeks. At 6 weeks, bone was evident on both graft materials from the periphery to the center of the defect ( At 12 weeks, the development of the marrow cavity and bone remodeling were observed as shown in Figure 8(b). As indicated by the arrow 5 in the figure, absorption of spherical granules was observed in both groups. This was observed as characteristic circular erosions and cavity formation within the granules (arrow 4, Figure 8). b) Furthermore, new bone formed in the defect area was observed as indicated by arrow 3 in Figures 8a and 8b. The trabeculae were longer and thinner, with a higher aspect ratio. The granules were substantially isotropic in shape, resulting in a high degree of regularity between the spherical granules. This can be observed in the present application.

[0068] At higher magnification, it is possible to visualize the orientation of the fibers within the new bone, as shown in Figure 9. At 6 weeks, bone that grew around the surface of the spherical granules was found to be in a control area close to the bone surface. The layers are piled up by layers of perpendicular axes showing well-oriented and lamellar structure on the surface of the granules. This structure continued (Figure 9a, arrow 6). The same structure was observed at 12 weeks (Figure 9b, arrow 6).

[0069] An interesting observation was also made at the interface between the SiMN implant and the new bone. The volume of the implant shrinks due to resorption, while dynamically integrating with the new bone. At 12 weeks, continuous bone growth was more evident, consistent with the resorption profile of the implant. As shown in Figure 9c, more than half of the granules were absorbed at 12 weeks. The remnants grew into the marrow cavity and into a circular shape (probably because they were formed before resorption occurred). The granules were encapsulated by bone fragments (which corresponded to the original shape of the granules). At the site, focal bone formation was observed on the implant, bridging the bone (arrow 7), which resulted in the formation of the remaining bone. The granules are encapsulated by another layer of bone. New bone grows over the granules without completely absorbing them. The fact that the particles infiltrated directly into the center of the granules indicates that the micropores present within the granules Instead of expanding and being gradually eroded from the outside during degradation, the granules break down further from their inside. makes it much easier to solve.

[0070] [Example 2]

[0071] Formulation using Bioglass 118 g of bioglass, 79 g of magnesium phosphate powder and 8.75 g of magnesium oxide ( The solid component consisting of MgO was mixed with 42 ml of colloidal silica solution (HS-40 silica) and 63 ml of Spherical granules were made by mixing with a liquid component consisting of water. The mixture was then subjected to the centrifugation method described in Example 1. The centrifugation was carried out starting at a higher number. The granulation was carried out under a series of different rpm conditions, with the rpm increasing to a lower value. The water was removed using an oven.

[0072] [Example 3] Antibiotic addition

[0073] The solid phase (powder) of spherical granules is used to treat methicillin-resistant Staphylococcus aureus ( It was mixed with 10% w / w vancomycin (VCM), an antibiotic effective against MRSA, and 0.1-g pellets of 10% w / w sodium CMC mixed with double-distilled water to form a batter. The pellets were then molded into pellets and air-dried. These pellets were then soaked in 1 mL of phosphate-buffered saline at 37°C. The amount of vancomycin released was measured at various time points using 280 nm UV / Measurement was by visible spectroscopy and the concentration was calculated using a standard curve of absorbance versus concentration.

[0074] CPCs containing CMCs of various chain lengths expressed as molecular weights (90,000, 250,000, or 700,000 Da) were investigated. The results showed that the addition of high molecular weight (700,000 Da) CMC delayed the drug release from CPC. This indicates that the drug delivery system is highly sensitive to the drug. Ta.

[0075] [Example 4] MgP formulation with or without granules

[0076] Magnesium phosphate, magnesium oxide (MgO), colloidal SiO2 liquid and sodium tetraborate A fluid cement prepared by mixing borax was prepared by the method described in Example 1. small, substantially spherical SiMN granules (with diameters between 250-750 micrometers) This formulation provides uniformly suspended microspheres throughout. A flowable cement with beads is obtained. This flowable cement can be administered by injection alone. It can also be used as a cement, gradually hardening to form a mass.

