3D Printed MOFs Particle Network Hydrogel and Preparation Method and Application Thereof, and Hydrogel-based Lubricious Meniscus Substitute and Preparation Method Thereof

Abstract

The present invention provides a 3D printed MOFs particle network hydrogel, its preparation method and application, as well as a hydrogel slippery meniscus substitute and its preparation method, which relate to the technical fields of hydrogel materials, 3D printing manufacturing and medical devices. In the present invention, an aqueous solution of polyvinyl alcohol, sodium carboxymethyl cellulose and an MOFs organic ligand are mixed, and the obtained hydrogel ink is subjected to direct writing 3D printing to obtain a 3D printed hydrogel structure containing the MOFs organic ligand; the 3D printed hydrogel structure is successively frozen and thawed, and then soaked in a metal salt organic solution and subjected to water exchange equilibrium to obtain a 3D printed MOFs particle network hydrogel. The 3D printed MOFs particle network hydrogel prepared by the present invention has excellent mechanical properties, hydrophilicity, swelling resistance, lubricity and high printing accuracy, and is used to prepare a meniscus substitute, and a hydrogel slippery meniscus substitute with both high load-bearing and water lubrication properties can be obtained.

Description

Technical Field

[0001] The present invention relates to the technical fields of hydrogel materials, 3D printing manufacturing, and medical devices, and particularly relates to a 3D printed MOFs particle network hydrogel and a preparation method and application thereof, as well as a hydrogel slippery meniscus substitute and a preparation method thereof. Background Art

[0002] The meniscus is a semi-circular fibrocartilaginous tissue located in the joint space of the knee joint. Its structure presents a wedge-shaped structure with a thicker outer periphery and a thinner and sharper inner edge, and is mainly divided into the medial and lateral menisci. The material of the meniscus is tough and elastic, and in a mild and humid environment, its shape fills the gap between the tibial condyle surface and the femoral condyle surface, can buffer the direct impact between the two bone surfaces during joint movement, and plays functions such as absorbing shock, buffering, reducing cartilage load, lubricating the joint, protecting articular cartilage, and maintaining the stability of the knee joint. However, it is difficult for the meniscus to heal itself after injury and tear. Whether it is a severe tear, or wear and fragmentation, or partial resection and total resection during surgery, these will all lead to an increase in the contact stress between the tibia and the femur, and further lead to persistent knee pain symptoms, significantly increasing the occurrence of knee joint and osteoarthritis. Meniscus replacement is the only means to solve these problems, and the meniscus substitute is the only transplantation substitute for meniscus replacement after meniscus tear.

[0003] The currently used meniscus substitutes mainly include autologous tissue transplantation for meniscus regeneration, allogeneic transplantation of meniscus, xenogeneic tissue transplantation substitutes, and synthetic material transplantation substitutes. However, allogeneic and xenogeneic tissue meniscus transplantation faces more research and challenges, and its efficacy has far from been proven, and there is still a very long way to go before entering the clinic. In addition, the currently available synthetic meniscus substitute materials on the market, such as polylactic acid, polyacetic acid, polyethylene, polytetrafluoroethylene, polyurethane, carbon fiber polymer and other materials, still have quite a lot of problems in simulating the structure, mechanical properties and functionality of the human physiological meniscus. For example, synovial fluid cannot enter the substitute, that is, there is poor mass exchange ability; at the same time, there is poor lubrication performance, and long-term implantation may cause discomfort such as wear and fatigue, and even complications such as arthritis. Developing artificial materials similar to the human physiological environment into artificial meniscus transplantation substitutes with excellent performance (wear resistance, toughness, stability, slipperiness, etc.) has become the main research direction of current meniscus replacement.

[0004] Among current synthetic materials, hydrogel is a hydrophilic polymer soft material with a three-dimensional network cross-linked structure containing a large number of water molecules. Due to its high water content, hydrogel has good water lubrication performance on its surface, which can significantly reduce the friction between solids and the contact surface. In addition, the polymer network of hydrogel endows it with good softness and elasticity as well as good mechanical matching with biological tissues, which is similar to natural biological tissue organs, such as muscles, tendons, cartilage, valves, and skin in biological tissues. At the same time, due to its good biocompatibility and biosafety, hydrogel has been widely used in the fields of tissue engineering scaffolds, drug delivery carriers, wound dressings, and biomedical devices. Therefore, hydrogel has very broad application prospects as a medical material. However, for most polymer hydrogel materials, there are scientific problems such as large brittleness, low energy consumption efficiency, poor mechanical properties, and technical problems such as poor processability. On the one hand, due to factors such as a large amount of water and uneven cross-linked structure in its network structure, the polymer segments are often in a highly swollen state, resulting in poor mechanical properties, such as toughness and strength, during the stress process. On the other hand, due to the high water content and softness of hydrogel, it is still challenging to manufacture hydrogels with good physical and chemical properties and personalized design and manufacturing structures.

[0005] The emerging 3D printing technology can prepare hydrogels with various complex structures, which greatly broadens the application of hydrogels in the biomedical field. However, the current 3D-printed structured and functionalized hydrogel systems still lack sufficient mechanical strength and will swell when in the physiological environment for a long time, further weakening the mechanical strength of the hydrogels. Developing a 3D-printed high-strength and tough hydrogel with more superior strength and toughness and capable of realizing multi-scale structure construction is particularly important for the manufacture of biological soft tissues. Summary of the Invention

[0006] In view of this, the purpose of the present invention is to provide a preparation method of 3D-printed MOFs particle network hydrogel and its application, as well as a wet and slippery meniscus substitute made of hydrogel and its preparation method. The preparation method provided by the present invention can prepare 3D-printed hydrogel materials with excellent strength and toughness.

