Composite PLA / PEG / Mg / Cu antibacterial and anti-tumor bone scaffold with double-trigger shape memory function and fused deposition modeling (FDM) preparation method of composite PLA / PEG / Mg / Cu antibacterial and anti-tumor bone scaffold

Abstract

The invention discloses a light-driven / temperature-driven double-trigger shape memory antibacterial and anti-tumor bone scaffold and a fused deposition modeling (FDM) preparation method thereof, and is characterized in that polylactic acid (PLA) is used as a matrix, and polyethylene glycol (PEG) and nano magnesium hydroxide (Mg (OH) 2) / copper oxide (CuO) are uniformly dispersed through an organic solvent blending method; a composite wire is prepared through the processes of drying and film forming, crushing and granulation and screw extrusion, and finally, the integrated molding of the three-dimensional porous scaffold is realized through an FDM (fused deposition modeling) process. According to the stent, temperature and near-infrared light double-triggered shape memory is achieved through cooperation of glass transition regulation and control of PLA-PEG and the photothermal effect of the nano metal oxide particles. Nano Mg (OH) 2 / CuO endows the scaffold with multi-mode antibacterial and anti-tumor functions: 1) Mg < 2 + > / Cu < 2 + > releases and destroys microbial membrane potential; according to the stent, the limitation of shape fixation of a traditional implant is broken through, shape self-adaption can be triggered through light / heat stimulation, irregular bone defects can be accurately attached, the risk of a secondary operation is avoided, and the stent has remarkable advantages in minimally invasive orthopedic repair.

Description

Technical Field

[0001] The present invention relates to an antibacterial and antitumor polymer bone scaffold with shape memory function and a preparation method and application thereof. In particular, a double-trigger shape memory composite PLA / PEG / Mg / Cu antibacterial and antitumor bone scaffold and a fused deposition molding (FDM) preparation method thereof are designed, belonging to the field of additive manufacturing of shape memory bone scaffolds. Background Art

[0002] With the increasing number of bone defect cases caused by trauma, tumors and degenerative diseases, the demand for bone repair materials has grown rapidly. Developing artificial bone scaffolds to treat bone defects is an emerging method with broad prospects. Polylactic acid (PLA), as a degradable polymer, is regarded as a tissue engineering material with great potential due to its good biocompatibility. However, the large-scale promotion of PLA in clinical applications faces multiple bottlenecks: on the one hand, PLA has low bone integration efficiency and lacks anti-tumor and antibacterial functions. On the other hand, complex bone defect morphology (such as irregular curved surfaces or narrow wound surfaces and deep wound interiors) requires the implanted scaffold to have topological adaptability. Traditional rigid implants may lead to poor fit during surgery. Although shape memory technology can improve fit through programmed deformation, the glass transition temperature (Tg) of PLA-based materials is high, and direct use for shape memory function will cause thermal damage to human tissues. In addition, there are also deficiencies in the design and preparation process of the porous structure of bone scaffolds in traditional technologies, making it difficult to achieve precise control and personalized customization, which to a certain extent limits the application prospects of PLA bone scaffolds in the repair of complex bone defects.

