A biomimetic absorbable composite bone implant and a method of making the same

Abstract

The application relates to a kind of bionic absorbable composite bone implants and preparation method thereof, and the preparation method comprises S1: inorganic non-metallic material, active ion doping, polymer raw material and hydrogel precursor are mixed to prepare 3D printing slurry;S2: bone implant semi-finished product is prepared by 3D printing;S3: plasma etching reaction is carried out;S4: be placed in specific mould, carry out pumping and discharging air treatment, then pressure relief, finally vacuum heat preservation reaction for a period of time;S5: after the heat preservation reaction is completed, the specific mould is translated to the freezing table and is carried out specific orientation freezing treatment;Then demoulding, the obtained implant is carried out freeze-drying treatment, and the final composite bone implant is obtained.The composite bone implant has long-range ordered porous structure, and simultaneously meets the medical use requirements in strength and toughness, and has excellent application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medical composite processing, in particular to a bionic absorbable composite bone implant and a preparation method thereof. BACKGROUND

[0002] Bone, as a load-bearing and supporting material with strength and toughness, has unmatched properties through natural evolution to perfectly match human functions. In bone tissue, collagen fibers and hydroxyapatite crystals are arranged in close proximity. In the bone matrix of mature bone tissue, the collagen fibers are thin but arranged in layers, and inorganic bone salt is deposited on them. The collagen fibers exhibit branching, often extending from one layer to its adjacent layer, and they interweave to form a three-dimensional network structure that penetrates the bone matrix. Hydroxyapatite crystals, as inorganic bone salt, are distributed in the form of needles on the collagen matrix, with their crystal direction along the long axis of the collagen fibers. This interconnected three-dimensional structure and the complex layering of biologically active bone salt enable it to withstand multiple pressures, allowing the bone tissue to have good osteogenic activity while maintaining high compressive performance and stability, effectively enhancing the support and toughness of the bone and meeting the needs of human behavior and movement.

[0003] Patent application publication CN103301511A discloses a composite implant for human bone fixation, which is prepared by mixing high polymers with inorganic non-metals such as polyamide 6 fibers, methyl methacrylate and N-vinyl pyrrolidone copolymer, and hydroxyapatite micro powder, and then hot pressing the mixture to obtain the final product. Only through simple mechanical mixing, the materials are only physically wrapped, without chemical or physical bond interaction. Patent application publication CN116924426A discloses a method for regulating the distribution of molecular sieve framework silicon and aluminum and a product thereof. Silicon and aluminum sol-gel and pure silicon sol-gel are aged to secondary gel state, respectively, and the silicon and aluminum atoms in the sol-gel interact with the structure directing agent under the action of mineralizer, resulting in structural rearrangement and the formation of short-range ordered structural units or crystallization embryos. However, it can only form ordered structures and compositions in a very small area, and still presents a disordered state in a long-range range. How to simulate the formation of a short-range ordered composite long-range ordered multi-level anisotropic structure to obtain a more matched medical implant has an urgent clinical need.

[0004] Compared with traditional material preparation technology, 3D printing technology can manufacture porous materials with complex geometry, which breaks through the shape limitation of traditional manufacturing method, wherein the extrusion type 3D printing technology has the characteristics of simple technical principle and low cost, the technology adopts slurry or molten material as forming raw material, the material is extruded through the extruder with micro nozzle, then the material is stacked layer by layer for forming processing, the extruded material is bonded with the material of the previous layer, and the material is stacked layer by layer until the workpiece is completely formed, due to the existence of directional extrusion mechanics, the material orientation characteristics can be shown, which can be used to form the oriented arrangement similar to bone collagen fibers. However, in the forming process of the extrusion type 3D printing technology, the nozzle extruded material will have time difference when building the structure, the nozzle material is in a molten or slurry state when printing, then solidification occurs, and the rheological property changes with time, the time difference is more obvious when the 3D printing is used to prepare large size products, which causes the interface compatibility and residual stress of the layers with different printing time due to the difference of solidification time and rheological property, the interface deterioration effect is obvious, which can cause micro cracks at the interface of the final material and product under static load or fatigue load, even if the stress is small, failure can also occur, it is difficult to obtain the special structure of the bionic bone and the corresponding strong and tough supporting material by using the extrusion type 3D printing method. SUMMARY

[0005] The purpose of the present application is to overcome the problem of poor strength of the bionic bone implant obtained by the existing extrusion type 3D printing method, and to provide a bionic absorbable composite bone implant and a preparation method thereof.

