Selective laser sintering of polymer powder embedded with water-soluble fluidity additives

Abstract

The present invention relates to a polymer powder, preferably a medical-grade polymer powder, for use in selective laser sintering (SLS) for applications including, but not limited to, medical, food, and pharmaceutical applications. The polymer, preferably medical-grade, is biodegradable and can be used to fabricate objects such as medical implants and tissue scaffolds. The powder is biocompatible and biodegradable and can include a flow additive. The flow additive can consist of an osteoconductive flow aid suitable for medical applications, a water-soluble salt flow aid that dissolves during device degradation, or a combination of both. The water-soluble salt flow aid is used in applications where no trace of implantation is observed in tissue after device degradation.

Description

[Technical Field]

[0001] This invention relates to polymer powders, preferably medical-grade polymer powders, for use in selective laser sintering (SLS) for application fields including but not limited to medical, food, and pharmaceutical applications. These preferably medical-grade polymers are biodegradable and can be used to manufacture objects such as medical implants and tissue scaffolds. The powders are biocompatible and biodegradable and may contain fluidity additives. The fluidity additives may consist of osteoconductive fluidizers suitable for medical applications, fluidizers that are water-soluble salts that dissolve during device disintegration, or a combination of both. Water-soluble fluidizers are used in applications where no implantation traces are observed in the tissue after device disintegration.

[0002] Background of the Invention Selective laser sintering (SLS) processes are widely used for metals and polymers. More specifically, selective laser sintering of polymers primarily utilizes engineered polymers such as nylon, polyarylether ketones, polyetherether ketones, polystyrene, and thermoplastic elastomers. The grades of these polymers are often not intended for medical applications. Furthermore, currently available engineered polymers are not biodegradable in the body. In addition, the fluidity additives typically used in selective laser sintering of polymer powders are not suitable for embedding in biodegradable polymer matrices. Typical fluidity additives used in the market include, but are not limited to, glass microspheres, carbon powder, fumed silica, carbon nanotubes, and colorants.

[0003] While current SLS polymer materials are not suitable for use as biodegradable implants, several materials are available on the market for this purpose. These materials include, but are not limited to, polycaprolactone, polylactide, polylactic acid-coglycolic acid, and their various copolymers. These materials are ideal for a variety of medical applications, depending on the mechanical, chemical, and degradation time requirements. For example, polydioxanone degrades much faster than polylactide, while polylactide is much more robust. Because of these characteristics, polylactide can be used for orthopedic applications, while polydioxanone can be used in applications that come into contact with blood, such as arterial plugs.

[0004] SLS printing is a relatively rapid manufacturing method that allows for the printing of a large number of parts in a single pass, requires no support material, and produces highly accurate 3D-printed items. Therefore, biodegradable polymers are attracting attention in SLS 3D printing. This process can be used for applications of all sizes within the body. While SLS 3D printing can be used for a variety of applications, one manufacturing condition is not applicable to all materials. For example, the conditions typically used for printing nylon cannot be used for printing polycaprolactone. As a result, specialized printing methods need to be developed. Biodegradable medical polymers printed using SLS will offer biocompatibility, biodegradability, and a precise manufacturing method for implantable medical devices.

[0005] To develop SLS powders of biodegradable polymers, it is necessary to optimize the powder by changing variables such as particle morphology and the possibility of adding fluidity additives. International Publication 2019 / 043137 shows the use of unsintered amorphous hydroxyapatite at a weight concentration of up to 10 weight percent to improve the fluidity of the powder. Its use is beneficial because water-soluble salts are removed in the body during implant degradation. As a result, there will be no solid material remaining at the implantation site after the polymer implant has completely degraded. Similar to International Publication 2019 / 043137, water-soluble fluidity additives would provide the benefit of powder fluidity to enable printing using SLS technology.

[0006] Summary of the Invention In one embodiment, a method for producing polymer-based materials and polymer-based composite materials is disclosed, which are used in the manufacture of medical implants that come into contact with blood, and which do not require decomposition, removal, or leave no residual material. The method for producing polymer-based materials or polymer-based composite materials includes, but is not limited to, impact grinding, pin mill grinding, shear grinding, centrifugal grinding, knife grinding, cryogenic grinding, mixed grinding, impact grinding, or air classification grinding. Furthermore, blending methods such as tumble blending, inversion blending, cryogenic grinding, mixed grinding, impact grinding, and especially high shear blending are used to produce polymer-based powder composite materials. The materials mentioned may exist in the form of blended powders, sintered powders, extruded powders, or injection-molded powders. The polymer powders used for these compositions are medical-grade bioabsorbable powders. Examples of medical-grade powders include, but is not limited to, polyvinyl alcohol, polyvinyl acetate, polylactide, polylactic acid-co-glycolic acid, polyglycolic acid, polycaprolactone, and especially polydioxanone. More specifically, bioabsorbable powders used in medical devices consist of materials manufactured from monomers including caprolactone, l-lactide, dl-lactide, glycolide, p-dioxanone, and mixtures thereof. As a result, this material can be used to manufacture implantable medical devices. Furthermore, since the material decomposes, there is no need for removal surgery.

[0007] In another embodiment, the additives used in polymer powder composites are water-soluble salts. Water-soluble salts are embedded on the surface of polymer particles by methods such as tumble blending, inversion blending, cryogenic grinding, mixed grinding, impact grinding, and especially high-shear blending, but are not limited to these. Water-soluble salts can also be embedded in polymer particles during manufacturing. Examples of water-soluble salts include, but are not limited to, non-toxic salts such as magnesium sulfate, sodium sulfate, potassium chloride, sodium chloride, sodium sulfate, potassium aluminum sulfate, magnesium chloride, and magnesium chloride hexahydrate. After implantation, as the polymer material decomposes, the salts dissolve into the bloodstream and are removed by urine via the kidneys. While water-soluble salts do not remain within the implantation site like other fluid additives such as ceramics, polymer powders with embedded water-soluble salts can be combined with other additives for specialized materials. More specifically, additives such as bioceramics can be added to polymer powders with embedded water-soluble salts to form powders specifically for orthopedic use.

[0008] In another embodiment, water-soluble salts benefit the flowability of polymer powders for SLS printing after being blended with or embedded on the surface of polymer powder particles. Water-soluble salts are thought to benefit the flowability of polymer powders by reducing hydrogen bonding between particles, reducing static electricity between materials, promoting tumbling by causing changes on the particle surface, and helping to lower water adsorption levels. Polymer powders are highly complex materials that can change with even slight fluctuations in particle size, temperature, or humidity. The use of flow aids and common additives allows for a wider process window.

[0009] In one embodiment, a composition of polymer-based material powder having suitable flow properties enabling greater manufacturing simplification and efficiency is disclosed. The polymer powder composite material was blended with additives of different concentrations, and its flowability was then analyzed using dynamic flow analysis. The dynamic flow analysis method used focused on avalanche energy, fracture energy, and surface fractal results. The minimum values ​​of these variables indicated the appropriate flow mechanics of the powder composition. Composite materials intended for powder processing applications, more preferably laser sintering applications, were optimal when they had surface fractal results closest to 1 compared to other additive blends. The flow behavior of the material can also be evaluated using tap density and qualitative blade testing. Qualitative blade testing is performed on powder compositions intended for laser sintering or binder injection applications, given that the material will be utilized in this apparatus. After the flowability of the composite powder is optimized, minimal mechanical force is required to bring the material to an unconsolidated state.

[0010] In another embodiment, compositions of polymer-based material powders usable by selective laser sintering, binder injection, selective absorption sintering, and hybrid methods thereof are disclosed. The aforementioned processing methods require powders that have excellent fluidity regardless of ambient temperature. This ensures that the polymer powder produces a smooth surface for powder processing techniques to fuse and produce 3D articles. If the powder has poor fluidity, the powder surface becomes more porous and irregular, which can result in defective printed parts. Printed parts manufactured using powders with insufficient fluidity may have unpredictable mechanical properties and a high failure rate. A typical printing process involves dispersing a powder layer on a platform, irradiating a portion of the material corresponding to the cross-sectional shape of the part, and then adding and irradiating additional layers until the part is complete.

[0011] In another embodiment, compositions of polymer-based material powders are disclosed that can be used to manufacture structures having different internal and external shapes or a uniform shape. The developed polymer powders can be used in laser sintering applications, enabling 3D printing of complex shapes that are not typically achievable by conventional manufacturing methods. These shapes can be designed for specific loads or for specific tissues, such as trabecular structures. The shape of the part varies depending on its function.

[0012] In one embodiment, a method for printing biodegradable polymer materials using laser sintering technology is disclosed. In particular, the printing method for polymer powder composite materials disclosed includes printing a base anchor layer. The base anchor layer is irradiated using an energy density lower than that of the printed portion. Energy density is a measure of the energy imparted to the material powder bed by the laser during the printing operation. The value is J / mm 3This can be reported and is calculated by dividing the laser wattage by the product of the scanning speed, hatch distance, and layer height. Furthermore, the base anchor layer can be thicker than 100 μm, particularly 50 μm to 1 mm, more specifically 50 to 500 μm, and especially 50 to 300 μm. The base anchor layer is printed to create a surface that is fixed to the powder bed. After printing the base anchor layer, the apparatus begins printing the desired part. However, the first layer of the part can be printed within the base anchor layer to further prevent curling, shifting, or inaccuracies in shape. The part is typically printed at a higher energy density, and the base anchor layer prevents shifting, warping, curling, and shrinkage of the printed part. More specifically, the base anchor layer allows for the printing of fine details without shifting, warping, curling, and shrinkage. Without a printed base layer, most fine printing will fail. After the printing operation is complete, the printed base layer can be removed from the printed part. Furthermore, the printed base anchor layer can be partially separated into powder that can be used in future printing operations. The printed base anchor layer can be printed in multiple locations on the same part. For example, if a part has a thin protruding portion, an additional base anchor layer can be printed on the powder bed before this portion of the part is irradiated in-process.