[0003] The present invention aims to provide a polymer bone scaffold with shape memory, anti-tumor and antibacterial functions and a preparation method thereof, by combining polyethylene glycol (PEG) and nano magnesium hydroxide (Mg(OH) 2 ) / copper oxide (CuO) synergistically optimizes the performance of polylactic acid (PLA)-based scaffolds. PEG as a plasticizer significantly reduces the glass transition temperature (Tg) of PLA, regulating it from the initial high value to a range close to the human body temperature, so that the bone scaffold can spontaneously recover from the programmed temporary shape to the preset initial shape under body temperature conditions, achieving morphological adaptive fit after minimally invasive implantation, while avoiding local tissue thermal damage that may be caused by traditional thermal drive. Nano-Mg(OH) 2 The introduction of CuO endows the scaffold with multimodal bioactivity: the Mg released by degradation under physiological conditions 2+ / Cu 2+ It can destroy the membrane potential of microorganisms and inhibit the proliferation of bacteria (including drug-resistant bacteria) in a broad spectrum; Mg(OH) 2The alkaline microenvironment formed by degradation inhibits biofilm formation and blocks bacterial adhesion; CuO, with its high photothermal conversion efficiency, quickly heats up under near-infrared light, which not only drives the scaffold to accurately adapt to irregular bone defects, but also induces apoptosis of bacteria and tumor cells through thermal effects. In addition, Mg(OH) 2 By promoting biomineralization and enhancing cell responsiveness, the biocompatibility and bone regeneration ability of the scaffold are synergistically improved. This technology further adopts the fused deposition modeling (FDM) process, combined with the customized development of PLA-PEG-nanoparticle composite wires, to achieve high-precision integrated molding of porous scaffolds, breaking through the limitations of traditional PLA scaffolds such as high rigidity, single function, and poor adaptability, and providing an intelligent solution for complex bone defect repair that combines mechanical adaptability, dynamic deformation ability, and long-term antibacterial and anti-tumor functions. Summary of the invention

[0004] In order to overcome the shortcomings of the prior art, the first object of the present invention is to provide a composite PLA / PEG / Mg / Cu bone scaffold, which not only has excellent body temperature-triggered and light-triggered shape memory functions, and significant near-infrared photothermal response capabilities, but also exhibits excellent antibacterial and anti-tumor properties.

[0005] The second object of the present invention is to provide a FDM 3D printing technology for a composite PLA / PEG / Mg / Cu bone scaffold, which can not only accurately control the internal porous structure and external shape of the bone scaffold, but also achieve personalized customization. By optimizing printing parameters such as nozzle temperature, printing speed and layer thickness, the molding quality and mechanical properties of the bone scaffold are ensured.

[0006] In order to achieve the above objectives, the present invention provides a scheme for constructing a composite PLA / PEG / Mg / Cu antibacterial and anti-tumor bone scaffold with dual-trigger shape memory function by using FDM 3D printing technology. 2 , CuO was dispersed in an organic solvent and mixed evenly, dried at room temperature to form a film, crushed and granulated, and screw extruded to prepare a composite filament, and finally the composite porous scaffold was prepared using FDM printing technology. Mg(OH) 2 The introduction of CuO and PEG improves the bioactivity, antibacterial properties and temperature / light responsive shape memory effect of the composite scaffold. The FDM technology can realize the personalized design of the scaffold according to the specific characteristics of the patient's bone defect and accurately control the pore size and external morphology.

[0007] The key to the technology of the present invention is to prepare the composite PLA / PEG / Mg / Cu bone scaffold. First, PLA, PEG, Mg(OH) 2, CuO are uniformly mixed, granulated and extruded into composite wires after film formation, and then the composite porous bone scaffold is prepared by FDM 3D printing technology. The present invention believes that Mg(OH) 2 It can promote osteoblast proliferation and adhesion; CuO achieves synergistic antibacterial and antitumor functions and light-driven shape memory effects through near-infrared photothermal effects. 2+ Ionic and physical contact can also have antibacterial and anti-tumor effects. In addition, PEG is introduced to regulate the glass transition temperature (Tg) of the composite bone scaffold to 37°C~55°C through molecular chain plasticization, giving the human body temperature triggered shape memory function. The synergistic effect of PEG and CuO gives the bone scaffold photothermal-body temperature dual-triggered shape memory capabilities. Finally, FDM technology generates a porous composite scaffold in one step. The porous structure of the bone scaffold promotes the transport of nutrients and the growth of blood vessels. The FDM process achieves one-time molding of complex pore structures, supporting the clinical needs of personalized bone defect repair.

[0008] As a preferred embodiment, the nano Mg(OH) 2 The content of is 2.5%~20% (weight percentage), the content of nano-CuO is 0.1%~5% (weight percentage), and the content of PEG is 5%~15% (weight percentage).

