CN111214700A - Preparation method of anti-bone tumor composite material stent - Google Patents

Preparation method of anti-bone tumor composite material stent Download PDF

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CN111214700A
CN111214700A CN202010199677.8A CN202010199677A CN111214700A CN 111214700 A CN111214700 A CN 111214700A CN 202010199677 A CN202010199677 A CN 202010199677A CN 111214700 A CN111214700 A CN 111214700A
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powder
composite material
bone tumor
bone
raw materials
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朱沛志
梅宇程
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Yangzhou University
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
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    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02Inorganic materials
    • A61L27/12Phosphorus-containing materials, e.g. apatite
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54Biologically active materials, e.g. therapeutic substances
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56Porous materials, e.g. foams or sponges
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58Materials at least partially resorbable by the body
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B33ADDITIVE MANUFACTURING TECHNOLOGY
    • B33YADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y70/00Materials specially adapted for additive manufacturing
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B33ADDITIVE MANUFACTURING TECHNOLOGY
    • B33YADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00Products made by additive manufacturing
    • AHUMAN NECESSITIES
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    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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    • A61L2430/00Materials or treatment for tissue regeneration
    • A61L2430/02Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

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Abstract

The invention discloses a preparation method of an anti-bone tumor composite material bracket in the technical field of medical orthopedic materials, which uniformly mixes methotrexate powder, nano-hydroxyapatite powder and medical polylactic acid powder; extruding the mixture into wire rods by a screw extruder; and printing by using a 3D printer to obtain the anti-bone tumor composite material support. The scaffold can slowly release drugs in vivo to inhibit the growth of cancer cells, and the scaffold has mechanical properties matched with the bone grafted by pine.