[0013] In another embodiment, the shape of the base anchor layer varies depending on the part being printed. Depending on the shape of the part being printed, the base anchor layer may need to be thinner, thicker, wider, or narrower.

[0014] In one embodiment, an in-process annealing process is disclosed in which, after printing of potential parts, an operator can optimize the process to define the crystallinity and mechanical properties of the final part. This embodiment involves annealing a polymer composite blend comprising polydioxanone, a potential additional polymer having a melting point of 50°C to 240°C, and a fluidity additive. The annealing method utilizes a processing temperature 10°C to 35°C lower than the lowest melting point of the polymer, and further, this temperature is maintained for a minimum of 1 second and a maximum of 8 hours before initiating a controlled cooling rate. The cooling rate is controlled at a rate of 0°C / min to 20°C / min. The annealing step is performed after the completion of the printing job. Furthermore, the printing time can be included in the annealing time. Printed parts annealed for a longer time at a slower cooling rate tend to have a higher yield tensile strength, a higher modulus of elasticity, and a lower elongation at break. Printed parts annealed for shorter periods at faster cooling rates have lower yield point tensile strength, lower modulus of elasticity, and greater elongation at fracture. In addition, materials annealed for longer periods have higher crystallinity. Operators can use this information to manufacture products with different mechanical properties and crystallinity depending on the application. For example, in soft tissue applications, high strength parts may not be necessary, but parts with high elongation may be required. Furthermore, in hard tissue applications, stronger parts with a higher modulus of elasticity may be required rather than parts with high elongation.

[0015] In one embodiment, the laser parameters used in the application of laser sintering can change the final structure and crystallinity of the printed part. Energy density (J / mm 3The strength is calculated by dividing the laser power (W) by the product of the scanning speed (mm / s), hatch distance (mm), and layer height (mm). Parts printed at higher energy densities tend to be stronger until they reach a baseline of mechanical properties. Once the baseline of mechanical properties is reached, the tensile yield strength, modulus of elasticity, and elongation at break become constant. Higher energy densities tend to produce stronger parts than parts manufactured using lower energy densities. Furthermore, higher energy densities result in higher crystallinity of the final part, while lower energy densities produce parts with lower crystallinity. However, annealing can achieve a similar degree of crystallinity regardless of the energy density used to print the part. As a result, parts requiring higher strength can be printed at higher energy densities, and parts not requiring high strength can be printed at lower energy densities.

[0016] Detailed description of the invention 1.Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. In case of any conflict, this specification, including its definitions, shall prevail. Preferred methods and materials are described below, but similar or equivalent methods and materials may be used in the practice or testing of the present invention. All publications, patent applications, patents, and other references referenced herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative and not intended to limit the scope of the invention.

[0017] The terms “comprise, include,” “having, has,” “can,” and “contain,” as used herein, and their variations, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. Unless explicitly indicated otherwise by the context, singular “a,” “an,” and “the” imply plural references. This disclosure also assumes other embodiments “comprise,” “consist of,” and “essentially consist of,” the embodiments or elements presented herein, whether expressly described or not.

[0018] The conjunction "or" includes any combination of one or more enumerated elements associated by the conjunction. For example, the phrase "a device containing A or B" may refer to a device containing A without B, a device containing B without A, or a device containing both A and B. The phrases "at least one of A, B, ... and N" or "at least one of A, B, ... and N or any combination thereof" are defined in the broadest sense, meaning one or more elements selected from the group containing A, B, ... and N. That is, any combination of one or more elements A, B, ... or N may contain any one element alone or in combination with one or more other elements, and may also contain additional elements that are not enumerated.

[0019] The modifier "approximately" used in relation to quantity includes the stated value and has a meaning indicated by the context (e.g., including an error of at least the degree relevant to the measurement of a particular quantity). The modifier "approximately" should also be considered to disclose a range defined by the absolute values ​​of the two endpoints. For example, the expression "approximately 2 to approximately 4" also discloses the range "2 to 4". The term "approximately" can mean plus or minus 10% of the given number. For example, "approximately 10%" can indicate a range of 9% to 11%, and "approximately 1" can mean a range of 0.9 to 1.1. Other meanings of "approximately" may be evident from the context, such as rounding, so for example, "approximately 1" may also mean 0.5 to 1.4.

[0020] In the enumeration of numerical ranges in this specification, it is explicitly assumed that each number in between has a similar degree of precision. For example, the range 6–9 includes the numbers 6 and 9, as well as 7 and 8, and the range 6.0–7.0 includes the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0.

[0021] The term "weight %" is used herein as an abbreviation for weight percentage. It refers to the weight percentage proportion of the ingredients in a blend. "Weight %" should not be confused with an indicator of the uniformity of the blend.

[0022] The terms “microencapsulated” and “encapsulated” are used herein to generally describe bioactive agents incorporated into any type of long-acting formulation or technology, regardless of shape or design. Therefore, “microencapsulated” or “encapsulated” bioactive agents may include bioactive agents incorporated into particles or microparticles, or bioactive agents incorporated into solid implants, etc.

[0023] The term "bioactive agent" as used herein is used to include a compound of interest that is contained in or on a pharmaceutical formulation or dosage form used for pharmaceutical or medical purposes to provide some form of therapeutic effect or elicit any type of biological response or activity. It is intended that "bioactive agent" includes a single such agent, and also includes a plurality of bioactive agents, including for example a combination of two or more bioactive agents.

[0024] As used herein, the term "biocompatible" refers to a substance that is generally non-toxic to a recipient, does not cause any significant adverse effects to a subject, and any metabolites or degradation products of the substance are also non-toxic to the subject. Typically, a "biocompatible" substance does not cause clinically relevant tissue irritation, injury, toxic reaction or immune reaction to living tissue.

[0025] As used herein, the term "biodegradable" refers to a substance that erodes into soluble species or degrades under physiological conditions into smaller units or chemical species that are themselves non-toxic (biocompatible) to the subject and can be metabolized, eliminated or excreted by the subject.

[0026] As used herein, the term "water-soluble" refers to substances that dissolve in water, particularly those found in environments such as body tissues and blood streams. The term may also refer to substances that dissociate into ions after exposure to an aqueous environment. Preferably, the term "water-soluble" according to the present invention refers to a salt having a solubility of 5 mg / ml to 1500 mg / ml, more preferably 50 mg / ml to 1150 mg / ml, or 70 mg / ml to 1000 mg / ml in water at 25°C. A person skilled in the art is aware of methods for determining solubility, for example by conductivity measurement. The following values can be used as reference values for measurement in water: MgSO₄ with a solubility of 351 mg / ml, magnesium sulfate heptahydrate with a solubility of 1130 mg / ml, sodium chloride with a solubility of 357 mg / ml, potassium chloride with a solubility of 340 mg / ml, anhydrous sodium sulfate with a solubility of 140 mg / ml, sodium sulfate heptahydrate with a solubility of 440 mg / ml, monopotassium phosphate with a solubility of 226 mg / ml, disodium phosphate heptahydrate with a solubility of 118 mg / ml, and disodium phosphate with a solubility of 77 mg / ml.

[0027] As used herein, the term "non-aggregating" refers to a powder that does not form large agglomerates of material formed by the presence of moisture or packing of the powder.

[0028] As used herein, the terms "embedded" or "embedding" refer to immobilization on or within a surface. An "embedded" article refers to an article that is fixed to or embedded within a surface by chemical, thermal, or physical integration methods.

[0029] The term "flow aid" refers to an additive which, when added to a polymer-based powder material, reduces the occurrence of aggregation and reduces the amount of energy required for the powder to avalanche or move.

[0030] As used herein, the term “improved fluidity” refers to the fluidization of powder particles by motion resulting from various stimuli, including impact forces from falling, dynamic powder flow analysis, and diffusion by blades, rollers, or feeding mechanisms, particularly during processing. Improved fluidity relates to the reduction in fracture energy or avalanche energy after the base powder has been treated with a fluidizing agent.

[0031] As used herein, the terms “unconsolidated” and “unconsolidated state” refer to the physical state of a powder when it is fluid and not compressed. In this state, the powder flows freely with minimal physical stimulation.

[0032] As used herein, the term "powder processing technology" refers to, but is not limited to, technologies such as SLS 3D printing, powder fluidization, powder mixing, and powder feeding.

[0033] As used herein, the term "avalanche energy" refers to the change in the force of the powder during an avalanche.

[0034] As used herein, the term "destructive energy" refers to the energy required for a powder to cause an avalanche.

