Shape memory type porous ink direct-writing printing implantation intervention type miniature medical device product and preparation method of shape memory type porous ink direct-writing printing implantation intervention type miniature medical device product

Abstract

The invention provides a shape memory type porous ink direct writing printing implantation intervention type micro medical device product and a preparation method thereof, dodecanedioic acid and glycerol are stirred and reacted under a vacuum condition to prepare a PGD prepolymer, then water-soluble inorganic salt particles are added, and curing is performed to obtain a PGD ink material for printing. The preparation method comprises the following steps: carrying out 3D printing molding by utilizing ink direct writing, curing, removing water-soluble inorganic salt particles, and freeze-drying to prepare an implanted and intervened micro medical device product. According to the preparation method disclosed by the invention, an implantation intervention type micro medical device product is prepared by coupling ink direct writing printing and PGD, and the PGD-based product is endowed with porous structure characteristics and drug loading property by utilizing water-soluble inorganic salt particles for the first time based on a particle percolation method; the effective scheme of the precise adjustment strategy of the mechanical strength and the drug loading characteristic required by clinical healing is realized, and particularly, a new thought is provided for related implantable miniature medical equipment products for intervertebral disc degeneration related research.

Description

Technical Field

[0001] This invention belongs to the field of implantable and interventional medical device products and their molding and processing, and relates to a shape memory porous ink direct-write printing implantable interventional micro medical device product and its preparation method. Specifically, it relates to a method of preparing shape memory porous ink direct-write printing implantable interventional micro medical device products with drug loading capacity using poly(glycerol-dodecanoate) material, which is particularly suitable for preparing micro high-precision nucleus pulposus stents. Background Technology

[0002] The nucleus pulposus of the intervertebral disc lacks a vascular supply, making oral or intravenous administration ineffective in reaching the degenerated site. Therefore, local minimally invasive drug delivery to the intervertebral disc has become the most effective option. In recent years, hydrogel scaffolds, due to their rheological properties, are often used to carry drugs for minimally invasive injection and have been widely used in the regenerative treatment of intervertebral disc degeneration. However, while traditional hydrogels (such as alginate, chitosan, and polyethylene glycol) are easy to inject, their compressive strength is insufficient to cope with the complex physiological loads of daily activities, leading to extrusion from the incision site postoperatively. Extruded gel may diffuse or leak into the spinal canal, increasing the risk of adverse reactions and increasing the load on the annulus fibrosus, causing it to bulge inward, further inducing rupture and protrusion, severely affecting long-term treatment outcomes. Although composite hydrogels (such as dual-network hydrogels, stimulus-responsive hydrogels, and cross-linked polymer hydrogels) have significantly improved stiffness and toughness, they still present challenges such as difficulty in controlling in-situ curing time, difficulty in controlling post-curing mechanical properties, and difficulty in uniform local injection. If its strength is too high after curing, it can lead to stress shielding effect, increase the risk of endplate settlement and low back pain, and accelerate the degeneration of intervertebral discs in adjacent vertebrae.

[0003] Therefore, the successful application of nucleus pulposus stents depends on good injection performance and precise mechanical properties. To ensure mechanical properties, some researchers have proposed using biodegradable polymer materials to construct nucleus pulposus stents. Research indicates that traditional stent molding methods currently include mold forming, laser etching, and 3D printing. However, as a cutting-edge implantable medical device, polymer-based nucleus pulposus stents are currently mostly used in animal experiments, such as in rabbit and rat modeling. This presents significant challenges to the selection of materials and the precision of stent molding.

[0004] For example, in rat animal modeling, in the modeling of rat caudal intervertebral disc degeneration, based on the physiological characteristics of the flattened disc morphology of the nucleus pulposus, the shape of the nucleus pulposus scaffold used is similar to a spiral disc to ensure that it can be uniformly filled after entering the nucleus pulposus cavity; the diameter of the disc surface of this nucleus pulposus scaffold is usually <5mm, and the diameter of the filaments that make up the spiral disc shape is usually less than 0.51mm, so that it can be applied to the needle tip cavity to achieve good injection implantation.

[0005] The above requirements clearly demonstrate that this not only places stringent demands on the selection of polymer materials but also poses a significant challenge to the molding process. Traditional mold-forming processes struggle to meet the required molding precision at a low cost. Furthermore, the dimensional requirements of the nucleus pulposus scaffold vary depending on the experimental animal and the location within the mold, making traditional mold-forming processes inadequate. While laser etching and 3D printing currently offer the necessary molding precision, the selection of polymer materials remains a challenge. Summary of the Invention

[0006] To address the problems mentioned in the background art, this invention provides a shape-memory porous ink-direct-write printed implantable micro-medical device and its preparation method. The invention couples ink-direct-write printing with poly(glycerol-dodecanoate) (PGD) to prepare implantable micro-medical devices. Furthermore, based on a particle percolation method, it is the first to utilize water-soluble inorganic salt particles to impart porous structural features and drug-loading capacity to the PGD-based product. This invention provides an effective solution for the precise adjustment strategy of mechanical strength and drug loading characteristics required for clinical healing, and in particular, offers new insights for research related to intervertebral disc degeneration and related implantable micro-medical devices.