[0006] The specific scheme is as follows:

[0007] A preparation method of a bionic absorbable composite bone implant, comprising the following steps:

[0008] S1: mixing inorganic non-metallic materials and doped active ions to obtain inorganic non-metallic materials doped with active ions; mixing a high molecular raw material with a solvent to obtain a high molecular solution, mixing the inorganic non-metallic material doped with active ions, the high molecular solution and a hydrogel precursor, and then stirring uniformly, then performing partial solvent evaporation to prepare a 3D printing slurry;

[0009] S2: injecting the printing slurry into a 3D printing forming machine to prepare a bone implant semi-finished product by 3D printing, and then performing drying treatment;

[0010] S3: placing the bone implant semi-finished product after drying treatment in a plasma generator cavity to perform plasma etching reaction;

[0011] S4: placing the bone implant semi-finished product after the plasma etching reaction into a special mold, the special mold comprising a cold surface for contacting a cold source, the side of the cold surface away from the cold source being provided with a heat preservation sleeve, the heat preservation sleeve having a containing space for carrying liquid;

[0012] adding a solution of the hydrogel precursor into the heat preservation sleeve to immerse the bone implant semi-finished product, and then performing vacuumization on the special mold, and performing heat preservation reaction under vacuum for a period of time;

[0013] S5: after the heat preservation reaction is completed, translating the special mold to a freezing table to perform special orientation freezing treatment, an ice mold plate extending in a direction perpendicular to the cold surface being formed on the cold surface of the special mold to realize special orientation molding of the hydrogel; then demolding to obtain the implant for freezing drying treatment, thereby obtaining the final composite bone implant.

[0014] Further, the inorganic non-metallic material is an inorganic artificial bone material, preferably one or more of hydroxyapatite, bioglass, β-TCP and α-TCP;

[0015] Preferably, the doped active ion is one or more of Mg2+, Ca2+and Sr2+ions.

[0016] Preferably, the doped active ion is added in the form of a salt, and the addition amount of the active metal ion in the salt is 0.2-1.5% of the total weight of the inorganic non-metallic material, more preferably 0.5-1%.

[0017] Further, the high molecular raw material is one or more of PCL, PLGA and PLLA, and the addition amount of the high molecular raw material is 5-80% of the total weight of the printing slurry, preferably 10-40%.

[0018] Preferably, the solvent is one or more of chloroform, dimethyl sulfoxide and tetrahydrofuran.

[0019] Further, the hydrogel precursor is one or more of collagen, polyvinyl alcohol, hyaluronic acid, gelatin and sodium alginate, and the addition amount of the hydrogel precursor is 0.1-10% of the total weight of the printing slurry, preferably 1-8%.

[0020] Preferably, the solution of the hydrogel precursor in step S4 is an aqueous solution of the hydrogel precursor, and the concentration is preferably 1-50 wt%.

[0021] Further, the 3D printing is performed by using an extrusion type 3D printing method; preferably, the extrusion rate is 1-5 mm / s, and a layer-by-layer printing method is used to obtain a bone implant semi-finished product with a certain thickness.

[0022] Further, the plasma etching adopts a mixed Ar and O2 gas inlet mode, preferably, the Ar gas inlet flow rate is 5-50 ml / min, the O2 gas inlet flow rate is 1-30 ml / min, and the etching time is 1-5 min.

[0023] Further, in step S4, the bone implant semi-finished product is placed in a specific mold, and the angle between the specific orientation direction, which is the height increasing direction in the 3D printing process, and the contact surface direction of the cold surface in the specific mold is between 75° and 105°.

[0024] Further, in step S4, the temperature of the vacuum heat preservation reaction is 80-90°C, and the heat preservation time is 30-60 min.

[0025] The application also protects the bionic absorbable composite bone implant prepared by the preparation method of the bionic absorbable composite bone implant.

[0026] The application also protects the use of the bionic absorbable composite bone implant in the field of medical composite materials.

[0027] Beneficial effects:

[0028] The application can form a composite form of simulated collagen fibers and inorganic active bone salt with directional orientation by mixing the high molecular raw material and the inorganic non-metallic material doped with active ions and adopting the extrusion type 3D printing mode, and the composite form has the characteristics of bone tissue simulation. The high molecular raw material plays the role of simulating bone fibers, and the inorganic non-metallic material doped with active ions serves as the bone salt distributed in the bone tissue, and together form the main body of the bone tissue-like structure.

[0029] Secondly, the surface of the 3D printing semi-finished product is treated by plasma etching to form a nano micro-morphology surface, which is beneficial to strengthening the mechanical micro-locking and contact area of the material; at the same time, the activated surface formed by etching is treated by vacuum suction in the hydrogel solution system (step S4 gas extraction treatment), so that the printing surface is more fully immersed in the hydrogel, and the surface activation formed by plasma and the vacuum heat preservation treatment accelerate the reaction between the groups of the hydrogel at the interface and the groups of the printing surface, which can further promote the chemical bonding and crosslinking between the surface high molecular material, the inorganic non-metallic material and the hydrogel, and eliminate the problem of poor interface bonding force of the mixed material.