[0035] As used herein, the term “interparticle friction” refers to the frictional force present between the surfaces of two contacting polymer particles. Additives reduce the contacting surface area, thereby reducing interparticle friction and resulting in a more fluid or more flowable powder.

[0036] As used herein, the term "Hausner ratio" refers to the ratio between the bulk density and tap density of a powder.

[0037] As used herein, the term "compressibility index" refers to a percentage representation of how much a powder is compressed during tap density measurement.

[0038] The polymer powder can be any biocompatible polymer. Biocompatible polymers include, but are not limited to, polyaryl ketones, polymethacrylates, polycarbonates, polyacetals, polyethylene, polypropylene, polylactide, polydioxanone, polycaprolactone, polyesteramides, polyurethanes, polytrimethyl carbonate, polyglycolide, poly(amino acids), as well as copolymers of their respective monomers such as poly(lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-trimethyl carbonate), poly(lactide-co-polyethylene glycol), poly(orthoesters), poly(phosphazene), poly(hydroxybutyrate), poly((hydroxybutyrate), poly(((hydroxybutyrate)))) Examples include copolymers containing hydroxybutarate, poly(lactide-co-caprolactone), polyanhydride, poly(dioxanone), poly(alkylene alkylate), copolymers of polyethylene glycol and polyorthoester, biodegradable polyurethane, polyamide, polyether ester, polyacetal, polycyanoacrylate, poly(oxyethylene) / poly(oxypropylene) copolymer, polyketal, polyphosphoester, polyhydroxyvalerate or polyhydroxyvalerate-containing copolymer, polyalkylene oxalate, polyalkylene succinate, poly(maleic acid), and copolymers, terpolymers, and combinations thereof.

[0039] Polymer powders can take on many particle forms as a result of their manufacturing method. These forms include, but are not limited to, porous, hollow, solid, spherical, or amorphous shapes.

[0040] Lactide-based polymers can contain any lactide residue, including all racemic and stereospecific forms of lactide, such as, but not limited to, L-lactide, D-lactide, and D,L-lactide, or mixtures thereof. Useful lactide-containing polymers include, but not limited to, poly(L-lactide), poly(D-lactide), and poly(DL-lactide); as well as poly(lactide-co-glycolide) such as poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), and poly(DL-lactide-co-glycolide); or copolymers, terpolymers, combinations, or blends thereof. Lactide / glycolide polymers can be readily produced by melt polymerization via ring-opening of lactide monomers and glycolide monomers. Furthermore, racemic DL-lactide, L-lactide, and D-lactide polymers are commercially available. L-polymers are more crystalline and absorb more slowly than DL-polymers. In addition to copolymers containing glycosides of DL-lactide or L-lactide, copolymers of L-lactide and DL-lactide are commercially available. Homopolymers of lactide or glycosides are also commercially available.

[0041] In certain embodiments, when the biodegradable polymer is poly(lactide-co-glycolide), any other copolymer (as described above), or a mixture of poly(lactide) and poly(glycolide), the amounts of lactide and glycolide in the polymer may vary. In further embodiments, the biodegradable polymer may contain 0-100 mol%, 40-100 mol%, 50-100 mol%, 60-100 mol%, 70-100 mol%, or 80-100 mol% of lactide and 0-100 mol%, 0-60 mol%, 10-40 mol%, 20-40 mol%, or 30-40 mol% of glycolide, where the amounts of lactide and glycolide are 100 mol%. In further embodiments, the biodegradable polymer may be poly(lactide), 95:5 poly(lactide-co-glycolide), 85:15 poly(lactide-co-glycolide), 75:25 poly(lactide-co-glycolide), 65:35 poly(lactide-co-glycolide), or 50:50 poly(lactide-co-glycolide), where these ratios are molar ratios.

[0042] In another embodiment, the polymer may be poly(caprolactone) or poly(lactide-co-caprolactone). In one embodiment, the polymer may be poly(lactide-co-caprolactone), which in various embodiments may be 95:5 poly(lactide-co-caprolactone), 85:15 poly(lactide-co-caprolactone), 75:25 poly(lactide-co-caprolactone), 65:35 poly(lactide-co-caprolactone), or 50:50 poly(lactide-co-caprolactone), where these ratios are molar ratios.

[0043] Examples of flow aids and bioceramics include, but are not limited to, calcium phosphate and its doped varieties (e.g., strontium, zinc, magnesium, fluoride, carbonate), calcium sulfate, calcium carbonate, and bioactive glass such as bioglass. Examples of calcium phosphate include, but are not limited to, hydroxyapatite, tricalcium phosphate, calcium-deficient carbonate-containing hydroxyapatite, octacalcium phosphate, dicalcium phosphate, biphasic calcium phosphate, or mixtures thereof.

[0044] As used herein, the term “water-soluble salt” refers to the use of salts that dissociate into their constituent ions, and furthermore, salts are also used as fluid additives for the development of SLS powders. Some of the salts referred to by the term “water-soluble salt” are magnesium sulfate, sodium sulfate, potassium chloride, sodium chloride, sodium sulfate, potassium aluminum sulfate, magnesium chloride, and magnesium chloride hexahydrate.

[0045] The term “osteoconductive additive” refers to a material that may be added to a composition to enhance the biological response and bone tissue growth promotion of the disclosed composition, and furthermore, osteoconductive additives can function as both a biological response enhancer and a flow aid as defined above.

[0046] The term "composite materials" refers to the use of polymer-based materials mixed with or treated with fluidizing agents, bioceramics, biomolecules, and / or bioactive agents.

[0047] The term "polymer-based material" refers to a material in which the most abundant component is a polymer.

[0048] The term "irradiation" refers to the act of introducing energy into polymer materials using various heat sources used in laser sintering applications. These include CO2 lasers, blue photodiodes, and argon lasers.

[0049] In one embodiment, a polymer powder pulverized at low temperatures is used as the base powder. To improve the flow behavior, it was necessary to add flow aids such as bioceramics. Interestingly, particularly effective flow aids appear to commonly have a low-crystalline (unsintered) form of bioceramic. This characteristic allows for fairly uniform mixing behavior and excellent flow properties. Mixing with the polymer powder can be done using a tumbler mixer or a high-shear mixer. These mixers are commercially available from Somakon and other companies.

[0050] Such flow aids typically range from 0.1 μm to 1 mm, 0.1 μm to 500 μm, 0.1 to 250 μm, 0.1 to 100 μm, or 0.1 to 50 μm, 0.1 to 40 μm, 0.1 to 30 μm, 0.1 to 20 μm, 0.1 to 10 μm, 0.1 to 5 μm, or 0.1 to 1 μm. Polymer composite blends typically have flow aid concentrations of 0.1 to 50 wt%, 0.1 to 40 wt%, 0.1 to 30 wt%, 0.1 to 20 wt%, 0.1 to 10 wt%, 0.1 to 5 wt%, 1 to 50 wt%, or 2 to 50 wt%. Mixtures of different flow aids can also be used, but the individual flow aids in a mixture of flow aids should not exceed the sum of their expressed weight percentages.

[0051] Such flow aids can be used in multiple powder particle shapes. These shapes include irregularly shaped polymer powders and spherical polymer powders.

[0052] A variety of bioactive agents can be used in the methods described herein. In one embodiment, the bioactive agent may be a releaseable bioactive agent, i.e., a bioactive agent that can be released from a controlled release system into adjacent tissues or body fluids of the target. In certain embodiments, the bioactive agent may be in or above the controlled release system.

[0053] Various forms of bioactive agents can be used, and these can be released from a controlled release system into adjacent tissues or body fluids. For this purpose, liquid or solid bioactive agents can be incorporated into the controlled release systems described herein. Bioactive agents are at least very slightly water-soluble, and preferably moderately water-soluble. Bioactive agents may contain salts of the active ingredient. Therefore, bioactive agents may be acidic, basic, or amphoteric salts. They may be nonionic molecules, polar molecules, or molecular complexes capable of hydrogen bonding. Bioactive agents may be included in a composition, for example, in the form of uncharged molecules, molecular complexes, salts, ethers, esters, amides, polymer drug conjugates, or in other forms to provide effective bioactivity or physiological activity.

[0054] Examples of bioactive agents incorporated into the systems of this specification include, but are not limited to, peptides, proteins such as hormones, enzymes, and antibodies; nucleic acids such as aptamers, iRNA, DNA, RNA, antisense nucleic acids, and antisense nucleic acid analogs; low molecular weight compounds; and high molecular weight compounds. Bioactive agents intended for use in the implantable composite materials disclosed include anabolic agents, antacids, anti-asthmatic agents, anticholesterolemia and antilipid agents, anticoagulants, anticonvulsants, antidiarrheals, antiemetics, antibacterial and antimicrobial agents, anti-infective agents, anti-inflammatory agents, anti-manic agents, antimetabolites, antitumor agents, antiobesity agents, antipyretic analgesics, antispasmodics, antithrombotic agents, antitussives, antitussives, antitussives, antitussives, antiuricemia agents, antianginic agents, antihistamines (e.g., terfenadine), appetite suppressants, antipyretics, analgesics, antispasmodics, antithrombotic agents, antitussives, antitussives, antiuricemia agents, antianginic agents, antihistamines (e.g., terfenadine), appetite suppressants, and other antimicrobial agents. Examples include inhibitors, biological agents, cerebral dilators, coronary artery dilators, bronchodilators, cytotoxic agents, decongestants, diuretics, diagnostic agents, erythropoiesis-promoting agents, expectorants, gastrointestinal sedatives, blood glucose-raising agents, hypnotics, blood glucose-lowering agents, immunomodulators, ion exchange resins, laxatives, mineral supplements, mucolytics, neuromuscular agents, peripheral vasodilators, psychotropic agents, sedatives, stimulants, thyroid and antithyroid agents, tissue growth agents, uterine relaxants, vitamins, or antigenic substances.

