A porous granular biomaterial with high filling capacity and a preparation method thereof

Abstract

The present invention provides a highly filling porous granular biomaterial and a preparation method thereof. The outer wall surface of the particles of the porous granular biomaterial is a continuous curved surface or a closed body composed of a curved surface and a flat surface. The pore structure inside the particles is a completely or partially connected porous network. The particle shape and internal porous structure are three-dimensionally modeled by a computer. A mixed slurry containing inorganic powder and photosensitive resin is added to a printing tank and photocured according to the model. The mixed slurry is then washed to remove uncured residual slurry, and then dried and sintered to obtain a highly filling porous granular biomaterial. The porous granular biomaterial of the present invention is designed through coordinated optimization of chemical composition, internal structure and particle shape, effectively ensuring that the material directly fills various bone defects, promotes rapid regeneration and repair of bone damage, and prevents complications. The porous granular biomaterial has clinical application value in the field of promoting bone defect repair.

Description

Technical Field

[0001] The present invention relates to biomedical materials, in particular to a biodegradable, highly filling, porous granular biomaterial and a preparation method thereof, belonging to the field of bone tissue regeneration and repair. Background Art

[0002] Bone injuries in various parts of the human body caused by various external and self-inflicted impacts (punctures), falls, acute / chronic diseases and their complications, as well as the need for surgical treatment of certain diseases, often require the implantation of repair materials within the bone injury to improve the efficiency of bone healing and repair. Bone injury morphology varies across age groups and locations, and considering the patient's underlying pathological factors, the scale and morphology of the bone injury determine the implant material's need for good filling properties and the prevention and control of side effects and complications. These issues are core issues that need to be considered and addressed in the design and manufacture of bone repair materials.

[0003] Generally, autologous bone and allogeneic bone transplantation have problems such as limited donor sources, uneven bone quality, and many complications at the donor site, which has prompted people to urgently develop artificial materials to meet the large demand for bone repair. At present, calcium silicate and calcium phosphate bioactive materials have been developed and clinically applied one after another. For example, wollastonite (β-calcium silicate), pseudowollastonite (α-calcium silicate), white calcite (Ca7Mg(SiO4)4), magnesian olivine (Ca3Mg(SiO4)2), magnesian feldspar (Ca2MgSi2O7), diopside (CaMgSi2O6), magnesium calcium olivine (CaMgSiO4), etc. have been proven to have their own unique biological effects and mechanical properties. Hydroxyapatite, tricalcium phosphate, octacalcium phosphate, calcium hydrogen phosphate, magnesium phosphate, etc. have excellent biocompatibility and extremely high biosafety, and can also conduct bone repair. At the same time, people have expanded the connotation of bioactivity and increased the development of degradable bioactive materials. In particular, a large number of bioactive glasses, bioactive glass ceramics and degradable metal materials have attracted attention, and ion doping, two-phase composites or bionic gradient material design have been used to improve the performance of bone repair materials.

[0004] A large number of studies have focused on improving the chemical composition or manufacturing technology of bone repair materials, such as developing granular materials or block scaffold materials with porous structures. These materials vary greatly in morphology and often deviate from the simultaneous performance and functional requirements of multiple aspects of material structure, function, morphology, etc. required for clinical application. This has resulted in a large number of innovative results from basic research being difficult to directly translate and apply clinically. It is worth emphasizing that conventional porous scaffold materials designed and manufactured according to different scales and specifications are often based solely on the convenience of measurement and pricing in purchase and sales transactions. The scale and appearance of conventional square porous scaffold blocks lack a match with individual clinical patients. When used in clinical bone defect filling, these porous scaffolds often need to be temporarily trimmed or even crushed. This not only adds additional labor to the surgical implantation process, but also causes treatment risks due to problems such as mismatch and instability in the integration of the porous block with the bone defect cavity. Secondly, conventional bioparticle materials are also produced and processed by first cutting and crushing the whole, which will cause a large number of edges and corners in the particles, making the particle size and shape extremely irregular and uniform, and the filling rate of bone defects is low. The filling is poor, and there will be a situation where the bone defect is not fully filled by the particles, resulting in a large cavity, which makes the new bone tissue grow slowly or even not grow. Therefore, the design, processing and clinical surgical implantation of these conventional bone repair biomaterials are out of the ideal requirements of clinical application. It is not difficult to understand that similar problems will be faced in the repair of bone trauma in living animals (or pets).

[0005] On the other hand, personalized repair therapy has become a trend in bone repair material development in recent years. To date, many 3D-printed porous materials have often focused on matching the overall morphology of the bone defect: custom-printed blocks are created through 3D scanning and reconstruction, tailored to each bone defect. However, the implantation of larger blocks requires pre-treatment, such as dissection and excavation of adjacent soft tissue, to ensure convenient implantation. This destructive surgical pre-treatment can cause persistent local inflammatory reactions, significantly increasing the risk of infection and significantly hindering subsequent bone repair. Consequently, this extensive excavation of the bone defect inevitably requires significant nursing care and pharmacological interventions for postoperative complications and inflammation control, hindering the goal of efficient and complete patient recovery. Therefore, the design and construction of personalized bone trauma repair materials that ignore the adverse effects of these porous materials on clinical treatment will be extremely detrimental to clinical medical advancement.

[0006] Thirdly, the bone repair process requires the coordinated management of inflammation, infection and vascularization efficiency within the trauma. Conventional apatite ceramics, tricalcium phosphate ceramics and two-phase composite ceramic materials have low degradability and insufficient bioactivity to promote the repair of bone defects in a large number of patients with osteoporosis, bone tumors and diabetes, causing delayed healing and non-healing risks for these clinical problems. Therefore, the innovative development of highly active and multifunctional biomaterials has great practical significance for solving clinical challenges. From a clinical perspective, current porous granular materials are generally derived from discarded bones (such as femoral heads removed from patients with severe femoral head necrosis) and cadaveric bones. These natural bones are processed and then crushed and sieved. Although the porous structure of the bone mineral is retained, the particle morphology and size are difficult to accurately control. At the same time, the bioactivity is significantly weakened in a series of processing processes, especially the natural bone mineral particles after high-temperature calcination have a significant decrease in degradability and activity. Secondly, there are also porous granular bioglass, bioceramics, and bioglass-ceramics materials developed by developers. These are generally large-scale hexagonal, cylindrical, and other porous scaffolds developed using certain pore-forming methods. If the scaffolds are then crushed and screened after calcination, although the fine particles retain their internal porosity, the appearance and particle size are also difficult to precisely control. For example, inorganic non-metallic biomaterial scaffolds using photocurable 3D printing are composed of layered porous structures with thicknesses ranging from tens to 200 microns. These silicon- or phosphorus-based bioglass, bioceramics, or bioglass-ceramics generally have poor sintering properties. When the porous scaffolds obtained after high heat treatment are crushed, the lamellae easily dissociate preferentially, forming lamellar structures, which greatly complicate the tight filling of bone defects. At the same time, the surfaces of these crushed particles often contain sharp edges. Not only is the mechanical transmission between the particles unstable after filling, which easily leads to dynamic displacement between the particles and damages the new vascular network, but they can also easily scratch the tissue within the bone defect and induce new inflammatory reactions. On the contrary, the applicant unexpectedly discovered that particles with continuous curved outer walls, such as those in the shape of balls used in some sports and plant seeds, will form high filling properties after stacking, and the particles will not slip over a significant distance due to small external forces.

[0007] A detailed analysis shows that the inorganic bioactive (porous, granular) bone repair materials to date still have the following problems:

[0008] 1) It is difficult to coordinate and optimize the appearance, internal macroscopic pore structure, and microscopic pore structure of the granular material unit simultaneously, and only one or two of the three are taken into account;

[0009] 2) The internal structure and macromorphology of porous blocks are primarily designed and manufactured based on the shape of the entire bone defect. This places stringent requirements on the size of the wound at the site of bone injury when the porous scaffold is implanted. This can lead to excessive wound size, prolonged inflammatory response, increased infection risk, and increased recovery time.