[0030] Again, the present application adopts an extrusion type 3D printing processing mode, which has low cost, but there is residual stress between layers, and only physical embedding effect exists between adjacent 3D printed ribbons, resulting in low overall mechanical strength. In view of this problem, the hydrogel precursor used in the present application can be oriented by directional freezing. Since the directional freezing hydrogel has orientation, the orientation direction is perpendicular to the height increasing direction of the 3D printed substrate. By adding long chain segment structure reinforced and toughened hydrogel fibers, the locking between different layers in the height increasing direction is increased, so as to obtain long-range ordered directional arrangement long-range ordered structure on the basis of the short-range ordered mechanism formed in the ribbons.

[0031] In summary, the preparation method of the bionic absorbable composite bone implant provided by the present application accurately biomimics the bonding relationship between collagen fibers, inorganic matter and each other in the human bone structure. The long-range ordered porous structure is obtained by forming fibers from high molecular raw materials, embedding with inorganic matter, and forming directional arrangement. On the other hand, the inner layer hydrogel in contact with the high molecular fiber reacts with the high molecular fiber to form chemical bonding. The outer layer hydrogel of the implant crosslinks with the inner layer hydrogel by freezing to form overall stable bonding effect, so that the bone implant has high strength and good toughness, meeting the material requirements of medical repair. BRIEF DESCRIPTION OF DRAWINGS

[0032] In order to more clearly illustrate the technical solutions of the present application, the following will briefly introduce the drawings. Obviously, the drawings described below only relate to some embodiments of the present application, rather than limiting the present application.

[0033] Figure 1 is a structure diagram of a specific mold provided by an embodiment 1 of the present application;

[0034] Figure 2 is a specific mold real photo provided by an embodiment 1 of the present application;

[0035] Figure 3 is a composite bone implant surface morphology diagram provided by an embodiment 1 of the present application. DETAILED DESCRIPTION

[0036] The following gives the definition of some terms used in the present application. Other terms not mentioned have the definition and meaning known in the art:

[0037] PCL: polycaprolactone

[0038] PLLA: poly-L-lactic acid

[0039] PLGA: poly(lactic-co-glycolic acid)

[0040] TCP: tricalcium phosphate, there are two kinds of which are mainly used: α-TCP, β-TCP.

[0041] The preferred embodiments of the present application will be described in more detail below. Although the preferred embodiments of the present application are described below, it is to be understood that the present application can be carried out in various forms and should not be limited by the embodiments set forth herein. If a specific technique or condition is not mentioned in the examples, it is carried out according to the technique or condition described in the literature in the art or according to the product manual. If the manufacturer of the reagent or instrument is not mentioned, it is a conventional product that can be obtained commercially. In the following examples, unless otherwise specified, "%" means "weight percent".

[0042] Example 1

[0043] 50 g of calcium chloride and 10 g of magnesium chloride hexahydrate were weighed and added to an aqueous solution to prepare an aqueous solution, and then 39.6 g of diammonium hydrogen phosphate was added to the solution, the pH of the mixed solution was adjusted to 11, and the reaction was carried out at 60-80°C for 12 h. After the reaction was completed, filtration separation and washing were carried out to obtain a magnesium ion-doped hydroxyapatite slurry for standby use.

[0044] 4 g of high molecular raw material L-polylactic acid PLLA was weighed and added to 50 mL of chloroform, and a uniform solution was obtained after sealed stirring for 4 h. Then 2 g of the prepared magnesium ion-doped hydroxyapatite and 0.5 g of hydrogel precursor polyvinyl alcohol PVA powder were added to the solution, and a small amount of surfactant was added to stir the slurry uniformly. Then, the slurry was placed in an oven to volatilize part of the solvent.

[0045] The above prepared slurry was injected into a 3D printer for extrusion printing, and the extrusion rate was 1.5 mm / s. The printing was carried out in a layer-by-layer stacking manner to obtain a bone implant semi-finished product with a certain thickness, which was then placed in an oven for drying treatment until the weight was constant. The above bone implant semi-finished product was transferred to the cavity of a plasma generator for plasma etching reaction. A mixture of Ar and O2 was used, the flow rate of Ar was 10 ml / min, and the flow rate of O2 was 5 ml / min, and the etching time was 5 min.

[0046] The etched implant semi-finished product was immediately transferred to a specific mold, as shown in Figure 1 The specific mold includes a cold surface for contacting a cold source, which can be a heat-conducting metal sheet, for example. A heat preservation sleeve is arranged on the side of the cold surface away from the cold source, and the heat preservation sleeve has a containing space for loading liquid and implant.

[0047] The actual photo of the specific mold used in this example is shown in Figure 2, aluminum foil is used as the cold surface, and the aluminum foil is wrapped around a hollow cylinder from the bottom to form a heat preservation sleeve structure. The cylinder is a polytetrafluoroethylene (Teflon) heat preservation sleeve, and the hollow part in the center of the cylinder is used to accommodate liquid and implants. After the implants are placed, the top of the cylinder can be closed, and the aluminum foil is tightly attached to the cylindrical sleeve by means of air extraction operation to form a sealed reaction system.