[0055] Other bioactive agents include androgen inhibitors, polysaccharides, growth factors (e.g., vascular endothelial growth factor - VEGF), hormones, angiogenesis inhibitors, dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, clofedanol hydrochloride, chlorpheniramine maleate, phenyndamine tartrate, pyriramine maleate, doxylamine succinate, phenyltroxamine citrate, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, codeine phosphate, codeine sulfate morphine, mineral supplements, cholestyramine, N-acetylprocainamide, acetaminophen, aspirin, ibuprofen, phenylpropanolamine hydrochloride, caffeine, guaifenesin, aluminum hydroxide, magnesium hydroxide, peptides, polypeptides, proteins, amino acids, interferons, cytokines, and vaccines.

[0056] Representative drugs that can be used as bioactive agents include, but are not limited to, peptide drugs, protein drugs, desensitizers, antigens, antiinfective agents such as antibiotics, antimicrobial agents, antiviral agents, antibacterial agents, antiparasitic agents, antifungal agents, and combinations thereof, antiallergic drugs, androgen steroids, decongestants, hypnotics, steroidal anti-inflammatory drugs, anticholinergics, sympathomimetic agents, sedatives, miotics, psychostimulants, tranquilizers, vaccines, estrogens, progesterones, humoral agents, prostaglandins, analgesics, antispasmodics, antimalarial drugs, antihistamines, cardiac agents, nonsteroidal anti-inflammatory drugs, antiparkinsonian drugs, antihypertensive drugs, β-adrenergic blockers, nutritional supplements, and benzophenanthridine alkaloids. The drugs may also be substances that can act as stimulants, sedatives, hypnotics, analgesics, anticonvulsants, etc.

[0057] Other biologically active agents include, but are not limited to, analgesics such as acetaminophen and acetylsalicylic acid; anesthetics such as lidocaine and xylocaine; appetite suppressants such as dexadrine and fendimetrazine tartrate; antiarthritis drugs such as methylprednisolone and ibuprofen; antiasthmatics such as terbutaline sulfate, theophylline, and ephedrine; antibiotics such as sulfisoxazole, penicillin G, ampicillin, cephalosporins, amikacin, gentamicin, tetracycline, chloramphenicol, erythromycin, clindamycin, isoniazid, and rifampin; antifungal drugs such as amphotericin B, nystatin, and ketoconazole; antiviral drugs such as acyclovir and amantadine; anticancer drugs such as cyclophosphamide, methotrexate, and etretinate; anticoagulants such as heparin and warfarin; and antispasmodics such as phenytoin sodium and diazepam. Convulsants; antidepressants such as isocarboxazede and amoxapine; antihistamines such as diphenhydramine hydrochloride and chlorpheniramine maleate; hormones such as insulin, progestin, 17-alpha-hydroxyprogesterone caproate, iso-allo-pregnanolon testosterone, prenisolone, prednisone, dexamethasone estrogen (e.g., estradiol), corticoids, glucocorticoids, androgens; tranquilizers such as soladine, diazepam, chlorpromazine hydrochloride, reserpine, and chlordiazepoxide hydrochloride; antispasmodics such as belladonna alkaloids and dicyclomine hydrochloride; essential amino acids, vitamins and minerals such as calcium, iron, potassium, zinc, and vitamin B12; cardiovascular agents such as prazosin hydrochloride, nitroglycerin, propranolol hydrochloride, hydralazine hydrochloride, pancrelipase, and succinate dehydrogenase;LHRH, somatostatin, calcitonin, growth hormone, glucagon-like peptide, growth-releasing factor, angiotensin, FSH, EGF, bone morphogenetic protein (BMP), erythropoietin (EPO), interferon, interleukin, collagen, fibrinogen, insulin, factor VIII, factor IX, ENBREL®, RITUXAM®, HERCEPTIN®, alpha-glucosidase, Cerazyme / CEREDOSE®, vasopressin, ACTH, human serum albumin, cancer Examples include peptides and proteins such as globulins, structural proteins, blood product proteins, complex proteins, enzymes, antibodies, and monoclonal antibodies; prostaglandins; nucleic acids; carbohydrates; fats; narcotics such as morphine and codeine; psychotherapeutic drugs; antimalarial drugs; L-dopa; diuretics such as furosemide and spironolactone; anti-ulcer drugs such as ranitidine hydrochloride and cimetidine hydrochloride; calcium channel antagonists such as nimodipine; and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors such as lumefantrine, sirengitide, and lovastatin.

[0058] Examples of biomolecules, though not limited to them, include fibrin, fibrinogen, cellulose, starch, collagen, and hyaluronic acid.

[0059] Characterization of various powders was performed using standard testing equipment, such as laser scattering devices for particle size determination (commercially available from Beckmann Coulter or Malvern). DSC testing was performed using equipment from TA instruments at a heating rate of 10°C / min and a cooling rate of 20°C / min. SEM was performed using a benchtop device (commercially available from Hitachi, Ltd.). BET measurements were performed using equipment from Micromeritics.

[0060] Selective laser sintering (SLS) was performed using a blade-based apparatus (e.g., EOS P series). This technique manufactures physical parts by selectively solidifying various fine powders. SLS constructs parts layer by layer using powders that are selectively bonded as a laser beam scans the powder across the cross-sectional area of ​​each layer. A typical laser energy density is 7 kJ / m³. 2 ~60kJ / m 2 This is within a certain range. SLS fuses a thin layer of powder (typically about 0.1 mm thick) spread across the build area using a blade. The construction of the part takes place in a sealed chamber filled with an inert gas. Nitrogen gas is preferred to minimize oxidation and decomposition of the powder material. The powder in the build platform is maintained at a high temperature slightly below the melting point of the powder material (semi-crystalline polymers only).

[0061] Quantitative methods used to characterize the flowability of powders included the use of a flowability test apparatus (Mercury Scientific Instruments) consisting of a rotating cylindrical drum with glass walls that characterize the movement of powder particles with a camera. This apparatus measures the maximum height of the powder deposit before an avalanche occurs. A higher height of powder before the avalanche indicates that the powder requires more energy to flow. This is an indicator of the minimum energy required to flow the powder particles. Unless otherwise stated, tests are conducted under ambient conditions (room temperature, humidity level approximately 40%).

[0062] Particle size determination is based on United States Pharmacopeia 36 (USP). <429> The analysis was carried out in accordance with the chapter and Chapter 7.0 (EP) 2.9.31 of the European Pharmacopoeia. The particle size distribution was determined using a laser scattering device (e.g., Fa. Sympatec GmbH, HELOS type with RODOS dry dispersion unit). Laser diffraction is based on the phenomenon that particles scatter light in all directions with an intensity pattern that depends on the particle size. A representative sample dispersed at an appropriate concentration in a suitable liquid or gas is usually passed through a monochromatic light source from a laser. The light scattered by the particles at various angles is measured by a multi-element detector, and then numerical values ​​related to the scattering pattern are recorded for subsequent analysis. Subsequently, the scattering values ​​are transformed using an appropriate optical model and mathematical procedure to obtain the ratio of the total volume to a number of individual size classes that form the volume particle size distribution (e.g., d 50 (This represents the granularity corresponding to the cumulative distribution under a 50% sieve.)

[0063] 2. Composition of the present invention This specification discloses polymer material compositions suitable for use in the manufacture and / or surface treatment of medical devices.

[0064] Furthermore, this specification discloses compositions of polymer materials suitable for use in the manufacture of devices or surfaces that come into contact with food.

[0065] Furthermore, this specification discloses polymer material compositions suitable for use in powder processing techniques such as selective laser sintering, binder injection, selective absorption sintering, and hybrid methods thereof.

[0066] Furthermore, this specification discloses compositions comprising a polymer material and a flow aid of various concentrations for improving the fluidity of the material during processing.

[0067] Furthermore, this specification discloses compositions comprising a polymer material and water-soluble salts of varying concentrations for benefiting the fluidity of polymer particles and for inducing or inhibiting biological responses resulting from pores formed by the leaching of water-soluble salts.

[0068] Furthermore, this specification discloses compositions comprising a polymer material and water-soluble salts of various concentrations to benefit the fluidity of polymer particles for various powder processing technologies.

[0069] Furthermore, this specification discloses compositions comprising a polymer material and bioceramics of varying concentrations for inducing or inhibiting a biological response and / or improving the fluidity of the material during processing.

[0070] Furthermore, this specification discloses compositions comprising a polymer material and biomolecules at various concentrations for inducing or inhibiting a biological response and / or improving the fluidity of the material during processing.

[0071] Furthermore, this specification discloses compositions comprising a polymer material and various concentrations of bioactive agents for inducing or inhibiting a biological response and / or improving the fluidity of the material during processing.