Description

Preparation method of anti-bone tumor composite material stent
Technical Field
The invention belongs to the technical field of medical orthopedic materials, and particularly relates to a preparation method of an anti-bone tumor composite material support.
Background
Osteosarcoma is the most common malignant tumor of bones, and is a disease with high malignant tumor death rate in children and adolescents. It develops from a mesenchymal cell line and the rapid growth of tumors is due to the direct or indirect formation of tumor bone-like and bone tissue by the tumor through the cartilage stage. Common osteosarcomas originate from intraosseous or connective tissue. The latter is less frequent and the prognosis is slightly better.
After pathological diagnosis of osteosarcoma, i.e. the initiation of a previous chemical or radiological treatment, resection of tumor tissue is an important step in the treatment of osteosarcoma. After removal of the tumor tissue, post-operative chemical or radioactive treatment is also required to treat residual tumor cells at the tumor growth site, which not only increases the physical burden on the patient, but also makes the surgical prognosis difficult. The invention is indicated to be urgently needed to invent an implant which can fill the vacant part after the bone tumor is removed, can kill the residual bone tumor cells and has corresponding mechanical property.
Methotrexate (MTX), an antifolate antineoplastic agent. The product is orange yellow crystalline powder. The inhibition of dihydrofolate reductase can block the synthesis of tumor cell DNA, and inhibit the growth and reproduction of tumor cells. In orthopedics, methotrexate is often indicated for rheumatoid arthritis and various bone tumors. When the bone tumor is treated, the burden of liver and kidney of a patient is increased because the dosage is larger; generally, the administration of the medicine is performed by adopting an interval administration mode, the blood concentration gradually rises in one administration period, and after the peak value is crossed, the medicine effect gradually decreases until the next administration period. In the medication period, the drug effect cannot be continuously and stably exerted, and the treatment effect is influenced.
Hydroxyapatite (nHA) (Ca)10(PO4)6(OH)2) Is the main inorganic component of human and animal bones, has good bioactivity and osteoconductivity, can guide the growth of bones, forms firm osseous combination with bone tissues, and is a bone repair substitute material with well-known performance. Compared with the common particle size, the nano HA particles have better physical and chemical properties, higher surface activity, higher solubility, better biological activity, anticancer effect and the like, and are a treatment material with better biocompatibility. Ca after nHA implantation in humans2+And P3+Will dissociate from the surface of nHA and thus beThe body tissue absorbs and new tissue grows out. The structure of the human bone apatite is about 40-60 nm long and about 20nm wide, and the main basic unit is a needle-shaped or rod-shaped apatite crystal.
The polylactic acid (PLA) plastic is synthesized by taking lactic acid as a monomer, and has good mechanical comprehensive performance and biocompatibility. PLA has excellent impact strength, good mechanical strength, hardness and certain wear resistance. Meanwhile, the material has good biological absorbability, can be degraded into lactic acid monomers in vivo, is further circularly metabolized into carbon dioxide and water along with lactic acid, and is an ideal material for preparing the bone repair scaffold. The PLA material has the defects of poor mechanical strength, insufficient hydrophilicity, weak cell adhesion, easy in-vivo local inflammatory reaction caused by degraded acidic products, unfavorable bone cell growth and the like. However, HA is basic and reduces and eliminates local aseptic inflammatory reactions caused by acidic products generated by degradation of polylactic acid, while providing a source of calcium as well as a source of phosphorus.
the method comprises the steps of preparing an internal object according with the shape of the resected bone tumor, and printing a three-dimensional model layer by using a computer, wherein the 3D printing technology is the best choice, is also called Additive Manufacturing (AM) and Rapid Prototyping (RP), and is a process of layering and printing the three-dimensional model layer by using the computer.
Disclosure of Invention
The invention aims to provide a preparation method of an anti-bone tumor composite material scaffold, which is based on a 3D printing technology and takes MTX, HA and PLA as raw materials to prepare a porous anti-bone tumor scaffold capable of slowly releasing drugs to inhibit the growth of cancer cells.
The purpose of the invention is realized as follows: a preparation method of an anti-bone tumor composite material scaffold sequentially comprises the following steps:
1) uniformly mixing Methotrexate (MTX) powder, nano-Hydroxyapatite (HA) powder and medical polylactic acid (PLA) powder;
2) feeding the mixed raw materials into a screw extruder from a feeding hole, extruding the mixed raw materials into wires through a die head of the screw extruder at the temperature of 160-170 ℃, and cooling the wires to obtain wires with the diameter of 1.75mm +/-0.05 mm;
3) winding the wire rod by using a wire spool for a 3D printer;
4) and importing the bone tumor model established by utilizing the CT data into the 3D printer, setting printing parameters of the 3D printer and printing to obtain the anti-bone-tumor composite material support.
Furthermore, in the mixed raw materials, the weight content of the methotrexate powder in the mixed raw materials is 0.1-5%, the weight content of the nano-hydroxyapatite powder in the mixed raw materials is 9-11%, and the balance is medical polylactic acid powder.
Further, the raw materials of methotrexate powder, nano-hydroxyapatite powder and medical PLA plastic powder are sieved by a 200-mesh sieve before mixing.
Further, the content of the nano-sized hydroxyapatite powder in the mixed raw material is preferably 10% by weight.
Characterized in that the nano-grade hydroxyapatite powder is prepared by a coprecipitation method.
The temperature of a 3D printer nozzle is controlled at 190 ℃, the temperature of a printing bottom plate is controlled at 30 ℃, the printing speed is controlled at 10mm/s, and the rotating speed of a cooling fan is controlled at 2000 rpm.
Compared with the prior art, the invention has the following advantages: the MTX-PLA/HA composite material anti-bone tumor stent prepared by adopting a 3D printing technology and taking methotrexate powder, nano-hydroxyapatite powder and medical polylactic acid powder as raw materials can slowly release drugs in vivo to inhibit the growth of cancer cells, and the stent HAs mechanical properties matched with the bone graft. The bone repair stent prepared by the invention can be degraded in a human body, methotrexate medicine can be slowly released along with the slow degradation of polylactic acid, stable blood concentration can be maintained for a long time, the condition of sudden release of the medicine can be avoided, and the burden of the human body is reduced. The presence of hydroxyapatite provides a source of phosphorus and calcium for growth at the defect, neutralizing the acidic environment caused by degradation of polylactic acid. Due to the high impact strength and hardness of the material, the material meets certain supporting performance at the bone defect part of a human body.
Drawings
FIG. 1 is a sample diagram of MTX-PLA/HA composite anti-tumor scaffold in example 1.
FIG. 2 is an FTIR spectrum of MTX, PLA, HA, MTX-PLA/HA used in example 1.
Fig. 3 is an XRD diffractogram of hydroxyapatite prepared by the co-precipitation method of example 1.
Fig. 4 is a transmission electron microscope image of hydroxyapatite prepared by the coprecipitation method of example 1.