[0007] In order to achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0008] The present invention provides a preparation method of 3D-printed MOFs particle network hydrogel, including the following steps:

[0009] Mix an aqueous solution of polyvinyl alcohol, sodium carboxymethyl cellulose, and MOFs organic ligand to obtain a hydrogel ink;

[0010] Perform direct writing 3D printing on the hydrogel ink to obtain a 3D-printed hydrogel structure containing MOFs organic ligand;

[0011] The 3D printed hydrogel structure containing the MOFs organic ligand is sequentially frozen and thawed to obtain a 3D printed hydrogel enhanced structure;

[0012] The 3D printed hydrogel enhanced structure is soaked in a metal salt organic solution and then subjected to water exchange equilibrium to obtain the 3D printed MOFs particle network hydrogel.

[0013] Preferably, the number average molecular weight of polyvinyl alcohol in the polyvinyl alcohol aqueous solution is 77,000 - 146,000, and the mass concentration of the polyvinyl alcohol aqueous solution is 10.0 - 15.0%; the viscosity of the sodium carboxymethyl cellulose is 5,000 - 15,000 mPa·s, and the mass of the sodium carboxymethyl cellulose is 3 - 5% of the mass of the polyvinyl alcohol aqueous solution; the MOFs organic ligand includes one or more of 2-methylimidazole, 4-pyrazolecarboxylic acid, benzenehexacarboxylic acid, and benzimidazole; the dosage ratio of the MOFs organic ligand to the polyvinyl alcohol aqueous solution is 0.25 - 1.0 mol:1 L.

[0014] Preferably, the printing parameters of the direct writing 3D printing include: the printing speed is 3 - 5 mm / s; the ink extrusion pressure is 0.2 - 0.5 MPa; the printing platform temperature is -5 - 20 °C.

[0015] Preferably, the freezing temperature is -20 - -15 °C, and the thawing temperature is room temperature; the freezing and thawing are carried out in cycles, with one freezing and one thawing in sequence being one operation, the total number of operations is 5 - 10 times, the single freezing time is 5 - 10 h, and the single thawing time is 5 - 10 h.

[0016] Preferably, the metal salt in the metal salt organic solution includes one or more of zinc nitrate, cobalt nitrate, copper nitrate, europium nitrate, and terbium nitrate, the solvent of the metal salt organic solution is methanol, and the concentration of the metal salt organic solution is 0.01 - 0.1 mol / L; the soaking time is 24 - 96 h; the water exchange equilibrium time is 24 - 96 h.

[0017] The present invention provides a 3D printed MOFs particle network hydrogel prepared by the preparation method described in the above technical solution, including a hydrogel matrix and MOFs nanoparticles filled in the network structure of the hydrogel matrix.

[0018] The present invention provides an application of the 3D printed MOFs particle network hydrogel described in the above technical solution in the preparation of a hydrogel slippery meniscus substitute.

[0019] The present invention provides a preparation method of a hydrogel slippery meniscus substitute, including the following steps:

[0020] Provide a hydrogel having a meniscus shape; the hydrogel is a 3D printed MOFs particle network hydrogel as described in the above technical solution;

[0021] Mix an aqueous solution of polyvinyl alcohol and polyvinylpyrrolidone to obtain a hydrogel filler;

[0022] Soak the hydrogel having a meniscus shape in the hydrogel filler, and freeze and thaw the soaked hydrogel in sequence to obtain the hydrogel slippery meniscus substitute.

[0023] Preferably, the mass content of polyvinyl alcohol in the hydrogel filler is 10-15%, and the mass content of polyvinylpyrrolidone is 1-5%; the soaking time is 5-10 h; the freezing temperature is -20 to -15 °C, and the thawing temperature is room temperature; the freezing and thawing are carried out cyclically, with one freezing and one thawing in sequence as one operation, the total number of operations is 5-10 times, the single freezing time is 5-10 h, and the single thawing time is 5-10 h.

[0024] The present invention provides a hydrogel slippery meniscus substitute prepared by the preparation method described in the above technical solution.

[0025] The present invention provides a preparation method of a 3D printed MOFs particle network hydrogel, comprising the following steps: mixing an aqueous solution of polyvinyl alcohol, sodium carboxymethyl cellulose and an MOFs organic ligand to obtain a hydrogel ink; performing direct writing 3D printing on the hydrogel ink to obtain a 3D printed hydrogel structure containing the MOFs organic ligand; freezing and thawing the 3D printed hydrogel structure containing the MOFs organic ligand in sequence to obtain a 3D printed hydrogel enhanced structure; soaking the 3D printed hydrogel enhanced structure in a metal salt organic solution and then performing water exchange equilibrium to obtain the 3D printed MOFs particle network hydrogel. The present invention utilizes the multiple hydrogen bond interactions between the MOFs organic ligand and polyvinyl alcohol and sodium carboxymethyl cellulose, so that the obtained hydrogel ink has adjustable rheological properties and appropriate viscoelasticity, so that the hydrogel ink can be smoothly extruded and can maintain a good macroscopic structure on the forming platform without structural deformation and collapse, realizing that the 3D printed soft hydrogel material presents sub-millimeter resolution and high shape fidelity; the present invention cleverly uses the soaking strategy to post-treat the 3D printed hydrogel structure containing the MOFs organic ligand, realizing the controllable assembly and multi-scale integration of the MOFs material inside the hydrogel structure, enhancing the overall mechanical properties of the hydrogel structure while in-situ generating MOFs particles. The present invention combines the hydrogel 3D printing technology and the MOFs nanomaterial to prepare a MOFs particle network hydrogel system with excellent strength and toughness, and capable of manufacturing multi-scale, high-precision complex functional structures with extreme mechanical behaviors.

