Method for producing a three-dimensional microporous filament structure

Abstract

A method for producing a three-dimensional macroporous filamentary structure having interconnected microporous filaments comprises the steps of: a) preparing a mixture comprising one or more metals, one or more metal alloys, or a combination thereof, one or more binders, a first liquid solvent for the one or more binders, and optionally one or more dispersants; b) dispersing particles comprising at least one removable additive into the mixture; and c) depositing the mixture in the form of filaments in a predetermined three-dimensional pattern of interconnected filaments, thereby forming a three-dimensional macroporous filamentary structure. d) contacting the three-dimensional filament-based porous green structure formed in step c) with a second solvent that is a non-solvent for the one or more binders to induce a phase transition and create a filament-based phase-transformed structure having filament microporosity and convert at least a portion of the filaments to a solid state; e) removing at least one removable additive by dissolving it in a removing agent to create additional microporosity in the phase-transformed porous structure; and f) heat-treating the resulting structure. The removing agent may comprise or consist of the second liquid solvent, or the removing agent may be a third liquid solvent different from the second liquid solvent.

Description

[Technical Field]

[0001] According to the preamble of claim 1, the present invention relates to a method for producing a three-dimensional macroporous filamentary structure having interconnected microporous filaments and having a suitable morphology.

[0002] The present invention also relates to three-dimensional macroporous filament structures obtained by said manufacturing method and their use in (bio)medical products, implants, bone grafts, drug delivery devices, three-dimensional catalysts, adsorbents, heat exchange structures. [Background technology]

[0003] Highly porous constructs are of great importance in applications such as orthopedic implants and bone tissue engineering. Various manufacturing methods have been developed for the preparation of highly porous polymeric, ceramic, or metallic scaffolds with pore sizes ranging from 100 to 1000 μm.

[0004] The applicant's previous patent publication EP2195131 describes a method for producing a porosity-free membrane with two levels of porosity: a first level of porosity comprising interconnected macropores between filaments, said macropores typically having an adjustable pore size distribution; a second level, which is a porous level containing interconnected pores within the filaments;

[0010] A method for producing a three-dimensional microporous filament structure has been disclosed.

[0005] The method disclosed in EP 2195131 comprises depositing a viscous paste in the form of filaments with a three-dimensional structure. This method comprises in particular the following steps: a) preparing a suspension comprising particles of a selected metallic material, such as titanium or a titanium alloy, a liquid solvent, one or more binders, and optionally one or more dispersants; b) precipitating said suspension in the form of filaments in a predetermined three-dimensional pattern, thereby creating a three-dimensional filament-based porous structure; c) the steps of: c1) contacting the filaments with vapor of a non-solvent during deposition of the filaments; and c2) immersing the structure of step c1) in a liquid non-solvent to produce a filament-based porous structure with the appropriate filament morphology. inducing a phase transition to convert the filaments from a liquid to a solid by d) firing and sintering the structure of step c) and subjecting it to a heat treatment; Includes.

[0006] However, the level of microporosity that can be achieved by this method is limited. The polymer binder can interfere with the formation of micropores, requiring the inclusion of a larger amount of binder to achieve higher porosity. However, it has been observed that the thermal decomposition of the polymer binder during heat treatment produces carbonaceous residues. Some of this carbonaceous residue, as well as reaction products between carbon and carbon-sensitive metallic materials, formed during heat treatment can accumulate between the particles of the material forming the construct and become trapped interstitially in the metallic structure during heat treatment. Particularly when the construct is made from a metallic material such as titanium or a titanium alloy, the carbonaceous residues can cause undesirable weakness in the three-dimensional construct. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] EP2195131 Summary of the Invention [Problem to be solved by the invention]

[0008] Therefore, there is a need for a method of producing a three-dimensional porous construct having interconnected pores and a desired, preferably higher microporosity than the prior art, without increasing the entrapment of residual impurities. There is also a need for a method of producing a three-dimensional construct comprising interconnected microporous filaments, the filaments arranged in a desired pattern, the filaments having a desired morphology and pore structure, and the pores in the filaments being accessible from the exterior of the construct. [Means for solving the problem]

[0009] The present invention therefore seeks to provide a method for producing three-dimensional macroporous filament structures comprising interconnected microporous filaments having a desired morphology, which method can increase the pore volume of the micropores compared to the prior art.

[0010] This is achieved according to the invention with a method having the technical features set forth in claim 1.

[0011] The present invention therefore provides a method for preparing a three-dimensional macroporous filamentary structure having interconnected microporous filaments and having a suitable morphology, comprising the steps of: a) preparing a mixture comprising particles of one or more metals, one or more metal alloys, or mixtures of these materials, one or more binders, such as a polymeric binder, a first liquid solvent for the one or more binders, and optionally one or more dispersants; b) dispersing particles having at least one removable additive compound in the mixture, preferably the particles having at least one removable additive compound are insoluble in the first solvent; c) depositing the mixture in the form of filaments in a predetermined three-dimensional pattern of interconnected filaments to create a three-dimensional filament-based porous green structure; d) contacting the three-dimensional filament-based porous green structure formed in step c) with a second solvent, which is a non-solvent for one or more binders, to induce a phase transition, thereby producing a filament-based porous phase-transformed structure with the appropriate filament morphology, in particular with filament microporosity, wherein at least a portion of the filaments are converted into a solid state; e) contacting the phase-transitioned structure with a removal agent to remove at least a portion of the at least one removable additive by dissolving the at least one removable additive in the removal agent, thereby creating additional microporosity in the phase-transitioned porous structure, the removal agent comprising or consisting of a second liquid solvent or comprising or consisting of a third liquid solvent, in particular the second liquid solvent, and advantageously a third liquid solvent different from the first liquid solvent; f) heat-treating the structure obtained above The present invention relates to a method comprising:

[0012] The inventors have surprisingly discovered that by incorporating at least one removable additive into a mixture containing particles of one or more metals, one or more metal alloys, or mixtures thereof, and then removing at least a portion of the removable additive, the porosity of a 3D filament construct can be increased to unexpected levels. The incorporation and subsequent removal of the removable additive can achieve an increase in porosity beyond the volume occupied by the at least one removable additive. In particular, micropores can be formed in the filament, and the porosity resulting from these micropores can be increased to unexpected levels. This can result in the formation of micropores in the filament having an unexpected volume.

[0013] The inventors have further discovered that a portion of the micropore volume can be created by a phase transition of the binder material in step d), in which a solvent for one or more binders is replaced with a non-solvent, solidifying the one or more binders. Furthermore, in step e), the phase-transformed 3D filament-based structure is contacted with a remover to remove at least a portion of the removable additive, thereby forming the micropore volume. Furthermore, in step f), a further portion of the micropore volume can be formed by a heat treatment, optionally achieving thermal decomposition of one or more binders. The micropores created in steps d), e), and f) are essentially interconnected.

[0014] Depending on the amount of removable additive incorporated into the mixture and the extent to which the removable additive is removed, a three-dimensional filament construct may be constructed with porosity greater than that achieved by phase transformation of the binder alone. Alternatively, incorporating at least one removable additive can result in a three-dimensional filament construct with a porosity similar to that achieved by using a small amount of one or more binders. It may be important to minimize the amount of one or more binders, since the heat treatment in step f), including, for example, debinding or calcination and / or sintering, can cause the formation of carbonaceous residues due to thermal decomposition of the binder during the heat treatment. At least a portion of the carbonaceous residues may remain in the pores of the three-dimensional construct, leading to embrittlement with the risk of reducing mechanical properties, particularly ductility, and / or increasing brittleness to undesirable levels. The inventors have observed that a small amount of one or more binders can interfere with the pore formation of the construct by forming microporosity in the filament. The inventors have also discovered that removable additives can increase the porosity of the three-dimensional construct to levels not obtainable by the presence of one or more binders alone.