[0077] So that this disclosure will be thorough and complete, and will fully convey the scope to those skilled in the art, exemplary embodiments will be described. To fully understand the embodiments of the present disclosure, specific components, data, and the like are provided. Numerous specific details are provided, including examples of devices and methods. The exemplary embodiments may be embodied in many different forms, and need not be limited to the specific embodiments illustrated. It is understood that nothing herein should be construed as limiting the scope of the present disclosure. In some exemplary embodiments, known processes, known devices, Some embodiments, materials, and compositions are not described in detail. and methods, make equivalent changes, modifications and variations within the scope of this technology. can be achieved, with essentially the same results.

Claims

1. 1. A composition for bone regeneration, wherein said composition comprises: Substantially spherical granules, wherein each of said spherical granules comprises: an outer shell comprising magnesium phosphate and nano-sized silica; a biologically active core encapsulated by said outer shell; wherein the granules have macropores and micropores, wherein the macro-pores are intergranular spaces between adjacent granules. and the micro-pores are on the outer shell of each of the granules. The nanopores are intragranular nanopores formed in the granules.

2. 10. The composition of claim 1, wherein the biologically active core is calcium phosphate. and biologically active glass.

3. 3. The composition of claim 2, wherein the calcium phosphate is hydroxyapatite, β-tricalcium phosphate, α-tricalcium phosphate, octacalcium phosphate, dicalcium phosphate anhydrous calcium, dicalcium phosphate dihydrate, and amorphous calcium phosphate, Also includes one type.

4. 3. The composition of claim 2, wherein the biologically active glass is selected from the group consisting of 45S5, S53P4, 1 3-93, 58S, 68S, 63S, 77S, 80S, 35SM, 85S, and 70S30C. nothing.

5. 3. The composition of claim 2, wherein the composition comprises dibasic sodium phosphate (Na 2 HPO 4 ) and monobasic sodium phosphate (NaH 2 PO 4 ) and further containing at least one selected from 。

6. 2. The composition of claim 1, wherein the magnesium phosphate is MgHPO 4 , MgHPO 4 ・xH 2 O , Mg 3 (PO 4 ) 2 , and Mg 3 (PO 4 ) 2 ・xH 2 O.

7. 10. The composition of claim 1, wherein said composition comprises strontium phosphate and iron phosphate. (II), further comprising at least one selected from the group consisting of:

8. A hydrogel comprising the composition of claim 1.

9. The hydrogel of claim 8, wherein the hydrogel is a biopolymer, a tannin, or a mixture thereof. The composition further comprises at least one of a protein, a gum, a sugar, and a cellulose.

10. 9. The hydrogel of claim 8, wherein the hydrogel is It further includes components such as:

11. 11. The hydrogel of claim 10, wherein the therapeutic component is vancomycin. , tobramycin, or gentamicin.

12. 9. The hydrogel of claim 8, wherein the hydrogel is a mixture of peptides, stem cells, and augmented reality. The composition further comprises at least one of a growth factor and a bone morphogenetic protein.

13. 1. A method for producing substantially spherical granules, said method comprising the steps of: Using biologically active powder, magnesium phosphate, and colloidal silica solution an initiator; spinning the mixture using a double asymmetric centrifuge for a predetermined period of time; Drying the resulting material.

14. 14. The method of claim 13, wherein the initiator is selected from the group consisting of MgO, CaO, and K. 2 O, one of include.

15. 14. The method of claim 13, wherein the mixture comprises strontium phosphate and iron phosphate. (II), including one of the following.

16. 14. The method of claim 13, wherein the centrifuging of the rotating step is for 1 minute. and the predetermined time is from about 20 seconds to about 2 minutes. 。

17. 14. The method of claim 13, wherein the drying step comprises drying the surface of the substrate with ambient air, a pressurized stream of air, or the like. Evaporation under an environment selected from air, ambient inert gas, and pressurized inert gas. evaporation process.

18. 14. The method of claim 13, wherein the drying step comprises evaporating under vacuum conditions. The evaporation process is also included.

19. 14. The method of claim 13, wherein the drying step is performed using a solvent with low vapor Evaporation process through repeated washing at high pressure ocess), including.

20. 14. The method of claim 13, wherein the drying step is via a heating process. , evaporation process.

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