[0007] To achieve the above objectives, the present invention employs a technical solution consisting of the following technical measures.

[0008] A method for preparing shape-memory porous ink direct-write printing implantable micro-medical devices mainly includes the following steps:

[0009] (1) Under inert atmosphere, dodecanoic acid and glycerol in a molar ratio of 1:(0.9~1.2) were mixed and stirred at 110~125℃ for 24~26h. Then, under vacuum with an absolute pressure of 0.021~0.041MPa, the mixture was stirred at 110~125℃ for 24~26h to prepare PGD prepolymer.

[0010] (2) Add water-soluble inorganic salt particles with a maximum particle size ≤ 7.5 μm to the PGD prepolymer prepared in step (1), mix evenly, and then cure at 105-125℃ for 6-12 hours in a vacuum environment with an absolute pressure of 0.001-0.021 MPa to obtain PGD ink material for printing.

[0011] The amount of water-soluble inorganic salt particles added is 65-75 wt% of the total mass of PGD prepolymer and water-soluble inorganic salt particles.

[0012] (3) The PGD ink material obtained in step (2) is used for printing to form a 3D printed part by ink direct writing;

[0013] The process parameters for ink-to-ink 3D printing include: printing temperature of 105-125℃, printing speed of 15-26mm / s, and printing pressure of 2.5-4.5bar.

[0014] (4) The printed part obtained in step (3) is cured in a vacuum environment with an absolute pressure of 0.001 to 0.021 MPa at a temperature of 105 to 125°C for at least 24 hours, then water-soluble inorganic salt particles are removed by immersion in deionized water, and finally the implantable interventional micro medical device is prepared by freeze drying.

[0015] In this document, the water-soluble inorganic salt particles mentioned in step (2) are selected from inorganic salts that can dissolve in deionized water under deionized water immersion conditions. Those skilled in the art can make specific selections based on the water solubility of the inorganic salts. However, it should be noted that the selected water-soluble inorganic salt particles should be able to maintain their particle morphology under subsequent vacuum and high temperature conditions.

[0016] To better illustrate the present invention and provide a technical solution for reference, the water-soluble inorganic salt particles in step (2) are selected from any one or more of sodium chloride particles (NaCl), potassium chloride particles (KCl), and sodium sulfate particles (Na2SO4).

[0017] In this paper, step (3) involves using the PGD ink material obtained in step (2) to form a printed part through ink-direct writing 3D printing. The specific structure, shape, and specifications of the printed part depend on the structure, shape, and specifications of the desired product, such as the spiral disc-shaped nucleus pulposus scaffold to be prepared in the following embodiments. Those skilled in the art can refer to the prior art and perform modeling and printing based on ink-direct writing 3D printing technology according to specific needs.

[0018] It should be noted that, in addition to the process parameters of ink direct writing 3D printing recorded in step (3), conventional setting parameters such as nozzle diameter are also included in order to perform ink direct writing 3D printing. These conventional setting parameters can be set by those skilled in the art according to the required printing accuracy or the parameters required for conventional 3D printing.

[0019] In this paper, the specific process steps / conditions / parameters of the freeze-drying process described in step (4) can follow the conventional principles of chemical processes.

[0020] To better illustrate the present invention and provide a preferred technical solution, the freeze-drying process described in step (4) is specifically freeze-drying at a temperature of -20 to -15°C for at least 24 hours, or freeze-drying until the quality does not change significantly.

[0021] The implantable or interventional micro-medical device products provided by this invention have a porous structure, which can load drugs and release drugs within the implanted or interventional body.

[0022] In one technical solution, the implantable interventional micro medical device product prepared in step (4) is immersed in a drug mixture and then freeze-dried to obtain an implantable interventional micro medical device loaded with drugs.

[0023] Because the implantable interventional micro-medical device products prepared by this invention are based on particle percolation and utilize water-soluble inorganic salt particles to impart porous structure characteristics to PGD-based products, while limiting the maximum particle size of water-soluble inorganic salt particles (≤7.5μm), those skilled in the art can reasonably infer that the implantable interventional micro-medical device products provided by this invention are compatible with conventional in vivo release drugs currently on the market.

[0024] To better illustrate the present invention and provide a reference technical solution, when the implantable interventional micro-medical device is a nucleus pulposus scaffold for a rat caudal intervertebral disc degeneration model, the drug mixture can be prepared by mixing conventional drugs for treating intervertebral disc degeneration with deionized water, such as any one of transforming growth factor-β1 (TGF-β1), bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 7 (BMP-7 / OP-1), and insulin-like growth factor 1 (IGF-1) with deionized water; the drug concentration can be adjusted according to common knowledge, reference to existing technical literature, and according to the needs of animal experimental modeling.

[0025] The inventive point of this invention lies in the selection of poly(glycerol-dodecanoate) (PGD) as the main ink material through comparison. PGD is a semi-crystalline biodegradable shape memory polymer with excellent shape memory properties, a stable in vivo degradation rate, and an adjustable shape transition temperature.