[0010] 3) The activity or degradation of conventional calcium phosphate ceramic biomaterial products does not match clinical needs and cannot ensure efficient repair and healing of pathological bone defects;

[0011] 4) In particular, there is a lack of development of high-performance, multifunctional non-self-curing porous materials based on minimally invasive surgery, as well as how to avoid slow local bone regeneration efficiency or even lack of a supporting network for new bone growth into the matrix due to poor filling properties of implanted particles, and how to accelerate bone regeneration and repair and prevent complications.

[0012] According to existing technical research, there is an urgent need to explore materials that are unified in chemical composition, internal microstructure, external morphology and biological effects, and can synergistically meet the needs of bone injury implantation and achieve efficient bone repair, so as to avoid the repair risks and complication prevention and control problems caused by excessive creation and insufficient filling.

[0013] Therefore, in order to optimize the chemical composition, internal microstructure, appearance, biological efficacy and mechanical conduction balance of biodegradable and highly active granular biomaterials, it is necessary to overcome the damage to the structure and morphology caused by secondary crushing and screening of conventional large-scale materials, so as to fundamentally solve a series of problems in the bone defect repair surgery and postoperative management, and to break through the existing material design strategies. Summary of the Invention

[0014] The purpose of the present invention is to provide a highly filling porous granular biomaterial and a preparation method thereof, to construct a porous granular biomaterial with high-density pores and curved appearance, so that effective contact and stable and balanced mechanical conduction can be formed between any porous granular biomaterials to achieve dense stacking. In addition, this type of porous granular biomaterial has high activity and can prevent and control complications (such as chronic inflammation or infection, etc.), effectively solving the problem of efficient regeneration and repair of various bone defects.

[0015] The applicants of this invention have previously developed artificial composite materials in the form of particles and fibers assembled from core-shell structures. These innovative bone repair materials offer a new and reliable solution to clinical challenges. While core-shell granular materials demonstrate significant advantages in regulating the degradation of their various components, the internal pore structure and particle morphology still rely on process engineering, and the biological morphology of the particles cannot be extensively adjusted, tailored, and optimized through mathematical modeling. Therefore, the applicants are conducting in-depth research to explore artificial materials whose chemical composition, processing technology, morphology, internal microstructure, and mechanical conduction can be precisely controlled and tailored, thereby potentially addressing the clinical challenges of repairing bone injuries at various locations.

[0016] Before explaining the specific content of this solution, we first explain a series of concepts that may be involved in the patent solution of this invention:

[0017] Highly filling porous granular biomaterials:

[0018] For the purposes of this invention, "highly filling porous granular biomaterials," also referred to as "porous granular biomaterials," refer to a class of artificially constructed, non-destructive granular materials with curved, volumetric features used to promote rapid repair of bone defects in various parts of the human body or living animals. The porous granular materials possess porous channels with ordered macropores both on the surface and within their interiors. The morphology, particle size, and internal macropore and micropore scales of the porous granular materials can be optimized through computer 3D modeling and the addition of pore-forming agents. Furthermore, the close contact between adjacent particles within the granular stack enables long-term, stable mechanical conduction, without displacement between particles that would alter the pore network. Furthermore, there are no strict restrictions on the morphology and scale of the porous granular materials, nor on the interpenetration of the macropores. These porous granular biomaterials can be implanted into a patient's bone defect via conventional surgical filling or by means of airflow delivery, thereby fully filling the defect area, providing structural support, and promoting new bone growth. Furthermore, these porous granular materials can be used as carriers to seed growth factors or cells into the defect, further promoting bone remodeling. High filling capacity means that due to the curved surface treatment of the granular material, the granular materials can be tightly stacked and maintained permanently and stably with each other, and the granular material has a high filling capacity in the bone defect area.

[0019] Components

[0020] For the purposes of the present invention, "component" refers to bioceramics and bioglass ceramics with incomplete chemical composition, and also includes inorganic salt bioceramics, biocompatible inorganic oxides and / or bioglass ceramics with consistent chemical composition but different degrees of crystallinity; "component" refers to the chemical composition and physical phase of the inorganic substance added to the photosensitive resin before digital optical three-dimensional printing, which can be a completely glassy phase substance or an inorganic chemical substance containing a partial glassy phase, and can contain oxides of a single metal or non-metal, or a complex of two or more metal or non-metal oxides. These chemical substances are transformed into completely crystalline bioceramics or non-completely crystalline glass ceramics containing a glassy phase after high-temperature treatment; the consistency of chemical composition refers to the types or relative content levels of all metal ions, acid ions or oxides, and the relative content level of the chemical composition refers to a difference of more than 0.01% in their molar percentage.

[0021] Biodegradation

[0022] For the purposes of the present invention, "biodegradation" means that inorganic biomaterials with excellent biosafety and biocompatibility can be dissolved in tissue fluid or degraded and absorbed by the metabolic processes of cells in the human body. There is no strict limit on the biodegradation rate of each component in the material, and the time span for complete degradation can be three months to two years. The composition of all inorganic ions and acid ions released during the degradation process can regulate / promote vascularization efficiency and bone regeneration efficiency, inhibit inflammatory reactions or inhibit and kill bacteria, and even mediate soft tissue repair at the interface with bones.

[0023] Doping

[0024] For the purpose of the present invention, "doping" refers to an inorganic substance formed by partial replacement of specific metal ions and acid ions in inorganic salt bioceramics and bioglass ceramics by one or more other metal ions and acid ions, and does not have a physically separated second independent phase; the doped heterogeneous ions and / or acid ions can be compounds containing doped heterogeneous ions and / or acid ions actively added to the reaction system of the synthetic bioceramic or bioglass ceramic powder, or the heterogeneous ions and / or acid ions brought by the chemical raw materials required for the synthetic powder are not actively and completely removed and remain in the synthetic powder.

[0025] 3D printing

[0026] For the purposes of the present invention, "three-dimensional printing" refers to the use of computer three-dimensional modeling software to design a porous granular biomaterial model whose appearance and internal porous structure match specific requirements, and then a mixture slurry of inorganic biomaterial powder, pore-forming agent particles and photosensitive resin is photocured and layered according to the three-dimensional model of the porous granular biomaterial. The unphotocured part of the slurry can be removed by water washing to form a printed product with a three-dimensional porous granular biomaterial whose appearance and internal structure match those of the porous granular biomaterial.

[0027] Redundant design

[0028] For the purpose of the present invention, "redundant design" refers to the use of computer three-dimensional modeling software to predict the degree of shrinkage during the sintering process of porous granular biomaterials and perform proportional adjustment of the three-dimensional model, which can avoid deviations between the appearance, size, and internal pore dimensions of the porous granular biomaterials after sintering and the specific requirements of the bone injury site.

[0029] Pore-forming particles

[0030] For the purpose of the present invention, "pore-forming particles" refer to fine particles that can decompose and volatilize in a high-temperature environment of 150°C or above. They can be organic particles that can be easily completely decomposed and volatilized by heat, or they can be inorganic particles whose residual inorganic ions after high-temperature decomposition do not affect the biosafety and biocompatibility of the material, such as calcium carbonate, sodium carbonate, etc.

[0031] micropores

[0032] For the purpose of the present invention, "micropores" are a collection of isolated, completely closed pores with a pore diameter of 20 μm or less, and the proportion of interconnections between the pores is not strictly limited.