FIG. 5 is a graph showing the results of the 1% MTX-PLA/HA CCK8 susceptibility test.
FIG. 6 is a graph showing the results of 1% MTX-PLA/HA Live-Dead experiment.
FIG. 7 is SEM scanning electron microscope image of 1% MTX-PLA/HA composite anti-tumor scaffold.
FIG. 8 is a spectrum diagram of 1% MTX-PLA/HA composite anti-tumor scaffold.
FIG. 9 is a graph showing the results of compression mechanics experiments with 1% MTX-PLA/HA.
Detailed Description
The present invention will be described in more detail with reference to the following examples and the accompanying drawings.
Methotrexate (MTX), used in the following examples, was purchased from meilunbio; medical grade PLA plastics are imported medical grade materials, purchased from Nature Works, and approved by FDA.
Example 1
(MTX mass ratio of 1%, MTX-PLA/HA composite material bone repair scaffold)
Preparing hydroxyapatite by a coprecipitation method: 185.4g of calcium chloride and 380g of sodium phosphate dodecahydrate are dissolved in 1L of water, respectively. Adding a sodium phosphate solution into a calcium chloride solution under the conditions of water bath at 90 ℃ and stirring, adjusting the pH value to 9-11 by using a sodium hydroxide solution and hydrochloric acid, and continuously stirring for 4 hours. Standing and aging for 12 hours. And after aging, washing to remove a byproduct sodium chloride, and drying to obtain the nano-hydroxyapatite.
The methotrexate powder, the hydroxyapatite powder and the PLA powder were respectively sieved by a 200-mesh sieve. Methotrexate (MTX) accounts for 1% of the mixed raw material by weight, the nano-hydroxyapatite powder accounts for 10% of the mixed raw material by weight, and the balance is PLA powder. The mixture was added to an internal mixer and mixed at 170 ℃ for 10 min. And putting the mixed materials into an extruder, drawing wires, controlling the melting temperature to be 160-170 ℃, and forming consumable materials for 3D printing, wherein the diameter of the consumable materials is 1.75mm +/-0.05 mm.
Winding MTX-PLA/HA consumables by using a wire reel, loading the MTX-PLA/HA consumables into an FDM type 3D printer, and adjusting parameters to control the temperature of a printing spray head to be 190 ℃ in the process of printing the anti-bone tumor stent; the temperature of the printing bottom plate is controlled to be 30 ℃; the printing speed is controlled to be 10 mm/s; the cooling fan speed should be controlled at 2000rpm, and printing is started after a model reversely built according to CT data is imported. And finally preparing the MTX-PLA/HA anti-bone tumor scaffold.
Example 2
(MTX mass ratio of 0.1%, MTX-PLA/HA composite material bone repair scaffold)
The difference from example 1 is that Methotrexate (MTX) is contained in an amount of 0.1% by weight in the mixed raw material, and nano-sized hydroxyapatite powder is contained in an amount of 9% by weight in the mixed raw material.
Example 3
(MTX mass ratio of 5%, MTX-PLA/HA composite material bone repair scaffold)
The difference from example 1 is that Methotrexate (MTX) is contained in an amount of 5% by weight of the mixed raw material, and nano-sized hydroxyapatite powder is contained in an amount of 11% by weight of the mixed raw material.
In the above embodiments, the specific dose of methotrexate needs to be controlled according to the patient's own condition and medical advice.
Fig. 1 is a sample diagram of an MTX-PLA/HA composite anti-tumor stent, and it can be seen that voids exist in the anti-tumor stent, the pore size is about 300 microns, and the existence of porous voids accelerates the degradation of polylactic acid in human body and also reduces the difficulty of drug release. And the pores provide convenience for the generation of new bone at the later stage. The support sample is not limited to be in a disc shape, and the specific shape can be automatically regulated according to CT data.
FIG. 2 is an FTIR spectrum of MTX, PLA, HA, MTX-PLA/HA used in example 1. As can be seen, the FTIR spectra of hydroxyapatite were found to be 1089, 1024 and 962cm-1The absorption peaks at (a) can be attributed to the υ 1 and υ 3 phosphate modes. 560 and 600 cm-1The absorption peak at (a) is due to the v 4 phosphate mode. At 1500-1400cm-1C-O (upsilon 3) in the range and at 875cm-1CO of3 2-The antisymmetric stretching vibration of upsilon 2 vibration shows that natural HA contains CO3 2-. Corresponding MTX, PLA and HA peaks can be found in an FTIR spectrogram of MTX-PLA/HA, and the MTX, the PLA and the HA are not decomposed or failed at the melting temperature of 160-170 ℃.
Fig. 3 is an XRD diffractogram of hydroxyapatite prepared by the co-precipitation method of example 1. As can be seen from the figure, almost all peaks in the XRD spectrum are consistent with those of standard HA (JCPDS No. 09-0432), and the diffraction peaks of the HA sample are consistent with those of pure HA having 2 theta values of 26.1, 32.1, 33.0, 40.1 (002), (211), (300), (310), (222), (213) and (004) planes of 47.0, 49.7 and 53.4, respectively. The strong peaks near 2 θ = 26 and 2 θ = 33 demonstrate that these samples are primarily HA.
Fig. 4 is a transmission electron microscope image of hydroxyapatite prepared by the coprecipitation method of example 1, and it can be seen from the image that the hydroxyapatite has a rod-like structure and an average length of 52-58 nm.
FIG. 5 is a graph showing the results of the 1% MTX-PLA/HA CCK8 susceptibility test. As can be seen, MG-63 (osteosarcoma) cells failed to grow normally in the MTX-PLA/HA scaffold group. The slow release of the drug from the anti-tumor stent leads to large-area death of MG-63 cells.
FIG. 6 is a graph showing the results of 1% MTX-PLA/HA Live-Dead experiment. As can be seen, MG-63 (osteosarcoma) cells failed to grow normally in the MTX-PLA/HA scaffold group. PLA groups and blanks grew normally. The MTX-PLA/HA scaffold group HAs the ability to kill osteosarcoma cells. The basic situation is in agreement with the CCK8 experiment.
FIG. 7 is SEM scanning electron microscope image of 1% MTX-PLA/HA composite anti-tumor scaffold. The SEM scanning electron micrograph shows that the MTX-PLA/HA composite material anti-tumor scaffold HAs a smooth surface, a porous morphology and a pore size of about 300 microns. The N-element surface scanning shows that the methotrexate drug is uniformly distributed in the polylactic acid-based composite material and almost has no agglomeration phenomenon.
FIG. 8 is a graph showing the energy spectrum of 1% MTX-PLA/HA composite anti-tumor scaffold, and it can be seen that methotrexate is well incorporated into the polylactic acid-based composite due to the presence of N element, and the results are consistent with the SEM surface scanning results.
FIG. 9 is a graph showing the results of compression mechanics experiments with 1% MTX-PLA/HA. The figure shows that the modulus is 20-25 MPA and meets the standard of cancellous bone. And the incorporation of MTX does not reduce the mechanical strength of PLA and does not generate stress shielding effect.
In conclusion, the MTX-PLA/HA composite material HAs good anti-tumor performance and mechanical property, can adapt to the complex body fluid environment in the human body to effectively control and kill tumor cells, and can resist strong external impact. The dosage of the methotrexate can be regulated and controlled according to medical advice and individual conditions, so that the burden of postoperative drug chemotherapy of patients is reduced.
The present invention is not limited to the above-mentioned embodiments, and based on the technical solutions disclosed in the present invention, those skilled in the art can make some substitutions and modifications to some technical features without creative efforts according to the disclosed technical contents, and these substitutions and modifications are all within the protection scope of the present invention.