[0026] In the rat caudal intervertebral disc degeneration model, based on the physiological characteristics of the flattened disc morphology of the rat nucleus pulposus, the permanent shape of the nucleus pulposus scaffold is designed as a spiral disc to ensure uniform filling after entering the nucleus pulposus cavity, sealing the needle inlet after deformation, and fully utilizing its mechanical properties. Therefore, the shape of the nucleus pulposus scaffold used is similar to a spiral disc to ensure uniform filling after entering the nucleus pulposus cavity; the disc diameter of this nucleus pulposus scaffold is usually <5mm, and the diameter of the filaments constituting the spiral disc shape is usually less than 0.51mm, so that it can be applied to the needle tip cavity to achieve good injection implantation.

[0027] Based on the above specific requirements, after selecting poly(glycerol-dodecanoate) as the main scaffold material, the inventors first referred to the laser etching process described in existing technical literature to prepare nucleus pulposus scaffolds. However, during the experiment, it was found that due to the self-healing properties of poly(glycerol-dodecanoate), the etched area gradually repaired and healed after a few seconds of laser etching, thus making it impossible to etch and form a nucleus pulposus scaffold. Increasing the laser power would lead to a significant decrease in its etching precision, making it unsuitable for the preparation of miniature high-precision nucleus pulposus scaffolds.

[0028] Based on the above findings, the inventors attempted to use ink-direct writing 3D printing technology to prepare nucleus pulposus scaffolds and were pleasantly surprised to find that they could successfully prepare miniature, high-precision nucleus pulposus scaffolds with clear lines and no adhesion. Furthermore, based on the printing precision of ink-direct writing 3D printing, PGD-based printed products can be applied to the needle tip cavity to achieve good injection performance.

[0029] It is worth noting that the above-mentioned inventive features of this invention are only applicable to ink-to-ink 3D printing. Other 3D printing processes are not applicable to this invention. For example, poly(glycerol-dodecanoate) needs to be acrylicized before photopolymerization 3D printing, but the technology of this invention does not have the above-mentioned defects.

[0030] Based on the above-mentioned points of invention, the inventors also investigated the effect of different curing times in step (4) on the melt crystallization enthalpy and melt crystallization temperature of the prepared implantable micro-medical device. Since poly(glycerol-dodecanoic acid ester) is a typical semi-crystalline polymer, its shape memory characteristics are caused by the formation and melting of internal crystals with temperature changes, and its melt transition temperature gradually decreases with the increase of curing time. However, based on the requirements of animal experimental modeling, the nucleus pulposus scaffold needs to be able to quickly fill and deform after entering the nucleus pulposus cavity, so its melt transition temperature should be close to the temperature inside the animal.

[0031] In one preferred embodiment, the printed part in step (4) is cured in a vacuum environment with an absolute pressure of 0.001 to 0.021 MPa at a temperature of 105 to 125°C for 48 to 72 hours.

[0032] In this document, the mixing, stirring, impregnation, etc., all follow the conventional principles of chemical processes, and those skilled in the art can perform the specific operations based on common knowledge.

[0033] The present invention has the following beneficial effects:

[0034] 1. This invention marks the first successful fabrication of poly(glycerol-dodecanoate)-based implantable micro-medical devices with shape memory function and adjustable deformation temperature using ink-direct writing 3D printing technology, particularly a miniature, high-precision nucleus pulposus stent. The fabrication process is simple, environmentally friendly, versatile, and highly designable. The raw materials are readily available and relatively inexpensive. Furthermore, the product can be temporarily shaped into a linear form, allowing for easy insertion of 21G fine needles, with the aid of a booster for minimally invasive placement.

[0035] 2. In one of the technical solutions, the product deformation temperature can be adjusted to about 37°C by selecting the curing time during preparation. When the permanent shape of the obtained product is a vortex disk, once it enters the nucleus pulposus cavity of an animal, the nucleus pulposus scaffold immediately adapts to the ambient temperature and restores the vortex disk shape, effectively sealing the injection port.

[0036] 3. Under the premise of meeting the injection performance requirements, the nucleus pulposus scaffold prepared by this invention has excellent mechanical properties, which meet the mechanical performance requirements of nucleus pulposus scaffolds in the treatment of intervertebral disc degeneration. Furthermore, as the curing time increases, the Young's modulus and ultimate tensile strength of the product increase while the ultimate strain decreases. When the curing time is 72 hours, the tensile strength can reach 2.2 MPa. At the same time, the material still has good elasticity, with a compressive elastic modulus of 1 MPa.

[0037] 4. The implantable interventional micro-medical device products prepared by the present invention are based on particle percolation method and utilize water-soluble inorganic salt particles to give the products a porous structure. Therefore, the implantable interventional micro-medical device products provided by the present invention can load conventional in vivo release drugs. Attached Figure Description

[0038] Figure 1 This is a photograph of the nucleus pulposus scaffold product prepared in Example 2 of the present invention.

[0039] Figure 2 Figure 1 shows the infrared spectra, DSC curves, and melting temperature and enthalpy comparison diagrams of the samples prepared in Examples 1-5 of this invention. Specifically, Figure A shows the infrared spectra of the samples prepared in Examples 1-5 and the raw materials used, where DDA corresponds to dodecanoic acid and Glycerol corresponds to glycerol; Figure B shows the DSC curves of the samples prepared in Examples 1-5; Figure C shows the melting temperature comparison diagram of the samples prepared in Examples 1-5; and Figure D shows the enthalpy comparison diagram of the samples prepared in Examples 1-5.