[0033] Three-periodic minimizing surface

[0034] For the purpose of this invention, "triply periodic minimal surfaces" refers to holes with completely curved surfaces at any local position on the hole surface, and are usually holes with triply periodic minimal surfaces (TPMS) structural characteristics, including but not limited to Gyroid, IWP, Diamond, and FRD structures.

[0035] Basically does not contain

[0036] For the purposes of the present invention, "substantially free" means that the molar percentage of specific inorganic ions and acid ions in inorganic matter in bioceramics and bioglass ceramics is less than 0.05%, preferably less than 0.02%, and more preferably less than 0.01%, and most preferably 0.0 to 0.01 mol%, including all ranges contained therein.

[0037] other

[0038] Except in the examples, or where otherwise explicitly indicated, all numbers in this description indicating amounts of material or reaction conditions, physical properties of materials and / or use may optionally be understood as modified by the term "about."

[0039] Unless otherwise stated, all bioceramic powders contain sodium or potassium ions, which are doping ions that have not been thoroughly washed out or actively added after chemical synthesis.

[0040] Unless otherwise stated, all amounts are based on the mass of the final porous particulate biomaterial.

[0041] It should be noted that within any range of stated values, any particular upper value can be associated with any particular lower value.

[0042] For the avoidance of doubt, the term "comprising" is used to mean "including" but not necessarily "consisting of" or "composed of...." In other words, the listed steps or options do not have to be exhaustive.

[0043] The disclosure of the invention found herein should be considered to cover all embodiments found in the claims as they are interdependent, regardless of the fact that the claims are not multiply dependent or redundant.

[0044] Where a feature is disclosed in relation to a particular aspect of the invention (eg, the porous particulate biomaterial of the invention), that disclosure should also be considered applicable to any other aspect of the invention (eg, the method of the invention).

[0045] For the present invention, when using biodegradable bioactive porous granular biomaterials for various bone injury indications, they can be designed and manufactured based on the size of the defect and the efficiency of bone reconstruction at the site, as well as the differences in the requirements for pore size, appearance size, and multifunctionality. For example, in oral and craniomaxillofacial surgery, the particle size can be less than 1.5 mm. In larger bone defects in limb bones, the particle size can be at the level of 1 to 8 mm. The optimal design of porous granular biomaterials is that the particle surface is mainly composed of a continuous curved surface or a continuous curved surface surrounded by one or two planes, which is convenient for manufacturing, implantation, and high filling capacity. Therefore, the chemical composition, component distribution, and pore structure design strategy of the porous granular biomaterials described in the present invention will comprehensively solve the functional requirements of material activity, degradation rate, and coordinated prevention and control of inflammation, infection, etc. involved in various clinical bone injury indications.

[0046] The technical solution adopted in the present invention is:

[0047] 1. A highly filling porous granular biomaterial:

[0048] The highly filling porous granular biomaterial is obtained by three-dimensional printing and sintering a biodegradable inorganic salt ceramic containing heterogeneous ions and a metal oxide and / or glassy oxide complex. The outer wall surface of the porous granular biomaterial is a continuous curved surface or a closed body composed of a curved surface and a flat surface. The internal pore structure of the porous granular biomaterial is a completely through or partially through porous network.

[0049] The pore walls of the highly filling porous granular biomaterial are curved surfaces, and the curved surface shapes include but are not limited to spherical curved surfaces, ellipsoidal curved surfaces, cylindrical side wall curved surfaces, honeycomb hole side wall curved surfaces, three-period minimal curved surface curved surfaces, or any combination of several of them.

[0050] The maximum size of the particles of the highly filling porous granular biomaterial does not exceed 8 mm.

[0051] The chemical composition of the particles of the highly filling porous granular biomaterial is composed of a single component or a composite of two or more components, with the composite components being distributed as a two-phase mixture or forming a gradient distribution along a specific direction of the particle. It should be noted that since the highly filling porous granular biomaterial is printed using three-dimensional printing technology, the composite components can be gradiently stacked along the layer-by-layer stacking direction during the particle printing process to print the highly filling porous granular biomaterial.

[0052] The distribution of the components of the highly filling porous granular biomaterial can be a gradient component distribution structure formed by sequential, alternating, or random stacking along any direction. Correspondingly, the pore structure of the highly filling porous granular biomaterial can be a gradient distribution structure formed by sequential, alternating, or random stacking of pores of different pore sizes or pore morphologies.

[0053] The highly filling porous granular biomaterial is composed of biodegradable inorganic salt ceramics containing heterogeneous ions, metal oxides and / or glassy oxide composites, wherein the glassy oxide composite comprises a glassy substance composed of at least two inorganic oxides, and the molar percentages of the various phase components are:

[0054] Biodegradable bioceramics containing foreign ions 5%-99.99%

[0055] Metal oxides 0.05%-30%

[0056] Glassy oxide complex 0.01%-65%.

[0057] The powder of the biodegradable inorganic salt ceramic containing heterogeneous ions can be any one of wollastonite, pseudowollastonite, dicalcium silicate, tricalcium silicate, magnesia chrysocolla, white wellstone, magnesia wellstone, disilicate calcium phosphate, blue silicate, α-tricalcium phosphate, β-tricalcium phosphate, hydroxyapatite, strontium metasilicate, distraditional silicate, tristrontium silicate, or a mixture of any at least two inorganic salt bioceramics; the heterogeneous ions contained are a combination of at least one of sodium ions and potassium ions and at least one of magnesium ions and zinc ions; and there is no particular restriction on the combination of doped heterogeneous ions in the inorganic salt bioceramics.

[0058] The biodegradable inorganic salt ceramic powder containing heterogeneous ions does not have strict requirements on the type and content level of the doped heterogeneous ions. Any inorganic ions or inorganic acid ions that are beneficial to improving anti-infection, reducing inflammation, promoting vascularization and bone regeneration and repair efficiency can be doped into the bioceramic or bioglass ceramic powder.

[0059] The bioceramic powder can be a completely or partially crystalline substance of silicates, phosphates, borates, and sulfates of calcium, magnesium, zinc, and strontium that are safe for human body and biodegradable, or a completely or partially crystalline substance of a metal complex salt of silicates, phosphates, borates, and sulfates of calcium-magnesium, calcium-zinc, calcium-strontium, magnesium-strontium, zinc-strontium, magnesium-zinc, sodium-calcium, sodium-magnesium, sodium-zinc, potassium-calcium, potassium-magnesium, and potassium-zinc, or a silicon-phosphate or silicon-borate of calcium, magnesium, and zinc.

[0060] The crystalline material of the powder of biodegradable inorganic salt ceramic containing heterogeneous ions is preferably one of β-wollastonite, α-wollastonite, white wellstone, zeolite, magnesia feldspar, anhydrous calcium phosphate, β-tricalcium phosphate, α-tricalcium phosphate, amorphous calcium phosphate, dicalcium silicate, magnesium silicate, magnesium phosphate, distrontium silicate, tristrontium silicate, calcium disilicate phosphate, and blue silicon apatite, or any combination thereof.

[0061] Preferably, the biodegradable inorganic salt ceramic containing heterogeneous ions is any one of wollastonite, magnesia chrysocolla, leonidite, magnesia chrysocolla, strontium metasilicate, distrontium silicate, tristrontium silicate, or a mixture of at least two inorganic salt bioceramics.

[0062] The pores of the highly filling porous granular biomaterial are composed of macropores and micropores.

[0063] The pore size and microstructure of the highly filling porous granular biomaterial are not strictly restricted. The pores can be larger pores of any shape designed by computer modeling. The larger pores in the calcined granular biomaterial can have a size of 150 to 800 μm. The pores can also be micropores with a size of less than 20 μm remaining after a pore-forming agent is added to the printing slurry and volatilized by high heat treatment. There are no strict restrictions on the combination of pores at different scale levels in the porous granular biomaterial, and there is no strict restriction on the porosity in any gradient pore interval.

