阅读说明：本技术 一种可控梯度降解螺旋状覆膜支架、其制备方法及其用途 (Controllable gradient degradation spiral tectorial membrane stent, preparation method and application thereof ) 是由 不公告发明人 于 2018-07-04 设计创作，主要内容包括：本发明公开了一种可控梯度降解螺旋状覆膜支架、其制备方法及其用途,由可降解医用聚氨酯和可降解镁合金材料组成,其中可降解医用聚氨酯中含有如下化学结构：PCL-PEG-PCL,其中PEG的分子量为200-1000,PCL的分子量为200-10000,可降解镁合金材料为螺旋状支架结构；可控梯度降解螺旋状覆膜支架的物理性能应满足如下技术参数：断裂强度应不小于1N,抗压力应不小于2N,镁合金经过表面处理后的降解特性为随不同时间而呈现梯度降解。(The invention discloses a controllable gradient degradation spiral tectorial membrane stent, a preparation method and application thereof, which are composed of degradable medical polyurethane and a degradable magnesium alloy material, wherein the degradable medical polyurethane contains the following chemical structures: the molecular weight of the PCL-PEG-PCL is 200-1000, the molecular weight of the PCL is 200-10000, and the degradable magnesium alloy material is of a helical scaffold structure; the physical properties of the controllable gradient degradation spiral tectorial membrane stent meet the following technical parameters: the breaking strength is not less than 1N, the compressive resistance is not less than 2N, and the magnesium alloy is subjected to surface treatment and then is subjected to gradient degradation along with different time.)

1. The controllable gradient degradation spiral tectorial membrane stent is characterized by consisting of degradable medical polyurethane and a degradable magnesium alloy material, wherein the soft segment of the degradable medical polyurethane contains the following chemical structures:

PCL-PEG-PCL, wherein the molecular weight of PEG is 200-10000 and the molecular weight of PCL is 200-10000;

the degradable magnesium alloy material has a spiral structure;

the physical properties of the controllable gradient degradation spiral tectorial membrane stent meet the following technical parameters:

the breaking strength is not less than 1N, the compressive resistance is not less than 2N, and the magnesium alloy after surface treatment has the degradation characteristic that the magnesium alloy is soaked in an aqueous solution and is degraded in a gradient manner along with different time.

2. The controllable gradient degradation spiral tectorial membrane stent of claim 1, which is composed of degradable medical polyurethane and degradable magnesium alloy material, wherein the hard segment of the degradable medical polyurethane is lysine diisocyanate, and the soft segment has the following chemical structure:

PCL-PEG-PCL, wherein the molecular weight of PEG is 200-1000, and the molecular weight of PCL is 200-5000;

the degradable magnesium alloy material has a spiral structure;

the physical properties of the controllable gradient degradation spiral tectorial membrane stent meet the following technical parameters:

the breaking strength is not less than 1N, the compressive resistance is not less than 2N, and the magnesium alloy after surface treatment has the degradation characteristic that the magnesium alloy is soaked in an aqueous solution and is degraded in a gradient manner along with different time;

the weight percentage of the degradable medical polyurethane and the degradable magnesium alloy material is 10-99 percent to 1-90 percent.

3. The controllable gradient degradation spiral tectorial membrane stent of claim 2, which is composed of degradable medical polyurethane and degradable magnesium alloy material, wherein the hard segment of the degradable medical polyurethane is lysine diisocyanate, and the soft segment has the following chemical structure:

PCL-PEG-PCL, wherein the molecular weight of PEG is 200-600, and the molecular weight of PCL is 300-3500; the chain extender is selected from one of propylene glycol and diamine or diamine-like;

the degradable magnesium alloy material has a spiral structure and can be a single-strand spiral or formed by weaving a plurality of strands of spirals;

the physical properties of the controllable gradient degradation spiral tectorial membrane stent meet the following technical parameters:

the breaking strength should not be less than 1N; the elongation at break should be not less than 50%; the compressive resistance is not less than 2N, and the magnesium alloy after surface treatment has the degradation characteristic that the magnesium alloy is soaked in an aqueous solution and is degraded in a gradient manner along with different time;

the weight percentage of the degradable medical polyurethane and the degradable magnesium alloy material is 30-99 percent to 1-70 percent.