[0040] Figure 3 These are comparative bar charts of the compressive Young's modulus and tensile Young's modulus of the samples prepared in Examples 3-5 of this invention. Specifically, Figure A (left) is a photograph of the sample prepared in Example 4 during the test of its compressive Young's modulus, and the right figure is a comparative bar chart of the compressive Young's modulus of the samples prepared in Examples 3-5; Figure B (left) is a photograph of the sample prepared in Example 4 during the test of its tensile Young's modulus, and the right figure is a comparative bar chart of the tensile Young's modulus of the samples prepared in Examples 3-5.

[0041] Figure 4 Figure 1 is a summary diagram of the shape memory tests of the samples prepared in Examples 2-5 of this invention. Figure A shows the angle shape memory test and the macroscopic diagram of the shape recovery speed of the sample prepared in Example 3; Figure B shows the shape fixation rate (R) of the samples prepared in Examples 2-5. f %) and shape recovery rate (R r (%); Figure C is a bar graph comparing the shape recovery rates of the samples prepared in Examples 2-5.

[0042] Figure 5 The images shown are simulated injection test photographs and SEM images of the samples prepared in Example 4 of this invention. Figure A1 shows the sample with its shape adjusted to a straight line; Figure A2 is a photograph showing the sample returning to a vortex disk shape after being injected into water at 37°C; Figures B1 and B2 are SEM images of the samples prepared in Example 4 at different magnifications; Figures C1 and C2 are SEM images of the samples obtained in Example 6 at different magnifications.

[0043] Figure 6This is a photograph of a nucleus pulposus scaffold product prepared by laser etching in Comparative Example 1 of the present invention. Two nucleus pulposus scaffolds were etched from right to left using laser etching. As can be seen from the photograph, after the second nucleus pulposus scaffold (left arrow) was etched, the etched area of ​​the first nucleus pulposus scaffold (right arrow) to its right had been repaired and healed. Detailed Implementation

[0044] To further understand the present invention, preferred embodiments are described below with reference to examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims. Those skilled in the art can refer to the content of this document to appropriately improve the process parameters. In particular, it should be noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of the present invention. The methods and applications of the present invention have been described through preferred embodiments, and those skilled in the art can obviously make modifications or appropriate changes and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to realize and apply the technology of the present invention. Although it is believed that those skilled in the art will fully understand the following terms, the following definitions are set forth to help illustrate the subject matter disclosed in the present invention.

[0045] A method for preparing shape-memory porous ink direct-write printing implantable micro-medical devices mainly includes the following steps:

[0046] (1) Under inert atmosphere, dodecanoic acid and glycerol in a molar ratio of 1:(0.9~1.2) were mixed and stirred at 110~125℃ for 24~26h. Then, under vacuum with an absolute pressure of 0.021~0.041MPa, the mixture was stirred at 110~125℃ for 24~26h to prepare PGD prepolymer.

[0047] (2) Add water-soluble inorganic salt particles with a maximum particle size ≤ 7.5 μm to the PGD prepolymer prepared in step (1), mix evenly, and then cure at 105-125℃ for 6-12 hours in a vacuum environment with an absolute pressure of 0.001-0.021 MPa to obtain PGD ink material for printing.

[0048] The amount of water-soluble inorganic salt particles added is 65-75 wt% of the total mass of PGD prepolymer and water-soluble inorganic salt particles.

[0049] (3) The PGD ink material obtained in step (2) is used for printing to form a 3D printed part by ink direct writing;

[0050] The process parameters for ink-to-ink 3D printing include: printing temperature of 105-125℃, printing speed of 15-26mm / s, and printing pressure of 2.5-4.5bar.

[0051] (4) The printed part obtained in step (3) is cured in a vacuum environment with an absolute pressure of 0.001 to 0.021 MPa at a temperature of 105 to 125°C for at least 24 hours, then water-soluble inorganic salt particles are removed by immersion in deionized water, and finally the implantable interventional micro medical device is prepared by freeze drying.

[0052] In one embodiment, the molar ratio of dodecanoic acid to glycerol in step (1) is 1:(0.9 to 1.2), for example, 1:0.9, 1:1, 1:1.1, 1:1.2 or any range or point value therebetween; the stirring reaction is carried out at a temperature of 110 to 125°C, for example, 110°C, 115°C, 120°C, 125°C or any range or point value therebetween.

[0053] In this document, the water-soluble inorganic salt particles mentioned in step (2) are selected from inorganic salts that can dissolve in deionized water under deionized water immersion conditions. Those skilled in the art can make specific selections based on the water solubility of the inorganic salts. However, it should be noted that the selected water-soluble inorganic salt particles should be able to maintain their particle morphology under subsequent vacuum and high temperature conditions.

[0054] To better illustrate the present invention and to provide an embodiment for reference, the water-soluble inorganic salt particles in step (2) are selected from any one or more of sodium chloride particles (NaCl), potassium chloride particles (KCl), and sodium sulfate particles (Na2SO4).