[0064] The porous granular biomaterial contains non-completely penetrating micropores, which are composed of incompletely densified micropores between bioglass particles of biodegradable inorganic salt ceramics, metal oxides, and glassy oxide complexes containing heterogeneous ions, or are micropores formed by the decomposition and volatilization of pore-forming agents. The non-completely penetrating micropores are pores no larger than 20 μm.

[0065] The porosity of the porous granular biomaterial is 25% to 78%. The pores of the porous granular material are composed of macropores with a scale level of 150 to 800 μm and non-completely penetrating micropores less than 20 μm. There is no strict limit on the scale of the through holes between the macropores, and the preferred scale is 250 to 650 μm.

[0066] The metal oxide may be one or a combination of sodium oxide, potassium oxide, zinc oxide, magnesium oxide, boron oxide and / or copper oxide.

[0067] The glassy oxide composite may be a glassy material powder composed of at least two substances selected from sodium oxide, potassium oxide, zinc oxide, magnesium oxide, calcium oxide, copper oxide, and strontium oxide and at least one substance selected from silicon dioxide, phosphorus pentoxide, and boron trioxide.

[0068] 2. A method for preparing a highly filling porous granular biomaterial:

[0069] 1) Inorganic powder and photosensitive resin are stirred and mixed in a mass ratio of 100:(40-120) to form a slurry capable of three-dimensional printing, and the slurry is then added to a printing pool. A three-dimensional model of the microstructure and appearance of a highly filled porous granular biomaterial is printed layer by layer using a photocuring printer until the three-dimensional model of the porous granular biomaterial is printed. The printed material is then washed with water to remove uncured slurry, and then dried to obtain a porous composite for later use;

[0070] 2) The porous composite obtained in the above step 1) is calcined at 620°C to 1450°C for 1 to 8 hours at a heating rate of 1°C to 8°C per minute, and when the temperature rises to 400°C to 500°C, it is kept warm for 20 to 60 minutes for degreasing. After the high-temperature calcination is completed, it is naturally cooled to obtain a highly filling porous granular biomaterial.

[0071] The inorganic powder can be any one of wollastonite, pseudowollastonite, dicalcium silicate, tricalcium silicate, magnesia chrysocolla, white wellstone, magnesia wellstone, disilicate calcium phosphate, blue silicate, α-tricalcium phosphate, β-tricalcium phosphate, hydroxyapatite, octacalcium phosphate, strontium metasilicate, dicalcium silicate, tristrontium silicate, or a mixture of any at least two inorganic salt bioceramics, and the doped heterogeneous ions in the inorganic salt bioceramics are a combination of at least one of sodium ions and potassium ions and at least one of magnesium ions and zinc ions.

[0072] The biodegradable inorganic salt ceramic powder containing heterogeneous ions does not have strict requirements on the type and content level of the doped heterogeneous ions. Any inorganic ions or inorganic acid ions that are beneficial to improving anti-infection, reducing inflammation, promoting vascularization and bone regeneration and repair efficiency can be doped into the bioceramic or bioglass ceramic powder.

[0073] The powder of the biodegradable inorganic salt ceramic containing heterogeneous ions can be a completely or partially crystalline substance of silicates, phosphates, borates, and sulfates of calcium, magnesium, zinc, and strontium that are safe for human body and biodegradable, or a completely or partially crystalline substance of metal complex salts of silicates, phosphates, borates, and sulfates of calcium-magnesium, calcium-zinc, calcium-strontium, magnesium-strontium, zinc-strontium, magnesium-zinc, sodium-calcium, sodium-magnesium, sodium-zinc, potassium-calcium, potassium-magnesium, and potassium-zinc, or a silicon-phosphate or silicon-borate of calcium, magnesium, and zinc.

[0074] The crystalline material of the inorganic powder is preferably one of β-wollastonite, α-wollastonite, white wellstone, zeolite, magnesia feldspar, anhydrous calcium phosphate, β-tricalcium phosphate, α-tricalcium phosphate, amorphous calcium phosphate, dicalcium silicate, magnesium silicate, magnesium phosphate, distrontium silicate, tristrontium silicate, calcium disilicate phosphate, and blue silicon apatite, or any combination thereof.

[0075] The metal oxide powder may also contain oxides such as sodium oxide, potassium oxide, zinc oxide, magnesium oxide, boron oxide and / or copper oxide.

[0076] The powder of the glassy oxide composite may further comprise a glassy substance powder composed of at least two substances selected from sodium oxide, potassium oxide, zinc oxide, magnesium oxide, calcium oxide, copper oxide, and strontium oxide and at least one substance selected from silicon dioxide, phosphorus pentoxide, and boron trioxide.

[0077] The inorganic powder can be any combination or eutectic of biodegradable inorganic salt ceramics, metal oxides and glassy oxide complexes containing heterogeneous ions.

[0078] The bioceramic powder can be a completely or partially crystalline substance of silicates, phosphates, and borates of calcium, magnesium, zinc, and strontium that is safe for human body and biodegradable, or a completely or partially crystalline substance of a metal complex salt of silicates, phosphates, and borates of calcium-magnesium, calcium-zinc, calcium-strontium, magnesium-strontium, zinc-strontium, magnesium-zinc, sodium-calcium, sodium-magnesium, sodium-zinc, potassium-calcium, potassium-magnesium, and potassium-zinc, or a silicon-phosphate or silicon-borate of calcium, magnesium, and zinc.

[0079] There are no strict restrictions on the chemical composition and distribution of the porous granular biomaterial, which can be a single inorganic substance or a composite of two or more inorganic components evenly mixed, or a composite of different inorganic components distributed in a gradient; there are no strict restrictions on the pore wall structure within the porous granular biomaterial, which can be a single curved pore or a gradient pore structure distribution composed of multiple curved pores, and there are no strict restrictions on the permeability of the pores.

[0080] The crystallinity of the porous particulate biomaterial is not strictly limited and can be a partially crystalline or completely crystalline inorganic single-phase or multi-phase material.

[0081] The appearance of the porous granular biomaterial is not strictly limited. Granular materials such as rugby ball shape, red blood cell shape, soybean shape, lentil shape, rice grain shape, wheat grain shape, and granular materials with grooves and holes in any part of the porous particle outer wall are all within the scope of the present invention.

[0082] The curved surface morphology of the pore wall is similar to the pore wall surface of cancellous bone and the pore structure composed of a three-periodic minimization surface of a porous network.

[0083] The curved surface in the porous granular biomaterial can be any pore composed of a three-periodic minimal surface similar to the pore network of cancellous bone, and the curved surface can be any pore composed of a three-periodic minimal surface similar to the pore network of cancellous bone, including but not limited to Gyroid, IWP, Diamond, and FRD structures.

[0084] There are no strict restrictions on the pore size and microstructure of the porous granular biomaterial. The pores can be larger pores of any shape designed by computer modeling. The larger pores in the calcined granular biomaterial can have a size of 150 to 800 μm. The pores can also be micropores with a size of less than 20 μm remaining after adding a pore-forming agent to the printing slurry and volatilizing it through high-temperature treatment. There are no strict restrictions on the combination of pores of different scale levels in the porous granular biomaterial, and there is no strict restriction on the porosity in any gradient pore interval.

[0085] The internal structure of the porous granular biomaterial is not strictly limited. Large-scale indented holes or recessed spaces may exist on the curved or flat surfaces of the outer surface of the granules, further reducing the mass of the individual porous granular materials and increasing the degradation rate of the granular materials and the ingrowth rate of new tissues.

