CN115569244A - Sandwich type degradable biological material and application thereof - Google Patents
Sandwich type degradable biological material and application thereof Download PDFInfo
- Publication number
- CN115569244A CN115569244A CN202211192479.4A CN202211192479A CN115569244A CN 115569244 A CN115569244 A CN 115569244A CN 202211192479 A CN202211192479 A CN 202211192479A CN 115569244 A CN115569244 A CN 115569244A
- Authority
- CN
- China
- Prior art keywords
- coating
- degradable
- polyurethane
- magnesium
- induction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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Abstract
The invention discloses a sandwich type degradable biological material and application thereof, belonging to the technical field of biomedical materials. The sandwich type degradable biological material comprises a magnesium-containing degradable metal core material, wherein a water control coating and an induction coating are sequentially coated on the surface of the degradable metal core material from inside to outside; the water control coating is a degradable polyurethane coating, and the induction coating is a polyurethane coating, a collagen coating or a mixed coating of polyurethane and collagen. The sandwich type degradable biomaterial has good biocompatibility, can well control the degradation speed of magnesium or magnesium alloy, and can be well applied to in-vivo implants, and animal implantation tests prove that the fibrous capsule is formed about 7 days after the fibrous capsule is implanted, is completely covered about 18 days, and has no obvious inflammatory reaction.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to a sandwich type degradable biological material and application thereof.
Background
Magnesium alloy has shown unique advantage as biodegradable material, because the metallic property of magnesium alloy is more active, is easy to corrode and degrade in vivo environment, lead to the corrosion rate too fast, thus make its structural properties lose, the product produced in the course of corroding can produce the potential danger to the human body at the same time, therefore has greatly limited the application of magnesium alloy in clinical medicine.
The prior art generally reduces the corrosion rate substantially by alloying and surface modification of magnesium, for example by converting the magnesium surface to magnesium fluoride (MgF) 2 ) Layers, etc. are less prone to corrosive or biodegradable inert magnesium compounds, but such coatings are not biocompatible and are brittle and tear or flake off. The surface of magnesium can also be coated with a polymer coating such as polycaprolactone or polylactide, however, the coating of such a polymer material has the following two disadvantages: 1. the polymer is easy to absorb water to expand and crack in the degradation process, and the degradation product is acidic, so that the magnesium material is catalyzed to accelerate degradation; 2. hydrogen can be dissolved in a large amount in animal tissues, a proper amount of hydrogen has the functions of clearing free radicals and diminishing inflammation, but the rapid degradation of the magnesium material can cause a large amount of generated hydrogen, the absorption and the excretion of all hydrogen can not be realized in a short time due to the hysteresis and the limitation of metabolism, subcutaneous bubbles can be formed when the large amount of hydrogen is gathered, so that the adverse reactions of body discomfort, inflammation, poisoning, vascular blockage, tissue necrosis and the like are caused, and the treatment period is greatly prolonged.
Therefore, it is necessary to develop a degradable biomaterial which can control the degradation rate of magnesium or magnesium alloy, match the release of hydrogen with the in vivo metabolism rate, and reduce the contact of magnesium degradation residues with local tissues.
Disclosure of Invention
In order to overcome the technical defects of hydrogen aggregation caused by excessively high degradation speed of magnesium materials and adverse reaction caused by contact of residues with human bodies in the prior art, the invention aims to provide the sandwich type degradable biological material.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
a sandwich type degradable biological material comprises a degradable metal core material containing magnesium, wherein the surface of the degradable metal core material is sequentially coated with a water control coating and an induction coating from inside to outside; the water-controlling coating is a degradable polyurethane coating, and the inducing coating is a degradable polyurethane coating, a collagen coating or a mixed coating of degradable polyurethane and collagen; wherein, the ratio of the weight of the degradable metal core material to the total weight of the water control coating and the induction coating is 1:1-10.
As a preferred embodiment of the present invention, the degradable metal core material is high-purity magnesium or magnesium alloy; the purity of the high-purity magnesium is more than 99.9 percent; the magnesium alloy comprises the following additive components of one or the combination of more than two of iron, copper, zinc, cobalt, manganese, chromium, selenium, iodine, nickel, fluorine, molybdenum, vanadium, tin, silicon, strontium, boron, rubidium, arsenic and silver.
More preferably, the magnesium alloy comprises 0 to 2.0 wt% of Fe, 0 to 2.0 wt% of Cu, 0 to 2.0 wt% of Zn, 0 to 2.0 wt% of Co, 0 to 2.0 wt% of Mn, 0 to 2.0 wt% of Cr, 0 to 2.0 wt% of Se, 0 to 2.0 wt% of I, 0 to 2.0 wt% of Ni, 0 to 2.0 wt% of F, 0 to 2.0 wt% of Mo, 0 to 2.0 wt% of V, 0 to 2.0 wt% of Sn, 0 to 2.0 wt% of Si, 0 to 2.0 wt% of Sr, 0 to 2.0 wt% of B, 0 to 2.0 wt% of Rb and 0.1 to 4 wt% of Ag.