[0055] In one embodiment, the curing in step (2) is carried out at a temperature of 105-125°C, for example, 105°C, 110°C, 115°C, 120°C, 125°C or any range or point value therebetween; the curing time is 6-12 hours, for example, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours or any range or point value therebetween; the amount of water-soluble inorganic salt particles added is 65-75 wt% of the total mass of PGD prepolymer and water-soluble inorganic salt particles, for example, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt% or any range or point value therebetween.

[0056] In this paper, step (3) involves using the PGD ink material obtained in step (2) to form a printed part through ink-direct writing 3D printing. The specific structure, shape, and specifications of the printed part depend on the structure, shape, and specifications of the desired product, such as the spiral disc-shaped nucleus pulposus scaffold to be prepared in the following embodiments. Those skilled in the art can refer to the prior art and perform modeling and printing based on ink-direct writing 3D printing technology according to specific needs.

[0057] It should be noted that, in addition to the process parameters of ink direct writing 3D printing recorded in step (3), conventional setting parameters such as nozzle diameter are also included in order to perform ink direct writing 3D printing. These conventional setting parameters can be set by those skilled in the art according to the required printing accuracy or the parameters required for conventional 3D printing.

[0058] In one embodiment, the printing temperature in step (3) is 105–125°C, for example, 105°C, 110°C, 115°C, 120°C, 125°C, or any range or value between them; the printing speed is 15–26 mm / s, for example, 15 mm / s, 16 mm / s, 17 mm / s, 18 mm / s, 19 mm / s, 20 mm / s, 21 mm / s, 22 mm / s, 23 mm / s, 24 mm / s, 25 mm / s, 26 mm / s, or any value between them. The printing pressure is 2.5 to 4.5 bar, for example, 2.5 bar, 2.6 bar, 2.7 bar, 2.8 bar, 2.9 bar, 3 bar, 3.1 bar, 3.2 bar, 3.3 bar, 3.4 bar, 3.5 bar, 3.6 bar, 3.7 bar, 3.8 bar, 3.9 bar, 4 bar, 4.1 bar, 4.2 bar, 4.3 bar, 4.4 bar, 4.5 bar, or any range or value between them.

[0059] In this paper, the specific process steps / conditions / parameters of the freeze-drying process described in step (4) can follow the conventional principles of chemical processes.

[0060] To better illustrate the present invention and provide a preferred embodiment, the freeze-drying process described in step (4) is specifically freeze-drying at a temperature of -20 to -15°C for at least 24 hours, or freeze-drying until the quality does not change significantly.

[0061] In one embodiment, the curing in step (4) is carried out at a temperature of 105 to 125°C, for example, 105°C, 110°C, 115°C, 120°C, 125°C or any range or point value between them.

[0062] The implantable or interventional micro-medical device products provided by this invention have a porous structure, which can load drugs and release drugs within the implanted or interventional body.

[0063] In one embodiment, the implantable interventional micro medical device product prepared in step (4) is immersed in a drug mixture and then freeze-dried to obtain an implantable interventional micro medical device loaded with drugs.

[0064] Because the implantable interventional micro-medical device products prepared by this invention are based on particle percolation and utilize water-soluble inorganic salt particles to impart porous structure characteristics to PGD-based products, while limiting the maximum particle size of water-soluble inorganic salt particles (≤7.5μm), those skilled in the art can reasonably infer that the implantable interventional micro-medical device products provided by this invention are compatible with conventional in vivo release drugs currently on the market.

[0065] To better illustrate the present invention and provide a reference embodiment, when the implantable interventional micromedical device is a nucleus pulposus scaffold for a rat caudal intervertebral disc degeneration model, the drug mixture can be prepared by mixing conventional drugs for treating intervertebral disc degeneration with deionized water, such as any one of transforming growth factor-β1 (TGF-β1), bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 7 (BMP-7 / OP-1), and insulin-like growth factor 1 (IGF-1) with deionized water; the drug concentration can be adjusted according to common knowledge, reference to existing technical literature, and the needs of animal experimental modeling.

[0066] The inventive point of this invention lies in the selection of poly(glycerol-dodecanoate) (PGD) as the main ink material through comparison. PGD is a semi-crystalline biodegradable shape memory polymer with excellent shape memory properties, a stable in vivo degradation rate, and an adjustable shape transition temperature.

[0067] In the rat caudal intervertebral disc degeneration model, based on the physiological characteristics of the flattened disc morphology of the rat nucleus pulposus, the permanent shape of the nucleus pulposus scaffold is designed as a spiral disc to ensure uniform filling after entering the nucleus pulposus cavity, sealing the needle inlet after deformation, and fully utilizing its mechanical properties. Therefore, the shape of the nucleus pulposus scaffold used is similar to a spiral disc to ensure uniform filling after entering the nucleus pulposus cavity; the disc diameter of this nucleus pulposus scaffold is usually <5mm, and the diameter of the filaments constituting the spiral disc shape is usually less than 0.51mm, so that it can be applied to the needle tip cavity to achieve good injection implantation.

[0068] Based on the above specific requirements, after selecting poly(glycerol-dodecanoate) as the main scaffold material, the inventors first referred to the laser etching process described in existing technical literature to prepare nucleus pulposus scaffolds. However, during the experiment, it was found that due to the self-healing properties of poly(glycerol-dodecanoate), the etched area gradually repaired and healed after a few seconds of laser etching, thus making it impossible to etch and form a nucleus pulposus scaffold. Increasing the laser power would lead to a significant decrease in its etching precision, making it unsuitable for the preparation of miniature high-precision nucleus pulposus scaffolds.