[0086] In some embodiments, the present scheme adds pore-forming particles, which are any fine particles that do not undergo rapid chemical reactions with photosensitive resins or ultrafine powders of inorganic materials and will decompose and volatilize in a high-temperature environment of 150°C or above. Preferred pore-forming particles are polystyrene and polymethyl methacrylate particles. There is no strict restriction on the shape of the pore-forming particles, which can be spherical, ellipsoidal, cylindrical or rod-shaped. The preferred shape is spherical, ellipsoidal or rod-shaped, and the scale of the pore-forming particles is less than 20 μm.

[0087] The three-dimensional printing method is a three-dimensional printing process of a powder material-photosensitive resin composite based on digital optical processing.

[0088] During the preparation of the porous granular biomaterial, there are no strict restrictions on the addition of other bioglasses, bioceramics or low-melting-point biocompatible oxide powders that are beneficial to sintering to the slurry of the specific biodegradable inorganic salt ceramics, metal oxides, and glassy oxide complex components containing heterogeneous ions. For example, boron oxide, magnesium oxide, zinc oxide, boron-rich bioglass, zinc-rich bioglass, etc. can be added to improve sintering performance or antibacterial properties. As long as the inorganic substances are beneficial to improving or increasing biological efficacy and / or aiding sintering without affecting biocompatibility and seriously endangering biodegradability, they can be added to the printing slurry to enrich its physical and chemical properties, mechanical properties or biological properties.

[0089] In some embodiments, this solution can simultaneously print and post-process granular material models of different particle sizes on a ceramic light-curing 3D printing device. The obtained granular materials of different sizes are mixed and implanted in a certain proportion, which can further improve the filling capacity of porous granular materials for bone defects and is conducive to the regeneration of new blood vessels and the growth of bone tissue.

[0090] 2. Application of highly filling porous granular biomaterials:

[0091] The highly filling porous granular biomaterial is used in various fields of bone defect regeneration and repair, fracture healing and repair, and improves or enhances bone damage repair and / or nutrient transport in pathological bone tissue sites.

[0092] The invention is constructed by three-dimensional printing using biodegradable inorganic salt ceramics containing heterogeneous ions, metal oxides, and glassy oxide composites.

[0093] The highly filling porous granular biomaterials of the present invention have no strict restrictions on whether the inner surface of the pores is secondary modified, and there are no strict restrictions on the additives in the pore network to improve the mechanical properties and biological effects of the highly filling porous granular biomaterials. A modified layer can be modified on the pore surface, or biomolecular hydrogel can be perfused to further improve the various functions of the highly filling porous granular biomaterials, thereby enhancing cell migration, vascularization efficiency or bone regeneration and repair.

[0094] This program uniquely develops:

[0095] 1) Using computer digital-aided design to optimize the internal pore microstructure and external morphology of the particles, achieve high-density pores and curved external shapes, and enable effective contact between any particles and effective and tight accumulation of particles, significantly reducing the formation of large spaces in the accumulation body;

[0096] 2) The use of digital light processing (DLP) 3D printing technology to prepare porous granular materials solves the problem of precise manufacturing of granular materials at various scales, thereby meeting the personalized needs of granular materials for filling bone defects of different shapes and scales;

[0097] 3) Constructing porous granular materials with a curved appearance that are convenient for implantation and repair of bone defects. The granular materials can be implanted into the bone defect with the help of a smaller incision to achieve high-density filling, while avoiding sharp edges that damage the host tissue at the material-tissue interface. Through the composite or gradient distribution design of multiple active and functional material components, bone regeneration and repair and the prevention and control of various complications can be promoted.

[0098] The beneficial effects of this program are reflected in:

[0099] 1) In terms of composition, the biodegradable, highly filling porous granular biomaterials that have been calcined at high temperatures are conducive to the granular materials filling the bone injury site and gradually degrading, exerting excellent biological activity and promoting tissue repair properties; at the same time, through selective antibacterial and anti-inflammatory functional ion doping, inorganic oxide modification and component gradient distribution design, it is also beneficial for the granular materials to autonomously resist infection and control inflammatory reactions in the contact area with bone injury, greatly improving the flexibility of porous granular biomaterial filling applications and the risk of postoperative complications.

[0100] 2) In terms of microstructure, the highly filled porous granular biomaterials prepared by 3D printing additive manufacturing technology have porous interiors that are conducive to rapid vascularization, blood supply, and nutrient transport; the micropore density within the macropore wall can also be widely adjusted, and the interconnection of adjacent macropores is very conducive to cell migration.

[0101] 3) In terms of material appearance, an outer wall with continuous curved surfaces is conducive to the relatively dense stacking of any number of particles and the maintenance of stable and balanced mechanical conduction between particles, reducing the problem of excessive local gaps that slows repair efficiency or even delays healing; secondly, it is also conducive to the creation of smaller soft tissues to implant materials into larger bone defects. The curved surface design can significantly improve the fluidity and filling density of all particles during the filling process, reduce the chronic inflammatory response of sharp edges to tissues, and reduce the risk of chronic inflammation and infection after surgery.

[0102] 4) In terms of operability, highly porous biomaterials fabricated using photopolymerization 3D printing achieve ideal control over the pore size, porosity, and inner and outer diameters of any localized pore size. Furthermore, after calcination, the materials can be directly sterilized, reducing the complexity of sterilization within the pores of the highly porous biomaterials. BRIEF DESCRIPTION OF THE DRAWINGS

[0103] Figure 1It is the appearance, cross-section and structural parameters of highly filling porous granular biomaterials.

[0104] Figure 2 It is the XRD spectrum of various heterogeneous ion (co) doped wollastonite porous granular biomaterials.

[0105] Figure 3 This is a scanning electron microscope image of the surface pore structure of the magnesium-sodium doped wollastonite ceramic particles of the present invention.

[0106] Figure 4 The microporous structure of the ellipsoidal curved surface and circular plane portion of the zinc-sodium doped wollastonite ceramic porous particle of the present invention is photographed by a scanning electron microscope.

[0107] Figure 5 This is the XRD spectrum of 45S5-0.5CuO bioglass-magnesia feldspar ceramic composite porous granular material.

[0108] Figure 6 This is a comparison of the appearance of 3D-printed strontium-sodium doped wollastonite porous particles and cylindrical porous scaffolds, as well as their appearance after crushing. DETAILED DESCRIPTION

[0109] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention are within the scope of protection of the present invention.

[0110] Example 1: [Magnesium-sodium co-doped wollastonite ceramic porous granular material]

[0111] 1) A co-doped wollastonite ceramic powder containing 0.62% sodium ions and 8.7 mol% magnesium ions replacing some calcium ions is mixed with a photocurable resin at a mass ratio of 100:60 to form a slurry capable of photocurable three-dimensional printing. The slurry is then added to the printing tank of a photocurable printer, and a 22% enlarged ellipsoidal porous structure model (the pore morphology is an IWP structure, the major axis diameter and minor axis diameter length of the ellipsoidal model are 6.8 mm and 3.8 mm, respectively, and the porosity of the ellipsoidal model is 62%) is densely arranged according to the redundant design, and the number of models on the synchronous printing format reaches 40. The printing device is turned on and three-dimensional printing is performed according to the ellipsoidal model until the model printing is completed. The printed material is then rinsed with water to remove the uncured resin slurry, and the porous composite is dried and set aside;

[0112] 2) The porous printed particles in step 1) were heated from room temperature to 480°C at a rate of 1°C / min and kept at that temperature for 30 minutes for degreasing, and then continued to be heated to 1120°C at a rate of 3°C / min and sintered for 2 hours. After the insulation was completed, the particles were naturally cooled with the furnace temperature to obtain magnesium-sodium co-doped wollastonite ellipsoidal porous particles.

[0113] After testing, the scale ratio of the sintered magnesium-sodium co-doped wollastonite ellipsoidal porous particles was less than 6% of the three-dimensional model before magnification. Flame plasma emission spectroscopy (ICP) analysis showed that the substitution rate of magnesium for calcium was 8.6 mol%, and the mass percentage of sodium in the ceramic was 0.67%.