Further preferably, the magnesium alloy may be one or a combination of two of a magnesium-iron alloy (1 weight percent to 0.01-10, preferably 1.01-0.1), a magnesium-zinc alloy (1 weight percent to 0.01-1), a magnesium-calcium alloy (1 weight percent to 0.01-1), a magnesium-aluminum alloy (1 weight percent to 0.01-0.1). Among them, magnesium-zinc alloy (preferably 1 weight percent: mg-Nd-Zn-Zr, mg-Zn-Mn-Se-Cu alloy, wherein the Zn content is 3.5wt%, the Mn content is 0.5-1.0wt%, the Se content is 0.4-1.0wt%, the Cu content is 0.2-0.5wt%, and the balance is Mg; the weight percentage of the magnesium-calcium alloy is preferably 1:0.01-0.1, such as: mg-Zn-Ca-Fe; the magnesium-aluminum alloy (preferably 1 weight percent) is selected from the group consisting of 2.0 to 3.0 weight percent of aluminum (Al), 0.5 to 1.0 weight percent of zinc (Zn), manganese (Mn) and the balance of Mg.
As a preferred embodiment of the present invention, the degradable polyurethane in the water-controlling coating layer is polycaprolactone type polyurethane; the polycaprolactone type polyurethane is polyurethane taking polycaprolactone diol as a soft segment and LDI (lysine methyl ester/ethyl ester diisocyanate) as a hard segment, and the viscosity average molecular weight is 3-50 ten thousand. Wherein the polycaprolactone diol is generated by the reaction of ethylene glycol, 1,3-propylene glycol or polyethylene glycol with the molecular weight of 200-2000 and epsilon-caprolactone under the action of a catalyst, and the catalyst is organic bismuth and/or organic tin. The chain extender is selected from small molecular diol or diamine, and is specifically selected from one of ethylene glycol, 1,3-propylene glycol, 1,4-butanediol, 1,5 pentanediol, 1,4-butanediamine or 1,5 pentanediamine.
As a preferable embodiment of the invention, the polycaprolactone type polyurethane in the water control coating is diol or diamine terminated polycaprolactone type polyurethane, and when the molecular weight of polycaprolactone diol is greater than 3000, the water control effect is better.
The inducing coating is selected from amino acid or derivatives thereof or polypeptide-terminated degradable polyurethane coating, collagen coating or a combination of the two, and can be one layer or multiple layers, wherein the degradable polyurethane in the inducing coating is selected from polymer diol prepared from one or two of CL, PLA, PGA, PLGA and PDO with the molecular weight of 200-1000 and PEG ring opening, the polymer diol is soft segment, LDI is hard segment, and the chain extender is selected from small molecular diol, diamine-like, amino acid or derivatives thereof or polypeptide-terminated.
Further, the blocked amino acid or its derivative or polypeptide is selected from lysine or lysine ethyl/methyl ester, arginine or arginine ethyl/methyl ester, histidine or histidine ethyl/methyl ester and active polypeptide containing both peptide bond and free amino group, such as CTP (collagen tripeptide), RGD linear peptide, OGP (osteogenic growth peptide) glutathione derivative (carboxyl groups at both ends are esterified into ethyl ester or methyl ester).
As a preferred embodiment of the present invention, the thickness or diameter of the degradable metal core material is 0.1mm to 2mm, preferably 0.1mm to 1mm; the total thickness of the water control coating and the induction coating is 10 mu m-1 mm; the thickness of the water control coating is 5 mu m-1 mm, and the thickness of the induction coating is 5 mu m-1 mm; the aperture of the water control coating is 1 nm-200 nm, and the aperture of the induction coating is 0.1 μm-200 μm.
The invention also aims to provide a preparation method of the sandwich type degradable biological material, which comprises the following steps:
s1, after cleaning a high-purity magnesium or magnesium alloy material, treating the material by a phosphate conversion film method, a phytic acid conversion film method, micro-arc oxidation, a rare earth salt conversion film method or an organic matter conversion film method, or performing fluorination treatment on the surface of a bare support, or performing polishing treatment on the material;
s2, dissolving degradable polyurethane in an organic solvent to prepare a solution with the concentration of 10-50%, forming a water-controlling coating on the surface of the material prepared in the S1 in a mode of electrostatic spraying, ultrasonic atomization spraying or dip-coating, and drying by blowing or vacuum drying;
s3, dissolving degradable polyurethane or collagen in an organic solvent to prepare a solution with the concentration of 5-30%, forming an induction coating on the surface of the material prepared in the S2 in a mode of electrostatic spraying, ultrasonic atomization spraying, electrostatic spinning or dip coating, and drying by blowing or vacuum drying;
and S4, performing EO sterilization and analysis on the material prepared in the S3, and sealing and packaging to obtain the material.
The invention also aims to provide another preparation method of the sandwich type degradable biological material, which comprises the following steps:
s1, cleaning a high-purity magnesium or magnesium alloy material by magnesium wire treatment, and then treating the material by a phosphate conversion film method, a phytic acid conversion film method, micro-arc oxidation, a rare earth salt conversion film method or an organic matter conversion film method, or performing fluorination treatment on the surface of a bare bracket, or performing polishing treatment on the material;
s2, preparing a water control layer: dissolving degradable polyurethane in an organic solvent to prepare a solution with the concentration of 10-50%, forming a water-controlling coating on the surface of the material prepared in the step S1 in a mode of electrostatic spraying, ultrasonic atomization spraying or dip coating, and drying by blowing or vacuum drying;
s3, preparing a drug release coating: preparation of a second inducing layer: preparing a collagen aqueous solution and a proper amount of BMP (bone morphogenetic protein) into a solution with the concentration of 2-5%, forming an induction coating on the surface of the material prepared in the step S2 in a mode of electrostatic spraying, ultrasonic atomization spraying, electrostatic spinning or dip coating, and drying by blowing or vacuum drying;
s4, preparing a first induction layer: dissolving degradable polyurethane in an organic solvent to prepare a solution with the concentration of 5-30%, forming an induction coating on the surface of the material prepared in the step S2 in a mode of electrostatic spraying, ultrasonic atomization spraying, electrostatic spinning or dip coating, and drying by blowing or vacuum drying;
s5, preparing a second induction layer: preparing a collagen aqueous solution into a solution with the concentration of 2-5%, forming an induction coating on the surface of the material prepared in the step S2 in a mode of electrostatic spraying, ultrasonic atomization spraying, electrostatic spinning or dip coating, and drying by blowing or vacuum drying;
and S6, performing EO sterilization and analysis on the material prepared in the S3, and sealing and packaging to obtain the material.