[0048] In this embodiment, the orientation of the implant semi-finished product placed in the heat preservation sleeve is in the direction of height increase in the 3D printing process, and the angle between the contact surface direction of the cold surface and the height increase direction is 90°. Then, the same kind of 10wt% hydrogel precursor aqueous solution is poured into the mold to immerse the implant semi-finished product, and then placed in a vacuum box with a set temperature of 80°C and extracted to a vacuum degree of -0.09 MPa. Then, the pressure is released to normal pressure, and this process is repeated 3 times, and then heat preservation is performed for 60 min.

[0049] Then, the treated composite bone implant and the mold are translated as a whole to a low-temperature freezing platform, the bottom aluminum foil is in contact with the cooling fin (i.e. the cold source), and the freezing treatment is performed for 24 h. During the freezing process, a plurality of ice templates parallel to the inner wall of the heat preservation sleeve are formed at the bottom of the accommodation space, as shown in Figure 1 The specific mold is surrounded by a polytetrafluoroethylene (Teflon) heat preservation sleeve, and the hollow bottom surface is paved with aluminum foil to provide a cold surface, and ice templates are formed on the surface of the aluminum foil. The principle of forming the ice templates is that the temperature of the solution near the cold surface is reduced due to the low temperature of the cold surface in contact with the cold source, and there is a temperature gradient between the upper and lower parts of the solution. The water in the hydrogel precursor aqueous solution will slowly grow into ice templates perpendicular to the contact surface of the cold surface, thereby guiding the material to form a long-range ordered structure.

[0050] After the composite bone implant is demolded, it is placed in a freeze-drying machine for drying for 24 h, and the final composite bone implant is obtained.

[0051] The surface morphology of the composite bone implant is analyzed, as shown in Figure 3 It can be seen that the composite bone implant has a regular and ordered pore structure, and the ordered pores are distributed in layers throughout the implant, i.e. long-range ordered. At the same time, the pore size of each layer is basically consistent, and they are arranged in parallel and equidistant. The pores of the composite bone implant are rectangular pores with a length of about (0.3-0.5) mm and a width of about (0.2-0.4) mm, which perfectly meet the structural requirements of the bionic bone.

[0052] The composite bone implant is placed under a load of 5 kg for 15 s, and the structure of the composite bone implant does not break and crack on the surface, indicating that the strength and toughness of the composite bone implant can meet the medical use requirements.

[0053] Example 2

[0054] Take 50 g of calcium chloride and 13.3 g of strontium chloride hexahydrate into an aqueous solution, then add 39.6 g of diammonium hydrogen phosphate to the solution, adjust the pH of the mixed solution to 11, and react at 60-80°C for 12 h. After the reaction is completed, filter separation and washing are performed to obtain a strontium ion-doped hydroxyapatite slurry for standby use.

[0055] Take 4.5 g of high molecular raw material L-polylactic acid (PLLA) and add it to 60 mL of chloroform. Stir for 4 h to obtain a uniform solution. Then take 2.5 g of the prepared magnesium ion-doped hydroxyapatite and 0.8 g of hydrogel precursor polyvinyl alcohol (PVA) powder and add them to the solution. Stir the slurry uniformly after adding a small amount of surfactant. Then put it into an oven to volatilize part of the solvent.

[0056] The above prepared slurry is injected into a 3D printer for extrusion printing at an extrusion rate of 1.5 mm / s. A certain thickness of bone implant semi-finished product is obtained by using the way of layer-by-layer printing. Then it is placed in an oven for drying treatment until the constant weight. The above bone implant semi-finished product is transferred to the cavity of the plasma generator for plasma etching reaction. The mixed gas of Ar and O2 is used, wherein the Ar gas flow is 10 ml / min and the O2 gas flow is 5 ml / min. The etching time is 5 min.

[0057] The etched implant semi-finished product is immediately transferred to a specific mold, which is the same as that in Example 1. The implant semi-finished product is placed in the orientation direction, which is the height increasing direction during the 3D printing process, and the angle between the cold surface contact surface is 80°. Then 10 wt% of the same kind of hydrogel precursor aqueous solution is poured into the mold to immerse the implant semi-finished product. Then it is placed in a vacuum box with a set temperature of 80°C and is pumped to a vacuum degree of -0.09 MPa. Then it is released to atmospheric pressure. This process is repeated for 3 times and then it is kept warm for 60 min.

[0058] Then the treated composite bone implant and the mold are translated to a low-temperature freezing table, the bottom aluminum foil is in contact with the cooling fin (i.e. the cold source), and the freezing treatment is performed for 24 h.

[0059] After the composite bone implant is demolded, it is placed in a freeze dryer for drying for 24 h to obtain the final composite bone implant. The composite bone implant has a regular and ordered pore structure. The ordered pores are distributed in a layer shape in the whole implant, i.e. long-range order. At the same time, the pore size of each layer is basically consistent, and they are parallel and arranged at equal intervals. The pores of the composite bone implant are rectangular pores with a length of about (0.3-0.5) mm and a width of about (0.2-0.4) mm, which perfectly meet the structural requirements of the bionic bone.