[0114] MicroCT three-dimensional reconstruction showed that the ellipsoidal porous particles Figure 1 As shown in A, the outer diameters along the long and short axes have no significant changes compared with the model, and the macropores remain continuous. The maximum pore size of the IWP is 570 μm, and the average pore size is 552 μm.

[0115] The XRD patterns of the tested porous granular materials (see attached) Figure 2 A) is consistent with the wollastonite phase and has no diffraction peaks of magnesium and sodium phases.

[0116] The outer surface layer of the ellipsoidal porous particles (such as the attached Figure 3 The IWP structural pores can be seen in the figure, which is consistent with the pore shape of the model design.

[0117] Example 2: Two porous granular materials of wollastonite ceramics partially replaced by calcium ions with zinc and strontium

[0118] 1) Two wollastonite ceramic powders, each containing 0.47% sodium ions and 4.8% zinc ions and 5.9% strontium ions replacing some calcium ions, were mixed with a photosensitive resin at a mass ratio of 100:55. Polyacrylic acid microspheres with a diameter of 8-10 μm were then added to the powders at a mass ratio of 100:10 and 100:8, respectively, and stirred to form two printable slurries. First, the zinc-sodium doped wollastonite ceramic powder slurry was added to a printing pool. A 3D biomaterial model of the particulate material was enlarged by 20% according to a redundant design (retaining the ellipsoidal 4 / 5 structure with a combined curved and flat surface, and an IWP structure with a pore structure; the major and minor axes of the ellipsoidal model were 5.1 mm and 3.8 mm, respectively, and the porosity was 56%). A total of 36 models were printed simultaneously. The photocurable printer was then activated to perform photocurable printing layer by layer until all 3D models were printed. The printed material was then rinsed with tap water to remove any uncured resin slurry. Similarly, another strontium-sodium doped wollastonite ceramic powder slurry was added to the printing tank and printed according to the redundant design. A 20% magnified three-dimensional model of the granular biomaterial (retaining the appearance of the combined curved and flat surfaces of the 3 / 5 ellipsoid structure, with the pores presenting an IWP structure; the major and minor axis lengths of the ellipsoid model were 4.6mm and 3.8mm, respectively, and the porosity was 60%). The printed particles were also rinsed. Then, the two printed particles were dried at 60°C and set aside.

[0119] 2) The two zinc-sodium and strontium-sodium doped ceramic powder printing particles obtained in the above step 1) are heated from room temperature to 450°C at a rate of 1°C, and are kept at 480°C for 45 minutes for degreasing. Then, the temperature is increased at a rate of 2°C per minute to 1150°C and calcined for 3 hours. After the insulation is completed, they are naturally cooled with the furnace temperature to obtain porous granular biomaterials of zinc and strontium doped wollastonite ceramics, respectively.

[0120] After testing, the two types of non-complete ellipsoidal porous particles that retain the ellipsoidal 4 / 5 structure and 3 / 5 structure of wollastonite doped with zinc-sodium and strontium-sodium respectively after sintering have a scale shrinkage of no more than 4.6% compared with the three-dimensional model. ICP analysis shows that the substitution rate of zinc for calcium is still 4.8 mol%, and the substitution rate of strontium for calcium is still 5.6 mol%. At the same time, the content of sodium ions has not changed.

[0121] The microCT three-dimensional reconstruction showed that the sintered zinc-sodium and strontium-sodium doped wollastonite porous granular biomaterials were Figure 1 As shown in Figures 1B and 1C, the outer diameters along the major and minor axes do not change significantly compared with the model, and the macropores remain continuous.

[0122] XRD spectrum of porous particles tested by XRD (see attached Figure 2B and 2C) are consistent with the physical phase of wollastonite, and there are no diffraction peaks of zinc-sodium and strontium-sodium phases.

[0123] The SEM observation of Zn-Na doped wollastonite ceramic porous granular materials (such as the attached Figure 4 The ellipsoidal surface and circular plane part (as shown in the figure) both present an IWP-type pore structure, which is consistent with the pore shape of the model design.

[0124] Example 3: [Wollastonite ceramic porous granular material with axially gradient magnesium-strontium-zinc distribution]

[0125] 1) Three kinds of wollastonite ceramic ultrafine powders containing 7.8% magnesium ions, 5.6% strontium ions and 3.9% zinc ions instead of calcium ions for ion doping and each containing 0.38% sodium ions were mixed and stirred evenly with polymethyl methacrylate with a particle size of 5 μm and a photocurable resin at a mass ratio of 100:10:65 to form three kinds of printing slurries. First, the 7.8% magnesium-sodium doped wollastonite ceramic slurry was added to the material tank of the photocurable printer. According to the redundant design, a semi-ellipsoidal three-dimensional structure model (using an IWP type structural channel, the channel is an IWP structure; the major axis diameter and the minor axis diameter of the ellipsoidal model are long) was simultaneously enlarged by 18%. The porous biomaterial is densely arranged with a diameter of 3.6 mm and 2.8 mm, and a porosity of 60%, and the number of models on the synchronous printing format reaches 42. The light-curing printing device is then started to perform three-dimensional printing in the direction of the long axis of the semi-ellipsoidal model. When the porous granular biomaterial is printed to one-third and two-thirds of the length, the residual slurry is respectively sucked out, and 5.6% strontium-sodium doped and 3.9% zinc-sodium doped wollastonite ceramic slurries are added in sequence and printing is continued until the model printing is completed. The printed particles are then rinsed with tap water to discharge the uncured resin slurry in the porous gaps. The porous composite is then dried at 60°C for standby use.

[0126] 2) The porous printed particles obtained in step 1) are heated from room temperature to 460°C at a rate of 1°C, and are kept at 460°C for 60 minutes for degreasing. The temperature is then raised at a rate of 2°C per minute to 1150°C and calcined for 20 minutes. The temperature is then rapidly cooled to 1080°C after 10 minutes and sintered for another 2 hours. After the insulation is completed, the particles are naturally cooled with the furnace temperature to obtain wollastonite porous particle biomaterials with different magnesium-strontium-zinc gradient distributions.

[0127] After testing, the replacement rate of magnesium, strontium and zinc for calcium in the sintered semi-ellipsoidal porous particles decreased by 52%, 69% and 78% respectively compared with the powder, and the sodium ions in each part remained stable, indicating that the curved particles shrank, causing the non-stoichiometric wollastonite component content in the post-printing part to decrease. The appearance of the three ion gradient co-doped wollastonite high-filling porous particle biomaterial is shown in the attached Figure 1As shown in D, the particle still has a semi-ellipsoidal appearance, and the internal large pores have excellent penetration. Because the redundant design is not enlarged enough to offset the shrinkage caused by sintering, the major axis diameter and minor axis diameter of the particle after sintering are longer than those of the model.