The organic solvent used in steps S2, S3 and S4 is selected from one or two of toluene, p-xylene, decane, ethanol, acetone, isoamyl acetate, hexane, benzene, dichloromethane, chloroform, cyclohexanone, ketone, dimethylformamide, heptane, dimethylaminobromide, tetrahydrofuran, petroleum ether, dimethyl sulfoxide and ethylene terephthalate, and preferably one or two of tetrahydrofuran, decane, isoamyl acetate, hexane, dichloromethane, chloroform, cyclohexanone, ethanol, acetone, dimethylformamide and heptane.
The fourth object of the present invention is to provide an application of the above-mentioned sandwich-type degradable biomaterial in the preparation of a medical product for implantation intervention, wherein the medical product for implantation intervention can be made into a specific shape according to the need, and the medical product for implantation intervention is one of a filiform, a columnar, a sheet-like or a laser-cut hollowed-out stent (for example, a magnesium material is cut into a shape of a coronary stent or a biliary stent, and a coating is coated to form a gradient degradable biomaterial for use), a surgical implant, a stent graft, a vascular prosthesis, a vascular access, a meningeal patch, a suture, a surgical mesh, a surgical thread, a monofilament lifting thread, a double-filigree lifting thread, a surgical plate, a surgical screw, a surgical anchor, a surgical clip or a wound closure. Wherein the surgical plate may be in the shape of a plate for fixation of hard tissue and the surgical screws are selected to be suitable for fixation of the bone plate. The operation anchor is a fixed anchor of the blood vessel occluder, and can also be in the shape of an anchor for fixing bone tissues.
The sandwich type degradable biological material of the invention can be added with polypeptide, protein and active ingredients such as growth factors which are sold or disclosed in the market according to the product performance and clinical requirements, including antiproliferative, anti-migration, anti-angiogenesis, anti-inflammation, cell growth inhibition, drugs with physiological activity and other biological materials with cytotoxicity added according to the treatment requirements, such as: polylactic acid (PLA), poly-L-lactic acid (PLLA), polyglycolide or polyglycolic acid, PGA, polycyanoacrylate (PACA), polycaprolactone (PCL), polyanhydrides, polylactic acid copolymers (PLGA), polyhydroxybutyrate amyl ester (PHBV), polyacetylglutamic acid (PAGA), polyorthoester (POE), polyorthoester, polycaprolactone, methacrylate or ester, and copolymers among the above polymers, collagen (type I collagen, type III collagen, which can be natural collagen or recombinant collagen), gelatin, BMP series, growth factors, active proteins, active polypeptides, chitin natural degradable high molecular materials; the polyanhydrides include aliphatic polyanhydrides, aromatic polyanhydrides, heterocyclic polyanhydrides, polyimide anhydrides and crosslinkable polyanhydrides.
Compared with the prior art, the invention has the beneficial effects that:
(1) The high-purity magnesium or magnesium alloy core material is coated in the degradable water-control coating, the water-control coating which takes polyester polyol synthesized by taking Caprolactone (CL) as a main raw material as a soft segment and takes LDI (L-lysine ethyl ester/methyl diisocyanate) as a hard segment is adopted, the thickness and the pore diameter of the coating are controlled by screening the polyester polyol with a specific structure, the magnesium material is completely degraded in the water-control coating, the degradation speed of the magnesium material is higher than that of the water-control coating, the water-control coating can effectively control the release speed of hydrogen, and magnesium degradation products are dissolved in body fluid in an ionic state and are safely metabolized by the body fluid;
(2) The degradable polyurethane coating blocked by the amino acid or the derivative thereof is screened as the induction coating, cells can be induced to grow along the induction coating rapidly to form a fiber or collagen coating, so that tissues contacting the material can not generate serious inflammatory reaction, animal implantation tests prove that the fiber coating is formed about 7 days after the implantation, is completely covered about 18 days without obvious inflammatory reaction (figure 6), water molecules are effectively slowed down to penetrate into the core material, and the degradation time of the core material is further delayed.
(3) Degradable polyurethane materials with different structures are screened, meanwhile, the average pore diameter of the water-control coating is smaller than that of the induction coating, and the thickness of the water-control coating is larger than that of the induction coating, so that the quantity of water molecules on the surface of the magnesium alloy is well controlled, and the magnesium alloy material is degraded in the coating;
(4) The further test shows that the total weight of the coating is larger than that of the core material, so that the magnesium alloy material can be degraded in the coating, the degradation time is prolonged, and formed bubbles can not be aggregated and can be metabolized quickly.