[0009] As a preferred embodiment, the nano Mg(OH) 2 The particle size is about 50~500 nm, and the purity is >99%; the particle size of nano CuO is about 50~500 nm, and the purity is >99%.

[0010] As a preferred embodiment, the organic solvents used in the present invention are dichloromethane and ethanol.

[0011] As a preferred embodiment, the uniform dispersion method of the present invention is ultrasonic dispersion, the ultrasonic dispersion time is 10-60 min, and the ultrasonic temperature is 30-38°C.

[0012] As a preferred embodiment, the mixing method used in the present invention is magnetic stirring, the magnetic stirring time is 1 to 1.5 hours, and the magnetic stirring temperature is 32 to 40°C.

[0013] As a preferred embodiment, the composite wire material prepared in the present invention is extruded by a single screw extruder, the screw speed is 25-45 rpm, the temperature of the plasticizing section is 165-180°C, and the temperature of the extrusion section is 165-180°C.

[0014] As a preferred solution, the FDM 3D printing parameters set in the present invention are: nozzle temperature is 170~200℃, 50~60℃, printing speed is 20~40mm / s, and layer thickness is 0.1~0.3mm.

[0015] The present invention also provides a PLA / PEG / Mg / Cu antibacterial and antitumor polymer bone scaffold with dual-trigger shape memory function, which is obtained by the above preparation method. The bone scaffold has good light / temperature driven shape memory ability, and has certain antibacterial and antitumor ability and mechanical support performance.

[0016] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention adopts the FDM 3D printing process, which can realize the integrated molding of porous structure bone scaffolds, has fast molding speed, simple process operation and can be personalized designed, thus broadening the application prospects of bone scaffolds.

[0017] (2) The composite bone scaffold prepared by the present invention has a shape memory function triggered by body temperature / photothermal dual triggering. PEG plasticization reduces the glass transition temperature of the composite bone scaffold to 37-55°C. Nano-CuO imparts near-infrared photothermal responsiveness, and the temperature rises to about 37°C within 60 seconds under external light. The body temperature / photothermal dual triggering mechanism effectively responds to bone defects with limited external incisions and large internal defect ranges, thereby achieving precise shape control.

[0018] (3) The composite bone scaffold prepared by the present invention has multimodal dual-ion synergistic antibacterial and anti-tumor-osteogenic functions. Nano-Mg(OH) 2 and nano-CuO to slowly release Mg 2+ / Cu 2+ It can play an antibacterial and anti-tumor role without the risk of antibiotic resistance. 2 Release of Mg 2+ , significantly enhancing osteoblast activity and effectively promoting bone integration. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Surface morphology of the brackets of comparative example 1, embodiment 1, embodiment 2 and embodiment 3.

[0020] Figure 2 The water contact angle diagrams of the samples of Comparative Example 1, Example 1, Example 2, and Example 3 are shown.

[0021] Figure 3 It is a diagram of the hydrothermal shape memory fixation and recovery process of the samples of Comparative Example 1 and Examples 1, 2, and 3.

[0022] Figure 4 Infrared imaging of Comparative Example 1 and Example 2 under near-infrared laser.

[0023] Figure 5 (a1-a5) is a diagram of the shape memory recovery of the sample in Example 2 within 1 minute of near-infrared laser irradiation. DETAILED DESCRIPTION

[0024] The present invention will be further described below in conjunction with the accompanying drawings and examples. It should be noted that the embodiments and comparative examples described below are all part of the present invention, but not all. Unless otherwise defined, the techniques used in all the following embodiments belong to the same meanings as those generally understood by those skilled in the art to which the present invention belongs. The experimental reagents used in the following examples, unless otherwise specified, are conventional reagents. The experimental methods, unless otherwise specified, are conventional experimental methods.