[0015] Depending on the nature of the additive, the desired porosity, and the intended use, removal of removable additives by the remover in step e) may be as complete as possible, or may allow the additive to remain at a desired level.

[0016] The incorporation of at least one removable additive into the mixture according to the present invention offers the advantage of limiting the amount of phase change binder to be incorporated into the mixture below a certain limit, or alternatively, reducing the amount of phase change binder incorporated into the mixture compared to prior art mixtures while still achieving the desired porosity. The present invention allows for the construction of porous three-dimensional constructs with comparable or greater porosity by reducing the amount of one or more phase change binders in the mixture, while simultaneously minimizing the risk of undesired increased brittleness of the three-dimensional filament construct after heat treatment. In other words, given a given porosity, the amount of one or more phase change binders that must be present in the mixture to achieve the desired porosity can be reduced compared to prior art mixtures that do not contain a removable additive. Instead, the incorporation of a removable additive according to the present invention offers the advantage of obtaining three-dimensional constructs with porosity levels that exceed the porosity levels that can be achieved solely through the presence of a phase change binder, i.e., without the presence of a removable additive. In other words, for the same amount of phase-transforming binder, it is possible to increase the porosity of the three-dimensional construct to a level greater than that predicted by the amount of removable additive in the mixture, which is advantageous because the use of removable additives can minimize the formation of carbonaceous residues during firing and sintering.

[0017] The method of the present invention provides an additional advantage in that it can form surface roughness on the outside of the filament and on the surfaces of the pores inside the filament. This is likely caused by a phase transition of one or more binders. Because the filament is formed from a mixture containing one or more binders, at least a portion of the one or more binders is present on the outside surface of the filament, and this phase transition can form roughness on the outside surface of the filament. A similar phenomenon can occur inside the filament, where micropores with a specific surface roughness are formed when one or more binders undergo a phase transition. A specific degree of surface roughness can provide important advantages, especially when the three-dimensional construct is used as part of an implant or graft. Surface roughness can therefore promote in vivo incorporation.

[0018] Within the scope of the present invention, heat treatment may serve the purpose of drying the component. However, heat treatment also involves the removal of binder materials and sintering the component. Conventional sintering conditions are used to obtain components with a controllable degree of microporosity and pore size distribution. It is noted that sintering may be accompanied by shrinkage of the component, and such shrinkage may reduce the overall porosity and average pore size.

[0019] Step b) of dispersing (particles of) at least one removable additive in the mixture of step a) comprising particles of one or more metals, one or more metal alloys, or mixtures of these materials, one or more binders, a first liquid solvent for the one or more binders, and optionally one or more dispersants may comprise a separate step or may be performed simultaneously with preparing the mixture.

[0020] The step of contacting the filaments formed in step c) with a non-solvent for the binder(s) can be carried out in several ways, depending on the nature of the binder(s), the nature of the at least one removable additive, and the desired microporosity.

[0021] According to a first preferred embodiment, the step of contacting the three-dimensional filament-based porous structure with a second solvent that is a non-solvent for the binder(s) to induce a phase transition of the binder(s) can be carried out during the deposition of the filaments. The step of contacting the three-dimensional filament-based porous structure with the second solvent for the purpose of inducing a phase transition can therefore be carried out while the filaments are being deposited.

[0022] According to a second preferred embodiment, the step of contacting the three-dimensional filament-based porous structure with the second solvent can be performed after the filaments have been deposited and the three-dimensional filament-based porous structure has been formed. For the purpose of inducing a phase transition, the step of contacting the three-dimensional filament-based porous structure with the second solvent can therefore be performed after the deposition of the filaments is complete.

[0023] According to a third preferred embodiment, step d) may include a first step of contacting the three-dimensional filament-based porous structure formed in step c) with a third non-solvent, preferably non-solvent vapor, for the one or more binders, thereby partially inverting the phase of the one or more binders. This first step of step d) may be performed before contacting the three-dimensional filament-based porous structure with the second liquid solvent, after contacting the three-dimensional filament-based porous structure with the second liquid solvent, or simultaneously. The step of contacting the filament-based porous structure formed in step c) with the third non-solvent, particularly non-solvent vapor, is preferably performed during the precipitation of the filaments, before contacting the filament-based porous structure with the second solvent. This may induce a partial phase transition, which may create porosity in the filaments, thereby facilitating the penetration of the second solvent and the resulting formation of pores. The partial phase transition may also provide early rigidity to the three-dimensional filament-based porous structure. Exposing the porous structure to a third non-solvent may facilitate removal of the removable additive in a subsequent step.

[0024] Advantageously, in step e), the remover is the second liquid solvent, or a mixture of the second liquid solvent and an acid or a base, or a third liquid solvent that is advantageously neither the second nor the first liquid solvent. Step e) can be carried out simultaneously with step d), for example by immersing the porous green structure in a first liquid bath comprising the second liquid solvent and optionally an acid or a base. Alternatively, step e) can be carried out subsequent to step d), for example by immersing the phase-transformed structure in a second liquid bath comprising the second liquid solvent, optionally with an acid or a base, or comprising the third liquid solvent, optionally with an acid or a base.

[0025] The present invention also relates to a three-dimensional macroporous filament structure obtainable by the above-described method. Advantageously, the porosity formed by interconnected micropores comprises between 1% and 50%, preferably between 5% and 30%, of the total porosity of the three-dimensional macroporous filament structure, wherein said micropores consist of pores with a pore size of 50 μm or less. Advantageously, the filaments have an average surface roughness (Ra) greater than 4 μm. The porosity of the macroporous filament structure due to macropores generally comprises between 50 and 95%, preferably between 60 and 85%, of the total porosity of the three-dimensional macroporous filament structure, wherein said macropores have a pore size greater than 100 μm. The total porosity of the three-dimensional macroporous filament structure is advantageously between 30.7% and 97.5%, advantageously between 50.7% and 97.5%.

[0026] In one embodiment, the porosity of the three-dimensional macroporous filament construct obtained by the above-described method, formed by interconnected micropores, is between 1% and 50%, preferably between 5% and 30% (relative to the total volume of the filaments in the three-dimensional macroporous filament construct). Advantageously, the three-dimensional macroporous filament construct obtained by the method of the present invention has a porosity formed by interconnected micropores (microporosity) due to removable additives of at least 11.5%, preferably between 11.5% and 15.2%, relative to the total volume of the filaments. In other words, the difference in microporosity between the three-dimensional macroporous filament construct obtained by the method of the present invention and a three-dimensional macroporous filament construct having the same mass ratio of phase-transfer binder and metal and / or metal alloy particles but without removable additives (i.e., a three-dimensional macroporous filament construct obtained by the same method except that step b) is omitted), is at least 11.5%, particularly 11.5% to 15.2%, relative to the total volume of the filaments. The terms "micropore" and "microporous" above refer to pores having a pore size of 50 μm or less.

[0027] One advantage of the three-dimensional macroporous filament structure described above is that a high level of microporosity can be achieved with a significantly lower amount of organic (polymeric) binder, resulting in a structure with significantly lower residual carbon content upon heat treatment, thereby significantly improving the mechanical properties of the structure, such as ductility and elasticity, compared to prior art structures with the same level of microporosity.

[0028] The porosity of the macroporous filament structure due to the macropores is advantageously between 30% and 95%, preferably between 50% and 95%, preferably between 60% and 85% (relative to the total volume of the three-dimensional macroporous filament structure).