Drawings
FIG. 1 is a cross-sectional structural view of a linear sandwich type degradable biomaterial according to the present invention, wherein 1 is a core material, 2 is a water control coating, and 3 is an inducing coating;
FIG. 2 is a radial cross-sectional structural view of the sheet-like sandwich type degradable biomaterial of the present invention, wherein 1 is magnesium alloy, 2 is a water control coating, 3 is a drug release coating, and 4 is an induction coating;
FIG. 3 is a structural view of an axial cross section of the sheet-like sandwich type degradable biomaterial, wherein 1 is a magnesium alloy, 2 is a water control coating, 3 is a drug release coating, and 4 is an induction coating;
FIG. 4 is a cross-sectional view of a screw A manufactured in example 2 of the present invention, in which 1 is high purity magnesium, 2 is a water control coating, 3 is a drug release coating, 4 is a first inducing coating, and 5 is a second inducing coating;
FIG. 5 is a cross-sectional view of a screw B manufactured according to example 2 of the present invention, in which 1 is high purity magnesium, 2 is a water control coating, 3 is a drug release coating, 4 is a first inducing coating, 5 is a second inducing coating, and 6 is a polyurethane casting layer;
FIG. 6 is a staining chart of a mouse muscle tissue section of the material prepared in example 2, wherein A is a tissue section enlarged 10 times of muscle implantation and B is a tissue section enlarged 40 times of muscle implantation.
Detailed Description
As shown in fig. 1, the invention provides a sandwich type degradable biomaterial with an inner-layer coating structure and an outer-layer coating structure, which comprises a magnesium-containing degradable metal core material, wherein the surface of the degradable metal core material is sequentially coated with a water control coating and an induction coating from inside to outside; wherein the degradable metal core material is high-purity magnesium or magnesium alloy with the purity of more than 99.0 percent, the water control coating is a degradable polyurethane coating, and the induction coating is a polyurethane coating, a collagen coating or a mixed coating of polyurethane and collagen.
The high molecular polymer in the degradable polyurethane coating is selected from at least one of polylactic acid, polyurethane, polycaprolactone and polydioxanone; the polyurethane is selected from polyester polyurethane or its derivative, polycaprolactone polyurethane or its derivative. Wherein the polyester polyurethane derivative or polycaprolactone polyurethane derivative is prepared by modifying organosilicon, polyamino acid or polysaccharide. More preferably, the polyurethane is prepared by using polyester polyol as a soft segment, polyisocyanate as a hard segment, and small molecular diol as a chain extender, and performing diol-end capping polymerization, and the viscosity average molecular weight of the polyurethane is 3 to 50 ten thousand, preferably 10 to 50 ten thousand. More specifically, the polyester polyol is generated by the reaction of ethylene glycol, propylene glycol or polyethylene glycol with the molecular weight of 200-2000 and epsilon-caprolactone; the polyisocyanate is at least one selected from 1,6-hexamethylene diisocyanate, isophorone diisocyanate, lysine methyl ester diisocyanate, cis-cyclohexane diisocyanate, trans-cyclohexane diisocyanate, 1,4-butane diisocyanate, 1,2-ethane diisocyanate, 1,3-propane diisocyanate, 4,4' -methylene-bis (cyclohexyl isocyanate), 2,4,4-trimethyl 1,6-hexane diisocyanate. The chain extender is selected from the group consisting of ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5 pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol.
The polyurethane in the polyurethane coating is prepared by end-capping polymerization of polyester polyol serving as a soft segment, polyisocyanate serving as a hard segment, micromolecular diol serving as a chain extender and amino acid or derivatives thereof, wherein the viscosity average molecular weight of the polyurethane is 2-20 ten thousand; the polyester polyol is generated by the reaction of polyethylene glycol, ethylene glycol, propylene glycol, PDO, LA or GA and caprolactone. More preferably, the polyurethane soft segment in the polyurethane coating is prepared by selecting polyester polyol prepared by one or two of CL, PLA, PGA, PLGA and PDO with the open loop of PEG with the molecular weight of 200-2000, the hard end is selected from lysine diisocyanate methyl ester or lysine diisocyanate ethyl ester, propanediol or 1,4-butanediol is used as a chain extender, and the polyurethane coating is prepared by blocking through amino acid or derivatives thereof. More specifically, the amino acid or derivative thereof is selected from one or more of lysine or lysine ethyl/methyl ester, arginine or arginine ethyl/methyl ester, histidine or histidine ethyl/methyl ester, collagen tripeptide or collagen tripeptide ethyl/methyl ester, fibronectin RGD, laminin or its ethyl/methyl ester, affinity TGF-beta 1 polypeptide, bone marrow homing polypeptide, osteogenic growth polypeptide, laminin sequence, bindable neural stem cell surface molecule, osteoblast adhesion molecule and VEGF.
The preparation method of the sandwich type degradable biological material comprises the following steps:
s1, after cleaning a high-purity magnesium or magnesium alloy material, treating the material by a phosphate conversion film method, a phytic acid conversion film method, a rare earth salt conversion film method or an organic matter conversion film method, or performing fluorination treatment on the surface of a bare stent, or performing polishing treatment on the material;
s2, dissolving polyurethane in an organic solvent to prepare a solution with the concentration of 5-50%, forming a water-control coating on the surface of the material prepared in the S1 in an electrostatic spraying, ultrasonic atomization spraying or dip-coating mode, and drying the material by blowing or drying;
s3, dissolving polyurethane or collagen in an organic solvent to prepare a solution with the concentration of 5-30%, forming an induction coating on the surface of the material prepared in the S2 in an electrostatic spraying, ultrasonic atomization spraying or dip-coating mode, and drying by blowing or drying;
and S4, sterilizing the material prepared in the S3 to obtain the material.