[0025] The surface morphology characterization process of the implementation of the present invention and the comparative example is as follows: using a digital camera to observe the macroscopic morphology of the bracket; using an industrial microscope to observe the surface morphology of the upper surface of the bracket.

[0026] The water contact angle test process of the present invention and the comparative example is as follows: the water contact angle of the sample is measured using a contact angle meter, the water drop size used is 5 μL, and the contact angle is measured using the software provided by the machine 10 s after the water drop is dropped onto the sample surface.

[0027] The hydrothermal shape memory fixation and recovery test process of the present invention and the comparative example is as follows: a hydrothermal environment is used to simulate the shape memory recovery environment in the human body. The 3D printed long strip sample is kept in hot water 5°C higher than the glass transition temperature for 5 minutes, then bent into a "U" shape as an intermediate shape, taken out of the hot water and the sample is quickly cooled to room temperature before unloading the external force. When the sample shape no longer changes as a temporary shape, the fixed spline is put into hot water higher than the glass transition temperature again, and the change process of the spline is recorded. If the spline does not change within 1 minute, the recording is stopped.

[0028] The photothermal shape memory test process of the present invention and the comparative example is as follows: first, the 3D printed long strip sample is folded in a hot water bath above the glass transition temperature of the material, and then fixed at room temperature. Finally, at room temperature and dry environment, an 808 nm near-infrared laser (0.38 W / mm 2 ) The emitter illuminates the curved part of the 3D printed long strip sample after folding and fixing, and observes the shape memory recovery of the long strip sample within 1 minute.

[0029] The photothermal performance test process of the implementation of the present invention and the comparative example is as follows: a circular porous bracket sample with a diameter of 10 mm is placed in a 24-well plate filled with deionized water to simulate the wet environment in vivo; a near-infrared laser with a wavelength of 808 nm is used to irradiate the bracket sample; while the laser is irradiated, an infrared thermal imager is used to dynamically monitor the temperature change of the bracket sample in real time. Example 1

[0030] 1) Place PLA in a beaker filled with dichloromethane, and then place the beaker in a magnetic stirrer at 40°C for stirring until the PLA particles are completely dissolved, then continue to add 5% by mass PEG and stir evenly. At the same time, add 5% by mass Mg(OH) 2 The powder (purity>99%) and 1% CuO (purity>99%) powder were placed in a beaker filled with ethanol, and then the beaker was placed in an ultrasonicator for 20 minutes at room temperature to promote powder dispersion. The dispersed mixed powder solution was poured into a beaker containing a PLA / PEG dichloromethane mixed solution and magnetically stirred to promote further uniform mixing and dispersion for 1 hour. The stirred solution was poured into a tray and dried at room temperature for 12 hours to evaporate the solvent and form a composite film.

[0031] 2) The composite film was then cut into pieces and granulated, and placed in a beaker and placed in an electric blower drying oven for 12 hours to remove excess moisture and dichloromethane. After drying, the granular composite material was poured into the trough of a single-screw extruder and melt-extruded (screw speed 40 rpm, plasticizing section temperature 170 ° C, extrusion section temperature 165 ° C) to obtain PLA-Mg(OH) with different contents. 2 -CuO / 5PEG composite wire.

[0032] 3) Finally, the drawn filament is printed with an FDM printing device. The designed model is saved in STL format, then imported into the slicing software Cura for slicing and saved as Gcode code. The code is imported into the printer and printed according to the designed printing method (nozzle temperature is 170~200℃, 50~60℃, printing speed is 20~40mm / s, layer thickness is 0.1~0.3mm), and the prepared PLA-Mg(OH) 2 -CuO / 5PEG 3D porous composite scaffold.

[0033] Through surface morphology observation, it was found that the support rods of Example 1 were well overlapped and the layers were tightly bonded, which reflects the feasibility and precision of FDM printing bone scaffolds.