4. The controllable gradient degradation spiral-shaped film-covered stent according to any one of claims 1 to 3, wherein the degradable polyurethane is prepared by one of the following preparation methods:

the first method comprises the following steps: synthesizing linear polycaprolactone diol by using CL and PEG with the molecular weight of 200-1000 in different proportions, reacting the product with lysine diisocyanate, using propylene glycol or amino acid diamine as a chain extender, and using organotin or organic bismuth as a catalyst to obtain the medical polyurethane used by the stent;

and the second method comprises the following steps: PDO and different dihydric alcohols are used for synthesizing linear PPDO polydiol, the product is reacted with different diisocyanate, different dihydric alcohol, amino acid diamine or diamine are used as chain extenders, organic tin or organic bismuth is used as catalysts, medical polyurethane is obtained by the reaction, and the medical polyurethane can be further added as a stent film-coating material for improving the degradation performance of the stent;

and the third is that: LA and GA with different molecular weights initiated by micromolecular diol are used for independently or copolymerizing to obtain polymer diol, adipic acid polyester diol and oxalic acid polyester diol which are used as soft chains, the soft chains are reacted with LDI and different micromolecular diols or diamine, and organotin or organic bismuth is used as a catalyst to obtain medical polyurethane through the reaction, so that the degradation performance of the stent can be improved, and the medical polyurethane can be further added as a stent coating material;

and fourthly: hydroxyl-terminated polydimethylsiloxane is used as a soft segment, the hydroxyl-terminated polydimethylsiloxane reacts with LDI and micromolecular dihydric alcohol or diamine, and organotin or organic bismuth is used as a catalyst to form an organosilicon-polyurethane block copolymer consisting of soft segments and hard segments which are alternately arranged.

5. The controllable gradient degradation spiral-shaped film-covered stent as claimed in any one of claims 1 to 3, wherein the degradable medical polyurethane material further comprises polymer diol obtained by copolymerization of one or two of LA, GA, CL, PDO and adipic anhydride as an initiator, wherein the chain extender is selected from small-molecule diol, diamine or diamine-like, specifically one or two of ethylene glycol, diethylene glycol, tetraethylene glycol, 1, 3-propanediol, 1, 4-butanediol, 1, 6-hexanediol, 1, 7-heptanediol, 1, 8-octanediol, 1, 9-nonanediol, 1, 10-decanediol, ethylenediamine, propylenediamine, butanediamine, pentanediamine and amino acid diamine.

6. The controllable gradient degradation spiral tectorial membrane scaffold of claim 1 or 2, which comprises other high molecular materials,

wherein the hydrophobic polymer material comprises: one or two of polylactic acid, polycaprolactone, poly-p-dioxanone and copolymers thereof, polytrimethylene carbonate, polylactic acid-trimethylene carbonate copolymer, polycaprolactone-trimethylene carbonate copolymer, polyglycolic acid and polylactic acid-glycolic acid copolymer, wherein the viscosity average molecular weight of the biodegradable high polymer material is 500-1000000, so as to adjust one of the hardness and the softness of the material;

wherein the hydrophilic polymer material comprises: alginate, modified alginate and alginate degraded into hexosamine and N-acetylglucosamine, polyethylene pyrrolidone series, starch grafted acrylonitrile, starch grafted hydrophilic monomer, polyacrylate, vinyl acetate copolymer, polyvinyl alcohol, modified polyvinyl alcohol, carboxymethyl cellulose, cellulose grafted acrylonitrile, cellulose grafted acrylate, cellulose xanthated grafted acrylate, cellulose grafted acrylamide, and one of cellulose carboxymethyl-post-epichlorohydrin cross-linking; or one or more of polymer antibacterial water-absorbing material, various polyamino acids, chitosan and its derivatives, and polylysine.