[0128] Example 4: [Axially Gradient 45S5-0.5CuO Glass Gradient Reinforced Magnesium Feldspar Ceramic Composite Porous Granular Material]

[0129] 1) 45S5 glass containing 0.5 mol% CuO instead of CaO (denoted as 45S5-0.5CuO) and magnesia chalcite ceramic powder were mixed and stirred evenly with photocurable resin at a mass ratio of 100:66 to form two photocurable 3D printable slurries. The magnesia chalcite ceramic slurry was first introduced into the photocurable printing tank, and the 3D structure model of the highly filling porous granular biomaterial was simultaneously enlarged by 24% according to the redundant design (the macropore channel was a diamond structure, and the curved and flat surface combination appearance model of the ellipsoid 4 / 5 structure was retained. The long axis diameter of the incomplete ellipsoid model was 2.8 mm, and the short axis was 2.8 mm). The number of models on the synchronous printing format is 30, and the light-curing printing device is started to perform three-dimensional printing in the axial direction of the model. When the length of the porous granular biomaterial is 10%, 20%, 40%, 60%, and 80% is printed, the residual slurry is sucked out, and 45S5-0.5CuO bioglass is added and five layers are printed continuously. The bioglass slurry is then replaced with magnesia feldspar ceramic slurry. The two slurries are replaced in this cycle until the model printing is completed. The printed material is then rinsed with tap water to remove the uncured resin slurry, and the porous composite is then dried with hot air for standby use;

[0130] 2) The porous printed particles obtained in the above step 1) are heated from room temperature to 500°C at a rate of 1°C, and are kept at 500°C for 30 minutes for degreasing. The temperature is then raised at a rate of 3°C per minute to 1180°C, calcined for 15 minutes, then lowered to 1120°C within 10 minutes, and kept sintered for 2 hours. After the insulation is completed, the particles are naturally cooled with the furnace temperature to obtain a porous granular biomaterial with a gradient chemical composition of 45S5-0.5CuO glass and magnesia feldspar ceramic.

[0131] Example 5: [Sodium-doped β-tricalcium phosphate ceramic porous granular material]

[0132] 1) Similar to step 1) in Example 1, except that the wollastonite ceramic powder containing sodium ions and partially substituted with magnesium ions was replaced with β-tricalcium phosphate ceramic powder doped with 6.8% sodium ions. The printed model was obtained by cutting off 1 / 5 of the upper and lower portions of the complete ellipsoid, leaving the middle 1 / 5. The other steps were the same as step 1) in Example 1. The ceramic slurry was then printed, and the granules were washed and dried to obtain a granular material for later use.

[0133] 2) The sodium-doped β-tricalcium phosphate printed particles obtained in the above step 1) are heated from room temperature to 450°C at a rate of 1°C, and are kept at 480°C for 45 minutes for degreasing. The temperature is then increased at a rate of 2°C per minute to 1160°C and calcined for 3 hours. After the insulation is completed, the particles are naturally cooled with the furnace temperature to obtain porous granular biomaterials of sodium-doped β-tricalcium phosphate ceramics.

[0134] After testing, the non-complete ellipsoidal porous particles of the sintered sodium-doped β-tricalcium phosphate that retain the structure of the middle 3 / 5 of the ellipsoid have a scale that is no smaller than 6.7% of the three-dimensional model. ICP analysis shows that the mass percentage of sodium ions in the β-tricalcium phosphate ceramic particles is 6.8%.

[0135] The microCT three-dimensional reconstruction showed that the sintered zinc-sodium and strontium-sodium co-doped wollastonite porous granular biomaterials were as shown in the attached figure. Figure 1 As shown in Figure E, the outer diameters along the major and minor axes do not change significantly compared with the model, and the macropores remain continuous.

[0136] Example 6: [45S5-0.5CuO bioglass-magnesia chalcedony ceramic composite porous granular material]

[0137] The steps are the same as those in Example 4, except that in step 1), the magnesia chalcedony ceramic and 45S5-0.5CuO glass are mixed in a ratio of 40:60, 60:40, 80:20 and 100:0, and then stirred and mixed with a light-curing resin to form a ceramic powder and glass powder mixed slurry. Then, the four groups of slurries are printed and post-processed once according to a semi-ellipsoidal model to obtain a glass ceramic porous granular material. As shown in the attached figure Figure 5 XRD detection shows that the four porous granular ceramics are composed of two crystalline material components: magnesia feldspar (Ca2MgSi2O7) and sodium calcium silicate (Na2Ca2Si3O9); as the 45S5-0.5CuO increases, the diffraction peak of sodium calcium silicate in the particles enhances, indicating that the content of this component increases.

[0138] Example 7: [ZnO-MgO-calcium disilicate phosphate ceramic composite porous granular material]

[0139] 1) First, the main steps and process conditions of step 1) in Example 1 were followed, except that the magnesium-sodium co-doped wollastonite ceramic powder was replaced with a mixture of 92% calcium disilicate phosphate powder (component A, with a sodium ion content of 0.29%) and a 2% ZnO-6% MgO mixed powder (component B). The pores of the three-dimensional model were replaced with a Gyroid structure instead of an IWP structure. The other steps were the same as step 1) in Example 1. After the porous particles were dried, they were set aside.

[0140] 2) The porous printed particles prepared in step 1) are heated from room temperature to 480°C at a rate of 2°C / min and kept at that temperature for 30 minutes for degreasing. The temperature is then further heated to 1250°C at a rate of 3°C / min and sintered for 5 hours. After the holding period is completed, the particles are naturally cooled with the furnace temperature to obtain a porous calcium disilicate phosphate ceramic biomaterial containing magnesium oxide and zinc oxide.

[0141] After testing, it was found that the outer diameter of the ellipsoidal porous granular biomaterial along the axis after sintering did not change significantly. The maximum size of the Gyroid pore was 640μm and the average pore diameter was 586μm.

[0142] Example 8:

[0143] A similar preparation process to that of the strontium-sodium doped wollastonite ceramic porous granular material in Example 2 was used, except that the three-dimensional model used for printing adopted a cylindrical bracket model with a diameter and height of 6 mm. The cylindrical bracket was obtained by printing, washing, drying and sintering.

[0144] The cylindrical support of this embodiment is crushed. Figure 6 As shown, the appearance and stacking morphology of the strontium-doped granular material prepared in Example 2 are compared with the stacking morphology of the cylindrical bracket and the broken particles. It can be seen that the three-dimensional printed particles can be tightly stacked, but the particles after the bracket is broken are lamellar and have sharp edges, and there is a risk of local large-scale voids in the stacking.

[0145] Example 9:

[0146] A similar preparation process is used for the strontium-sodium doped wollastonite ceramic porous granular material in Example 2, except that the three-dimensional model used for printing retains the appearance of the combined curved and flat surfaces of the ellipsoid 4 / 5 and 3 / 5 structures, and there is a hemispherical recessed space with a diameter of one-third of the diameter of the circular plane in the center of the circular plane. According to such a partially ellipsoidal bracket model, printing, washing, drying and sintering treatments are performed to obtain a bracket with the appearance of the combined curved and flat surfaces of the ellipsoid 4 / 5 and 3 / 5 structures, and a hemispherical recess appears in the center of the circular plane.

[0147] Examples 10-15:

[0148] The same as the above-mentioned Example 7, except that in steps 1) and 2), the ultrafine powder composition, microporous pore-forming agent composition, certain preparation conditions and parameters are carried out as shown in the table below, thereby obtaining a variety of different granular biomaterials.

[0149]

[0150]

[0151] Example 16

[0152] 5.2 g of the magnesium-sodium co-doped wollastonite ellipsoidal porous granular material obtained in Example 1 was placed in 200 ml of cell culture medium a-MEM and continuously immersed at 37°C. The release of magnesium, silicon, sodium, calcium, and phosphorus from 0 to 168 hours was monitored by ICP. The results showed that the concentrations of calcium and silicon ions in a-MEM continued to increase steadily, while the concentrations of magnesium and sodium ions increased slowly. The phosphorus ion concentration remained essentially stable, showing a downward trend at 120 and 168 hours, indicating that the ellipsoidal porous granular biomaterial has a certain degree of degradability.

[0153] The magnesium-sodium co-doped wollastonite ellipsoidal porous granular material obtained in Example 1 and a similar β-tricalcium phosphate ceramic porous granular material were ground into ultrafine powders with a particle size of approximately 5 microns. These powders were then co-cultured in human venous endothelial cells cultured in standard sterile in vitro culture flasks. Testing showed that cell activity in the flask containing the magnesium-sodium co-doped wollastonite powder increased rapidly after 1, 3, and 7 days of culture, with a significant difference between the two groups. The proliferation rate reached a maximum of 28% compared to the β-tricalcium phosphate group. These test results demonstrate that the magnesium-sodium co-doped wollastonite ellipsoidal porous granular material obtained in Example 1 exhibits excellent activity in promoting the proliferation of cells closely related to vascularization.