[0026] Furthermore, the present invention can easily achieve a wide range of adjustable mechanical properties by regulating the content and type of MOFs organic ligands in the hydrogel ink and the type and content of metal ions in the metal salt organic solution of the immersed 3D printed hydrogel reinforcement structure, making the strength and toughness more controllable.

[0027] The present invention provides a 3D printed MOFs particle network hydrogel prepared by the preparation method described in the above technical solution. The MOFs particle network hydrogel provided by the present invention is a reinforced and toughened 3D printed MOFs particle network hydrogel, which has excellent mechanical properties, hydrophilic properties, swelling resistance properties, lubricating properties, and high printing structure accuracy, and solves the contradiction between the poor mechanical properties and poor processing properties of traditional hydrogels.

[0028] The present invention provides an application of the 3D printed MOFs particle network hydrogel described in the above technical solution in the preparation of a hydrogel slippery meniscus substitute. Using the 3D printed MOFs particle network hydrogel provided by the present invention to prepare a hydrogel slippery meniscus substitute, on the one hand, the construction of an individualized and fine hydrogel structure can be realized through 3D printing technology, and a hydrogel slippery meniscus substitute that can match the patient's own can be customized according to the appearance contour and size of the patient's meniscus, greatly improving the accuracy and safety of the replacement surgery; on the other hand, the MOFs particle network hydrogel has good mechanical properties and can provide sufficient support for joint movement; in addition, by virtue of the water lubrication property of the hydrogel, the meniscus substitute can have the effect of promoting lubrication, which is helpful for the reconstruction of the meniscus structure and the subsequent recovery of normal function after meniscus replacement. By virtue of the material exchange ability of the hydrogel, it is beneficial to the penetration of synovial fluid, promotes the growth of new tissue and postoperative repair, and further improves the stability of the combination between the substitute and the surrounding tissues. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is a schematic flow chart for preparing the 3D printed MOFs particle network hydrogel of the present invention;

[0030] Figure 2 is a microscopic morphology diagram of the reinforced and toughened 3D printed MOFs particle network hydrogel prepared in Example 1;

[0031] Figure 3 is a rheological test diagram of the hydrogel ink used in Example 1 for preparing the reinforced and toughened 3D printed MOFs particle network hydrogel, Figure 3 where a is a curve graph of the viscosity of the hydrogel ink changing with the shear rate, and b is a curve graph of the storage modulus (G') and loss modulus (G") of the hydrogel ink changing with the shear stress;

[0032] Figure 4Wettability effect diagram of the enhanced and toughened 3D-printed MOFs particle network hydrogel prepared in Example 2;

[0033] Figure 5 Optical photograph of the grid structure of the enhanced and toughened 3D-printed MOFs particle network hydrogel described in Example 3;

[0034] Figure 6 Optical photograph of the grid structure of the enhanced and toughened 3D-printed MOFs particle network hydrogel described in Example 4;

[0035] Figure 7 Optical photograph of the hydrogel slippery meniscus substitute prepared in Example 5;

[0036] Figure 8 Lubrication performance effect diagram of the hydrogel slippery meniscus substitute prepared in Example 5. Detailed implementation mode

[0037] The present invention provides a preparation method of a 3D-printed MOFs particle network hydrogel, comprising the following steps:

[0038] Mix an aqueous solution of polyvinyl alcohol, sodium carboxymethylcellulose and an MOFs organic ligand to obtain a hydrogel ink;

[0039] Perform direct writing 3D printing on the hydrogel ink to obtain a 3D-printed hydrogel structure containing an MOFs organic ligand;

[0040] Freeze and thaw the 3D-printed hydrogel structure containing an MOFs organic ligand in sequence to obtain a 3D-printed hydrogel enhanced structure;

[0041] Immerse the 3D-printed hydrogel enhanced structure in a metal salt organic solution and then perform water exchange equilibrium to obtain the 3D-printed MOFs particle network hydrogel.

[0042] Figure 1 Schematic flow diagram for preparing the 3D-printed MOFs particle network hydrogel of the present invention. The following combines Figure 1 Describe the present invention in detail.

[0043] In the present invention, unless otherwise specified, the raw materials involved are commercially available products well known to those skilled in the art.