7. The spiral tectorial membrane stent capable of controlled gradient degradation according to claim 1 or 2, wherein the degradable magnesium alloy material is selected from materials refined by various chemical elements harmless to human body, and specifically comprises one or two combinations of high-purity magnesium, magnesium-iron alloy, magnesium-zinc alloy, magnesium-calcium alloy and magnesium-aluminum alloy, preferably high-purity magnesium and magnesium-zinc alloy, such as: Mg-Nd-Zn-Zr, Mg-Zn-Mn, Mg-Zn-Zr, Mg-Zn-Mn-Se-Cu and Mg-Zn binary alloy.

8. The controlled gradient degradation helical coating stent of any one of claims 1-3, comprising a contrast agent, in particular one selected from the group consisting of zirconium dioxide, barium sulfate and iodine preparations.

9. A preparation method of a controllable gradient degradation spiral tectorial membrane stent, which is characterized in that,

one of the preparation methods is as follows:

(1) preparing gradient degradable magnesium wires: completely soaking round or flat magnesium wires with the length of 1 meter in a dipotassium hydrogen phosphate aqueous solution containing phytic acid with a certain concentration or a hydrofluoric acid solution with the concentration of 5% -30%, lifting for 1-10cm every 1-10 minutes to form a gradient passivation protective film, marking one end with short passivation time as a B end and one end with long passivation time as an A end;

(2) coiling the degradable magnesium alloy wire processed in the step (1) to prepare a spiral pattern, dissolving the degradable medical polyurethane material or composite material in an organic solvent to prepare a coating material, and uniformly spraying the coating material on the surface of the stent through an electrostatic spinning nozzle in the continuous rotating process in the step (1) to prepare a film-coated composite stent with the thickness of 0.001-1mm, preferably 0.01-0.5 mm;

(3) dissolving hydrophilic material in water to prepare the required concentration, and dip-coating or uniformly spraying the hydrophilic material on the surface of the stent to prepare a water-soluble coating which is convenient for a clinician to place and use;

the second preparation method is as follows:

(1) preparing gradient degradable magnesium wires: completely soaking round or flat magnesium wires with the length of 1 meter in a dipotassium hydrogen phosphate aqueous solution containing phytic acid with a certain concentration or a hydrofluoric acid solution with the concentration of 5% -30%, lifting for 1-10cm every 1-10 minutes to form a gradient passivation protective film, marking one end with short passivation time as a B end and one end with long passivation time as an A end;

(2) coiling the degradable magnesium alloy wire processed in the step (1) to form a spiral pattern, threading the spiral pattern with tetrafluoro or a metal rod, spirally fixing the magnesium wire in a special corrugated pipe manufacturing grinding tool according to the processing technology for manufacturing the corrugated pipe, extruding the degradable medical polyurethane material by using a small pipe extruder to form a film-covered composite stent with the thickness of 0.001-1mm, preferably 0.1-0.5 mm;

(3) the hydrophilic material is dissolved in water to prepare the required concentration, and the hydrophilic material is dipped or evenly sprayed on the surface of the bracket to prepare the water-soluble coating which is convenient for a clinician to place and use.

10. The application of the gradient-controlled degradation spiral tectorial membrane stent is characterized in that the gradient-controlled degradation spiral tectorial membrane stent is used for preparing various internal pipeline stents and specifically comprises the following steps: a blood vessel, vein, esophagus, biliary tract, trachea, bronchus, small intestine, large intestine, urethra, ureter, or other segment near the passageway of the tubular body is a vascular stent, tracheal stent, bronchial stent, urethral stent, esophageal stent, biliary stent, ureter stricture stent, stent for small intestine, stent for large intestine, laryngeal implant, bypass catheter, or ileostomy.

Technical Field

The invention belongs to the technical field of medical biomaterials and medical treatment, and particularly relates to a controllable gradient degradable spiral covered stent, a preparation method and application thereof.

Background

Degradable stents may be used in a variety of vessels within the body, including natural body passages or body lumens, but also including artificial body openings and body lumens such as bypasses or ileostomies. Examples include: coronary artery stent, intracranial stent, peripheral stent, splenic artery stent, intraoperative stent, heart valve stent, biliary stent, esophageal stent, intestinal stent, pancreatic stent, urethral stent, tracheal stent and ureteral stent, the clinical stent research and application is the most mature, and the vascular stent using polylactic acid as a drug-loaded coating has been reported in literature, and the vascular stent can be directly prepared by using PLLA (polylactic acid) through processing technologies such as 3D (three-dimensional) printing or carving.