[0029] The invention further relates to the use of the three-dimensional macroporous filament structure described above or to a structure obtained by the method described above for the manufacture of catalysts, adsorbents or chromatographic materials.

[0030] The present invention further relates to biomedical products, such as artificial bone implants or grafts, tissue engineering scaffolds, drug delivery devices, etc., comprising the above-mentioned three-dimensional macroporous filament constructs or the three-dimensional macroporous filament constructs obtained by the above-mentioned methods. The biomedical products may contain bone morphogenetic proteins (BMPs), stem cells, osteoblasts, pharmaceuticals, and / or mixtures thereof, which may be incorporated into the three-dimensional macroporous filament constructs, usually after firing and sintering. [Brief explanation of the drawings]

[0031] The above and other features and advantages of embodiments of the present invention will be described in more detail with reference to the accompanying drawings. [Figure 1] FIG. 1 illustrates diagrammatically the different steps in the method of the invention. [Figure 2] FIG. 2 shows the variation in microporosity as a function of the amount of phase-transforming binder in the mixture deposited as filaments in prior art compositions. [Figure 3] FIG. 3 shows the porosity of 3D constructs with varying amounts of phase-transition binder and varying amounts of NaCl as a removable additive. [Figure 4] Figures 4A-4B show electron microscope images of 3D constructs obtained from a mixture containing titanium and 2.3 wt% of a phase-transforming polysulfone binder, with and without NaCl as a removable additive, respectively. [Figure 5] Figures 5A-5B show electron microscope images of 3D constructs obtained from a mixture containing titanium and 1.7 wt% of a phase-transformed polysulfone binder, with and without NaCl added as a removable additive, respectively. DETAILED DESCRIPTION OF THE INVENTION

[0032] An embodiment of the present invention provides a method for producing three-dimensional macroporous constructs with suitable microporous filament morphology based on a combination of 3D printing and phase transformation. The sintered constructs obtained by the method according to the present invention comprise interconnected microporous structures and filament struts with rough surfaces.

[0033] As used herein, the term "phase inversion" refers to a process using a mixture containing a dissolved polymer to convert the polymer, e.g., a deposited polymer, in the form of filaments in a controlled manner from a liquid state to a solid state. This process involves creating a mixture of the desired materials, e.g., in the form of a viscous paste, suspension, or solution, depositing filaments of the mixture in three dimensions into the desired shape, forming a suitable solvent / phase inversion binder mixture, and exposing the printed 3D structure to a non-solvent for the phase inversion binder to cause the phase inversion binder to precipitate from the suspension or solution, forming a three-dimensional filament construct of the desired shape. Phase inversion techniques involve the formation of a solid matrix by precipitation or solidification of a phase inversion binder upon exposure to a non-solvent. The term "phase inversion" is well known in the field of porous structure fabrication and is clearly defined, for example, in the text "Basic Principles of Membrane Technology" by Mulder M., published by Kluwer Academic Publishers in 1996.

[0034] As used herein, the term "porosity" refers to the degree of voids in a material after sintering, and is measured herein as a percentage between 0 and 100%. Porosity is determined by image analysis of SEM images based on gray value differentiation.

[0035] As used herein, the terms "macroporous" or "macroporous" or "highly porous" refer to the porosity of a composition having macropores with pore sizes greater than 50 μm in diameter. The terms "macroporous" or "macropores" are considered synonymous in some embodiments of the present invention. The term "macroporous" therefore refers to compositions of the present invention having macropores with pore sizes greater than 50 μm in diameter.

[0036] The term "microporous" or "microporous" refers to the porosity of the filaments after sintering, including pores with a pore size of 50 μm or less. The terms "microporous" and "micropore" are considered synonymous in some embodiments of the present invention. The term "microporous" thus refers to filaments of the present invention having pores with a pore size of 50 μm or less in diameter, such as 0.1 to 50 μm, or 0.5 to 50 μm, or 1 to 30 μm, and for example, pores with a pore size of less than 40, 30, 20, 15, 10, 5, or 1 μm.

[0037] The terms "strut filaments," "struts," and "filaments" are used synonymously herein and refer to a suspension or solution, as defined herein, that has been deposited in the form of filaments, for example by (co)extrusion.

[0038] The term "interconnected microporosity" as used herein in relation to microporous filaments means that the (micro)pores in the various filaments deposited according to a predetermined 3D pattern are interconnected, thereby providing passages for transporting, for example, gases or liquids, within the construct according to the invention and between the filaments.

[0039] The term "interconnected macroporosity" as used herein in relation to a macroporous composition means that the (macro)pores of the composition are interconnected, thereby providing passageways for transporting, for example, gases or liquids, within the composition according to the invention.

[0040] The term "roughened" and its cognates are intended to refer to the surface texture on a micron scale. Surface roughening is not intended to refer to more macroscopic features of the implant, such as threads.

[0041] The term "surface roughness" as used herein is also defined in ISO standard 4287-1:1984 (Surface roughness - Terminology - Part 1: Surface and its parameters). Surface roughness can be measured, for example, by non-contact optical profilometry based on interferometry (VEECO, Wyko NT3300 - AG Olszak, J. Schmit, MG Heaton, "Interferometry: Technology and Applications," Veeco Instruments, Inc., 2650 E. Elvira Road, Tucson, AZ 85706, 2001).

[0042] The term "green structures" refers to 3D printed structures of interconnected filaments that are not subjected to heat treatment.

[0043] It should be noted that in some embodiments of the present invention, the terms "construct," "structure," and "scaffold" are used synonymously. In some embodiments of the present invention, the terms "suspension," "solution," and "paste" are used synonymously.

[0044] method The present invention provides a method for producing three-dimensional macroporous filamentary structures containing interconnected microporous filaments and having a desired morphology.

[0045] Steps a) and b) The first step of the process of the present invention involves preparing a mixture, typically a suspension, in the form of a viscous paste or suspension or dispersion, comprising: - particles of one or more metals, one or more metal alloys or a mixture of one or more metals and one or more metal alloys, a first liquid solvent, - one or more binders soluble in the first liquid solvent; preparing a mixture comprising:

[0046] Suitable metals or metal alloys may be selected from the following: aluminum, aluminum alloys; stainless steel alloys, including austenitic, ferritic, and martensitic stainless steel alloys; cobalt alloys; copper alloys; nickel alloys; silver alloys; gold alloys; platinum alloys; titanium, titanium alloys such as Ti-6Al-4V, zinc alloys, tantalum, tungsten, molybdenum, tantalum, tungsten, silver, molybdenum, iron, gold, platinum, and stainless steel, and combinations of two or more thereof. In particularly preferred embodiments, the predetermined particulate material comprises particles of titanium or a titanium alloy. In the following description, embodiments of the method of the present invention are described with reference to the use of titanium and titanium alloy particles.

[0047] Preferably, the metal or metal alloy has a particulate morphology and shape, typically characterized by a specific particle size distribution and a specific surface area. The particles may be provided in powder form. Within the scope of the present invention, the average particle size can be determined using laser diffraction. By way of example, the particles of one or more metals and one or more metal alloys may have an average particle size of up to 2000 μm, with an average minimum diameter typically of 10 nm, although powder materials with smaller or larger particle sizes may also be used, and those skilled in the art can select an appropriate particle size depending on the intended application. Advantageously, the average particle size of the particles is 100 μm or less, more preferably less than 90 μm, most preferably less than 80 μm or less than 70 μm, and particularly less than 60 μm or less than 50 μm. The particles preferably have an average particle size of at least 20 nm, preferably at least 25 nm, or at least 30 nm, but the average particle size may also be at least 1 μm.