The sandwich type degradable biological material can be applied to the preparation of a plant intervention medical product, the plant intervention medical product can be made into a specific shape according to the needs, the plant intervention medical product is in one of a filamentous shape (as shown in figure 1), a columnar shape, a sheet shape (as shown in figures 2 and 3) or a laser cutting hollowed-out stent (for example, a magnesium material is cut into the shape of a coronary stent or a biliary stent, and a coating is coated to be made into a gradient degradable biological material for use), a surgical implant, a stent graft, a vascular prosthesis, a vascular access, a wound dressing, a suture, a surgical mesh, a surgical silk thread, a monofilament lifting line, a double-silk lifting line, a surgical plate, a surgical thread, a surgical nail, a surgical anchor, a surgical clip or a wound closure.
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.
Example 1
Polyurethane materials with different structures are made into films with the thickness of 0.2mm, the porosity of more than 90 percent of the films ranges from 5nm to 100nm, the films are soaked in physiological saline at the temperature of 37 ℃, the aqueous solution is replaced every day, the degradation condition is observed, and the result is shown in table 1.
TABLE 1 degradation Properties of polyurethane materials of different structures
The test results in Table 1 show that the polyurethane with PCL as the soft segment has better water resistance, the molecular weight of the soft end is increased, and the water resistance is correspondingly increased. The water resistance of the polyurethane film obtained by using the soft segment molecular weight of more than 3000 can reach 90 days, and the polyurethane film with PDO and LA as soft ends is degraded quickly and is not suitable for being used as a material of a water control layer.
Example 2
A method of making a gradiently degradable bone screw comprising the steps of:
s1, preparing a high-purity magnesium core material: respectively taking high-purity magnesium wires (the purity is 99.9%) with the thickness of 0.7mm and 2mm, and passivating the surfaces by using hydrofluoric acid with the concentration of 5% during surface polishing;
s2, preparing a polyurethane material A: the polycaprolactone diol prepared by ring-opening 1,3-propanediol is used as a soft segment (the soft segment has a molecular weight of 5000), lysine diisocyanate ethyl ester is used as a hard segment, 1,3-propanediol is used as a chain extender, and hydroxyl-terminated polyurethane has a viscosity-average molecular weight of 15-18 ten thousand;
s3, preparing a polyurethane material B: the polyethylene glycol (PEG) 600 open-loop polycaprolactone diol is used as a soft segment (the soft segment has a molecular weight of 3000), lysine diisocyanate ethyl ester is used as a hard segment, 1,4-butanediol is used as a chain extender, OGP (osteogenic growth peptide) is used for end capping, and the viscosity-average molecular weight range is 7-10 ten thousand.
S4, preparing a water control layer: immersing the core material into a polyurethane material A trichloromethane solution with the concentration of 40% to obtain a water control coating with the surface thickness of 50-100 um;
s5, preparing a first induction layer: quantitative BMP (5 microgram BMP-2 is dissolved in 4 milliliters of 5mM acetic acid containing 2 percent recombinant collagen, filtered and sterilized, and stored in a refrigerator at 4 ℃ for standby) is sprayed on the surface of the screw prepared in the S4 by ultrasonic atomization;
s6, preparing a second induction layer: preparing a 5-8% trichloromethane solution from the polyurethane material B, and spraying the trichloromethane solution onto the surface of the screw prepared in the step S5 through ultrasonic atomization to obtain the screw coated with the first induction layer with the thickness of 10-50 um;
according to the above production method, a screw a and a screw B were produced, in which:
and (3) a screw A: coating a core material with the diameter of 2mm after passivation with a water control layer, coating a first induction layer, coating a second induction layer (as shown in figure 4), preparing a chloroform solution with the concentration of 5% by using the screw coated with the first induction layer and a polyurethane material B, and performing ultrasonic atomization spraying to obtain a second induction layer, wherein the thickness of the coating is 20-50um, more than 90% of the screw has the porosity of 2-10 um, and the mass ratio of the total mass of the coating to the core material is =2:1;
and B, screws B: taking a passivated core material with the diameter of 0.7mm, coating a water control layer, coating a first induction layer, closely arranging 3 screws coated with the first induction layer (as shown in figure 5), putting the screws into a screw mold, and melting and pouring a polyurethane material B into the screws, wherein the thickness of the coating is 20-100um, the porosity range of more than 90% is 0.2-5 um, and the mass ratio of the total mass of the coating to the core material is = 2.3.
In vitro degradation testing of screws a and B:
screws a and B were immersed in commercially available artificial interstitial fluid, the interstitial fluid was changed weekly under aseptic conditions at 37 degrees, the PH was measured, air bubbles and degradation time on the surface of the material were observed, and the test phenomena and results are shown in table 2:
TABLE 2 degradation testing of screw A and screw B in Artificial tissue fluid
The test result shows that the screw B is made of 3 strands of high-purity magnesium wires with the diameter of 0.7mm, can be degraded in a coating material, does not fall off in the observation period of an in vitro test, and has complete appearance; the high-purity magnesium wire of the screw A can be seen in 5 months in fragments of degraded polyurethane and magnesium wire fragments which are not completely degraded.