[0072] Furthermore, this specification discloses compositions comprising polymer materials and various concentrations of flow aids, bioceramics, biomolecules, osteoconductive additives, water-soluble salts, and / or bioactive agents for increasing the bulk density of the base powder formulation.

[0073] Furthermore, this specification discloses compositions comprising a polymer material and water-soluble salts of various concentrations for increasing the bulk density of a base powder formulation.

[0074] Furthermore, this specification discloses compositions comprising polymer materials and various concentrations of flow aids, bioceramics, biomolecules, osteoconductive additives, water-soluble salts, and / or bioactive agents, which have different part densities depending on the processing parameters when processed using various powder processing techniques.

[0075] Furthermore, this specification discloses compositions comprising a polymer material and water-soluble salts of various concentrations having different part densities depending on the processing parameters when processed using various powder processing techniques.

[0076] Furthermore, this specification discloses compositions comprising a polymer material and a selected water-soluble salt and water-soluble salts of different concentrations depending on the weight percentage ratio of the salts, the salts being used to obtain specific mechanical properties of articles manufactured from the composite powder.

[0077] Furthermore, this specification discloses compositions comprising polymer materials that are mixed with various concentrations of flow aids, water-soluble salts, bioceramics, biomolecules, osteoconductive additives, and / or bioactive agents before being processed into articles.

[0078] Furthermore, this specification discloses compositions comprising polymer materials that are mixed with water-soluble salts of various concentrations before being processed into articles.

[0079] Furthermore, this specification discloses compositions comprising polymer material composite blends used to manufacture articles having various shapes on their inner and outer surfaces.

[0080] Furthermore, this specification discloses compositions comprising polymer material composite blends used to manufacture articles that are biodegradable, biocompatible, and / or both.

[0081] Furthermore, this specification discloses compositions comprising polymer material composite blends used to produce articles from which composite material additives can be removed after manufacturing.

[0082] Furthermore, this specification discloses polymer-based composite materials in which the polymer material accounts for 0% to about 100% by weight of the composition, for example, 1% to about 100% by weight of the composition, for example, 5% to about 100% by weight of the composition, for example, 10% to about 100% by weight of the composition, for example, 20% to about 100% by weight of the composition, for example, 30% to about 100% by weight of the composition, for example, 40% to about 100% by weight of the composition, for example, 50% to about 100% by weight of the composition, for example, 60% to about 100% by weight of the composition, for example, 70% to about 100% by weight of the composition, for example, 80% to about 100% by weight of the composition, for example, 85% to about 100% by weight of the composition, for example, 90% to about 100% by weight of the composition, for example, 95% to about 100% by weight of the composition. Polymer materials can be substantially composed of polyesters containing polydioxanone, polycaprolactone, polylactide, polylactic acid-co-glycolic acid, polyglycolic acid, polyvinyl acetate, polyvinyl alcohol, and blends thereof.

[0083] Furthermore, this specification includes polymer materials containing polyaryl ketones, polymethacrylates, polycarbonates, polyacetals, polyethylene, polypropylene, polylactide, polydioxanone, polycaprolactone, polyesteramides, polyurethanes, polytrimethyl carbonate, polyglycolide, poly(amino acids), and copolymers of each monomer such as poly(lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-trimethyl carbonate), poly(lactide-co-polyethylene-glycol), poly(orthoester), poly(phosphazene), poly(hydroxybutyrate), and poly(hydroxybutarate). Polymer-based composite materials are disclosed, which may be polymers, poly(lactide-co-caprolactone), polyanhydride, poly(dioxanone), poly(alkylene alkylate), copolymers of polyethylene glycol and polyorthoesters, biodegradable polyurethanes, polyamides, polyether esters, polyacetals, polycyanoacrylates, poly(oxyethylene) / poly(oxypropylene) copolymers, polyketals, polyphosphoesters, polyhydroxyvalerate or polyhydroxyvalerate-containing copolymers, polyalkylene oxalates, polyalkylene succinates, poly(maleic acid), and copolymers, terpolymers, and combinations thereof.

[0084] Furthermore, in this specification, polydioxanone, polylactide, polyglycolide, or polycaprolactone powder is used to describe copolymers of their respective monomers such as polyarylketone, polymethacrylate, polycarbonate, polyacetal, polyethylene, polypropylene, polylactide, polydioxanone, polycaprolactone, polyesteramide, polyurethane, polytrimethylcarbonate, polyglycolide, poly(amino acids), and poly(lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-trimethylcarbonate), poly(lactide-co-polyethylene-glycol), poly(orthoester), poly(phosphazene), poly(hydroxybutyrate), and poly(hydroxy Polymer-based composite materials are disclosed that can be blended with other polymer materials such as butarate-containing copolymers, poly(lactide-co-caprolactone), polyanhydride, poly(dioxanone), poly(alkylene alkylate), copolymers of polyethylene glycol and polyorthoesters, biodegradable polyurethanes, polyamides, polyether esters, polyacetals, polycyanoacrylates, poly(oxyethylene) / poly(oxypropylene) copolymers, polyketals, polyphosphoesters, polyhydroxyvalerate or polyhydroxyvalerate-containing copolymers, polyalkylene oxalate, polyalkylene succinate, poly(maleic acid), and other polymer materials such as copolymers, terpolymers, and combinations thereof.

[0085] Furthermore, as specified herein, osteoconductive additives, fluidizers, bioceramics, biomolecules, and / or bioactives may be present in amounts of 0% to about 99% by weight of the composition, for example, 0% to about 97% by weight of the composition, for example, 0% to about 95% by weight of the composition, for example, 0% to about 95% by weight of the composition, for example, 0% to about 90% by weight of the composition, for example, 0% to about 80% by weight of the composition, for example, 0% to about 70% by weight of the composition, for example, 0% to about 60% by weight of the composition, for example, 0% to about 50% by weight of the composition, for example, 0% to about 40% by weight of the composition, for example, 0% to about 30% by weight of the composition, for example, 0% to about 20% by weight of the composition, for example, 0% to about 10% by weight of the composition, for example, 0% to about 5% by weight of the composition, for example A polymer-based composite material is disclosed that constitutes 0.5% to about 99% by weight of the product, for example 0.5% to about 97% by weight of the composition, for example 0.5% to about 95% by weight of the composition, for example 0.5% to about 95% by weight of the composition, for example 0.5% to about 90% by weight of the composition, for example 0.5% to about 80% by weight of the composition, for example 0.5% to about 70% by weight of the composition, for example 0.5% to about 60% by weight of the composition, for example 0.5% to about 50% by weight of the composition, for example 0.5% to about 40% by weight of the composition, for example 0.5% to about 30% by weight of the composition, for example 0.5% to about 20% by weight of the composition, for example 0.5% to about 10% by weight of the composition, and / or for example 0.5% to about 5% by weight of the composition.

[0086] Furthermore, the Specified herein discloses polymer-based composite materials in which osteoconductive additives, fluidizers, bioceramics, biomolecules, and / or bioactive agents may constitute at least 99% by weight, at least 95% by weight, at least 90% by weight, at least 80% by weight, at least 70% by weight, at least 60% by weight, at least 50% by weight, at least 40% by weight, at least 30% by weight, at least 20% by weight, at least 10% by weight, and at least 5% by weight of the final composite material.

[0087] Furthermore, this specification discloses polymer-based composite materials in which water-soluble salts may constitute at least 99% by weight, at least 95% by weight, at least 90% by weight, at least 80% by weight, at least 70% by weight, at least 60% by weight, at least 50% by weight, at least 40% by weight, at least 30% by weight, at least 20% by weight, at least 10% by weight, and at least 5% by weight of the final composite material.

[0088] Furthermore, this specification discloses polymer-based composite materials in which osteoconductive additives, flow aids, bioceramics, biomolecules, and / or bioactive agents may have diameters of 250 μm or less, 200 μm or less, 150 μm or less, 100 μm or less, 75 μm or less, 55 μm or less, 50 μm or less, 25 μm or less, 15 μm or less, 10 μm or less, 5 μm or less, about 0.1 μm to about 250 μm, about 0.1 μm to about 200 μm, about 0.1 μm to about 150 μm, about 0.1 μm to about 100 μm, about 0.1 μm to about 75 μm, about 0.1 μm to about 55 μm, about 0.1 μm to about 50 μm, about 0.1 μm to about 25 μm, about 0.1 μm to about 10 μm, and about 0.1 μm to about 5 μm.

[0089] 3. Manufacturing method of the present invention The methods for producing the compositions disclosed below are not exhaustive, and it should be understood that the methods can be combined and modified to suit any of the compositions disclosed above.

[0090] This specification discloses methods for manufacturing, preparing, and processing the aforementioned polymer-based materials. The polymer-based materials, polydioxanone, polycaprolactone, polyglycolides, and polylactides, can be blended in multiple ways with various concentrations of osteoconductive additives, flow aids, bioceramics, biomolecules, water-soluble salts, and / or bioactives before processing using multiple possible powder processing techniques.

[0091] In one embodiment, composite powders of polymer-based materials can be processed using selective laser sintering, binder injection, selective absorption sintering, and hybrid methods thereof.