[0048] According to a preferred embodiment of the present invention, the mixture formed in step a) may comprise at least 45% by volume, preferably at least 50% by volume, more preferably at least 55% by volume or at least 60% by volume of particles of one or more metals and / or metal alloys, based on the total volume of the mixture. It is also conceivable that the mixture of step a) preferably comprises up to 90% by volume, preferably up to 85% by volume, more preferably up to 80% by volume of particles of one or more metals or metal alloys, based on the total volume of the mixture. In a particularly preferred embodiment, the mixture of step a) comprises 45% to 92% by volume, preferably 50% to 85% by volume of particles of one or more metals and / or metal alloys, based on the total volume of the mixture.

[0049] The first liquid solvent used in the method of the present invention is a solvent for one or more binders and serves to prepare the mixture so that it takes the form of a suspension, a viscous paste, or a dispersion. Preferably, the first solvent is a non-volatile liquid, a volatile liquid, or a mixture of one or more volatile solvents and one or more non-volatile solvents. The first liquid solvent may include one or more organic solvents and inorganic solvents. Suitable organic solvents include N-methylpyrrolidone (NMP), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), s-caprolactam, 4-butyrolactone, methyl ethyl ketone, acetone, acetic acid, formylpiperidine, morpholine, chlorinated solvents such as chloroform, carbon tetrachloride, and dioxane. Preferably, the non-volatile liquid in the first solvent is N-methyl-2-pyrrolidone, and the volatile solvent in the first solvent is acetone. It is understood that the first liquid solvent is a solvent for the binder(s), but is incapable of dissolving the removable additive.

[0050] In a preferred embodiment, the first liquid solvent is soluble in or miscible with the second solvent as defined herein.

[0051] The second solvent may be in a liquid or gas phase. The second solvent is intended as a non-solvent for one or more binders contained in the mixture and is selected from solvents capable of inducing a phase transition of one or more binders upon contact with the binder(s). Solvents suitable for use as the second solvent may be selected from the list of solvents listed above as the first solvent. However, it will be apparent to those skilled in the art that the first and second solvents are different from each other, and the solubility of one or more binders in the mixture of the first and second solvents is lower than the solubility of the one or more binders in the first solvent. Examples of solvents suitable for use as the second solvent include water, ionic liquids, and aqueous solutions containing acids or bases. The latter offer the additional advantage of improving the solubility of the removable additive, depending on the nature of the removable additive. The acid may be a weak or strong acid, such as acetic acid, HCl, or other acids deemed appropriate by those skilled in the art. The use of acidic or basic solutions may be preferred to precisely control the microporous structure of the filaments, especially during the phase inversion process or during the process of removing removable additives to improve additive solubility. It should be understood that the second solvent is a non-solvent for one or more binders and, in some embodiments, acts as a remover for at least one removable additive.

[0052] Advantageously, the one or more binders may comprise a single phase-changing binder or a mixture of two or more phase-changing binders. The one or more binders may comprise one or more rheology-modifying binders. As used herein, the term "phase-changing binder" refers to a binder that undergoes a phase change in a suitable non-solvent medium (second solvent) for the phase-changing binder, such as water, alcohol, acid, or a mixture thereof, or in a suitable medium comprising a mixture of a non-solvent and a solvent (see below) for the phase-changing binder. According to the present invention, the phase-changing binder preferably comprises one or more polymers selected from the group consisting of polysulfone, polyethersulfone, cellulose acetate, polyvinylidene fluoride, polyacrylonitrile, polyethylene-co-vinyl alcohol, polyimide, polyetherimide, polyamide, and combinations thereof.

[0053] The term "rheology-modified binder" as used herein refers to a binder capable of modifying the rheology or flow properties of the mixture prepared in step a). The rheology of the mixture is advantageously adjusted to allow proper deposition of the filaments. Rheology-modified binders suitable for use in the present invention may be pressure-responsive binders, i.e., binders whose viscosity decreases when pressure is applied. According to the present invention, the rheology-modified binder is preferably selected from the group consisting of hydrocolloids, cellulose derivatives, and combinations thereof.

[0054] In a preferred embodiment, the mixture prepared in step a) contains a total amount of binder, i.e., the combined phase change binder and rheology-modifying binder, of at least 0.5% by volume, preferably at least 1% by volume, more preferably at least 2% by volume, even more preferably at least 3% by volume, more preferably at least 4% by volume, and most preferably at least 5% by volume, based on the total volume of the mixture. It is further understood that the mixture prepared in step a) contains a total amount of binder of up to 30% by volume, more preferably up to 28% by volume, even more preferably up to 25% by volume, more preferably up to 24% by volume, even more preferably up to 22% by volume, and most preferably up to 20% by volume, based on the total volume of the mixture. The total amount of binder depends, for example, on the type of powder, such as its density, particle size, and specific surface area, and may be 5, 7, 10, 12, 15, 18, 20, 22, 25, or 28% by volume, based on the total volume of the mixture. The volume measurement can be performed at atmospheric pressure and room temperature.

[0055] According to a particular embodiment, the mixture prepared in step a) comprises from 0.5% to 30% by volume, preferably from 1% to 25% by volume, more preferably from 1% to 15% by volume of the binder that induces a phase change, and from 0% to 30% by volume, preferably from 0% to 15% by volume of the rheology-modifying binder, relative to the total volume of the mixture.

[0056] Advantageously, the at least one removable additive is dispersed in the mixture prepared in step a) in the form of particles. Particles are understood to include solid particles, liquid droplets, for example droplets of a liquid solvent or gel. The at least one removable additive may therefore comprise particles of a solid material or droplets of a liquid material or gel suitable for being dispersed in the mixture.

[0057] At least one removable additive in a mixture containing one or more metals and / or one or more metal alloys can be dispersed simultaneously with the preparation of the mixture or in a separate step. In a preferred embodiment, the volume ratio of the at least one removable additive to the volume of the particles of one or more metals and / or one or more metal alloys is at least 0.01:100, preferably at least 0.1:100, more preferably at least 1:100, even more preferably at least 5:100, and most preferably at least 10:100. It is further understood that the mass ratio of the at least one removable additive to the particles is at most 50:100, preferably at most 45:100, more preferably at most 40:100, even more preferably at most 35:100, and most preferably at most 30:100. By varying the amount or volume of additive incorporated into the mixture, the porosity of the three-dimensional macroporous filament construct can be controlled as described above.

[0058] In a preferred embodiment, one skilled in the art can select the average particle size of the removable additive, taking into account the expected pore volume and average pore diameter of the construct. It is known that the pore diameter of micropores can be varied by varying the particle size of the additive. Furthermore, the presence of at least one removable additive can result in a pore volume that exceeds the volume occupied by the removable additive. In one example, the particle size of the removable additive can range from about 0.01 μm to 500 μm, preferably from about 0.05 μm to 250 μm, and more preferably up to 100 μm.

[0059] When extrusion is used as the filament deposition technique, the particle size of the metal(s), metal alloy(s), and at least one removable additive is preferably selected to be sufficiently small for use with a particular extrusion nozzle, with the largest particles (d99 value) having a diameter that is preferably at least 5 times smaller, especially at least 10 times smaller, than the diameter of the nozzle.

[0060] According to one embodiment, the at least one removable additive is not primarily soluble in the first solvent (solvent for the binder to be phase-transferred), but is soluble in the remover.

[0061] According to an alternative embodiment, the at least one removable additive is not primarily soluble in the first solvent (solvent for the binder undergoing phase change), but is soluble in a second solvent that is a non-solvent for the binder undergoing phase change. This allows the additive to be at least partially removed after partial phase change has been achieved. A preferred embodiment of the method of the present invention comprises the step of contacting the at least one removable additive with the second solvent, and dissolving at least a portion of the at least one removable additive in the second solvent.