[0060] The composite bone implant was placed under a 5kg load pressure for 15s, and no damage or surface cracks occurred in the structure of the composite bone implant, indicating that the strength and toughness of the composite bone implant could meet the requirements of medical use.

[0061] Example 3

[0062] 40g of 1% Sr element-doped 45S5 bioactive glass prepared by a melting method was weighed, ball milled, sieved, washed, and dried to obtain a bioactive glass powder for standby use.

[0063] 6g of a high molecular raw material PLGA was weighed and added to 80mL of chloroform, and a uniform solution was obtained after sealed stirring for 4h. Then, 3g of the prepared Sr-doped 45S5 bioactive glass and 1g of a hydrogel precursor sodium alginate were added to the solution, and a small amount of a surfactant was added to stir the slurry uniformly. Subsequently, the slurry was placed in an oven to volatilize part of the solvent.

[0064] The slurry was injected into a 3D printer for extrusion printing at an extrusion rate of 3.0mm / s, and a certain thickness of a bone implant semi-finished product was obtained by using a layer-by-layer printing method. Subsequently, the bone implant semi-finished product was placed in an oven for drying treatment until a constant weight was obtained. The bone implant semi-finished product was transferred to the cavity of a plasma generator for plasma etching reaction, and a mixture of Ar and O2 was used, wherein the Ar gas flow was 8ml / min, and the O2 gas flow was 6ml / min, and the etching time was 6min.

[0065] The semi-finished product was immediately transferred to a specific mold, and the mold was the same as that in Example 1. The implant semi-finished product was placed in the orientation direction, and the angle between the height increasing direction in the 3D printing process and the cold surface contact surface direction was 100°. Then, the same kind of 15wt% hydrogel precursor aqueous solution was poured into the mold to immerse the implant semi-finished product. Subsequently, the mold was placed in a vacuum box set at a temperature of 80℃ and pumped to a vacuum degree of -0.09MPa. Then, the pressure was released to atmospheric pressure, and the above process was repeated for 3 times, and then the temperature was kept for 60min.

[0066] Subsequently, the treated composite bone implant and the mold were translated to a low-temperature freezing table, and the bottom aluminum foil was in contact with the cooling fin (i.e. the cold source). The freezing treatment was performed for 24h.

[0067] After the composite bone implant was demolded, it was placed in a freeze dryer for drying for 24h to obtain a final composite bone implant. The composite bone implant had a regular and ordered pore structure, and the ordered pores were distributed in layers throughout the implant, i.e. long-range order. Meanwhile, the pore size of each layer was basically consistent, and the pores were arranged in parallel and at equal intervals. The pores of the composite bone implant were rectangular pores with a length of about (0.3-0.4)mm and a width of about (0.2-0.3)mm, which perfectly met the structural requirements of a biomimetic bone.

[0068] The composite bone implant was placed under a 5 kg load pressure for 15 s, and no damage or surface cracks occurred in the structure of the composite bone implant, indicating that the strength and toughness of the composite bone implant could meet the requirements of medical use.

[0069] Example 4

[0070] 50 g of calcium chloride and 13.3 g of strontium chloride hexahydrate were weighed into an aqueous solution, and then 39.6 g of diammonium hydrogen phosphate was added to the solution, and the pH of the mixed solution was adjusted to 11. The reaction was carried out at 60-80°C for 12 h. After the reaction was completed, filtration separation and washing were performed to obtain a strontium ion-doped hydroxyapatite slurry for standby use.

[0071] 6.5 g of a high molecular material PLGA was weighed into 80 mL of chloroform, and a uniform solution was obtained after sealed stirring for 4 h. Then, 4 g of the prepared strontium ion-doped hydroxyapatite and 0.6 g of a hydrogel precursor gelatin were added to the solution, and a small amount of a surfactant was added to stir the slurry uniformly. Subsequently, the slurry was placed in an oven to volatilize part of the solvent.

[0072] The slurry prepared above was injected into a 3D printer for extrusion printing at an extrusion rate of 1.5 mm / s. A certain thickness of a bone implant semi-finished product was obtained by using a layer-by-layer printing method, and then the bone implant semi-finished product was placed in an oven for drying treatment until a constant weight was obtained. The bone implant semi-finished product was transferred to the cavity of a plasma generator for plasma etching reaction. A mixture of Ar and O2 was used, wherein the Ar gas flow rate was 10 ml / min, and the O2 gas flow rate was 5 ml / min. The etching time was 5 min.