[0069] Based on the above findings, the inventors attempted to use ink-direct writing 3D printing technology to prepare nucleus pulposus scaffolds and were pleasantly surprised to find that they could successfully prepare miniature, high-precision nucleus pulposus scaffolds with clear lines and no adhesion. Furthermore, based on the printing precision of ink-direct writing 3D printing, PGD-based printed products can be applied to the needle tip cavity to achieve good injection performance.

[0070] It is worth noting that the above-mentioned inventive features of this invention are only applicable to ink-to-ink 3D printing. Other 3D printing processes are not applicable to this invention. For example, poly(glycerol-dodecanoate) needs to be acrylicized before photopolymerization 3D printing, but the technology of this invention does not have the above-mentioned defects.

[0071] Based on the above-mentioned points of invention, the inventors also investigated the effect of different curing times in step (4) on the melt crystallization enthalpy and melt crystallization temperature of the prepared implantable micro-medical device. Since poly(glycerol-dodecanoic acid ester) is a typical semi-crystalline polymer, its shape memory characteristics are caused by the formation and melting of internal crystals with temperature changes, and its melt transition temperature gradually decreases with the increase of curing time. However, based on the requirements of animal experimental modeling, the nucleus pulposus scaffold needs to be able to quickly fill and deform after entering the nucleus pulposus cavity, so its melt transition temperature should be close to the temperature inside the animal.

[0072] In one preferred embodiment, the printed part in step (4) is cured in a vacuum environment with an absolute pressure of 0.001 to 0.021 MPa at a temperature of 105 to 125°C for 48 to 72 hours.

[0073] In this document, the mixing, stirring, impregnation, etc., all follow the conventional principles of chemical processes, and those skilled in the art can perform the specific operations based on common knowledge.

[0074] The present application will be further explained in detail below with reference to embodiments. However, those skilled in the art should understand that these embodiments are provided for illustrative purposes only and are not intended to limit the present application.

[0075] Example

[0076] The embodiments of this application will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be construed as limiting the scope of this application. Where specific conditions are not specified in the examples, conventional conditions or conditions recommended by the manufacturer shall apply. Where the manufacturers of reagents or instruments are not specified, they are all commercially available conventional products. This application should not be construed as being limited to the specific embodiments described.

[0077] 1. Raw materials

[0078] Dodecanoic acid (99% (HPLC), RG) was provided by Shanghai Titan Technology Co., Ltd. (China).

[0079] Glycerol (AR) was provided by Chengdu Jixin Technology Co., Ltd. (China).

[0080] Sodium chloride (NaCl, GR, ≥99.8%) was provided by Shanghai Aladdin Biochemical Technology Co., Ltd. (China).

[0081] Transforming growth factor-β1 (TGF-β1, 96T) was provided by Beijing Myruida Technology Co., Ltd. (China).

[0082] 2. Preparation method

[0083] (1) Under nitrogen atmosphere, dodecanoic acid and glycerol with a molar ratio of 1:1 were mixed and stirred at a stirring rate of 200 r / min. The mixture was stirred and reacted at 120℃ for 24 h, and then stirred and reacted at 120℃ for 24 h in a vacuum environment with an absolute pressure of 0.021~0.041 MPa to obtain PGD prepolymer.

[0084] (2) Add sodium chloride particles with a maximum particle size ≤ 7.5 μm after sieving to the PGD prepolymer prepared in step (1), mix evenly, and then cure at 120°C for 6 hours in a vacuum environment with an absolute pressure of 0.001~0.021MPa to prepare PGD ink material for printing.

[0085] The amount of sodium chloride particles added is 65 wt% of the total mass of the PGD prepolymer and sodium chloride particles;

[0086] (3) The PGD ink material obtained in step (2) is used for printing to form a vortex disk-shaped nucleus pulposus scaffold printed part by ink direct writing 3D printing.

[0087] The ink direct writing 3D printer used is a Developer Series model. The process parameters for ink direct writing 3D printing include: printing temperature of 120℃, printing speed of 20mm / s, printing pressure of 4bar, and nozzle diameter of 0.4mm.

[0088] (4) The printed part of the nucleus pulposus scaffold obtained in step (3) is cured at 120°C for at least 24 hours in a vacuum environment with an absolute pressure of 0.001 to 0.021 MPa. Then it is soaked in deionized water for 5 days, and the water is changed every 12 hours to remove sodium chloride particles. Finally, the nucleus pulposus scaffold product is prepared by freeze drying.

[0089] Example 1

[0090] Example 1 is a sample prepared by referring to the steps of "2. Preparation method" above. The nuclear scaffold product is used as a sample. In step (4), the nuclear scaffold printed part is cured at 120°C for 24 hours in a vacuum environment with an absolute pressure of 0.001 to 0.021 MPa. The sample is recorded as PGD-24.

[0091] Example 2

[0092] Example 2 is a sample prepared by referring to the steps of "2. Preparation method" above. The nuclear scaffold product is used as a sample. In step (4), the nuclear scaffold printed part is cured at 120°C for 48 hours in a vacuum environment with an absolute pressure of 0.001 to 0.021 MPa. The sample is recorded as PGD-48.