[0062] The at least one removable additive is preferably selected from one or a combination of polymers and inorganic salts that are soluble in a solvent, especially the remover or the second solvent.

[0063] Inorganic salts suitable for use as removable additives in the present invention include inorganic salts that are soluble in organic or inorganic solvents or water, or in a mixture of one or more of the above solvents containing an acid or base to enhance the solubility of the salt. Preferred salts include salts containing alkali metal ions, alkaline earth metal ions, earth metal ions, ammonium salts, or mixtures of two or more thereof as a positive charge. Particularly preferred salts include salts containing sodium, potassium, calcium, magnesium, aluminum, or mixtures of two or more thereof as a positive charge. The negative charge of at least one removable additive may include nitrate ions, sulfate ions, phosphate ions, chloride ions, carbonate ions, or halide ions, as well as mixtures of two or more thereof. Particularly preferred removable additives include one or more compounds selected from the group consisting of ionic liquids, NaCl, KCl, CaCO3, and mixtures of two or more thereof.

[0064] According to an alternative embodiment, the particles of the at least one removable additive comprise droplets. Suitable examples of such removable additives include, but are not limited to, solutions of polymers, particularly aqueous solutions of said polymers, such as polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polylactic acid, polyethylene oxide, and mixtures of two or more thereof.

[0065] According to yet another alternative embodiment, the particles of the at least one removable additive comprise droplets of a suspension of the at least one removable additive in a dispersant.

[0066] The total volume percent of organic compounds present in the mixture generally depends on the density, particle size distribution, morphology, and specific surface area of ​​the metal(s) and / or metal alloy(s) particles. Preferably, the mixture is developed with minimal ash residue after heat treatment. Preferably, less than 6 volume percent of rheology-modifying binders, plasticizers, and / or dispersants is incorporated into the mixture.

[0067] In one example, a mixture in the form of a powder paste can be prepared by mixing 20 to 85 volume percent titanium or titanium alloy powder with one or more binders and a sodium salt in a first liquid solvent in which the one or more binders are soluble.

[0068] In one embodiment of the present invention, the mixture obtained in step a) is -1 At shear rates of 100 to 10,000 Pa·s, the viscosity is between 100 and 10,000 Pa·s.

[0069] The above-described compositions may be advantageously used for additive manufacturing or 3D printing of 3D objects using filament deposition by extrusion of a viscous paste or suspension or dispersion (see description of step b) below).

[0070] Process c) The next step of the method of the present invention involves forming the mixture obtained in steps a) and b) into filaments and depositing the mixture in the form of filaments in a predetermined three-dimensional pattern, thereby creating a three-dimensional filament-based porous green structure. The filaments are typically deposited as stacked filaments. The filaments within a layer may be positioned adjacent to each other or spaced apart from each other. The filaments of the next layer are typically positioned at an angle to the filaments of the previous layer. This allows the filaments in different layers to be connected to each other with macropores between the filaments, forming a 3D material.

[0071] Filament deposition can be achieved in several ways, depending on the nature of the composition and the intended application. Suitable 3D printing techniques that allow filaments to be formed and arranged into three-dimensional porous structures include fused filament fabrication (FFF), direct ink writing (DIW; also known as (micro)extrusion using a nozzle or orifice), three-dimensional fiber or filament deposition (3D FD), and stereolithography, digital direct light processing (DLP), direct ink writing, microextrusion, robocasting, etc. Among these, 3D printing techniques that deposit filaments in a multi-layered configuration are preferred, particularly three-dimensional fiber or filament deposition (3DFD) or microextrusion, in which a mixture is extruded or dispensed through a nozzle to obtain a filament.

[0072] A first embodiment of filament deposition according to the present invention involves extrusion or dispensing of the mixture in the form of filaments and deposition of the three-dimensional filaments in a conventional system, e.g., a non-reactive system, which does not affect the composition and physical state of the filaments.

[0073] A second embodiment of the filament deposition according to the present invention involves extruding the mixture and depositing the filaments in a non-solvent system for one or more binders. The term "non-solvent system" refers to a system in which the relative vapor pressure of the non-solvent for one or more binders, in particular for at least one phase-transfer binder, is at least 5% by volume, preferably at least 10, 15, 20, or 25% by volume. The non-solvent medium can be a humid environment or air with a relative humidity of at least 50%. In a preferred embodiment, the non-solvent system is formed by a water vapor fluid contacting the three-dimensional filament-based porous structure formed in steps a) and b).

[0074] As mentioned above, the precipitation of the mixture obtained in steps a) and b) in the form of filaments can be carried out by various techniques, including extrusion of the prepared suspension through a nozzle. For this purpose, various types and designs of nozzles can be used according to the present invention. Suitable types and designs of nozzles are known in the art, in particular from EP 2 195 131 B1, paragraphs

[0073] to

[0086] and

[0089] to

[0092] , which are incorporated by reference.

[0075] The method involves the fabrication of 3D structures or scaffolds or constructs by controlled deposition, for example of extruded filaments, in a non-solvent system for one or more binders, according to a predetermined or pre-set pattern.

[0076] Step d) The next step of the method of the present invention involves subjecting the porous green structure formed in step c) to a phase inversion, in particular a liquid induced phase inversion (LIPS) and / or vapor induced phase inversion (VIPS) step, which involves contacting the filaments formed in step c) with a second solvent with the aim of inverting the phase of one or more binders, thereby creating a filament-based porous structure with the appropriate filament morphology, and converting at least a portion of the filaments into a solid state.

[0077] According to a first embodiment of step d), the phase transition of one or more binders of the three-dimensional filament-based porous green structure formed in step c) can be induced by contacting the porous green structure obtained in step c) with a second solvent that is a non-solvent for one or more binders, in particular a non-solvent for the binder that undergoes the phase transition.

[0078] According to a second embodiment of step d), the phase transition of one or more binders of the three-dimensional filament-based porous green structure can be achieved by contacting the green structure with a non-solvent for one or more binders already during the filament deposition in step c). Inducing a phase transition to form a 3D structure while the filaments are being deposited has the advantage that rapid solidification of the filaments and the formation of a pore structure can be achieved already during the filament deposition. As a result, structures with higher rigidity and better shape retention can be obtained early in the manufacturing process. Contact with the non-solvent during filament deposition can be achieved, for example, by using a liquid non-solvent during filament deposition or by using a non-solvent vapor, a technique known as vapor-induced phase transition, in which a suitable non-solvent vapor is poured onto the filaments (step d1).

[0079] If desired, according to a third embodiment of step d), it is possible to combine the first and second embodiments by contacting the filament with a non-solvent system already during the deposition of the filament and contacting the 3D printed green structure with a further non-solvent after the printing of the 3D construct is completed. Thus, the non-solvent used during the deposition of the filament can be the same or different from the substance used as the further solvent after the printing of the construct is completed. In other words, the non-solvent vapor and the liquid non-solvent can be derived from the same solvent, for example, water vapor and water, or alcohol vapor and liquid alcohol. According to different embodiments, the non-solvent vapor and the liquid non-solvent can be derived from different solvents. The second solvent can correspond to the non-solvent, the further non-solvent, or both.

[0080] According to one embodiment of the present invention, a non-solvent vapor is flowed onto the filaments during their deposition (step d1). After the non-solvent vapor treatment is completed, the resulting structure may be contacted with a liquid non-solvent, for example by immersion in the liquid non-solvent (step d2), in order to induce a further phase transition, thereby creating a three-dimensional filament-based porous structure with the appropriate filament morphology.