[0154] The ultrafine powder prepared by the above method was soaked in PBS at a solid-liquid mass / volume ratio of 0.2 g / ml for 72 hours, and the soaking liquid was then added dropwise to a culture dish pre-inoculated with Staphylococcus aureus. It was found that the bacterial count rapidly decreased to 66% and 19% after continued culture for 8 and 24 hours, respectively. However, there was no significant change in the bacterial count when the β-tricalcium phosphate ultrafine powder extract was added (97% and 95% of the bacterial count when the extract was supplemented), indicating that the magnesium-sodium co-doped wollastonite ellipsoidal porous granular material prepared in Example 1 has excellent antibacterial activity.

[0155] Example 17: Four porous granular materials prepared in Example 1, Example 2 and Example 3 were used to

[0156] Femoral defect tissue regeneration repair and reconstruction testing.

[0157] Beagle femoral defect experiment:

[0158] Ten 9-month-old male beagle dogs, weighing 30±2 kg, were divided into five groups. Following the animal experiment and clinical surgical procedures, four groups of the four porous granular biomaterials, steam-sterilized and prepared in Examples 1, 2, and 3, were efficiently implanted into cylindrical femoral defects, forming a dense accumulation. The defects measured 15 mm in diameter and 12 mm in depth. After cleaning, the wounds were closed layer by layer, and the skin was sutured. Two beagle dogs in the blank defect group underwent wound closure and suture after defect creation. Postoperatively, 8 million units of penicillin were injected intramuscularly. The dogs were fed under normal conditions. In vivo X-ray imaging analysis was performed after 6 and 18 weeks, and the femoral specimens of the beagle dogs were anesthetized and fixed for MicroCT three-dimensional reconstruction analysis and hard tissue section staining analysis. It was found that the porous granular biomaterials of Examples 1, 2, and 3 did not cause inflammatory reactions and infection at the femoral defect site at 6 weeks after surgery, and neovascularization and good bone regeneration occurred. New bone tissue was diffused between the particles and within the pores of each particle. The degradation rate of the granular biomaterial was 25% to 40%. At 18 weeks, the material showed obvious degradation, with a degradation rate of 76% to 88%. The new bone was almost diffused throughout the defect area, and most of the new bone had undergone bone remodeling and formed mature bone tissue. However, the blank group still had a large defect cavity 18 weeks after surgery, and only a small amount of new bone tissue was generated around the initial defect wall.

[0159] As shown in the above examples, the highly filling porous granular material of the present invention can significantly promote the repair of femoral defects. The pore network of the granular material facilitates the ingrowth of new bone in the early and middle stages. Furthermore, the granular material forms a dense packing structure after filling, without uneven gaps, allowing new bone to grow more evenly inward. Over time, the granular material undergoes significant degradation, leading to the complete repair of the bone defect. Therefore, this type of granular material significantly improves filling convenience and rapidly promotes bone regeneration and repair, showing promising application prospects.

[0160] The present invention is not limited to the above-mentioned optimal implementation mode. Anyone can derive other forms of products under the inspiration of the present invention. However, no matter what changes are made in the shape or structure, any technical solution that is the same or similar to that of the present application falls within the scope of protection of the present invention.

Claims

1. A highly filling porous granular biomaterial, characterized in that: The porous granular biomaterial is obtained by 3D printing and sintering a biodegradable inorganic salt ceramic containing heterogeneous ions and a metal oxide and / or glassy oxide composite, wherein the heterogeneous ions contained are a combination of at least one of sodium ions and potassium ions and at least one of magnesium ions and zinc ions, the outer wall surface of the particle of the porous granular biomaterial is a continuous curved surface or a closed body composed of a curved surface and a plane, and the pore structure inside the particle is a fully through or partially through porous network, wherein the pore wall of the porous granular biomaterial is a curved surface, and the curved surface shape includes one of spherical curved surface, ellipsoidal curved surface, cylindrical side wall curved surface, honeycomb pore side wall curved surface, three-periodic minimal curved surface or a combination of any several thereof, and the pore structure is composed of macropores and micropores, wherein the porosity of the porous granular biomaterial is 25%~78%, the pores of the porous granular material are composed of macropores with a scale level of 150~800μm and non-fully through micropores less than 20μm, and the maximum scale of the granular biomaterial does not exceed 8 The pore structure of porous granular biomaterials is a gradient distribution of sequential, alternating or disordered superposition of different pore sizes or different pore morphologies.

2. The highly filling porous granular biomaterial according to claim 1, characterized in that: The micropores are composed of incompletely densified micropores of biodegradable inorganic salt ceramics, metal oxides, and glassy composite oxides containing heterogeneous ions, or are formed by the decomposition and volatilization of pore-forming agents.

3. The highly filling porous granular biomaterial according to claim 1, characterized in that: The invention is composed of biodegradable inorganic salt ceramics, metal oxides and / or glassy oxide composites containing heterogeneous ions, wherein the glassy oxide composite comprises a glassy substance composed of at least two inorganic oxides, and the molar percentages of various phase components are: Biodegradable bioceramics containing foreign ions 5%−99.99% Metal oxides 0.05%−30% Glassy oxide complex 0.01%−65%.

4. The highly filling porous granular biomaterial according to claim 1, characterized in that The chemical composition is composed of a biodegradable inorganic salt bioceramic containing heterogeneous ions and a single component or two or more metal oxide components. The composite components are uniformly mixed and distributed or have a gradient distribution formed along a specific direction of the particles.

5. The highly filling porous granular biomaterial according to claim 4, characterized in that: The biodegradable inorganic salt bioceramic containing heterogeneous ions is a completely or partially crystalline substance of silicates, phosphates, borates, and sulfates of calcium, magnesium, zinc, and strontium that is safe for human biology and biodegradable, or a completely or partially crystalline substance of a metal complex salt of silicates, phosphates, borates, and sulfates of calcium-magnesium, calcium-zinc, calcium-strontium, magnesium-strontium, zinc-strontium, magnesium-zinc, sodium-calcium, sodium-magnesium, sodium-zinc, potassium-calcium, potassium-magnesium, and potassium-zinc, or a silicon-phosphate or silicon-borate of calcium, magnesium, and zinc; the metal oxide is one or a combination of sodium oxide, potassium oxide, zinc oxide, magnesium oxide, boron oxide, and / or copper oxide; and the glassy oxide complex is a glassy substance powder composed of at least two of sodium oxide, potassium oxide, zinc oxide, magnesium oxide, calcium oxide, copper oxide, and strontium oxide and at least one of silicon dioxide, phosphorus pentoxide, and boron trioxide.

6. A method for preparing the highly filling porous granular biomaterial according to any one of claims 1 to 5, characterized in that: include: 1) Inorganic powder and photosensitive resin are stirred and mixed in a mass ratio of 100:(40-120) to form a slurry for three-dimensional printing, and the slurry is then added to a printing pool. A three-dimensional model of the microstructure and appearance of a redundantly designed highly filling porous granular biomaterial is printed layer by layer using a photocuring printer until the three-dimensional model of the porous granular biomaterial is printed. The printed material is then washed with water to remove uncured slurry, and then dried for later use; 2) calcining the porous composite obtained in step 1) at 620°C to 1450°C for 1 to 8 hours at a heating rate of 1°C to 8°C per minute, and maintaining the temperature at 400°C to 500°C for 20 to 60 minutes for degreasing. After the high-temperature calcination is completed, the composite is naturally cooled to obtain a highly filling porous granular biomaterial.

Images