Example 3
A method of making a gradiently degradable suture or facial pull line comprising the steps of:
s1, polishing the surface of a wire (the diameter of the wire is 2 mm) made of high-purity magnesium or magnesium-zinc alloy with the purity of 99.99%, and then soaking the wire into a trichloromethane solution with the concentration of 40% of polyurethane for less than 1 minute to obtain the wire coated with a water control coating with the thickness of 50-100um on the surface;
s2, carrying out ultrasonic atomization spraying or dip-coating on the surface of the wire prepared in the step S2 by using a dichloromethane solution with the polyurethane concentration of 10% to obtain a wire with the first induction coating thickness of 0.1-1 um;
and S3, putting the single-strand or double-strand wire material prepared in the step S2 into a die, and carrying out hot melting extrusion to form a double-wire suture or a face pulling wire.
Application examples
Magnesium alloy material degradation behavior analysis and cell proliferation rate research prepared by different high polymer material coatings
A ZK61M magnesium alloy wire rod (the diameter is 1mm, the length is 50 mm) is taken, and after cleaning and polishing, a phytic acid conversion film is firstly prepared (the conversion temperature is 40 ℃, the pH of a treatment solution is =3.0, the phytic acid concentration is 7.5ml/L, the conversion time is respectively 20min, and the complete, compact and crack-free conversion film is obtained). The influence of the coating on the degradation behavior and the biocompatibility of the magnesium alloy material is tested by selecting different polyurethane materials and coating porosity.
Sample 1: the polyurethane of the formula 3 in the example 1 and the arginine methyl ester end-capping polyurethane of the formula 4 in the example 1 are selected, and the preparation method comprises the following steps:
a ZK61M magnesium alloy wire rod is prepared by taking a polyurethane (viscosity average molecular weight range is 15-20 ten thousand) solution (30 percent prepared by trichloromethane) of the formula 3 in the embodiment 1, dip-coating magnesium wires, and airing to form a water control layer (the thickness of the obtained water control layer is 0.1-0.15mm, and the porosity range of more than 90 percent is 10-50 nm);
preparing reconstructed collagen fiber with molecular weight more than 250KDa into 3% solution acid with acetic acid water solution of PH 2-3; a polyurethane (viscosity average molecular weight range of 5-7 ten thousand) (arginine methyl ester end capping) solution (mixed solution of chloroform and DMF is prepared into 10%) of the formula 4 in the example 1;
and (3) putting the magnesium alloy material coated with the water control layer in an electrostatic spinning machine, uniformly rotating, spraying the collagen solution and the polyurethane solution oppositely, wherein the spinning voltage is 10-15KV, the receiving distance is 10cm, the spinning speed of the collagen solution is 2ml/h, and the spinning speed of the polyurethane solution is 10ml/h, so that the magnesium alloy wire coated with the inducing layer is obtained.
Sample 2: the polyurethane of formula 1 of example 1 and the hydroxyl terminated polyurethane of formula 4 of example 1 were selected and prepared as follows:
the preparation method comprises the following steps:
(1) A ZK61M magnesium alloy wire rod is prepared by taking a polyurethane (viscosity average molecular weight range is 15-20 ten thousand) solution (30 percent prepared by trichloromethane) of the formula 1 in the embodiment 1, dip-coating and airing to form a water control layer (the thickness of the obtained water control layer is 0.1-0.15mm, and the porosity range of more than 90 percent is 10-50 nm);
(2) Preparing type III recombinant collagen with molecular weight of more than 250KDa into 3% solution with acetic acid solution of PH 2-3; a polyurethane (viscosity average molecular weight range of 5-7 ten thousand) solution (10% prepared by a mixed solution of chloroform and DMF) of the formula 4 in example 1;
(3) The magnesium alloy material coated with the water control layer is placed in an electrostatic spinning machine and uniformly rotated, a collagen solution and a polyurethane solution are oppositely sprayed, the spinning voltage is 10-15KV, the receiving distance is 10cm, the spinning speed of the collagen solution is 2ml/h, the spinning speed of the polyurethane solution is 10ml/h, the magnesium alloy wire coated with the inducing layer is obtained, the thickness of the inducing layer is 0.1-0.15mm, and the porosity range of more than 90% is 1umnm-100um porosity.
Sample 3: influence of different porosity ranges of water control layers on degradation behavior of magnesium alloy material
The preparation method comprises the following steps:
(1) A ZK61M magnesium alloy wire rod is prepared by taking a polyurethane (viscosity average molecular weight range is 15-20 ten thousand) solution (20 percent prepared by trichloromethane) of the formula 3 in the embodiment 1, dip-coating and airing to form a water control layer (the thickness of the obtained water control layer is 0.1-0.15mm, and the porosity range of more than 70 percent is 0.05-0.2 mm);
(2) Preparing 3% solution acid from reconstructed collagen fiber with molecular weight larger than 250KDa with acetic acid aqueous solution with PH 2-3; a polyurethane solution (with viscosity-average molecular weight ranging from 5 to 7 ten thousand) (arginine methyl ester end capping) of the formula 4 in example 1 (10% of a mixed solution of chloroform and DMF) is prepared);
(3) And (3) putting the magnesium alloy material coated with the water control layer in an electrostatic spinning machine, uniformly rotating, spraying the collagen solution and the polyurethane solution oppositely, wherein the spinning voltage is 10-15KV, the receiving distance is 10cm, the spinning speed of the collagen solution is 2ml/h, and the spinning speed of the polyurethane solution is 10ml/h, so that the magnesium alloy wire coated with the inducing layer is obtained.