[0073] The semi-finished product was immediately transferred to a specific mold, and the mold was the same as that in Example 1. The orientation direction of the semi-finished product was 95° to the direction of height increase during the 3D printing process and the direction of the cold surface contact surface. Then, the same kind of 10 wt% hydrogel precursor aqueous solution was poured into the mold to immerse the semi-finished product. Subsequently, the mold was placed in a vacuum box set at a temperature of 80°C and pumped to a vacuum degree of -0.09 MPa. Then, the pressure was released to atmospheric pressure. This process was repeated for 3 times, and then the mold was kept at a constant temperature for 60 min.

[0074] Subsequently, the treated composite bone implant and the mold were translated to a low-temperature freezing platform, and the bottom aluminum foil was in contact with the cooling fin (i.e., the cold source). The freezing treatment was carried out for 24 h.

[0075] After the composite bone implant is demolded, it is placed in a freeze dryer for drying for 24 h to obtain a final composite bone implant having a regular and ordered pore structure. The ordered pores are distributed in layers throughout the implant, i.e., long-range order. Meanwhile, the pores in each layer are substantially uniform in size and arranged in parallel and at equal intervals. The pores of the composite bone implant are rectangular pores having a length of about (0.4-0.5) mm and a width of about (0.3-0.4) mm, which perfectly meet the structural requirements of a biomimetic bone.

[0076] The composite bone implant is placed under a load of 5 kg for 15 s, and the structure of the composite bone implant is not damaged or cracked, indicating that the strength and toughness of the composite bone implant can meet the medical use requirements.

[0077] Example 5

[0078] 50 g of calcium chloride and 10 g of magnesium chloride hexahydrate are weighed and added to an aqueous solution to prepare an aqueous solution, and then 39.6 g of diammonium hydrogen phosphate is added to the solution, and the pH value of the mixed solution is adjusted to 11. The solution is reacted at 60-80 °C for 12 h. After the reaction is completed, filtration separation and washing are performed to obtain a magnesium ion-doped hydroxyapatite slurry for standby use.

[0079] 4.5 g of a high molecular material PCL is weighed and added to 50 mL of dimethyl sulfoxide, and a uniform solution is obtained after sealed stirring for 4 h. Then, 2.2 g of the prepared magnesium ion-doped hydroxyapatite and 0.6 g of a hydrogel precursor polyvinyl alcohol PVA powder are added to the solution, and a small amount of a surfactant is added to stir the slurry uniformly. Then, the solution is placed in an oven to volatilize part of the solvent.

[0080] The slurry prepared above is injected into a 3D printer for extrusion printing at an extrusion rate of 5.0 mm / s. A certain thickness of a bone implant semi-finished product is obtained by using a layer-by-layer printing method, and then the bone implant semi-finished product is placed in an oven for drying treatment until the weight is constant. The bone implant semi-finished product is transferred to the cavity of a plasma generator for plasma etching reaction. A mixture of Ar and O2 is used, wherein the flow rate of Ar is 12 ml / min, and the flow rate of O2 is 6 ml / min. The etching time is 3 min.

[0081] The implant semi-finished product after etching is immediately transferred to a specific mold, which is the same as that in Example 1. The implant semi-finished product is placed in the orientation direction, and the angle between the height increasing direction in the 3D printing process and the cold surface contact surface direction is 85°. Then, the same kind of 20 wt% hydrogel precursor aqueous solution is poured into the mold to immerse the implant semi-finished product. Subsequently, the vacuum box is set to a temperature of 90 °C, and the vacuum degree is extracted to -0.09 MPa. Then, the pressure is released to normal pressure. This process is repeated for 3 times, and then the temperature is kept for 30 min.

[0082] Subsequently, the processed composite bone implant and the mold are translated to a low-temperature freezing table, the bottom aluminum foil is in contact with the cooling fin (i.e. the cold source), and the freezing treatment is performed for 24 hours.

[0083] After the composite bone implant is demolded, it is placed in a freeze dryer for drying for 24 hours to obtain a final composite bone implant. The composite bone implant has a regular and ordered pore structure. The ordered pores are distributed in layers throughout the implant, i.e. long-range order. Meanwhile, the pore size of each layer is basically consistent, and the pores are arranged in parallel and at equal intervals. The pores of the composite bone implant are rectangular pores with a length of about (0.3-0.4) mm and a width of about (0.2-0.3) mm, which perfectly meet the structural requirements of the bionic bone.

[0084] The composite bone implant is placed under a 5kg load pressure for 15 seconds, and the structure of the composite bone implant does not break and no surface cracks occur, indicating that the strength and toughness of the composite bone implant can meet the medical use requirements.

[0085] Comparative Example 1

[0086] Referring to Example 1, 50g of calcium chloride and 10g of magnesium chloride hexahydrate are weighed and added to an aqueous solution to prepare an aqueous solution. Then, 39.6g of diammonium hydrogen phosphate is added to the solution, and the pH value of the mixed solution is adjusted to 11. The reaction is carried out at 60-80°C for 12 hours. After the reaction is completed, filtration separation and washing are performed to obtain a magnesium ion-doped hydroxyapatite slurry for standby use.