The degradable scaffold comprises a high polymer material scaffold and a degradable metal scaffold, wherein the degradable high polymer material comprises: PLLA, PLA, PGA, PDO and PCL, wherein the PLLA has better rigidity, flexibility, stability and heat resistance, has been successfully applied to a coating material of a metal stent and a stent prepared by the PLLA, the PLA, the PGA, the PDO and the PCL, but the application of the PLLA as an implant product is limited by the aseptic inflammation problem caused by a local acidic environment caused by degradation products of the PLLA.

Magnesium is an essential element for human metabolism, and is present in the human body in an amount next to potassium, sodium and calcium, and approximately half of all magnesium in the body is contained in bone tissues. Magnesium is considered a cofactor for many enzymes, with stable DNA and RNA structures; magnesium is maintained between O.7 and 1.05mmol/L through the kidneys and intestinal tract in vivo; magnesium stimulates new bone growth and has good histocompatibility. The main drawback of magnesium is its low corrosion resistance, and in the physiological environment of pH (7.4-7.6), magnesium has a strong reducing action and therefore loses its mechanical integrity before the tissue has healed sufficiently, and generates hydrogen that the body cannot absorb in time. Magnesium-based materials applied to human bodies in early days generate a large amount of gas after being implanted into the human bodies, so that magnesium cannot be applied to the human bodies, the preparation of magnesium-based alloys with controllable gradient degradation has a very practical significance in that hydrogen generated in the magnesium degradation process is metabolized by tissue fluid, and magnesium alloy materials with different degradation and processing properties are hot spots of research in the future.

The degradable metal stent material comprises a magnesium alloy material and an iron alloy material, wherein the magnesium alloy material gradually becomes the mainstream of the research of the degradable stent due to the excellent processing performance of the magnesium alloy material. Because tissue organs at different parts such as blood vessels, trachea, urethra and the like have different performance requirements on the biological material for tissue engineering, the acquisition of a series of biological materials with different mechanical properties, degradation properties, processability and the like is very important, and because the mechanical properties of a single material and the acid-base environment generated by degradation cause aseptic inflammation in vivo and other problems, a better stent design process is adopted, and the search for a more appropriate composite polymer material is the main direction for developing an in vivo implanted stent.

Many literature researches report that various polyurethane materials have the characteristics of good mechanical property, biocompatibility, blood compatibility, easiness in processing and the like, and have attractive prospects in the fields of drug sustained-release carriers, medical surgical materials, tissue engineering scaffolds and the like. However, due to the difficulty in controlling the material synthesis process, and the need for a large amount of basic research and experiments to synthesize and evaluate the material with controllable gradient degradation, no medical polyurethane material with controllable gradient degradation is on the market at present.

The degradable medical polyurethane is polymerized by four parts of different compounds, and the specific reaction process is as follows: different initiators initiate polymer diols synthesized by different monomers, different diisocyanates react with the polymer diols, then different chain extenders further react and extend the chain of the obtained products, therefore, the change of any one raw material can lead the obtained polyurethane material to have different physicochemical properties and degradation properties, even if the same raw material is adopted, the dosage of the monomer or the chain extender and the reaction conditions are different in the reaction process, the specific chemical structures of the obtained polyurethane are also different, the degradation properties are also different, and the obtained polyurethane material has great difference in specific application. We have found that the degradation time of the polyurethane obtained by using different proportions of monomers and under the same process conditions is different, so that the material shows different degradation performance on the prepared product.

Due to the complex diversity of biopolymer materials, the structure and the feeding amount of monomers with different compositions and different proportions are different, the chemical structure, the degradation performance and the physical and chemical properties of the generated degradable polyurethane are greatly different, and in a strict sense, even though the fed monomers are completely the same, the chemical structures of final products obtained under different feeding amounts and reaction conditions are completely different. Especially, the degradation time of the degraded material, synthesis of one batch and test of one batch are also needed to obtain the optimal data, so the invention is creative in this respect.