Sample 4: the polyurethane of the formula 3 in the example 1 and the arginine methyl ester end-capped polyurethane of the formula 4 in the example 1 (viscosity average molecular weight range is 5-7 ten thousand) are selected, and collagen is not added, and the preparation method is as follows:
(1) A ZK61M magnesium alloy wire rod is prepared by taking a polyurethane (viscosity average molecular weight range is 15-20 ten thousand) solution (30 percent prepared by trichloromethane) of the formula 3 in the embodiment 1, dip-coating magnesium wires, and airing to form a water control layer (the thickness of the obtained water control layer is 0.1-0.15mm, and the porosity of more than 90 percent is 10-50 nm);
(2) And (3) putting the magnesium alloy material coated with the water control layer in an electrostatic spinning machine, uniformly rotating, preparing 10% of solution (trichloromethane and DMF mixed solution) of polyurethane (with viscosity average molecular weight ranging from 5 to 7 ten thousand) (blocked by arginine methyl ester), spinning at the voltage of 10-15KV, the receiving distance of 10cm and the spinning speed of 10ml/h, and obtaining the magnesium alloy wire coated with the induction layer.
The wires obtained from samples 1,2, 3 and 4 were soaked in simulated body fluid (SBF solution), surface corrosion was observed, the prepared scaffolds were simultaneously taken to directly contact L929 mouse fibroblasts, and after 72h of co-culture, the proliferation rate of cells was determined by MTT method to determine the biocompatibility of magnesium alloy wires with different surface treatments, the results are shown in table 4:
TABLE 4 degradation results of degradable biomaterials prepared from samples 1-4 in simulated body fluids
The experimental results in table 4 show that the addition of collagen contributes to the proliferation of cells, but no significant difference exists, the degradable polyurethane blocked by arginine methyl ester shows good cell proliferation, and the porosity of the water control layer has significant effect on realizing the control of the degradation process of the magnesium alloy material.
The sandwich type degradable biological material takes high-purity magnesium or magnesium alloy as a core material, is coated by at least two layers of degradable coatings, and can effectively control the area of body fluid contacting the magnesium alloy material by controlling the thickness and the aperture of the material, thereby effectively controlling the degradation speed of the magnesium material. The degradable polyurethane material with hydroxyl end capping and polycaprolactone diol as soft segment is screened in the research process, the degradation speed of the degradable polyurethane material in the water control coating is effectively longer than that of the magnesium alloy material by controlling the porosity of the material in the processing process, the degradable polyurethane material with amino acid or derivative end capping is selected in the induction coating, the new tissue can be induced to grow and cover on the surface of the material rapidly, the magnesium material and the degradation product thereof are covered by the degradable polyurethane material and are separated from the tissue, the degradation product of the magnesium material is gradually converted into ions in the water control coating, and the ions slowly permeate into body fluid through the gaps of the degradable polyurethane material to be absorbed and metabolized, and after the magnesium material is completely degraded, the degradable polyurethane is also gradually degraded and absorbed and metabolized in the growth process of the new tissue.
The above description is only an example of the present invention and is not intended to limit the scope of the present invention, and all similar structures or processes used in the present specification or directly or indirectly applied to other related technical fields are encompassed by the present invention.
Claims (10)
1. A sandwich type degradable biological material is characterized in that: the magnesium-containing degradable metal core material is characterized by comprising a magnesium-containing degradable metal core material, wherein a water control coating and an induction coating are sequentially coated on the surface of the degradable metal core material from inside to outside; the water-controlling coating is a degradable polyurethane coating, and the inducing coating is a degradable polyurethane coating, a collagen coating or a mixed coating of degradable polyurethane and collagen; wherein, the ratio of the weight of the degradable metal core material to the total weight of the water control coating and the induction coating is 1:1-10.
2. The sandwich-type degradable biomaterial of claim 1, wherein: the degradable metal core material is high-purity magnesium or magnesium alloy; the purity of the high-purity magnesium is more than 99.9 percent; the magnesium alloy comprises the following additive components of one or the combination of more than two of iron, copper, zinc, cobalt, manganese, chromium, selenium, iodine, nickel, fluorine, molybdenum, vanadium, tin, silicon, strontium, boron, rubidium, arsenic and silver.
3. The sandwich-type degradable biomaterial of claim 1, wherein: the degradable polyurethane in the water control coating is polycaprolactone type polyurethane; the polycaprolactone type polyurethane has the structure that polycaprolactone dihydric alcohol is used as a soft segment, LDI is used as a hard segment, and the viscosity average molecular weight is 3-50 ten thousand.
4. The sandwich degradable biomaterial of claim 3, wherein: the polycaprolactone diol is generated by the reaction of ethylene glycol, 1,3-propylene glycol or polyethylene glycol with the molecular weight of 200-2000 and epsilon-caprolactone under the action of a chain extender; the chain extender is one of ethylene glycol, 1,3-propylene glycol, 1,4-butanediol, 1,5 pentanediol, 1,4-butanediamine and 1,5 pentanediamine.
5. The sandwich-type degradable biomaterial of claim 3 or 4, wherein: the polycaprolactone type polyurethane in the water control coating is diol or diamine terminated polycaprolactone type polyurethane; the degradable polyurethane used in the induction coating is amino acid or polypeptide-terminated degradable polyurethane.