[0044] The present invention mixes an aqueous solution of polyvinyl alcohol, sodium carboxymethyl cellulose, and an MOFs organic ligand to obtain a hydrogel ink. In the present invention, the number-average molecular weight of polyvinyl alcohol in the aqueous solution of polyvinyl alcohol is preferably 77,000 to 146,000, more preferably 89,000 to 146,000, and further preferably 89,000 to 98,000; the mass concentration of the aqueous solution of polyvinyl alcohol is preferably 10.0 to 15.0%, more preferably 12.0 to 14.0%, and further preferably 12.5 to 13.5%. In the present invention, the viscosity of the sodium carboxymethyl cellulose is preferably 5000 to 15000 mPa·s, more preferably 8000 to 12000 mPa·s; the mass of the sodium carboxymethyl cellulose is preferably 3 to 5% of the mass of the aqueous solution of polyvinyl alcohol, more preferably 4%. In the present invention, the MOFs organic ligand preferably includes one or more of 2-methylimidazole, 4-pyrazolecarboxylic acid, benzenehexacarboxylic acid, and benzimidazole. When the MOFs organic ligand is a mixture of several kinds, the present invention has no special requirements for the mixing ratio and can be mixed in any ratio; in the embodiments of the present invention, the MOFs organic ligand is preferably 2-methylimidazole. In the present invention, the MOFs organic ligand has good water solubility. In the present invention, the dosage ratio of the MOFs organic ligand to the aqueous solution of polyvinyl alcohol is preferably 0.25 to 1.0 mol:1 L, more preferably 0.50 to 1.0 mol:1 L, and further preferably 0.50 to 0.75 mol:1 L. The present invention utilizes the molecular entanglement and multiple hydrogen bond interactions of the MOFs organic ligand with polyvinyl alcohol and sodium carboxymethyl cellulose, so that the obtained hydrogel ink has adjustable rheological properties and appropriate viscoelasticity, and is a hydrogel ink with shear thinning and stress yield characteristics, so that the hydrogel ink can be smoothly extruded for printing and can maintain a good macroscopic structure on the forming platform without structural deformation and collapse, realizing 3D printing of soft hydrogel materials with sub-millimeter resolution and high shape fidelity; in addition, polyvinyl alcohol itself has swelling resistance, which is further conducive to improving the swelling resistance of the hydrogel.

[0045] After obtaining the hydrogel ink, the present invention performs direct writing 3D printing on the hydrogel ink to obtain a 3D printed hydrogel structure containing an MOFs organic ligand. The present invention has no special requirements for the equipment and specific operation method of the direct writing 3D printing, and the corresponding equipment and operation method well-known to those skilled in the art can be used. In the present invention, the printing parameters of the direct writing 3D printing preferably include: the printing speed is 3 to 5 mm / s, preferably 4 mm / s; the ink extrusion pressure is 0.2 to 0.5 MPa, preferably 0.3 MPa; the printing platform temperature is -5 to 20 °C, preferably -5 to 5 °C. In the present invention, the shape of the 3D printed hydrogel structure can be set accordingly during the process of direct writing 3D printing according to actual needs.

[0046] After obtaining the 3D-printed hydrogel structure containing the MOF organic ligand, the present invention subjects the 3D-printed hydrogel structure containing the MOF organic ligand to freezing and thawing in sequence to obtain a 3D-printed hydrogel enhanced structure. In the present invention, the temperature of the freezing is preferably -20 to -15 °C, and the freezing is specifically carried out by placing the 3D-printed hydrogel structure containing the MOF organic ligand in a cold trap at -20 to -15 °C; the temperature of the thawing is preferably room temperature; the freezing and thawing are preferably carried out cyclically, with one freezing and one thawing in sequence being one operation, and the total number of operations is preferably 5 to 10 times. The time for single freezing is preferably 5 to 10 h, more preferably 6 h, and the time for single thawing is preferably 5 to 10 h, more preferably 6 h. During the freezing and thawing process, the polyvinyl alcohol (PVA) molecular chains in the 3D-printed hydrogel structure containing the MOF organic ligand crystallize to form a PVA crystal network, enhancing the mechanical properties of the hydrogel.

[0047] After obtaining the 3D printed hydrogel reinforced structure, the 3D printed hydrogel reinforced structure is soaked in a metal salt organic solution and then subjected to water exchange equilibrium to obtain the 3D printed MOFs particle network hydrogel. In the present invention, the metal salt in the metal salt organic solution preferably includes one or more of zinc nitrate, cobalt nitrate, copper nitrate, europium nitrate and terbium nitrate. When the metal salt is a mixture of several kinds, the present invention has no special requirements for the mixing ratio and can be mixed in any ratio; in the embodiments of the present invention, the metal salt is preferably zinc nitrate or cobalt nitrate. In the present invention, the solvent of the metal salt organic solution is preferably methanol, and the concentration of the metal salt organic solution is preferably 0.01 - 0.1 mol / L, more preferably 0.05 - 0.1 mol / L, and further preferably 0.05 - 0.07 mol / L. In the present invention, the soaking time is preferably 24 - 96 h, more preferably 36 - 84 h, and further preferably 48 - 72 h, and the soaking can be carried out at room temperature. During the soaking process, the in-situ growth of MOFs nanoparticles and the chelation of metal ions with sodium carboxymethyl cellulose are simultaneously achieved to obtain a 3D printed hydrogel structure containing MOFs particles. Among them, the in-situ growth of MOFs particles is that metal ions and MOFs organic ligands form an ordered porous organic framework material through metal coordination interactions. Metal-organic frameworks (MOFs) are a kind of porous nanobiomaterials. The present invention uses a dynamic coordination chemistry strategy to form physical cross-linking points to improve the strength and toughness of the hydrogel. The present invention cleverly uses the soaking strategy to post-treat the 3D printed hydrogel structure containing MOFs organic ligands, realizing the controllable assembly and multi-scale integration of MOFs materials inside the hydrogel structure, enhancing the overall mechanical properties of the hydrogel structure while in-situ generating MOFs particles, and the reinforcement and toughening of MOFs particles can further weaken the swelling property of the hydrogel; the chelation of metal ions with sodium carboxymethyl cellulose introduces a metal coordination network into the hydrogel network, and this metal coordination network can significantly improve the mechanical properties of the hydrogel. In addition, soaking the 3D printed hydrogel reinforced structure in a methanol solution of a metal salt can cause phase separation (the water in the original hydrogel is replaced by methanol), and the hydrogen bond interaction between the components promotes the densification of the gel network, and the molecular configuration of the gel changes from an extended network to a coiled skeleton, enhancing the mechanical properties of the hydrogel while improving its swelling resistance.