Although there are many documents reporting degradable medical polyurethane and its application in medicine, the scheme for preparing the material is also various due to the diversity of the material. Such as: CN1950098A (Federal scientific and industrial research organization) in specification No. 18.4.4.2001 discloses a biodegradable polyurethane degradable vessel support in example CN1950098A, the document does not give detailed technical parameters, and the specific physical properties of the obtained product are difficult to evaluate; such as: CN101636187A (Mobunk corporation) discloses a medical polyurethane, wherein the soft segment of the polyurethane adopts polyol with molecular weight of 200-1000, and the polyol is basically of a hydrophobic structure, the molecular weight of polymer diol in the invention is far higher than 1000, and the chemical structure is completely different, and the behavior of the obtained polymer in the degradation process is also greatly different due to the introduction of soft segment hydrophilic group PEG (200-1000); such as: CN104744661A was written before the formation of the patent, and since the chain extender employs BDO, the synthesized polyurethane product generates slight cytotoxicity, for this reason, we have made further research, improvement and optimization in the prior art scheme, and finally abandon the scheme of employing BDO as the chain extender.

At present, through years of research, the batch production of the degradable polycaprolactone type polyurethane material with PEG (200-.

The degradable polycaprolactone polyurethane with LDI as the hard segment has more advantages:

(1) the degradation product is lysine;

(2) the degradation products do not lower the pH of the nearby tissue, and therefore do not cause inflammation;

(3) the surface is easy to connect with biological reagents;

(4) friendly interface between the surface and the cells, small non-biological specific action and the like.

Research on the application of the degradable polycaprolactone type polyurethane with PEG (200-1000) as an initiator as a coating covered stent has not been reported, and related products are not on the market.

Disclosure of Invention

The controllable gradient degradation of degradable materials is a big problem in the field, such as polylactic acid materials, the degradation fragments are not controllable, so that the size of the degradation product fragments is too large, and the stent tube cannot be used in the invention, such as the degradable ureteral stent in the embodiment of the invention, because the secondary tube drawing is not needed clinically, the risk and the pain of the secondary operation of the patient are greatly reduced, has positive medical effect in clinic, the clinician hopes that the product can be on the market, a great deal of research data reports the scheme that scholars develop degradable ureter stents, however, the requirements of clinical use are not met, so that similar products are not sold on the market all over the world, and the development difficulty of medical high polymer materials with physical properties, biodegradation performance and biological safety meeting the requirements of clinical use is very visible.

In order to finely adjust the degradation fragments of the degradable stent and achieve better clinical effect, the controllable gradient degradation spiral covered stent is realized by the cooperative degradation behavior of the controllable gradient degradation medical polyurethane material prepared by different processes and the gradient degradation characteristic of the magnesium alloy after gradient surface treatment.

The invention discloses a controllable gradient degradation spiral tectorial membrane stent,

the degradable medical polyurethane consists of degradable medical polyurethane and a degradable magnesium alloy material, wherein the soft segment of the degradable medical polyurethane contains the following chemical structure:

PCL-PEG-PCL, wherein the molecular weight of PEG is 200-10000 and the molecular weight of PCL is 200-10000;

the degradable magnesium alloy material has a spiral structure;

the physical properties of the controllable gradient degradation spiral tectorial membrane stent meet the following technical parameters:

the breaking strength is not less than 1N, the compressive resistance is not less than 2N, and the magnesium alloy after surface treatment has the degradation characteristic that the magnesium alloy is soaked in an aqueous solution and is degraded in a gradient manner along with different time.

The invention relates to a controllable gradient degradation spiral tectorial membrane bracket, which consists of degradable medical polyurethane and a degradable magnesium alloy material, wherein the hard segment of the degradable medical polyurethane is lysine diisocyanate, and the soft segment contains the following chemical structure:

PCL-PEG-PCL, wherein the molecular weight of PEG is 200-1000, and the molecular weight of PCL is 200-5000;

the degradable magnesium alloy material has a spiral structure;

the physical properties of the controllable gradient degradation spiral tectorial membrane stent meet the following technical parameters:

the breaking strength is not less than 1N, the compressive resistance is not less than 2N, and the magnesium alloy after surface treatment has the degradation characteristic that the magnesium alloy is soaked in an aqueous solution and is degraded in a gradient manner along with different time.