[0093] Example 3

[0094] Example 3 is a sample prepared by referring to the steps of "2. Preparation method" above. The nuclear scaffold product is used as a sample. In step (4), the nuclear scaffold printed part is cured at 120°C for 72 hours in a vacuum environment with an absolute pressure of 0.001 to 0.021 MPa. The sample is recorded as PGD-72.

[0095] Example 4

[0096] Example 4 is a sample prepared by referring to the steps of "2. Preparation method" above. The nuclear scaffold product is used as a sample. In step (4), the nuclear scaffold printed part is cured at 120°C for 96 hours in a vacuum environment with an absolute pressure of 0.001 to 0.021 MPa. The sample is recorded as PGD-96.

[0097] Example 5

[0098] Example 5 is a sample prepared by referring to the steps of "2. Preparation method" above. The nuclear scaffold product is used as a sample. In step (4), the nuclear scaffold printed part is cured at 120°C for 120h in a vacuum environment with an absolute pressure of 0.001 to 0.021 MPa. The sample is recorded as PGD-120.

[0099] Example 6

[0100] Example 6 is a sample of a nucleus pulposus scaffold product prepared in Example 4. The product was immersed in a 90 wt% aqueous solution of transforming growth factor-β1 for 6 hours. After the time was up, it was freeze-dried to obtain a nucleus pulposus scaffold product loaded with transforming growth factor-β1.

[0101] Comparative Example 1

[0102] Comparative Example 1 describes the fabrication of a nucleus pulposus scaffold using laser etching, which mainly includes the following steps:

[0103] (1) Under nitrogen atmosphere, dodecanoic acid and glycerol with a molar ratio of 1:1 were mixed and stirred at a stirring rate of 200 r / min. The mixture was stirred and reacted at 120℃ for 24 h, and then stirred and reacted at 120℃ for 24 h in a vacuum environment with an absolute pressure of 0.021~0.041 MPa to obtain PGD prepolymer.

[0104] (2) Add sodium chloride particles with a maximum particle size ≤ 7.5 μm after sieving to the PGD prepolymer prepared in step (1), mix evenly, and then cure at 120°C for 6 hours in a vacuum environment with an absolute pressure of 0.001~0.021MPa to prepare PGD ink material for printing.

[0105] The amount of sodium chloride particles added is 65 wt% of the total mass of the PGD prepolymer and sodium chloride particles;

[0106] (3) The PGD ink material obtained in step (2) is added to a mold with an inner diameter of 60 mm and a thickness of 1 mm. It is cured at 120°C for 72 h in a vacuum environment with an absolute pressure of 0.001 to 0.021 MPa. Then it is soaked in deionized water for 5 days, and the water is changed every 12 hours to remove sodium chloride particles. Finally, the film sample is prepared by freeze drying.

[0107] (4) The thin film sample obtained in step (3) was etched and shaped using an AOFemtoMDM-4 femtosecond laser cutter to prepare a nucleus pulposus scaffold. The laser power was set to 0.8W. The results are as follows: Figure 6 As shown, the etched area heals quickly, making it impossible to prepare a nucleus pulposus scaffold.

[0108] 3. Testing Methods

[0109] The chemical composition of the thin film sample (prepared according to steps (1) to (3) of Comparative Example 1, with a thickness of 1 mm) was analyzed using the ATR mode of a Fourier transform infrared spectrometer (FT-IR, Nicolet 50, Madison Wisconsin, USA). The scanning wavelength range was set to 4000–400 cm⁻¹. -1 And scanned 32 times.

[0110] Differential scanning calorimetry (DSC,TA) (Q250, New Castle, DE, USA) Thermodynamic properties of samples under different curing times were tested. 3–5 mg of sample was sealed in an aluminum crucible and placed in the instrument. The sample was heated from 10 °C to 70 °C at a rate of 10 °C / min under a nitrogen atmosphere, and held for 1 minute to eliminate thermal history effects. A temperature scan program was then used to lower the temperature from 70 °C to -10 °C at a rate of 10 °C / min, and then raise it back to 70 °C at a rate of 10 °C / min.

[0111] The morphology and microstructure of the samples were observed using a field emission scanning electron microscope (SEM, JSM-5900LV, Tokyo, Japan). The prepared samples were first dried in a vacuum oven at 60℃ for 24 h at an absolute pressure of 0.001 MPa. Before scanning, the samples were sputtered with gold for 90 s, and the scanning acceleration voltage was 10 kV.

[0112] The compression and tensile properties of the samples were tested using an Instron 5967 electronic universal tensile testing machine. The samples were first equilibrated in the chamber for 30 minutes at 37°C. According to ASTM D638, the tensile Young's modulus of the samples at different curing times was determined. The tensile samples were dumbbell-shaped specimens (35×6×1 mm), stretched at 5 mm / min until fracture at 37°C. According to ASTM D395, the compressive Young's modulus of the samples at different curing times was determined. The compressive sample had a diameter of 13 mm and a height of 6 mm, compressed to 25% of its original height at 0.1 mm / min at 37°C.