[0048] In the present invention, the time for water exchange equilibrium is preferably 24 to 96 h, more preferably 36 to 84 h, and further preferably 48 to 72 h. The specific operation for water exchange equilibrium is as follows: Immerse the 3D printed hydrogel structure with MOFs nanoparticles grown thereon, which has been soaked in the metal salt organic solution, in deionized water to cause solvent exchange. The present invention has no special requirements for the number of times of water exchange equilibrium, as long as it can ensure complete removal of the organic solvent inside the hydrogel.

[0049] The present invention combines hydrogel 3D printing technology and MOFs nanomaterials to prepare a MOFs particle network hydrogel system with excellent strength and toughness, and capable of manufacturing multi-scale, high-precision complex functional structures with extreme mechanical behaviors.

[0050] The present invention provides a 3D printed MOFs particle network hydrogel prepared by the preparation method described in the above technical solution, which includes a hydrogel matrix and MOFs nanoparticles filled in the network structure of the hydrogel matrix. The 3D printed MOFs particle network hydrogel provided by the present invention has excellent mechanical properties, hydrophilic properties, swelling resistance, wet lubrication properties, good biocompatibility and bioactivity, as well as high printing structure precision, and solves the contradiction between the poor mechanical properties and poor processing properties of traditional hydrogels.

[0051] The present invention provides the application of the 3D printed MOFs particle network hydrogel described in the above technical solution in the preparation of a hydrogel wet slippery meniscus substitute.

[0052] The present invention also provides a preparation method for a hydrogel wet slippery meniscus substitute, which includes the following steps:

[0053] Provide a hydrogel having a meniscus shape; the hydrogel is the 3D printed MOFs particle network hydrogel described in the above technical solution;

[0054] Mix an aqueous solution of polyvinyl alcohol and polyvinylpyrrolidone to obtain a hydrogel filler;

[0055] Immerse the hydrogel having a meniscus shape in the hydrogel filler, and sequentially freeze and thaw the soaked hydrogel to obtain the hydrogel wet slippery meniscus substitute.

[0056] The present invention provides a hydrogel having a meniscus shape; the hydrogel is the 3D printed MOFs particle network hydrogel described in the above technical solution. In the present invention, the meniscus shape can be set during the above-mentioned direct writing 3D printing. Specifically, the advantages of 3D printing manufacturing that can achieve individualized and refined hydrogel structures can be utilized. According to the appearance contour and size of the patient's meniscus, a hydrogel wet and slippery meniscus substitute that can match the patient's own can be customized, which can greatly improve the accuracy and safety of the replacement surgery.

[0057] The present invention mixes an aqueous solution of polyvinyl alcohol and polyvinylpyrrolidone to obtain a hydrogel filler. The present invention has no special requirements for the mixing method, and it is only necessary to ensure uniform mixing. In the present invention, the mass content of polyvinyl alcohol in the hydrogel filler is preferably 10-15%, more preferably 12-14%, and further preferably 12.5-13.5%; the mass content of polyvinylpyrrolidone in the hydrogel filler is preferably 1-5%, more preferably 2-4%, and further preferably 2.5-3.5%; the role of polyvinyl alcohol is to introduce a crystalline network to enhance the mechanical properties of the hydrogel filler network structure, and the role of polyvinylpyrrolidone is to endow the hydrogel with water lubrication performance. In the present invention, the hydrogel filler is a viscous polymer aqueous solution composed of polyvinyl alcohol and polyvinylpyrrolidone, and it has a water lubrication function.

[0058] After obtaining the hydrogel and hydrogel filler with the shape of meniscus, the present invention soaks the hydrogel with the shape of meniscus in the hydrogel filler, and freezes and thaws the soaked hydrogel in sequence to obtain the hydrogel slippery meniscus substitute. In the present invention, the soaking time is preferably 5-10 h, more preferably 5-9 h, and the soaking can be carried out at room temperature; during the soaking process, the hydrogel filler slowly diffuses into the network skeleton of the 3D printed MOFs particle network hydrogel to enhance the interfacial bonding. In the present invention, the freezing temperature is preferably -20 to -15 °C, and the freezing is specifically carried out in a cold trap at -20 to -15 °C; the thawing temperature is preferably room temperature; the freezing and thawing are carried out in cycles, with one freezing and one thawing in sequence as one operation, and the total number of operations is preferably 5-10 times, the single freezing time is preferably 5-10 h, more preferably 6 h, and the single thawing time is preferably 5-10 h, more preferably 6 h. During the freezing and thawing process, physical crystallization crosslinking of PVA occurs in polyvinyl alcohol to form a crosslinked network, thereby ensuring the mechanical properties of the water lubricating phase. Through the soaking, freezing and thawing treatments, the present invention composes the hydrogel filler with water lubricating function into the high-load network structure of the hydrogel with the shape of meniscus, on the one hand, improving the water lubricating performance of the hydrogel, and on the other hand, imitating the bionic gradient structure of the natural meniscus, and finally obtaining a hydrogel slippery meniscus substitute with both high load-bearing and water lubrication.