The weight percentage of the degradable medical polyurethane and the degradable magnesium alloy material is 10-99 percent to 1-90 percent.

The invention relates to a controllable gradient degradation spiral tectorial membrane bracket, which consists of degradable medical polyurethane and a degradable magnesium alloy material, wherein the hard segment of the degradable medical polyurethane is lysine diisocyanate, and the soft segment contains the following chemical structure:

PCL-PEG-PCL, wherein the molecular weight of PEG is 200-600, and the molecular weight of PCL is 300-3500;

the degradable magnesium alloy material has a spiral structure and can be a single-strand spiral or formed by weaving a plurality of strands of spirals;

the physical properties of the controllable gradient degradation spiral tectorial membrane stent meet the following technical parameters:

the breaking strength should not be less than 1N; the elongation at break should be not less than 50%; the compressive resistance should be not less than 2N.

The weight percentage of the degradable medical polyurethane and the degradable magnesium alloy material is 70-99 percent and 1-30 percent.

The chain extender is selected from one of propylene glycol (more preferably 1, 3-propylene glycol) and diamine or diamine-like, and the weight percentage of the chain extender in the degradable medical polyurethane is 1.0-20%.

The diamine or diamine-like substance specifically comprises amino acid diamine as chain extender, and the structural formula is as follows:

wherein, P is dihydric alcohol, X is a number between 2 and 20, m and n are one of 20 common amino acids, and m and n can be the same or different.

The diamine comprises amino acid with two amino groups, derivatives and salts thereof, and specifically comprises amino acid hydrochloride, such as lysine methyl ester dihydrochloride, lysine ethyl ester dihydrochloride, cystine methyl ester dihydrochloride, cystine ethyl ester dihydrochloride, ornithine methyl ester dihydrochloride, and ornithine ethyl ester dihydrochloride.

The dihydric alcohol is selected from one or two of ethylene glycol, diethylene glycol, tetraethylene glycol, 1, 3-propylene glycol, 1, 4-butanediol, 1, 5-pentanediol, 1, 6-hexanediol, 1, 7-heptanediol, 1, 8-octanediol, 1, 9-nonanediol, and 1, 10-decanediol;

such as: the compound which is obtained by esterification reaction of two molecules of glycine and one molecule of 1 and 3 of propylene glycol and is connected through two ester bonds and has two active amino groups is as follows:

similar examples are: two molecules of alanine and one molecule of 1 and 3 propylene glycol are subjected to esterification reaction to obtain a compound which is connected through two ester bonds and has two active amino groups, one molecule of alanine is subjected to esterification reaction with one molecule of valine and one molecule of 1 and 3 propylene glycol to obtain a compound which is connected through two ester bonds and has two active amino groups, two molecules of leucine and one molecule of 1 and 3 propylene glycol are subjected to esterification reaction to obtain a compound which is connected through two ester bonds and has two active amino groups, isoleucine is subjected to esterification reaction with leucine and one molecule of 1 and 3 propylene glycol to obtain a compound which is connected through two ester bonds and has two active amino groups, two molecules of phenylalanine and one molecule of 1 and 3 propylene glycol are subjected to esterification reaction to obtain a compound which is connected through two ester bonds and has two active amino groups, proline and one molecule of 1 and 1, 3-propanediol through esterification reaction to obtain a compound which is connected through two ester bonds and has two active amino groups, two molecules of tryptophan and one molecule of 1, 3-propanediol through esterification reaction to obtain a compound which is connected through two ester bonds and has two active amino groups, two molecules of serine and one molecule of 1, 3-propanediol through esterification reaction to obtain a compound which is connected through two ester bonds and has two active amino groups, two molecules of cysteine and one molecule of 1, 3-propanediol through esterification reaction to obtain a compound which is connected through two ester bonds and has two active amino groups, two molecules of methionine and one molecule of 1, 3-propanediol through esterification reaction to obtain a compound which is connected through two ester bonds and has two active amino groups, two molecules of asparagine and one molecule of 1, 3-propanediol through esterification reaction to obtain a compound which is connected through two active amino groups, the compound with two active amino groups is obtained by esterification reaction of two molecules of glutamine and one molecule of 1 and 3 propanediol through two ester bonds, the compound with two active amino groups is obtained by esterification reaction of two molecules of threonine and one molecule of 1 and 3 propanediol through two ester bonds, the compound with two active amino groups is obtained by esterification reaction of one molecule of aspartic acid, one molecule of glutamic acid and one molecule of 1 and 3 propanediol through two ester bonds, and the compound with two active amino groups is obtained by esterification reaction of one molecule of 1 and 3 propanediol through two ester bonds.