[0092] In another embodiment, polymer-based materials, osteoconductive additives, flow aids, bioceramics, biomolecules, water-soluble salts, and / or bioactive powders are produced by grinding processes such as jet grinding, impact grinding, centrifugal grinding, pin mill grinding, knife grinding, cryogenic grinding, mixed grinding, impact grinding, air classification grinding, and hybrid methods thereof.

[0093] In another embodiment, polymer-based materials are blended with osteoconductive additives, flow aids, bioceramics, biomolecules, water-soluble salts, and / or bioactives using, but not limited to, high-shear mixing, inversion blending, solvent blending, and hybrid methods thereof.

[0094] In another embodiment, polymer-based materials are blended with water-soluble salts using high-shear mixing, inversion blending, solvent blending, and hybrid methods thereof.

[0095] In another embodiment, polymer-based materials are blended with water-soluble salts using high-shear mixing, inversion blending, solvent blending, jet grinding, impact grinding, centrifugal grinding, pin mill grinding, knife grinding, cryogenic grinding, mixed grinding, impact grinding, air classification grinding, and combinations of these hybrid methods.

[0096] In another embodiment, polymer-based materials are blended with water-soluble salts using grinding media of various sizes and a wide range of temperatures within a mixed grinding manufacturing method. The grinding media here are medical-grade stainless steel materials of various shapes and sizes, ranging from 1mm to 100mm, 1mm to 90mm, 1mm to 80mm, 1mm to 70mm, 1mm to 60mm, 1mm to 50mm, 1mm to 40mm, 1mm to 30mm, 1mm to 20mm, 1mm to 10mm, or 1mm to 5mm. Furthermore, the temperature range for mixed grinding may range from the melting temperature of the polymer material to low-temperature conditions.

[0097] In another embodiment, a polymer-based material is blended with a second high modulus polymer material, such as polyglycolide and polyvinyl alcohol, using a mixing and grinding manufacturing method with a variety of grinding media sizes and a wide range of temperatures. The grinding media here are medical-grade stainless steel materials of various shapes and sizes, ranging from 1mm to 100mm, 1mm to 90mm, 1mm to 80mm, 1mm to 70mm, 1mm to 60mm, 1mm to 50mm, 1mm to 40mm, 1mm to 30mm, 1mm to 20mm, 1mm to 10mm, or 1mm to 5mm. Furthermore, the temperature range for mixing and grinding may range from the melting temperature of the polymer material to low-temperature conditions.

[0098] In another embodiment, polymer-based materials blended with osteoconductive additives, flow aids, bioceramics, biomolecules, and / or bioactives can be used in melt processing techniques such as uniscrew extrusion, twin-screw extrusion, injection molding, compression molding, and electrospinning, but are not limited to these. The resulting blended and processed materials form composite materials.

[0099] In another embodiment, polymer-based materials blended with water-soluble salts can be used in melting processes such as uniscrew extrusion, twin-screw extrusion, injection molding, compression molding, electrospinning, 3D printing, or a hybrid combination thereof.

[0100] In another embodiment, polymer-based composite materials can be granulated, pelletized, or extruded into stock shapes for other applications.

[0101] In another embodiment, a composite powder of polymer-based materials is prepared for processing by a drying method which may or may not utilize temperatures within approximately 10°C of the polymer's glass transition temperature, within approximately 20°C of the polymer's glass transition temperature, within approximately 30°C of the polymer's glass transition temperature, within approximately 40°C of the polymer's glass transition temperature, within approximately 50°C of the polymer's glass transition temperature, within approximately 60°C of the polymer's glass transition temperature, within approximately 10°C of the polymer's melting temperature, within approximately 20°C of the polymer's melting temperature, within approximately 30°C of the polymer's melting temperature, within approximately 40°C of the polymer's melting temperature, within approximately 50°C of the polymer's melting temperature, and within approximately 60°C of the polymer's melting temperature.

[0102] In another embodiment, a composite powder of polymer-based materials is prepared for processing by a drying method that may or may not utilize a vacuum.

[0103] In another embodiment, a composite powder of polymer-based materials is prepared for processing by a drying method which may or may not function as an annealing step for the polymer material.

[0104] In another embodiment, a composite powder of polymer-based materials is prepared for processing by a drying method which may or may not prepare the material for processing using powder processing techniques in which the drying process increases the initiation of melting of the polymer material.

[0105] In another embodiment, composite powders of polymer-based materials can be processed using powder processing techniques such as selective laser sintering, binder injection, selective absorption sintering, and hybrid methods thereof, enabling annealing of the printed articles by cooling them slowly within the apparatus.

[0106] In another aspect, blending water-soluble salts by conventional blending methods is unsuitable because they do not adhere to the surface of polymer particles or do not provide any advantage to the flow of the powder. When water-soluble salts are integrated into polymer powder, high-shear blends and tumble blends do not result in a uniform distribution of the salt additive on the surface of the polymer particles. Furthermore, grinding the salt to submicron particle size before the blending operation does not improve the adhesion of the salt to the surface of the polymer particles. Instead, unground salt and polymer particles can be easily embedded using a mixed grinding method under room temperature or low temperature conditions. The mixed grinding method utilizes the impact of the grinding medium to embed the salt additive on the surface of the polymer particles.

[0107] 4. Examples The following examples are provided to give a complete disclosure and description of how the compounds, compositions, articles, apparatus, and / or methods claimed herein are manufactured and evaluated, and are intended to be purely illustrative of the invention and not intended to limit the scope of what the inventors consider to be the invention. Efforts have been made to ensure accuracy with respect to numerical values ​​(e.g., quantities and temperatures), but some error or deviation should be taken into consideration. Unless otherwise indicated, parts are parts by weight, temperatures are °C or ambient temperature, and pressures are atmospheric pressure or near atmospheric pressure.

[0108] Example 1 Crushing The composite powder was produced by blending two types of ground powders. The polydioxanone polymer used to produce the powder composite material was ground after obtaining the raw materials. The grinding procedure for polydioxanone required a cryogenic grinding method. The polydioxanone granules fed into the cryogenic grinding process had a particle size of 1-3 mm and a bulk density of 0.62 kg / L. After grinding, the polydioxanone powder material had a particle size of less than 100 microns for 90% of the powder, and a bulk density of 0.41 kg / L. The particle size of the ground polydioxanone polymer, measured using laser diffraction, can be seen in Table 1. All aggregates were removed from the polydioxanone powder before blending with additives or before use in powder processing techniques.

[0109] [Table 1]

[0110] The production of polydioxanone powder by grinding is far more efficient compared to emulsions and other solvent methods. Dissolving polydioxanone requires highly corrosive and toxic solvents such as hexafluoro-2-propanol (HFIP). After emulsion formation, the solvent must be removed to a level safe for implantation. Consequently, while emulsions can produce particles within a suitable size range for laser sintering applications, they are not recommended for polydioxanone.

[0111] In accordance with International Publication No. 2019 / 043137, additional polymer powders of polycaprolactone and polylactide were produced. A particle size of less than 100 μm was achieved. The particle sizes of the pulverized polycaprolactone and polylactide polymers, achieved using a method similar to that of polydioxanone, can be seen in Table 2.

[0112] [Table 2]

[0113] Example 2 Fluidity due to additives Multiple compositions containing both polydioxanone powder and additives are manufactured. The additives can be varied depending on the application. Furthermore, multiple additives can be blended together to create multifunctional powder composites. The additives considered in this example can be classified into osteoconductive additives, bioglass, and bioceramics. The fluidity of each composition was evaluated using dynamic flow analysis with Mercury Scientific's Revolution Powder Analyzer. 40 mL of each powder composition was used for testing at 90°C. This temperature was chosen because it is close to the printing temperature that may be used during the laser sintering process. Three parameters useful for developing fluid powders for powder manufacturing technology are the avalanche energy, fracture energy, and surface fractal, as defined above. The baseline fluidity results for the polydioxanone powder can be seen in Table 3.

[0114] [Table 3]

[0115] Dynamic flow analysis of pure polydioxanone suggests that the powder flow is unsuitable for SLS or similar laser sintering processes, as the surface fractal of the powder surface is 9.77. Blending additives with the polydioxanone powder rapidly reduced the surface fractal. The best surface fractal result was 1, while the desirable polymer surface fractal is less than 2. This result suggests that the powder produces a smooth surface after material avalanche or migration. SLS processes requiring a smooth powder surface require powder with a surface fractal as close to 1 as possible. However, this may not be necessary for material transport technologies, as powder surface smoothness does not affect processing. Powder processing technologies requiring material flow suitable for consistent material distribution should select the powder composition with the lowest fracture and avalanche energies. Blends of polydioxanone powder with additives can be seen in Table 4. For all additives, their particle size is referenced. The term "submicron" refers to additives with particle sizes less than 2 μm. The term "10 microns" refers to additives with an average particle size of 10 μm.

[0116] [Table 4]

[0117] Fluidity results for blends with submicron unsintered hydroxyapatite (submicron UHA) of different particle sizes indicate that the best fluidity result is with a 3 wt% additive. This additive concentration yielded the lowest surface fractals, the lowest fracture energy, and the third lowest avalanche energy. Qualitative blade testing was performed by placing blends of 3 wt% and 5 wt% submicron UHA with polydioxanone powder into a selective laser sintering machine, generating a smooth surface with a blade, lowering the platform by 100 microns, adding more of the composite powder blend, and then distributing a 100 micron layer with the blade. A smooth surface with no aggregates on the powder was considered acceptable for 3D printing applications. The blend of 5 wt% submicron UHA with polydioxanone powder showed the best blade test results and should be selected for the development of selective laser sintering printing parameters. Unsintered hydroxyapatite was obtained from Himed.