[0081] The step of contacting the 3D-printed structure with the non-solvent can be carried out by several methods well known to those skilled in the art. Suitable methods include immersing the structure, flowing a liquid over the structure, and equivalent techniques known to those skilled in the art. The contacting of the 3D-printed structure can include immersion-induced phase inversion, whereby a microporous filament structure with a specific filament surface morphology is created by dipping, immersing, or submerging the green 3D-printed structure in a liquid non-solvent for the binder (polymer) that undergoes the phase inversion (step d2). Suitable liquid non-solvents include water, alcohols, acids, or mixtures of two or more thereof. Suitable examples of alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and octanol. Suitable examples of acids include inorganic acids and organic acids, such as, but not limited to, acetic acid and citric acid. Non-solvent / solvent mixtures can also be used in this step. To optimize the morphology of the structure, the addition of a (liquid) solvent as defined herein to a non-solvent can change the morphology and pore structure of the filaments and can determine the diffusion of removable additives into the pores and the dissolution of removable additives.

[0082] Advantageously, the at least one removable additive and the one or more binders may react differently to the second solvent. This may allow for at least partially independent control of the solidification of the one or more binders, which may induce additional pore formation upon removal of the at least one removable additive. The phase-transition binder and the second solvent are preferably selected so that the phase-transition binder precipitates and solidifies its structure upon contact with the second solvent in step d). The solidified binder is typically thermally decomposed in the heat treatment in step f), which is believed to expel the pores created by the phase transition of the one or more binders.

[0083] Process e) The method of the present invention further comprises a step e) for removing at least a portion of the removable additive from the phase-transformed 3D structure.

[0084] According to a first embodiment of the present invention, at least one removable additive is dissolved in the second solvent. According to the first embodiment, both a phase transition of the one or more binders and dissolution of at least a portion of the removable additive can occur in step d). As a result, microporosity is created by the phase transition of the one or more binders, and additional microporosity is created by removal of at least a portion of the at least one removable additive upon contact of the structure obtained in step c) with a second solvent acting as a remover for the removable additive. The contacting can be carried out, for example, by dipping or immersion, or by any other suitable method.

[0085] According to an alternative embodiment, the solvent for dissolving the at least one removable additive may comprise a second solvent made more acidic or more basic by adding an acid or base to the second solvent that the green structure is immersed in. In this embodiment, the microporosity is created by a phase transition of the binder(s), and the additional microporosity is created by acidifying or increasing the pH of the second solvent used to remove at least a portion of the at least one removable additive from the green structure, for example by dipping or immersion.

[0086] According to a further alternative embodiment, the at least one removable additive is insoluble or poorly soluble in the second solvent, or is partially dissolved upon contact with the second solvent in step d). The method according to this embodiment typically further comprises an additional step e) of contacting the phase-inverted structure obtained in step d) with a third solvent for the at least one removable additive, with the aim of dissolving the at least one removable additive. This contacting may involve, for example, dipping or immersion or other suitable methods. The dissolution of the removable additive from the phase-inverted structure creates additional microporosity prior to the firing step.

[0087] It should be understood that the removal agent can be the second liquid solvent, a modified second liquid solvent, or a third liquid solvent that is not the second liquid solvent and does not include the second liquid solvent. Combinations are also possible, for example, the removable additive is partially removed upon contact of the porous green structure with the second liquid solvent (as performed in step d) of the method) and partially removed upon contact with the third liquid solvent and / or the modified second liquid solvent, as performed in step e) of the method. It should further be understood that the removal agent (i.e., the second liquid solvent, the modified second liquid solvent, or the third liquid solvent) is a solvent for the removable additive but not for the (phase-transition) binder(s).

[0088] The third solvent, which dissolves the at least one removable additive, can be an acidic medium or a basic medium, capable of dissolving the at least one removable additive.

[0089] The method of the present invention provides the additional advantage of being able to create unexpected levels of additional microporosity on top of the microporosity induced by the phase transformation of the binder(s) by removing at least one removable additive without increasing the brittleness of the three-dimensional macroporous filament construct. This is important because the amount of binder(s) that can be incorporated into the mixture is limited by the decomposition of the phase-transformed binder(s) resulting in the formation of carbon-based materials that remain in the construct. The formation of carbon-based materials can lead to embrittlement of the construct, potentially increasing brittleness to unexpected levels.

[0090] At least the following: - the composition of the mixture (including but not limited to the nature and composition ratio of the components, the particle size and particle size distribution of the given particulate material and at least one removable additive); - Extrusion parameters, including the initiation of the phase transition by the use of non-solvent vapor; - the rate of dipping and the residence time of the green structure in the second solvent, the type of non-solvent, the addition of the solvent to the non-solvent, and the temperature of the solvent (or solvent mixture); - the solubility characteristics of at least one removable additive in the second solvent; - the type of remover (second or third liquid solvent) and the solubility characteristics of the at least one removable additive in the remover; It is clear that the parameters of influence the phase transition process, thereby allowing the tailoring of the filament structure.

[0091] Process f) In a further step of the method of the invention, the phase-transferred structure obtained in step e) is subjected to a heat treatment, which may include a drying step of the phase-transferred structure obtained in step e), but may also include an additional firing and / or sintering of the phase-transferred structure obtained in step e).

[0092] Preferably, the structure obtained in step e) is dried before being subjected to firing and / or sintering. The drying step can be carried out, for example, by air drying at room temperature or under a controlled atmosphere (temperature, humidity). Drying, firing, and sintering can be carried out in the same or different environments. As with drying, firing and / or sintering can be carried out in air or under a controlled atmosphere, the temperature and humidity of which can be selected taking into account the nature of the material and the expected degree of porosity and wrinkling or shrinkage.

[0093] Step f) may further comprise a calcination step, comprising heating the green structure obtained after step e) at a rate of between 5°C / h and 50°C / h to a temperature of between 200°C and 600°C, for example between 400°C and 600°C, preferably below 500°C. Preferably, especially when using titanium or titanium alloy powder particles in the suspension, the calcination is carried out under an inert atmosphere such as argon or under low pressure, preferably at a temperature of 10 -3 The process is carried out under pressure of less than 1000 mbar. During this process, most of the organic material is pyrolyzed.

[0094] The method may further include a pre-sintering step, which involves heating the construct to a temperature between 900°C and 1000°C between the firing and sintering steps. If the mixture includes titanium or a titanium alloy, pre-sintering causes the titanium or titanium alloy powder particles to begin sintering together, making the structure more manageable. Preferably, the pre-sintering step is performed in an inert atmosphere or on a YO-coated substrate for at least 10 minutes. -4 The procedure is carried out under a vacuum of 1000 mbar.

[0095] The resulting structure is then sintered onto the Y2O3 coated substrate or Y2O3 powder bed, particularly if the mixture contains titanium or titanium alloy particles, to further shrink the structure. -4 Sintering can be carried out under high vacuum, above 1000 mbar. Sintering is preferably carried out by heating the three-dimensional phase-transformed structure to a temperature between 1000 and 1500°C, for example between 1200 and 1500°C, at a rate between 1 and 10°C / min, keeping the structure at said temperature for a predetermined time, for example between 1 and 5 hours, and then advantageously cooling to room temperature, for example at a rate of 20°C / min.

[0096] Depending on the dimensional requirements, one or more machining processes may be performed, such as machining the 3D construct obtained by the above steps, machining after pre-sintering, etc. The machining processes may include, for example, one or more drilling, cutting, tumbling, etc.

[0097] While the present invention has been described above with reference to particular embodiments, this is for purposes of illustration and not limitation, the scope of which is defined by the claims. Those skilled in the art will readily appreciate that various combinations of features other than those described herein are possible without departing from the scope of the invention as claimed.