[0087] 4g of high molecular raw material L-polylactic acid (PLLA) is weighed and added to 50mL of chloroform, and a uniform solution is obtained after sealed stirring for 4 hours. Then, 2g of the prepared magnesium ion-doped hydroxyapatite and 0.5g of hydrogel precursor polyvinyl alcohol (PVA) powder are added to the solution. After adding a small amount of surfactant, the slurry is stirred uniformly. Then, the solution is placed in an oven to volatilize part of the solvent.

[0088] The above-prepared slurry is injected into a 3D printer for extrusion printing at an extrusion rate of 1.5mm / s. A certain thickness of bone implant semi-finished product is obtained by using the layer-by-layer printing method. Then, the bone implant semi-finished product is placed in an oven for drying treatment until the weight is constant. The above-prepared bone implant semi-finished product is transferred to the cavity of a plasma generator for plasma etching reaction. The mixed gas of Ar and O2 is used, the flow rate of Ar is 10ml / min, and the flow rate of O2 is 5ml / min. The etching time is 5 minutes.

[0089] The above-prepared bone implant is placed in a freeze dryer for drying for 24 hours to obtain a final composite bone implant. After being placed under a 5kg load pressure for 15 seconds, the structure of the bone implant is broken and surface cracks occur.

[0090] Although the hydrogel precursor PVA is contained in Comparative Example 1, no directional freezing is performed, the orientation of the hydrogel cannot be played, and the material has a long-range disorder problem in structure, so the strength and toughness decrease significantly, and the structure is damaged and surface cracks appear under pressure.

[0091] Comparative Example 2

[0092] Referring to Example 1, 50 g of calcium chloride and 10 g of magnesium chloride hexahydrate were weighed and added to an aqueous solution to prepare an aqueous solution, then 39.6 g of diammonium hydrogen phosphate was added to the solution, the pH value of the mixed solution was adjusted to 11, and the reaction was carried out at 60-80°C for 12 h. After the reaction was completed, filtration separation and washing were performed to obtain a magnesium ion doped hydroxyapatite slurry for standby.

[0093] 4 g of high molecular material L-polylactic acid PLLA was weighed and added to 50 mL of chloroform, and a uniform solution was obtained after sealing and stirring for 4 h. Then 2 g of the prepared magnesium ion doped hydroxyapatite was added to the solution, a small amount of surfactant was added, and the slurry was stirred uniformly. Then it was placed in an oven to volatilize part of the solvent.

[0094] The above prepared slurry was injected into a 3D printer for extrusion printing, the extrusion rate was 1.5 mm / s, and the printing was performed in a layer-by-layer stacking manner to obtain a bone implant semi-finished product with a certain thickness, which was then placed in an oven for drying treatment until the weight was constant. The above bone implant semi-finished product was transferred to the cavity of a plasma generator for plasma etching reaction, using a mixture of Ar and O2, the Ar gas flow was 10 ml / min, the O2 gas flow was 5 ml / min, and the etching time was 5 min.

[0095] The etched implant semi-finished product was immediately transferred to a specific mold, which was the same as in Example 1. The implant semi-finished product was placed in the orientation direction, the angle between the height increasing direction in the 3D printing process and the cold surface contact surface direction was 90°, then the aqueous solution was poured into the mold to immerse the implant semi-finished product, and then it was placed in a vacuum box set at a temperature of 80°C and pumped to a vacuum degree of -0.09 MPa, then released to atmospheric pressure, and this process was repeated for 3 times, and then heat preservation was carried out for 60 min.

[0096] Then the treated composite bone implant and the mold were translated to a low-temperature freezing table, the bottom aluminum foil was in contact with the cooling fin (i.e. the cold source), and the freezing treatment was carried out for 24 h. After the composite bone implant was demolded, it was placed in a freeze dryer for drying for 24 h to obtain the final composite bone implant. The porous structure of the implant is irregularly distributed, and the structure of the bone implant is damaged and surface cracks appear after 15 s under a load pressure of 5 kg.

[0097] The preferred embodiments of the present application are described in detail above, but the present application is not limited to the specific details of the above-described embodiments, and various simple modifications can be made to the technical solutions of the present application within the technical concept of the present application, and these simple modifications all belong to the protection scope of the present application.

[0098] In addition, it should be noted that each specific technical feature described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, various possible combinations are not described again by the present application.

[0099] In addition, various different embodiments of the present application can also be combined in any manner, as long as it does not deviate from the idea of the present application, and it should also be considered as disclosed by the present application.