[0118] [Table 5]

[0119] Compared to submicron unsintered hydroxyapatite, 10-micron unsintered hydroxyapatite has higher avalanche and fracture energies (Table 5). This suggests that more energy is required to produce an unconsolidated powder that induces flow. Qualitative blade testing of a blend of 3 wt% 10-micron UHA and polydioxanone powder showed suitability for selective laser sintering. Development of printing parameters for selective laser sintering of this blend should begin with 3 wt% 10-micron UHA.

[0120] [Table 6]

[0121] Submicron unsintered fluoroapatite (submicron unsintered FHA) is a fluorine-doped apatite that can be used as a bone conduction additive and flow aid. Fluidity results from a blend of polydioxanone and submicron unsintered FHA indicate that the optimal concentration of the additive for selective laser sintering is 7% by weight. (Table 6) [Table 7]

[0122] Although submicron bioglass has not been shown to be an excellent fluidizer at addition levels of 1–10 wt%, it can be blended with other fluidizing additives mentioned for bone-specific blends. Furthermore, when surface fractals were graphed using additive concentrations, the trend line equation shows that a surface fractal of 2 can be achieved with 21.5 wt% bioglass. This suggests that bioglass can be used as a fluidizing agent at high concentrations. Bioglass was obtained from Schott (Table 7).

[0123] [Table 8]

[0124] Submicron unsintered tricalcium phosphate (submicron UTPP) was found to be an excellent fluidizer at concentrations of 1–10 wt%, and concentrations of 3–7 wt% were found to be acceptable for selective laser sintering. Submicron UTPP was obtained from Himed.

[0125] Example 3 Manufacturing of composite materials The composite powders exhibit different mechanical properties depending on the additives used (Table 9). A polydioxanone (RESOMER® X206S) powder blend containing bioglass with silane as a surface treatment exhibited the greatest mechanical strength, a polydioxanone powder blend containing unsintered FHA exhibited the highest modulus of elasticity, and a polydioxanone powder blend containing 10 micron UHA exhibited the greatest elongation at break (Table 9). These results suggest that the additives selected as flow aids can also be used to induce a mechanical response in the final product manufactured from the powder composite material blends. The tensile bars manufactured by injection molding have a shape similar to that of ISO 20753 A14.

[0126] [Table 9]

[0127] Example 4 DSC, annealing process The crystallinity of the composite powder can be controlled by the operator before or after printing. This process can be described, but is not limited to, annealing, tempering, strengthening, curing, and solidification. In all annealing tests, a processing temperature of 98°C was used for the composite material PDO + 3 wt% 10 micron UHA. The cooling rate of the annealing method was controlled between 2.5°C and 10°C. The crystallinity of the untreated composite powder was 57.6%, while the crystallinity of the treated powder was 56.3%. The treated composite powder was cooled overnight in a Formiga P110 SLS machine at a rate of less than 2°C / min from the processing temperature of 98°C. The crystallinity of the polymer powder observed at a cooling rate of 2.5°C / min was 57.25%, and the crystallinity of the polymer powder observed at a cooling rate of 10°C / min was 59.32%. The crystallinity of the polymer powder observed at 5°C / min was the highest at 62.18%. Crystallinity data for the annealing test can be found in Table 10.

[0128] In addition to changes in crystallinity, the annealing procedure affected the onset of melting in the polymer powder. Each material under controlled cooling rates initiated melting at at least 98°C. The highest melting onset was 99.21°C for materials cooled at 2.5°C / min, while materials cooled at both 5°C / min and 10°C / min initiated melting at 98.97°C. Furthermore, untreated materials and materials treated without controlled cooling initiated melting much lower, at 92.16°C and 94.46°C, respectively. This indicates that post-treatment annealing or controlled cooling of materials can be beneficial for processing PDO composite powders. Higher processing temperatures prevent curling and shifting of the material during the printing process, resulting in a higher success rate for printing jobs.

[0129] [Table 10]

[0130] Example 5 Preparation method for the SLS process - blend Polydioxanone complex powder blends are prepared by mixing ground polydioxanone powder with multiple potential additives at varying concentrations. The polydioxanone powder and additives were weighed under room conditions using a balance accurate to 1 milligram. The polydioxanone powder and additives were then placed in a Somakon MP-LB Labormischer Speedmix and mixed at 300 rpm for 2 minutes, repeated three times. The volume of the mixing vessel was 0.5 liters. While inversion mixing can also be used to blend the polydioxanone powder and additives, this procedure is significantly more time-consuming.

[0131] Example 6 Preparation method for SLS process - Mixing and grinding A mixing and grinding procedure was developed by placing 5 grams of polymer particles and 0.26 grams of salt into a container containing 25 mm stainless steel balls. This container was shaken at a frequency of 30 Hz for 3 minutes. After this mixing and grinding procedure was completed, the salt was embedded in a uniform distribution on the surface of the polymer particles. Furthermore, no salt additive was observed on the imaging platform, suggesting that a uniform powder blend was obtained.

[0132] Example 7 Improving the fluidity of polymer powders using water-soluble salts as fluidizing agents. Three polymer powders were blended with water-soluble salts, and the fluidity of these powders at high temperatures was evaluated. RESOMER® X206S (polydioxanone), RESOMER® C212 (polycaprolactone), and RESOMER® L207S polymers were pulverized and sieved until the size of all recovered material was less than 100 μm. The three polymers were mixed and pulverized by adding 0.26 g of salt additive to 5 g of polymer powder to achieve a salt concentration of 5 wt% relative to the polymer powder. All materials were placed in a stainless steel container containing 25 mm stainless steel balls and shaken at a frequency of 30 Hz for 3 minutes. The resulting base powders and powder blends were evaluated using dynamic fluid analysis techniques to investigate the effect of water-soluble salts on powder fluidity. All base powders showed improved powder fluidity after mixing and pulverizing with water-soluble salts.

[0133] [Table 11]

[0134] [Table 12]

[0135] [Table 13]

[0136] Example 8 Optimization of powder flowability using RESOMER(registered trademark) X206S The use of water-soluble salts to improve the fluidity of polymer powders is evaluated using RESOMER® X206S with multiple salt concentrations. The polymer powders were mixed and ground with water-soluble salts at concentrations of 1% by weight, 5% by weight, and 10% by weight using the mixed grinding method identified in Example 6. The use of different concentrations showed that while each salt contributes to the fluidity of the polymer powder, the concentration of each salt used varies depending on the desired fluidity characteristics.

[0137] [Table 14]

[0138] [Table 15]

[0139] [Table 16]

[0140] Example 9 Processing method The disclosed composite powder processing procedure can be optimized to obtain the desired degree of crystallinity of the printed article. The fluidity of the PDO composite powder containing 3 wt% of 10 micron unsintered calcium phosphate was sufficient for the printing process until it reached 105°C in the printing chamber. As a result, the recommended printing chamber temperature range is 95°C to 100°C, more preferably 98°C ± 1.5°C. All materials were heated in a Formiga P110 SLS machine for a minimum of 1 hour after reaching 98°C to ensure the material temperature reached 98°C. Furthermore, the layer height (L) of the printing process was set to 100 microns (0.1 mm). The printing parameters that were changed in each printing setting were laser wattage (W), scanning speed (S), and hatch distance (D). The printing parameters and layer height were used to determine the energy density of the print. The formula for the energy density used can be seen in Equation 1.

number

[0141] Before printing the parts, apply a base support with dimensions of 300 x 75 x 0.3 mm to a pressure of 0.15 J / mm². 3 The print was created using the following energy density. The tensile rod was printed on a second base support. After the third layer of the base support, laser irradiation was performed only on the cross-section corresponding to the shape of the tensile rod. The tensile rod was printed at various energy density ranges.

[0142] As the printing energy density increases, the degree of crystallinity of the resulting printed articles increases. All printed articles defined as "unannealed" were removed from the printing chamber immediately after the completion of the printing job. In unannealed printed articles, the degree of crystallinity increased to 41.71% at 0.15 J / mm3 and 47.31% at 0.3 J / mm3. Furthermore, by cooling the printed articles at a rate of less than 2°C / min in a Formiga P110 SLS machine, the degree of crystallinity at an energy density of 0.25 J / mm3 after annealing increased to 48.14%. As a result, the energy density of the printing parameters used can be set to enable the designed degree of crystallinity in the 3D printed articles. For example, parts can be printed at multiple different energy densities to meet the desired mechanical requirements for use.

[0143] [Table 17]

[0144] Example 10 Use of a base support for processing other bioabsorbable polymers In addition to the polydioxanone material printed on a 300×75×0.3mm base, additional materials required the use of a base support for successful part printing. Materials for which a base support is beneficial include polycaprolactone, polylactic acid (poly-L,lactide), and poly(lactide-co-glycolic acid). Polycaprolactone and polylactide materials would curl or shrink without a base support. The observed curling and shrinkage were severe due to the blade catching on and shifting the printed article during recoating of a new powder layer. For poly(lactic acid-co-glycolic acid) material, a base was beneficial because the material is very brittle and could break during recoating if thin. Without a base anchor layer, it was not possible to successfully print the part to completion.