[0034] The water contact angle test showed that the incorporation of PEG in Example 1 can effectively reduce the water contact angle of the composite scaffold and increase the hydrophilicity of the composite scaffold. This allows PEG to contain oxygen atoms with strong negative polarity, and the negatively charged part of oxygen forms hydrogen bonds with the hydrogen part of polar water molecules, significantly improving the hydrophilicity.

[0035] Through hydrothermal shape memory fixation and recovery experiments, it was found that adding 5% PEG can effectively improve the recovery rate of the composite scaffold at human body temperature. When PLA and PEG are mixed, the flexible segments in the PEG molecular chain combine with the PLA molecular chain, enhancing the flexibility of the molecular chain of the PLA matrix. Compared with PLA without PEG, the molecular chain is more flexible. The PLA-PEG structure can be transformed into a glassy state at a lower temperature, enabling it to achieve shape memory fixation and recovery at a temperature close to that of the human body.

[0036] The antibacterial experiment found that Example 1 can improve the antibacterial rate against Staphylococcus aureus and Escherichia coli. Example 2

[0037] 1) The only difference between this embodiment and embodiment 1 is that PEG with a mass fraction of 10% is added, and the other conditions are the same.

[0038] Through surface morphology observation, it was found that the support rods in Example 2 were well overlapped and the layers were tightly bonded, which reflects the feasibility and precision of FDM printing bone scaffolds.

[0039] The water contact angle test showed that the incorporation of PEG in Example 2 can effectively reduce the water contact angle of the composite scaffold and increase the hydrophilicity of the composite scaffold. This allows PEG to contain oxygen atoms with strong negative polarity, and the negatively charged part of oxygen forms hydrogen bonds with the hydrogen part of polar water molecules, significantly improving the hydrophilicity.

[0040] Through hydrothermal shape memory fixation and recovery experiments, it was found that adding 10% PEG can effectively improve the recovery rate of the composite scaffold at around human body temperature.

[0041] When PLA and PEG are mixed, the flexible segments in the PEG molecular chain combine with the PLA molecular chain, enhancing the flexibility of the molecular chain of the PLA matrix. Compared with PLA without PEG, the molecular chain is more flexible. The PLA-PEG structure can be transformed into a glassy state at a lower temperature, enabling it to achieve shape memory fixation and recovery at a temperature close to that of the human body.

[0042] The photothermal shape memory experiment found that Example 2 began to recover its shape after 15 seconds of illumination. This result shows that after PEG effectively lowered the glass transition temperature of the composite material and CuO gave the composite scaffold photothermal response performance, Example 2 can achieve non-contact driving of the shape memory function through the photothermal conversion effect.

[0043] The photothermal performance experiment found that after 1 minute of laser irradiation, the temperature of Example 2 quickly rose to 46.1° C., and finally slowly balanced at 48.63° C. This result shows that Example 2 has good photothermal response performance.

[0044] The antibacterial experiment showed that Example 2 could improve the antibacterial rate against Staphylococcus aureus and Escherichia coli. Example 3

[0045] 1) The only difference between this embodiment and embodiment 1 is that PEG with a mass fraction of 15% is added, and the other conditions are the same.

[0046] Through surface morphology observation, it was found that the support rods in Example 3 were well overlapped and the layers were tightly bonded, which reflects the feasibility and precision of FDM printing bone scaffolds.

[0047] The water contact angle test showed that the incorporation of PEG in Example 3 can effectively reduce the water contact angle of the composite scaffold and increase the hydrophilicity of the composite scaffold. This allows PEG to contain oxygen atoms with strong negative polarity, and the negatively charged part of oxygen forms hydrogen bonds with the hydrogen part of polar water molecules, significantly improving the hydrophilicity.

[0048] Through hydrothermal shape memory fixation and recovery experiments, it was found that adding 15% PEG can effectively improve the shape memory recovery rate around human body temperature. When PLA and PEG are mixed, the flexible segments in the PEG molecular chain combine with the PLA molecular chain, enhancing the flexibility of the molecular chain of the PLA matrix. Compared with PLA without PEG, the molecular chain is more flexible. The PLA-PEG structure can be transformed into a glassy state at a lower temperature, enabling it to achieve shape memory fixation and recovery at a temperature close to that of the human body.