[0059] The present invention provides a hydrogel slippery meniscus substitute prepared by the preparation method described in the above technical solution. The hydrogel slippery meniscus substitute provided by the present invention, on the one hand, can realize the construction of individualized and fine hydrogel structures through 3D printing technology, and can customize the hydrogel slippery meniscus substitute that can match the patient's own according to the appearance contour and size of the patient's meniscus, greatly improving the accuracy and safety of the replacement surgery; on the other hand, the meniscus substitute combines the high-load network structure of the MOFs particle network hydrogel with the water lubricating performance of the hydrogel filler to form a hydrogel meniscus substitute with both high load-bearing and water lubrication, which can provide sufficient support for joint movement; in addition, relying on the water lubricating property of the hydrogel, the meniscus substitute can have the effect of promoting lubrication, which helps the reconstruction of the meniscus structure and the subsequent recovery of normal function after meniscus replacement. Relying on the mass exchange ability of the hydrogel, it is beneficial to the penetration of synovial fluid, promotes the growth of new tissues and postoperative repair, and further improves the stability of the combination between the substitute and the surrounding tissues.

[0060] The following combines examples to elaborate in detail on the 3D printed MOFs particle network hydrogel provided by the present invention, the preparation method and application, and the hydrogel slippery meniscus substitute and the preparation method, but they cannot be understood as limiting the protection scope of the present invention.

[0061] Example 1

[0062] 40 g of an aqueous solution of polyvinyl alcohol with a molecular weight of 77000 and a mass concentration of 12.5%, 1.6 g of sodium carboxymethyl cellulose with a viscosity of 15000 mPa·s, and 2.88 g (1.0 mol / L relative to the aqueous polyvinyl alcohol solution) of 2-methylimidazole were uniformly mixed to obtain a hydrogel ink with shear thinning and stress yielding; the shear thinning and stress yielding hydrogel ink was printed using ink direct writing 3D printing technology at printing parameters of a printing speed of 4 mm / s, an extrusion pressure of 0.3 MPa, and a printing platform temperature of -5°C to obtain a 3D printed hydrogel structure containing an organic ligand; the 3D printed hydrogel structure containing an organic ligand was cryocrystallized in a cold trap at -20°C for 6 h and thawed at room temperature for 6 h, and an enhanced 3D printed hydrogel structure containing an organic ligand was obtained after 5 freeze-thaw cycles; the enhanced 3D printed hydrogel structure containing an organic ligand was immersed in a 0.1 mol / L zinc nitrate methanol solution to in-situ grow MOFs particles for 24 h; finally, an enhanced and toughened 3D printed MOFs particle network hydrogel was obtained after 24 h of water exchange equilibrium.

[0063] Among them, the water content of the enhanced and toughened 3D printed MOFs particle network hydrogel is 83.7 ± 1.8%; the swelling ratio is 1.31 ± 0.06 g / g; the fracture strength is 1.26 ± 0.26 MPa; the elastic modulus is 0.78 ± 0.03 MPa; the toughness is 1.86 ± 0.19 MJ / m 3 ; the water contact angle is 55.8 ± 0.6°.

[0064] Figure 2 is the microscopic morphology diagram of the enhanced and toughened 3D printed MOFs particle network hydrogel prepared in Example 1. From Figure 2 it can be seen that the MOFs particles are uniformly filled in the hydrogel network to act as cross-linking points (equivalent to the MOFs particles acting as cross-linking agents to further cross-link with PVA and sodium carboxymethyl cellulose) to enhance the mechanical properties.

[0065] Figure 3 is the rheological test diagram of the hydrogel ink used to prepare the enhanced and toughened 3D printed MOFs particle network hydrogel in Example 1, Figure 3 in which a is the curve of the viscosity of the hydrogel ink changing with the shear rate, b is the curve of the storage modulus (G') and loss modulus (G") of the hydrogel ink changing with the shear stress, and the intersecting part of the two curves in b is the yield strain. From Figure 3 it can be seen that the hydrogel ink has good shear thinning and appropriate yield strain.