6. The sandwich-type degradable biomaterial of claim 1, wherein: the thickness or the diameter of the degradable metal core material is 0.1 mm-2 mm; the total thickness of the water control coating and the induction coating is 10 mu m-2 mm; the thickness of the water control coating is 5 mu m-1 mm, and the thickness of the induction coating is 5 mu m-1 mm; the aperture of the water control coating is 1 nm-200 nm, and the aperture of the induction coating is 0.1 μm-200 μm.
7. A method for preparing the sandwich-type degradable biomaterial according to any one of claims 1 to 6, wherein: the method comprises the following steps:
s1, magnesium wire treatment: after cleaning high-purity magnesium or magnesium alloy materials, treating the materials by a phosphate conversion film method, a phytic acid conversion film method, micro-arc oxidation, a rare earth salt conversion film method or an organic matter conversion film method, or performing fluorination treatment on the surface of a bare bracket, or performing polishing treatment on the materials;
s2, preparing a water control layer: dissolving degradable polyurethane in an organic solvent to prepare a solution with the concentration of 10-50%, forming a water-controlling coating on the surface of the material prepared in the step S1 in a mode of electrostatic spraying, ultrasonic atomization spraying or dip coating, and drying by blowing or vacuum drying;
s3, preparing an inducing layer: dissolving degradable polyurethane or collagen in an organic solvent to prepare a solution with the concentration of 5-30%, forming an induction coating on the surface of the material prepared in the step S2 in a mode of electrostatic spraying, ultrasonic atomization spraying, electrostatic spinning or dip coating, and drying by blowing or vacuum drying;
and S4, performing EO sterilization and analysis on the material prepared in the S3, and sealing and packaging to obtain the material.
8. A method for preparing the sandwich-type degradable biomaterial according to any one of claims 1 to 6, wherein: the method comprises the following steps:
s1, magnesium wire treatment: after cleaning high-purity magnesium or magnesium alloy materials, treating the materials by a phosphate conversion film method, a phytic acid conversion film method, micro-arc oxidation, a rare earth salt conversion film method or an organic matter conversion film method, or performing fluorination treatment on the surface of a bare bracket, or performing polishing treatment on the materials;
s2, preparing a water control layer: dissolving degradable polyurethane in an organic solvent to prepare a solution with the concentration of 10-50%, forming a water-controlling coating on the surface of the material prepared in the step S1 in a mode of electrostatic spraying, ultrasonic atomization spraying or dip coating, and drying by blowing or vacuum drying;
s3, preparing a drug release coating: preparation of a second inducing layer: preparing a collagen water solution and a proper amount of BMP into a solution with the concentration of 2-5%, forming an induction coating on the surface of the material prepared in the step S2 in a mode of electrostatic spraying, ultrasonic atomization spraying, electrostatic spinning or dip coating, and drying by blowing or vacuum drying;
s4, preparing a first induction layer: dissolving degradable polyurethane in an organic solvent to prepare a solution with the concentration of 5-30%, forming an induction coating on the surface of the material prepared in the step S2 in a mode of electrostatic spraying, ultrasonic atomization spraying, electrostatic spinning or dip coating, and drying by blowing or vacuum drying;
s5, preparing a second induction layer: preparing a collagen aqueous solution into a solution with the concentration of 2-5%, forming an induction coating on the surface of the material prepared in the step S2 in a mode of electrostatic spraying, ultrasonic atomization spraying, electrostatic spinning or dip coating, and drying by blowing or vacuum drying;
and S6, performing EO sterilization and analysis on the material prepared in the S3, and sealing and packaging to obtain the material.
9. Use of a sandwich-type degradable biomaterial according to any one of claims 1 to 6 in the preparation of a plant intervention medical product, wherein: the implant intervention medical product is one of a hollowed-out stent, a surgical implant, a stent graft, a vascular prosthesis, a vascular access, a meningeal patch, a suture, a surgical mesh, a surgical thread, a monofilament pull line, a double-filament pull line, a surgical plate, a surgical thread, a surgical nail, a surgical anchor or a surgical clip.
10. Use of a sandwich-type degradable biomaterial according to claim 9 for the preparation of an implantable interventional medical product, characterized in that: the plant intervention medical product also contains polypeptide, protein, growth factor or medicine with physiological activity.
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| US20110076319A1 (en) * | 2007-01-30 | 2011-03-31 | Michael Orlowski | Bioresorbable metal stent with controlled resorption |
| CN106267341A (en) * | 2016-08-30 | 2017-01-04 | 圆容生物医药无锡有限公司 | One can organize induction bio-medical material |
| CN110680960A (en) * | 2018-07-04 | 2020-01-14 | 苏州纳晶医药技术有限公司 | Controllable gradient degradation spiral tectorial membrane stent, preparation method and application thereof |
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| US20110076319A1 (en) * | 2007-01-30 | 2011-03-31 | Michael Orlowski | Bioresorbable metal stent with controlled resorption |
| CN106267341A (en) * | 2016-08-30 | 2017-01-04 | 圆容生物医药无锡有限公司 | One can organize induction bio-medical material |
| CN110680960A (en) * | 2018-07-04 | 2020-01-14 | 苏州纳晶医药技术有限公司 | Controllable gradient degradation spiral tectorial membrane stent, preparation method and application thereof |
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