[0098] The constructs of the present invention may be used for the manufacture of (bio)medical products such as artificial bone implants or bone grafts, tissue engineering scaffolds, drug delivery devices, etc., where the constructs may comprise bone morphogenetic proteins (BMPs), stem cells, osteoblasts, pharmaceutical agents, and / or mixtures thereof.

[0099] The present invention further relates to biomedical products, such as artificial bone implants or bone grafts, tissue engineering scaffolds, drug delivery devices, etc., comprising the above-described constructs.

[0100] The invention further relates to the use of the components obtainable by the process of the invention for the manufacture of catalysts, adsorbents, chromatographic materials and heat exchange materials. [Example]

[0101] Experimental section The porosity (microporosity) within the filaments was measured using image analysis of the SEM images. By using the difference in gray values, software (KS400, C. Zeiss) makes it possible to calculate the ratio of the number of pixels representing pores to the number of pixels representing material.

[0102] The 3D structure or scaffold can be prepared by the following steps shown in Figure 1: - Based on an image or a predetermined software pattern, create a near-net scaffold design in Box 1, taking into account the shrinkage of the scaffold during sintering. If desired, allow some over-dimensioning or simplification of the shape, and use final machining to achieve the required dimensions and tolerances. In box 2, a viscous paste is prepared by mixing, for example, a powder of particles of a given material in a specified amount with a phase-transition binder, a removable additive, and a solvent. The binder is made from a phase-transition binder and a rheology-modifying binder. - The paste is transferred to a dispensing unit containing a syringe tube and a nozzle, which is mounted on a CNC machine and connected to a pneumatic plunger to control the flow rate of the paste. - The CNC machine is programmed to deposit the filament with a nozzle movement according to a precisely controlled pattern and within a precisely controlled configuration. The CNC machine is programmed to deposit the filament continuously layer by layer in a predetermined pattern. Depending on the desired filament thickness, the opening of the corresponding diaphragm of the nozzle is selected, for example, between 0.1 and 0.2 mm. The deposition parameters, such as the distance between the nozzle and the surface of the structure, the vapor-induced phase change non-solvent system for solidifying the filament, the nozzle movement speed, the air pressure and temperature, and the air flow of the system, etc. The 3D structure is built in box 3 by depositing the filament layer by layer according to the programmed pattern and the desired dimensions. - After the scaffold is dried, the filaments are exposed to a second non-solvent system to create microporosity in the filament struts (Box 4). The structure is then subjected in box 5 to a heat treatment by firing in an inert atmosphere or under vacuum, and in box 6 to a heat treatment by sintering in an inert atmosphere or under vacuum. - Depending on the dimensional requirements, a final machining step may be performed in box 7. was used and constructed by extrusion of filaments of a viscous paste.

[0103] Comparative examples I~IV The 3D green structure has a density of 4.43 g / cm 3 Titanium powder (55-95 mass%), ethyl cellulose (0.1-3 mass%), density 1.03 g / cm 3 The fibers were prepared using filament microextrusion of suspensions containing N-methylpyrrolidone (5-30% by mass). The density was 1.25 g / cm 3 The amount of polysulfone binder to undergo phase transition was varied between 0.5 and 20 mass% (based on titanium).

[0104] The porosity (microporosity) within the filaments was measured using image analysis of SEM images. By using the difference in gray values, software (KS400, C. Zeiss) is able to calculate the ratio of the number of pixels representing pores to the number of pixels representing material. Figure 2 shows the effect of the amount of phase-transferring polysulfone binder (volume % of PSf) on the microporosity (%) of the filaments of the inventive construction. Increasing the amount of phase-transferring binder to be precipitated in the suspension results in an increase in the microporosity within the filaments (see Figure 2).

[0105] Examples 1-5. Varying Amounts of Phase-Change Binders and Additives The 3D construct has the following composition: - Average particle size up to 45 μm and density up to 4.43 g / cm 3 125g of titanium powder - Density is 1.03g / cm 3 16.6g of N-methylpyrrolidone - Density 1.25g / cm 3 2.9g to 2.24g and 0g of phase-transferable polysulfone binder, respectively. - d90 is 6 μm and density is 2.16 g / cm 3 of 0 g, 2.0 g, and 4.0 g of NaCl as a water-soluble additive, respectively. It is created by 3D filament deposition of a viscous powder paste having

[0106] The mass ratio of the amount of phase-transformed binder to titanium and the volume ratio of the amount of NaCl as a removable additive to titanium were varied as shown in Table 1 below. The 3D printed constructs were dried and fired at 1350°C as described above.

[0107] The microporosity of Examples 1 to 5 was measured using the image analysis described above. The results are shown in Figures 4a to 4b and Figures 5a to 5b. Figures 4a to 4b show electron microscope images of 3D constructs obtained using the compositions described above, particularly Examples 1 and 2. Figures 5a and 5b show electron microscope images of 3D constructs obtained in Examples 3 and 4.

[0108] [Table 1]

[0109] Comparing Figures 4a and 4b with Figures 5a and 5b, respectively, it can be observed that the addition of NaCl as a removable additive leads to the formation of additional microporosity in the filaments. Mercury porosimetry measurements show that the pore system is accessible and the pores are interconnected.

[0110] Aspects of the present invention are described in the following alphanumeric sections.

[0111] A1. A method for producing a three-dimensional macroporous filamentary structure having interconnected microporous filaments and having a suitable morphology, comprising the steps of: a) preparing a mixture comprising particles of one or more metals, one or more metal alloys, or a combination thereof, one or more binders, a first liquid solvent for the one or more binders, and optionally one or more dispersants; b) dispersing particles having at least one removable additive in said mixture; c) depositing said mixture in the form of filaments in a predetermined three-dimensional pattern of interconnected filaments, thereby obtaining a three-dimensional filament-based porous green structure; d) contacting the three-dimensional filament-based porous green structure formed in step c) with a second solvent that is a non-solvent for the one or more binders to induce a phase transition, thereby producing a filament-based phase-transformed porous structure with the appropriate filament morphology, wherein at least a portion of the filaments are transformed into a solid state; e) contacting the phase-transformed structure with a removal agent to remove at least a portion of the at least one removable additive; f) heat-treating the structure obtained above A method comprising:

[0112] A2. The method of paragraph A1, wherein the heat treatment comprises firing and sintering the structure.

[0113] A3. Step d) is the following step: d1) inducing a phase transition by contacting the filaments with vapor of a non-solvent during deposition of the filaments; and d2) immersing the structure of step d1) in the second liquid solvent to complete the phase transition and create a filament-based porous structure with the appropriate filament morphology. The method of clause A1 or A2, comprising:

[0114] A4. The method of any of paragraphs A1-A3, wherein the at least one removable additive comprises one or more of a group of solvent-soluble polymers and inorganic salts.

[0115] A5. The method of any of paragraphs A1-A3, wherein the particles of the at least one removable additive comprise droplets of a suspension of the at least one removable additive in a dispersant.

[0116] A6. The method of any one of paragraphs A1-A3, wherein the at least one removable additive comprises droplets comprising one or more liquids, preferably selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polylactic acid, polyethylene oxide, and the like, and mixtures of two or more thereof.

[0117] A7. The method of any of paragraphs A1-A6, wherein the particle size of the at least one removable additive ranges from about 0.01 microns to 500 microns, preferably from about 0.05 microns to 250 microns, and more preferably from about 0.05 microns to 100 microns.

[0118] A8. The method of any of paragraphs A1-A3, wherein step e) comprises contacting the structure obtained in step d2) with a third liquid solvent that is a solvent for the at least one removable additive to at least partially dissolve the removable additive.

[0119] A9. The method of paragraph A8, further comprising adding an acid or a base to the third liquid solvent to increase the solubility of the at least one removable additive.