[0066] Example 2

[0067] 40 g of an aqueous solution of polyvinyl alcohol with a molecular weight of 77,000 and a mass concentration of 12.5%, 1.6 g of sodium carboxymethyl cellulose with a viscosity of 15,000 mPa·s, and 1.44 g (0.5 mol / L relative to the aqueous polyvinyl alcohol solution) of 2-methylimidazole were uniformly mixed to obtain a hydrogel ink with shear thinning and stress yielding; the shear thinning and stress yielding hydrogel ink was printed using an ink direct writing 3D printing technique at printing parameters of a printing speed of 4 mm / s, an extrusion pressure of 0.3 MPa, and a printing platform temperature of -5°C to obtain a 3D printed hydrogel structure containing an organic ligand; the 3D printed hydrogel structure containing an organic ligand was cryocrystallized in a cold trap at -20°C for 6 h and thawed at room temperature for 6 h, and after 5 freeze-thaw cycles, an enhanced 3D printed hydrogel structure containing an organic ligand was obtained; the enhanced 3D printed hydrogel structure containing an organic ligand was immersed in a 0.1 mol / L zinc nitrate methanol solution to in-situ grow MOF particles for 24 h; finally, after water exchange equilibrium for 24 h, an enhanced and toughened 3D printed MOF particle network hydrogel was obtained.

[0068] Among them, the water content of the enhanced and toughened 3D printed MOF particle network hydrogel is 83.7 ± 0.9%; the swelling ratio is 1.40 ± 0.04 g / g; the breaking strength is 2.50 ± 0.21 MPa; the elastic modulus is 1.01 ± 0.05 MPa; the toughness is 2.45 ± 0.30 MJ / m 3 。

[0069] Figure 4 It is a wettability effect diagram of the enhanced and toughened 3D printed MOF particle network hydrogel prepared in Example 2. From Figure 4 it can be seen that the water contact angle of the enhanced and toughened 3D printed MOF particle network hydrogel is 58.6 ± 1.7°.

[0070] Example 3

[0071] 40 g of an aqueous solution of polyvinyl alcohol with a molecular weight of 77,000 and a mass concentration of 12.5%, 1.6 g of sodium carboxymethyl cellulose with a viscosity of 15,000 mPa·s, and 2.88 g (1.0 mol / L relative to the aqueous polyvinyl alcohol solution) of 2-methylimidazole were uniformly mixed to obtain a hydrogel ink with shear thinning and stress yielding; the shear thinning and stress yielding hydrogel ink was printed using the ink direct writing 3D printing technique at printing parameters of a printing speed of 4 mm / s, an extrusion pressure of 0.3 MPa, and a printing platform temperature of -5°C to obtain a 3D printed hydrogel structure containing organic ligands; the 3D printed hydrogel structure containing organic ligands was cryocrystallized in a cold trap at -20°C for 6 h and thawed at room temperature for 6 h, and an enhanced 3D printed hydrogel structure containing organic ligands was obtained after 5 freeze-thaw cycles; the enhanced 3D printed hydrogel structure containing organic ligands was immersed in a 0.05 mol / L zinc nitrate methanol solution to in-situ grow MOF particles for 24 h; finally, an enhanced and toughened 3D printed MOF particle network hydrogel was obtained after 24 h of water exchange equilibrium.

[0072] Among them, the water content of the enhanced and toughened 3D printed MOF particle network hydrogel is 85.4 ± 2.4%; the swelling ratio is 1.23 ± 0.07 g / g; the breaking strength is 1.72 ± 0.14 MPa; the elastic modulus is 0.51 ± 0.02 MPa; the toughness is 1.89 ± 0.15 MJ / m 3 ; the water contact angle is 51.2 ± 1.4°.

[0073] Figure 5 It is an optical photograph of the grid structure of the enhanced and toughened 3D printed MOF particle network hydrogel described in Example 3. From Figure 5 it can be seen that the 3D printed MOF particle network hydrogel grid structure has good shape fidelity.

[0074] Example 4

[0075] 40 g of an aqueous solution of polyvinyl alcohol with a molecular weight of 77,000 and a mass concentration of 12.5%, 1.6 g of sodium carboxymethyl cellulose with a viscosity of 15,000 mPa·s, and 2.88 g (1.0 mol / L relative to the aqueous polyvinyl alcohol solution) of 2-methylimidazole were uniformly mixed to obtain a hydrogel ink with shear thinning and stress yielding; the shear thinning and stress yielding hydrogel ink was printed using an ink direct writing 3D printing technique with printing parameters of a printing speed of 4 mm / s, an extrusion pressure of 0.3 MPa, and a printing platform temperature of -5°C to obtain a 3D printed hydrogel structure containing organic ligands; the 3D printed hydrogel structure containing organic ligands was cryocrystallized in a -20°C cold trap for 6 h and thawed at room temperature for 6 h, and after 5 freeze-thaw cycles, an enhanced 3D printed hydrogel structure containing organic ligands was obtained; the enhanced 3D printed hydrogel structure containing organic ligands was immersed in a 0.1 mol / L cobalt nitrate methanol solution to in-situ grow MOF particles for 24 h; finally, after 24 h of water exchange equilibrium, an enhanced and toughened 3D printed MOF particle network hydrogel was obtained.

[0076] Among them, the water content of the enhanced and toughened 3D printed MOF particle network hydrogel is 82.9 ± 0.3%; the swelling ratio is 1.31 ± 0.04 g / g; the breaking strength is 2.02 ± 0.18 MPa; the elastic modulus is 0.62 ± 0.04 MPa; the toughness is 2.42 ± 0.19 MJ / m 3 ; the water contact angle is 57.8 ± 2.1°.

[0077] Figure 6 is the optical photograph of the grid structure of the enhanced and toughened 3D printed MOF particle network hydrogel described in Example 4. From Figure 6 it can be seen that the 3D printed MOF particle network hydrogel grid structure has good shape fidelity.