[0113] The shape retention and recovery ability of the samples were determined using the bending-unfolding method. A rectangular sample (30×5×2mm) was immersed in a 40℃ water bath for 3 minutes, then placed in a mold to fix it, and finally placed on the upper shelf of a refrigerator (6℃) for approximately 3 minutes to cool and set. The angles on both sides of the sample were recorded as θ. max The value is determined by removing the sample and measuring the angle again, which is then recorded as θ. fix Value. Immerse the sample in a 37℃ water bath to observe its unfolding process and recovery time, and record the final angle as θ. iThe shape fixation rate (R) of the sample is calculated using the following formula. f ) and shape recovery rate (R r ):

[0114] R f =θ fix / θ max R r =(θ max -θ i ) / θ max

[0115] In the in vivo experiment, SD rats with intervertebral disc degeneration were used as the research subjects. The caudal intervertebral disc of the SD rats was exposed and a 21G needle was used to puncture and create a model. After modeling, the nucleus pulposus scaffold was placed in the 21G needle and the scaffold was slowly pushed into the intervertebral disc using a No. 6 suture needle core. After the operation, each layer was sutured.

[0116] 4. Test Results

[0117] Figure 1 This is a photograph of the nucleus pulposus scaffold prepared according to Example 2 of the present invention. As can be seen from the ruler below, the nucleus pulposus scaffold is shaped like a spiral disk, with a disk diameter of <5mm.

[0118] Combination Figure 2 As shown in Table 1, poly(glycerol-dodecanoic acid ester) (PGD) is a typical semi-crystalline polymer successfully obtained by esterification polycondensation of glycerol and dodecanoic acid. Its shape memory properties are caused by the formation and melting of internal crystals that change with temperature. The melt transition temperature of PGD is 30-41℃, and it gradually decreases with the increase of curing time.

[0119] Table 1. Melting enthalpy and melting temperature of samples with different curing times.

[0120]

[0121] like Figure 3 As shown, with the extension of curing time, the ultimate compressive strength, tensile strength and Young's modulus of PGD increase, while the ultimate strain decreases. When the curing time is 72h (sample of Example 3), the tensile strength can reach 2.2MPa. At the same time, the material still has good elasticity, with a compressive elastic modulus of 1MPa.

[0122] Figure 4 This indicates that, in shape memory testing, PGD samples with a curing time exceeding 72 hours exhibit better shape recovery rates, with both shape fixation and recovery rates exceeding 98%.

[0123] Figure 5The nucleus pulposus scaffold prepared in Example 4 is shown to have an adjustable linear shape and can accommodate 21G fine needles. After injection into water at 37°C, the scaffold recovers its vortex disk shape. SEM results after perforation treatment using a particle permeation method show the pore size, shape, and distribution, meeting drug loading requirements. Figures C1 and C2 demonstrate successful loading of transforming growth factor-β1.

[0124] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A method for the production of a shape memory porous ink direct writing printed implantable interventional micro medical device article, characterized by The method comprises the following steps: (1) mixing dodecanedioic acid and glycerol in a molar ratio of 1:(0.9-1.2) under an inert atmosphere, stirring and reacting at a temperature of 110-125°C for 24-26 hours, and then stirring and reacting at a temperature of 110-125°C under a vacuum environment with an absolute pressure of 0.021-0.041 MPa for 24-26 hours to prepare a PGD prepolymer; (2) adding water-soluble inorganic salt particles with a maximum particle size of ≤7.5 μm to the PGD prepolymer prepared in step (1), uniformly mixing, and then curing at a temperature of 105-125°C under a vacuum environment with an absolute pressure of 0.001-0.021 MPa for 6-12 hours to prepare a PGD ink material for printing; wherein the amount of the water-soluble inorganic salt particles added is 65-75 wt% of the total mass of the PGD prepolymer and the water-soluble inorganic salt particles; (3) forming a printing part by ink direct writing 3D printing of the PGD ink material for printing obtained in step (2); wherein the process parameters of the ink direct writing 3D printing include a printing temperature of 105-125°C, a printing speed of 15-26 mm / s, and a printing pressure of 2.5-4.5 bar; (4) curing the printing part obtained in step (3) at a temperature of 105-125°C under a vacuum environment with an absolute pressure of 0.001-0.021 MPa for at least 24 hours, removing the water-soluble inorganic salt particles by immersion in deionized water, and finally preparing an implant interventional micro medical device product by freeze-drying treatment.

2. The method of claim 1, wherein: The water-soluble inorganic salt particles in step (2) are selected from any one or more of sodium chloride particles, potassium chloride particles, and sodium sulfate particles.

3. The method of claim 1, wherein: The freeze-drying treatment in step (4) is specifically freeze-drying at a temperature of -20 to -15°C for at least 24 hours or until the mass does not change significantly.

4. The method of claim 1, wherein: The printing part in step (4) is cured at a temperature of 105-125°C under a vacuum environment with an absolute pressure of 0.001-0.021 MPa for 48-72 hours.

5. The implant interventional micro medical device product obtained by the method of claim 1.

6. An implantable drug-loaded interventional micro-device article of manufacture, characterized by The implant interventional micro medical device product of claim 5 is immersed in a drug mixture, and then freeze-dried to obtain a drug-loaded implant interventional micro medical device.

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