Claims

1. A method of making a biomimetic absorbable composite bone implant, the method comprising: The method comprises the following steps: ​ S1: mixing inorganic non-metallic materials and active ion doping to obtain inorganic non-metallic materials doped with active ions; mixing polymer raw materials with a solvent to obtain a polymer solution, and then mixing the inorganic non-metallic materials doped with active ions, the polymer solution, and a hydrogel precursor, stirring uniformly, and then preparing a 3D printing slurry after partial solvent evaporation; S2: injecting the printing slurry into a 3D printing forming machine to prepare a bone implant semi-finished product by 3D printing, and then performing drying treatment; the 3D printing is performed by an extrusion type 3D printing method; S3: placing the bone implant semi-finished product after drying treatment in a plasma generator cavity to perform a plasma etching reaction; S4: placing the bone implant semi-finished product after the plasma etching reaction in a special mold, wherein the special mold comprises a cold surface for contacting a cold source, a heat preservation sleeve is arranged on the side of the cold surface away from the cold source, and the heat preservation sleeve has a containing space for loading a liquid; adding a solution of the hydrogel precursor into the heat preservation sleeve to immerse the bone implant semi-finished product, and then performing vacuumization on the special mold, and performing heat preservation reaction under vacuum for a period of time; S5: after the heat preservation reaction is completed, translating the special mold to a freezing table to perform a special orientation freezing treatment, forming an ice mold along a direction perpendicular to the cold surface on the cold surface of the special mold to realize special orientation forming of the hydrogel, and then demolding to obtain an implant for freezing drying treatment, thereby obtaining a final composite bone implant.

2. The method for preparing the biomimetic absorbable composite bone implant according to claim 1, characterized in that: The inorganic non-metallic material is an inorganic artificial bone material.

3. The method for preparing the biomimetic absorbable composite bone implant according to claim 2, characterized in that: The inorganic non-metallic material is one or more of hydroxyapatite, bioglass, β-TCP, and α-TCP.

4. The method for preparing the biomimetic absorbable composite bone implant according to claim 2, characterized in that: The doped active ions are one or more of Mg 2+ , Ca 2+ , Sr 2+ ions.

5. The method for preparing the biomimetic absorbable composite bone implant according to claim 2, characterized in that: The active ion doping is added in the form of a salt, and the addition amount of the active metal ion in the salt is 0.2-1.5% of the total weight of the inorganic non-metallic material.

6. The method for preparing the biomimetic absorbable composite bone implant according to claim 5, characterized in that: The addition amount of the active metal ion in the salt is 0.5-1% of the total weight of the inorganic non-metallic material.

7. The method for preparing the biomimetic absorbable composite bone implant according to claim 1, characterized in that: The polymer raw material is one or more of PCL, PLGA, and PLLA, and the addition amount of the polymer raw material is 5-80% of the total weight of the printing slurry.

8. The method for preparing the biomimetic absorbable composite bone implant according to claim 7, characterized in that: The addition amount of the polymer raw material is 10-40% of the total weight of the printing slurry.

9. The method for preparing the biomimetic absorbable composite bone implant according to claim 7, characterized in that: The solvent is one or more of chloroform, dimethyl sulfoxide, and tetrahydrofuran.

10. The method for preparing the biomimetic absorbable composite bone implant according to claim 1, characterized in that: The hydrogel precursor is one or more of collagen, polyvinyl alcohol, hyaluronic acid, gelatin, and sodium alginate, and the addition amount of the hydrogel precursor is 0.1-10% of the total weight of the printing slurry.

11. The method for preparing the biomimetic absorbable composite bone implant according to claim 10, characterized in that: The addition amount of the hydrogel precursor is 1-8% of the total weight of the printing slurry.

12. The method for preparing the biomimetic absorbable composite bone implant according to claim 10, characterized in that: The solution of the hydrogel precursor in step S4 is an aqueous solution of the hydrogel precursor, and the concentration is 1-50 wt%.

13. The method for preparing the biomimetic absorbable composite bone implant according to claim 1, characterized in that: The 3D printing is performed by an extrusion rate of 1-5 mm / s in a layer-by-layer stacking manner to obtain a bone implant semi-finished product with a certain thickness.

14. The method of claim 1 or 13, wherein the method further comprises the step of: The plasma etching is performed by mixing Ar and O2 as the inlet gas. ​ 15. The method for preparing the biomimetic absorbable composite bone implant according to claim 14, characterized in that: The Ar inlet flow rate is 5-50 ml / min, the O2 inlet flow rate is 1-30 ml / min, and the etching time is 1-5 min.

16. The method for preparing the biomimetic absorbable composite bone implant according to claim 1, characterized in that: In step S4, the bone implant semi-finished product is placed in a specific mold, and the angle between the specific orientation direction, which is the height increasing direction in the 3D printing process, and the contact surface direction of the cold surface in the specific mold is between 75° and 105°.

17. The method of claim 1 or 16, wherein the method further comprises the step of: In step S4, the temperature of the vacuum heat preservation reaction is 80-90°C, and the heat preservation time is 30-60 min. ​ 18. The bionic absorbable composite bone implant prepared by the method of any one of claims 1-17.

19. The use of the bionic absorbable composite bone implant of claim 18 in the field of medical composite materials.

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