[0120] A10. The method of any of paragraphs A1-A9, wherein the second liquid solvent is a solvent for the at least one removable additive.

[0121] A11. The method of any of paragraphs A1-A10, wherein the volume ratio of the at least one removable additive to particles of the one or more metals and / or metal alloys is at least 0.01:100, preferably at least 0.1:100, more preferably at least 1:100, most preferably at least 5:100, in particular at least 10:100.

[0122] A12. The method according to any one of clauses A1 to A11, wherein the volume ratio of the at least one removable additive to the particles of the one or more metals and / or metal alloys is at most 50:100, preferably at most 45:100, more preferably at most 40:100, even more preferably at most 35:100, and most preferably at most 30:100.

[0123] A13. The method of any of clauses A1-A12, wherein the mixture of step a) comprises at least 45% by volume, preferably at least 50% by volume, more preferably at least 55% by volume or at least 60% by volume of particles of the one or more metals or metal alloys, based on the total volume of the mixture.

[0124] A14. The method of any of clauses A1-A13, wherein the mixture of step a) comprises up to 90% by volume, preferably up to 85% by volume, more preferably up to 80% by volume, and most preferably 50 to 85% by volume of particles of one or more metals or metal alloys, based on the total volume of the mixture.

[0125] B1. A three-dimensional macroporous filament structure obtainable by the method of any one of paragraphs A1 to A14, wherein the porosity formed by the interconnected micropores comprises 1 to 50%, preferably 5 to 30%, of the total porosity of the three-dimensional macroporous filament structure, the micropores consisting of pores with a particle size of 50 μm or less, and the average surface roughness (Ra) of the filaments is greater than 4 μm.

[0126] B2. A three-dimensional macroporous filament construct according to clause B1, wherein the porosity of the macroporous filament construct provided by the macropores comprises 50 to 95%, preferably 60 to 85%, of the total porosity of the three-dimensional macroporous filament construct, and the pore size of the macropores is greater than 100 μm.

[0127] C1. A biomedical product, such as an artificial bone implant or bone graft, a tissue engineering scaffold, a drug delivery device, etc., comprising a three-dimensional macroporous filament construct according to paragraph B1 or B2 or obtainable by the method of any one of paragraphs A1 to A14.

Claims

1. 1. A method for producing a three-dimensional macroporous filamentary structure having interconnected microporous filaments and having a suitable morphology, comprising the steps of: a) preparing a mixture comprising particles of one or more metals, one or more metal alloys, or a combination thereof, one or more binders, a first liquid solvent for the one or more binders, and optionally one or more dispersants; b) dispersing particles having at least one removable additive in said mixture; c) depositing said mixture in the form of filaments in a predetermined three-dimensional pattern of interconnected filaments, thereby obtaining a three-dimensional filament-based porous green structure; d) contacting the three-dimensional filament-based porous green structure formed in step c) with a second solvent that is a non-solvent for the one or more binders to induce a phase transition, thereby producing a filament-based phase-transformed porous structure with filament microporosity, wherein at least a portion of the filaments are converted to a solid state; e) removing at least a portion of the at least one removable additive by dissolving the at least one removable additive in a removing agent, thereby creating additional microporosity in the phase-transformed porous structure, wherein the removing agent comprises or consists of the second liquid solvent, or the removing agent is a third liquid solvent; f) heat-treating the structure obtained above A method comprising:

2. The method of claim 1 , wherein the heat treatment comprises firing and sintering the structure.

3. Step d) is the following step: d1) inducing a phase transition by contacting the filaments with a non-solvent vapor during deposition of the filaments; and d2) immersing the structure of step d1) in said second liquid non-solvent to complete the phase transition and produce a filament-based porous structure with the appropriate filament morphology.

3. The method of claim 1 or 2, comprising:

4. 4. The method of claim 1, wherein the at least one removable additive is selected from one or more of the group consisting of a polymer and an inorganic salt, which are soluble in a solvent.

5. 5. The method of claim 1, wherein the particles comprising the at least one removable additive comprise droplets of a suspension of the at least one removable additive in a dispersant.

6. 6. The method of claim 1, wherein the particles comprising the at least one removable additive comprise droplets comprising one or more liquids, preferably a liquid selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polylactic acid, polyethylene oxide, and mixtures of two or more thereof.

7. 7. The method according to claim 1, wherein the size of the particles comprising the at least one removable additive ranges from about 0.01 μm to 500 μm, preferably from about 0.05 μm to 250 μm, more preferably from about 0.05 μm to 100 μm, and the particle size is measured by laser diffraction.

8. 4. The method according to claim 1, wherein step e) comprises contacting the structure obtained in step d2) with a third liquid solvent, which is a solvent for the at least one removable additive, to at least partially dissolve the removable additive.

9. 9. The method of claim 1, wherein the removal agent comprises the second liquid solvent and an acid or base added to the second liquid solvent to increase the solubility of the at least one removable additive.

10. 10. The method of any one of claims 1 to 9, wherein the second liquid solvent is a solvent for the at least one removable additive.

11. 11. The method according to any one of claims 1 to 10, wherein the volume ratio of the at least one removable additive to particles of the one or more metals and / or metal alloys is at least 0.01:100, preferably at least 0.1:100, more preferably at least 1:100, most preferably at least 5:100, in particular at least 10:

100.

12. 12. The method according to any one of claims 1 to 11, wherein the volume ratio of the at least one removable additive to the one or more metals and / or metal alloys is at most 50:100, preferably at most 45:100, more preferably at most 40:100, even more preferably at most 35:100, and most preferably at most 30:

100.

13. 13. The method according to any one of claims 1 to 12, wherein the mixture of step a) comprises at least 45% by volume, preferably at least 50% by volume, more preferably at least 55% by volume or at least 60% by volume of particles of said one or more metals and / or metal alloys, relative to the total volume of the mixture.

14. 14. The method according to any one of claims 1 to 13, wherein the mixture of step a) comprises up to 90% by volume, preferably up to 85% by volume, more preferably up to 80% by volume, and most preferably 50 to 85% by volume of particles of said one or more metals and / or metal alloys, relative to the total volume of the mixture.

15. A three-dimensional macroporous filament structure preparable by the method described in any one of claims 1 to 14, wherein the mass ratio of the binder to be phase-transformed to particles of one or more metals and / or metal alloys is 1.7% to 2.3%, the porosity formed by interconnected micropores, as determined by image analysis of SEM images based on the distinction between gray values, is 17.2% to 23.9%, and the micropores consist of pores with a size of 50 μm or less.

16. 15. A three-dimensional macroporous filament structure obtainable by the method of claim 1, wherein step b) is omitted, the three-dimensional macroporous filament structure having a first microporosity that is at least 11.5% higher than the second microporosity, the first microporosity and the second microporosity being pores with a size of 50 μm or less, as determined by image analysis of SEM images based on gray value differentiation.

17. 17. The three-dimensional macroporous filament construct of claim 16, wherein the difference between the first microporosity and the second microporosity is between 11.5% and 15.2%.

18. 18. The three-dimensional macroporous filament construct of any one of claims 15 to 17, wherein the metal is titanium and the metal alloy is a titanium alloy.

19. 19. The three-dimensional macroporous filament construct of any one of claims 15 to 18, wherein the filaments have an average surface roughness (Ra) of greater than 4 μm, the surface roughness being measured by non-contact optical profilometry based on interferometry and defined in ISO standard 4287-1:1984.

20. 20. A biomedical product, such as an artificial bone implant or bone graft, a tissue engineering scaffold, a drug delivery device, comprising a three-dimensional macroporous filament construct according to any one of claims 15 to 19 or a three-dimensional macroporous filament construct obtainable by the method according to any one of claims 1 to 14.

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