Claims (6)

1. The preparation method of the anti-bone tumor composite material scaffold is characterized by sequentially comprising the following steps of:
1) uniformly mixing Methotrexate (MTX) powder, nano-Hydroxyapatite (HA) powder and medical polylactic acid (PLA) powder;
2) feeding the mixed raw materials into a screw extruder from a feeding hole, extruding the mixed raw materials into wires through a die head of the screw extruder at the temperature of 160-170 ℃, and cooling the wires to obtain wires with the diameter of 1.75mm +/-0.05 mm;
3) winding the wire rod by using a wire spool for a 3D printer;
4) and importing the bone tumor model established by utilizing the CT data into the 3D printer, setting printing parameters of the 3D printer and printing to obtain the anti-bone-tumor composite material support.
2. The method for preparing the composite scaffold for resisting bone tumor according to claim 1, wherein in the mixed raw materials, the weight content of methotrexate powder in the mixed raw materials is 0.1-5%, the weight content of nano-hydroxyapatite powder in the mixed raw materials is 9-11%, and the balance is medical polylactic acid powder.
3. The method for preparing an anti-bone tumor composite material scaffold according to claim 1 or 2, wherein the raw materials of methotrexate powder, nano-hydroxyapatite powder and medical grade PLA plastic powder are sieved by a 200 mesh sieve before mixing.
4. The method for preparing an anti-bone tumor composite material scaffold according to claim 1 or 2, wherein the weight content of the nano-hydroxyapatite powder in the mixed raw materials is 10%.
5. The method for preparing an anti-bone tumor composite material scaffold according to claim 1 or 2, wherein the nano-sized hydroxyapatite powder is prepared by a coprecipitation method.
6. The method for preparing an anti-bone tumor composite material scaffold according to claim 1 or 2, wherein the temperature of a 3D printer nozzle is controlled at 190 ℃, the temperature of a printing bottom plate is controlled at 30 ℃, the printing speed is controlled at 10mm/s, and the rotating speed of a cooling fan is controlled at 2000 rpm.
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CN112891620A (en) * 2021-01-28 2021-06-04 中南大学湘雅医院 Artificial bone material carrying anti-tumor medicine and method for preparing artificial bone
CN113274560A (en) * 2021-05-28 2021-08-20 扬州大学 Preparation method of anti-tumor composite material bracket loaded with 5-FU

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