[0078] Example 5

[0079] The enhanced and toughened 3D printed MOF particle network hydrogel manufactured in Example 1 was used as a semi-circular high-load bearing network structure; at room temperature, the semi-circular high-load bearing network structure was immersed in a hydrogel filler with a water lubricating function composed of 10 wt.% polyvinyl alcohol and 5 wt.% polyvinylpyrrolidone for 5 h, and was cryocrystallized in a -20°C cold trap for 6 h and thawed at room temperature for 6 h. After 5 freeze-thaw cycles, a hydrogel wet and slippery meniscus substitute with both high load bearing and water lubrication was obtained.

[0080] Figure 7 is the optical photograph of the hydrogel wet and slippery meniscus substitute prepared in Example 5. Figure 8The lubrication performance effect diagram of the hydrogel slippery meniscus substitute prepared in Example 5 shows that the friction coefficient of the hydrogel slippery meniscus substitute is 0.2018.

[0081] As can be seen from the above examples, the reinforced and toughened 3D printed MOFs particle network hydrogel prepared by the present invention has excellent mechanical properties, hydrophilic properties, swelling resistance and high printing structure accuracy. The hydrogel filler with composite water lubrication function can obtain a hydrogel slippery meniscus substitute with both high load-bearing and water lubrication properties.

[0082] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A preparation method of 3D printed MOFs particle network hydrogel, comprising the following steps: Mix an aqueous solution of polyvinyl alcohol, sodium carboxymethyl cellulose and MOFs organic ligands to obtain a hydrogel ink; the MOFs organic ligands include one or more of 2-methylimidazole, 4-pyrazolecarboxylic acid, benzenehexacarboxylic acid and benzimidazole; the dosage ratio of the MOFs organic ligands to the aqueous solution of polyvinyl alcohol is 0.25 - 1.0 mol: 1 L; Perform direct writing 3D printing on the hydrogel ink to obtain a 3D printed hydrogel structure containing MOFs organic ligands; Freeze and then thaw the 3D printed hydrogel structure containing MOFs organic ligands in sequence to obtain a 3D printed hydrogel enhanced structure; Immerse the 3D printed hydrogel enhanced structure in a metal salt organic solution and then perform water exchange equilibrium to obtain the 3D printed MOFs particle network hydrogel; the solvent of the metal salt organic solution is methanol; the metal salts in the metal salt organic solution include one or more of zinc nitrate, cobalt nitrate, copper nitrate, europium nitrate and terbium nitrate, and the concentration of the metal salt organic solution is 0.01 - 0.1 mol / L.

2. The preparation method according to claim 1, characterized in that, The number average molecular weight of polyvinyl alcohol in the aqueous solution of polyvinyl alcohol is 77000 - 146000, and the mass concentration of the aqueous solution of polyvinyl alcohol is 10.0 - 15.0%; the viscosity of the sodium carboxymethyl cellulose is 5000 - 15000 mPa·s, and the mass of the sodium carboxymethyl cellulose is 3 - 5% of the mass of the aqueous solution of polyvinyl alcohol.

3. The preparation method according to claim 1, characterized in that, The printing parameters of the direct writing 3D printing include: the printing speed is 3 - 5 mm / s; the ink extrusion pressure is 0.2 - 0.5 MPa; the printing platform temperature is -5 - 20 °C.

4. The preparation method according to claim 1, wherein The temperature of the freezing is -20 - -15 °C, and the temperature of the thawing is room temperature; the freezing and thawing are carried out cyclically, with one freezing and one thawing in sequence as one operation, the total number of operations is 5 - 10 times, the time of single freezing is 5 - 10 h, and the time of single thawing is 5 - 10 h.

5. The preparation method according to claim 1, characterized in that, The time of the immersion is 24 - 96 h; the time of the water exchange equilibrium is 24 - 96 h.

6. The 3D printed MOFs particle network hydrogel prepared by the preparation method according to any one of claims 1 - 5, comprising a hydrogel matrix and MOFs nanoparticles filled in the network structure of the hydrogel matrix.

7. The application of the 3D printed MOFs particle network hydrogel according to claim 6 in the preparation of a hydrogel slippery meniscus substitute.

8. A preparation method of a hydrogel slippery meniscus substitute, characterized in that, Comprising the following steps: Provide a hydrogel having a meniscus shape; the hydrogel is the 3D printed MOFs particle network hydrogel according to claim 6; Mix an aqueous solution of polyvinyl alcohol and polyvinylpyrrolidone to obtain a hydrogel filler; Immerse the hydrogel having a meniscus shape in the hydrogel filler, and freeze and then thaw the immersed hydrogel in sequence to obtain the hydrogel slippery meniscus substitute.

9. The preparation method according to claim 8, characterized in that, The mass content of polyvinyl alcohol in the hydrogel filler is 10-15%, and the mass content of polyvinylpyrrolidone is 1-5%; the soaking time is 5-10 h; the freezing temperature is -20 to -15 °C, and the thawing temperature is room temperature; the freezing and thawing are carried out cyclically, with one freezing and one thawing in sequence being one operation, the total number of operations is 5-10 times, the single freezing time is 5-10 h, and the single thawing time is 5-10 h.

10. A hydrogel slippery meniscus substitute prepared by the preparation method according to claim 8 or 9.

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