[0049] The antibacterial experiment showed that Example 3 could improve the antibacterial rate against Staphylococcus aureus and Escherichia coli. Comparative Example 1

[0050] 1) The difference between this embodiment and embodiment 1 is that PEG is not added, and nano-Mg(OH) 2 , nano-CuO particles, and the rest are consistent.

[0051] After surface morphology observation, it was found that the rods of comparative example 1 were well overlapped and the layers were tightly bonded, which reflects the feasibility and precision of FDM printing bone scaffolds.

[0052] The water contact angle test found that the water contact angle of Comparative Example 1 was larger, which indicates that it has poorer hydrophilicity than Comparative Example 1.

[0053] The hydrothermal shape memory fixation and recovery experiments showed that the shape memory recovery rate of Comparative Example 1 was poor.

[0054] The light-thermal performance experiment found that the light-thermal performance of comparative example 1 was poor.

[0055] The antibacterial experiment showed that the comparative example 1 had poor inhibition on Staphylococcus aureus and Escherichia coli.

Claims

1. A composite PLA / PEG / Mg / Cu antibacterial and anti-tumor bone scaffold with dual-trigger shape memory function, characterized in that: The bone scaffold is made of a composite material of polylactic acid (PLA), polyethylene glycol (PEG), nano-magnesium hydroxide (Mg(OH)2), and nano-copper oxide (CuO), is prepared by fused deposition modeling (FDM) technology, and has an internal orderly and interconnected porous structure.

2. The composite PLA / PEG / Mg / Cu antibacterial and anti-tumor bone scaffold with dual-trigger shape memory function according to claim 1, characterized in that: The content of PEG is 5-15% (weight percentage), the content of Mg(OH)2 is 2.5-20% (weight percentage), and the content of CuO is 0.1-5% (weight percentage).

3. The composite PLA / PEG / Mg / Cu antibacterial and anti-tumor bone scaffold with dual-trigger shape memory function according to claim 1 or 2, characterized in that: The bone scaffold has a glass transition temperature (Tg) of 37-55°C and is configured to achieve shape recovery under body temperature triggering.

4. The composite PLA / PEG / Mg / Cu antibacterial and anti-tumor bone scaffold with dual-trigger shape memory function according to claim 1 or 2, characterized in that: When irradiated with near-infrared light with a wavelength of about 808 nm and a power density of 0.27-0.43 W / mm², the bone scaffold can be heated to above 37°C within 1 minute, realizing the shape memory function driven by photothermal conversion.

5. The composite PLA / PEG / Mg / Cu antibacterial and anti-tumor bone scaffold with dual-trigger shape memory function according to claim 1 or 2, characterized in that: The bone scaffold has good antibacterial and anti-tumor properties, and has obvious inhibitory effects on Escherichia coli, Staphylococcus aureus and bone tumors.

6. A method for preparing a composite PLA / PEG / Mg / Cu antibacterial and antitumor bone scaffold with dual-trigger shape memory function as claimed in claim 1, characterized in that: The method comprises the following steps: ultrasonically dispersing PLA, PEG, nano magnesium hydroxide (Mg(OH)2), and nano copper oxide (CuO) particles in an organic solvent and mixing them by magnetic stirring, with the ultrasonic temperature being 30-38°C and the magnetic stirring temperature being 32-40°C, to form a uniform slurry; casting the slurry into a film, and then melt-extruded into a composite filament after drying, crushing and granulating; and using fused deposition modeling (FDM) technology to print layer by layer according to a preset three-dimensional model to form a porous scaffold.

7. The preparation method according to claim 6, characterized in that: The process parameters of the FDM printing include: nozzle temperature of 170-200°C, hot bed temperature of 50-60°C, printing speed of 20-40 mm / s, and layer thickness of 0.1-0.3 mm.

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