[0145] Example 11 Mechanical results after processing The composition can have mechanical properties controlled according to the processing method. For example, when processing a 10 μm unsintered calcium phosphate composite powder of polydioxanone + 3 wt% with a selective laser sintering machine, the mechanical properties of the printed article depend heavily on the laser energy density and the part removal process. The effect of the printing process on the mechanical properties was evaluated using the shape of a small tensile bar. The energy density of the printing parameters used for both sets of mechanical samples was 0.25 J / mm². 3 That is the case.

[0146] When the printed article of polydioxanone and 3 wt% calcium phosphate was removed immediately after the completion of the printing operation, the yield strength was 20.65 ± 0.85 MPa, the modulus was 551 ± 11.5, and the elongation at break was 79.39 ± 40.64%. However, when the printed article was slowly cooled in the system, the yield strength was 32 ± 0.47 MPa, the modulus was 827 ± 25.8 MPa, and the elongation at break was 9.36 ± 0.90%. Furthermore, the crystallinity of the mechanical test sample cooled during processing was 48.14%, while the crystallinity of the mechanical test sample removed immediately after processing was 44.05%. The mechanical test samples were printed on a base support structure in the print bed at 98°C ± 1.5°C. The Formiga P100 SLS machine used in this process required 4 hours to cool to room temperature of 25°C. The data obtained demonstrates that, when the cooling rate is controlled within the process, articles printed from polydioxanone + 3% unsintered calcium phosphate can possess the designed engineering stress.

[0147] Furthermore, increasing the energy density setting increases the mechanical strength of the part. Parts manufactured at high energy density have higher tensile strength at fracture and more consistent elongation at fracture compared to parts manufactured at low energy density (Table 18). If necessary, multiple energy densities can be used within a single print run. This allows some parts of the printed 3D article to have internal structures specially printed at higher energy densities to accommodate the direction of mechanical load. As an example, this could enable the design of highly optimized medical implants tailored to the individual. Personalized medical implants can be printed at multiple energy densities in the direction of mechanical load on the final 3D article, thus optimizing both tensile strength and modulus.

[0148] [Table 18]

[0149] Example 12 Effect of water-soluble salts on the mechanical properties of materials The effect of water-soluble salts on the final mechanical properties of articles manufactured from polymer powder composites is evaluated by injection molding different compositions and testing the resulting tensile bars. Tables 19-22 show the mechanical results for various weight percentages of water-soluble salts in polydioxanone. All composite powder blends show an increase in modulus of elasticity with increasing weight percentage of water-soluble salts. Magnesium sulfate also increases the elongation at break of the polymer composite with increasing weight percentage of water-soluble salts. Furthermore, potassium chloride and sodium chloride salts both had a significant effect on the elongation at break of the powder composites. None of the water-soluble salts significantly decreased or increased the yield point tensile strength of the powder composites. This indicates that each water-soluble salt has a specific effect on the mechanical properties of the material. It would be possible to combine multiple salts with varying concentrations for the desired mechanical properties.

[0150] [Table 19]

[0151] [Table 20]

[0152] [Table 21]

[0153] [Table 22]

[0154] Item 1: A composite powder material comprising a polymer powder and a water-soluble salt, preferably having flow properties optimized for powder processing technology.

[0155] Item 2: The material according to Item 1, wherein the water-soluble salt is embedded on the surface of polymer powder particles.

[0156] Item 3 The material according to Item 1, wherein the water-soluble salt is embedded on the surface of the polymer powder particles by mixing or grinding.

[0157] Item 4 The material according to any one of items 1 to 3, wherein the polymer powder comprises treated polymer powder or untreated polymer powder.

[0158] Item 5 The material according to any one of items 1 to 4, wherein the polymer powder is a blend mixture of virgin polymer powder and treated polymer powder, and the treated polymer powder is annealed during a laser sintering process.

[0159] Item 6 The material according to any one of items 1 to 5, wherein the polymer forming the polymer powder is made from p-dioxanone monomer, l-lactide monomer, d-lactide monomer, glycolide monomer, caprolactone monomer, or a combination thereof.

[0160] Item 7 The material according to any one of items 1 to 6, wherein the water-soluble salt is magnesium sulfate, sodium sulfate, potassium chloride, sodium chloride, sodium sulfate, potassium aluminum sulfate, magnesium chloride, magnesium chloride hexahydrate, or a mixture thereof.

[0161] Item 8 The material according to any one of items 1 to 7, wherein the water-soluble salt constitutes about 50% by weight or less, preferably 0.01% to 30% by weight, and more preferably 0.01% to 20% by weight of the composite powder material.

[0162] Item 9 The material according to any one of items 1 to 8, wherein the polymer powder constitutes about 99% by weight or less, preferably 70% to 95% by weight, or 80% to 99% by weight of the composite powder material.

[0163] Item 10 A method for manufacturing a 3D article comprising a composite powder material described in any one of items 1 to 9, (a) Applying a base anchor layer of polymer having a base shape similar to the 3D article to be manufactured, and irradiating the base anchor layer, (b) Applying the composite powder material layer to the printing area, (c) Sintering the cross-sectional area of ​​the 3D article to be manufactured, (d) Applying multiple layers of the composite powder material to the printing area on the base anchor layer until a complete 3D article is printed. (e) Annealing the composite powder material for 1 second to 8 hours at a temperature preferably 8°C to 60°C, more preferably 9°C to 50°C, and most preferably 10°C to 35°C lower than the initial polymer melting temperature, and (f) Cooling the composite powder material at a controlled cooling rate, preferably 0.1°C / min to 35°C / min, more preferably 1°C / min to 20°C / min, and most preferably 2°C / min to 5°C / min. Methods that include...

[0164] Item 11. The method of Item 10, wherein the base anchor layer on which said irradiation is performed is further supported by an underlying base support, or a base support is added to any structure separate from said base shape.

[0165] Item 12. The method of Item 11, wherein irradiation is performed on the base support at an energy density different from that of the 3D article manufactured by laser sintering.

[0166] Item 13. The method of Item 11 or 12, wherein said base support is removable from said manufactured 3D article, and said base shape is separable into its initial powder form by sieving.

[0167] Item 14. The energy density of the laser sintering process is 0.01J / mm 3 ~5.0J / mm 3 The method according to any one of Items 10 to 13, wherein engineering stress can be embedded in the manufactured 3D article by changing

Claims

1. A composite powder material comprising a polymer powder and a water-soluble salt, wherein the water-soluble salt is a flow aid in the form of powder particles.

2. The material according to claim 1, wherein the water-soluble salt is embedded on the surface of the polymer powder particles.

3. The material according to claim 1, wherein the water-soluble salt is embedded on the particle surface of the polymer powder by mixing or grinding.

4. The material according to any one of claims 1 to 3, wherein the polymer powder comprises treated polymer powder or untreated polymer powder.

5. The material according to any one of claims 1 to 4, wherein the polymer powder is a blend mixture of virgin polymer powder and treated polymer powder, and the treated polymer powder is annealed during a laser sintering process.

6. The material according to any one of claims 1 to 5, wherein the polymer forming the polymer powder is produced from p-dioxanone monomer, l-lactide monomer, d-lactide monomer, glycolide monomer, caprolactone monomer, or a combination thereof.

7. The material according to any one of claims 1 to 6, wherein the water-soluble salt is magnesium sulfate, sodium sulfate, potassium chloride, sodium chloride, sodium sulfate, potassium aluminum sulfate, magnesium chloride, magnesium chloride hexahydrate, or a mixture thereof.

8. The material according to any one of claims 1 to 7, wherein the water-soluble salt constitutes 50% by weight or less of the composite powder material.

9. The material according to any one of claims 1 to 8, wherein the polymer powder constitutes 99% by weight or less of the composite powder material.

10. A method for manufacturing a 3D article comprising a composite powder material according to any one of claims 1 to 9, (a) Apply a base anchor layer of polymer having the same base shape as the 3D article to be manufactured, and irradiate the base anchor layer. (b) Applying the composite powder material layer to the printing area, (c) Sintering the cross-sectional area of ​​the 3D article to be manufactured, (d) Applying multiple layers of the composite powder material to the printing area on the base anchor layer until a complete 3D article is printed. (e) Annealing the composite powder material at a temperature lower than the initial polymer melting temperature for 1 second to 8 hours, and (f) Cooling the composite powder material at a controlled cooling rate. Methods that include...

11. The method according to claim 10, wherein the base anchor layer on which the irradiation is performed is further supported by a base support located below, or the base support is added to any structure other than the base shape.

12. The method according to claim 11, wherein the base support is irradiated with an energy density different from that of the 3D article manufactured by laser sintering.

13. The method according to claim 11 or 12, wherein the base support is removable from the manufactured 3D article, and the base shape is separable to its initial powder form by sieving.

14. The energy density of the laser sintering process is 0.01 J / mm². ３ ~5.0 J / mm ３ The method according to any one of claims 10 to 13, wherein engineering stresses can be embedded in the manufactured 3D article by changing the coefficient.

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