The preparation method of the gradient degradable magnesium wire is as follows:

the method comprises the steps of completely soaking 1 meter long magnesium wire (0.2-0.5 mm in width and 0.15mm in thickness) in 10-30% hydrofluoric acid solution or other passivation solutions with good biological safety (such as phosphate-potassium permanganate solution, phosphate buffer salt-phytic acid solution and the like in a certain proportion disclosed by documents), lifting for a certain distance every 0.4-5 minutes to form a gradient passivation protective film with different degradation times, cleaning with acetone after passivation, and drying for later use.

The invention relates to a controllable gradient degradation spiral tectorial membrane stent, wherein the degradable medical polyurethane material can also comprise polymer diol obtained by copolymerization of one or two of LA, GA, CL, PDO and adipic anhydride by taking micromolecule diol as an initiator (one of PEG200, PEG300, PEG400, PEG600, ethylene glycol, diethylene glycol, 1, 3-propanediol, 1, 4-butanediol, 1, 6-hexanediol, 1, 7-heptanediol, 1, 8-octanediol, 1, 9-nonanediol and 1, 10-decanediol), the chain extender is selected from micromolecule diol, diamine or diamine-like, specifically selected from ethylene glycol, diethylene glycol, tetraethylene glycol, 1, 3-propanediol, 1, 4-butanediol, 1, 6-hexanediol, 1, 7-heptanediol, 1, 8-octanediol and 1, 9-nonanediol, 1, 10-decanediol, ethylenediamine, propylenediamine, butylenediamine, pentylenediamine, and amino-acid diamine (for example, two-segment compounds with amino groups obtained by esterification of carboxyl groups in two-molecule amino acids with small-molecule diol); the degradable polyurethane is prepared by one of the following preparation methods:

the first method comprises the following steps: synthesizing linear polycaprolactone diol by using CL and PEG with molecular weight of 200-600 in different proportions, reacting the product with lysine diisocyanate, using different diols or diamines as chain extenders and using organic tin or organic bismuth as catalysts to obtain the medical polyurethane adopted by the invention;

and the second method comprises the following steps: PDO and different dihydric alcohols are used for synthesizing linear PPDO polydiol, the product is reacted with different diisocyanate, different dihydric alcohol or diamine is used as a chain extender, organic tin or organic bismuth is used as a catalyst, medical polyurethane is obtained by the reaction, and the medical polyurethane can be further added as a stent film-coating material for improving the degradation performance of the stent;

and the third is that: using LA, GA polymer diol, adipic acid polyester diol and oxalic acid polyester diol with different molecular weights initiated by small molecular diol (one of PEG200-600, ethylene glycol, diethylene glycol, 1, 3-propanediol, 1, 4-butanediol, 1, 6-hexanediol, 1, 7-heptanediol, 1, 8-octanediol, 1, 9-nonanediol and 1, 10-decanediol) as soft chains, reacting the soft chains with LDI and different small molecular diols or diamines, using organic tin or organic bismuth as a catalyst, and obtaining medical polyurethane through reaction, wherein the medical polyurethane can be further added as a stent coating material in order to improve the degradation performance of a stent;

and fourthly: hydroxyl-terminated polydimethylsiloxane is used as a soft segment, the hydroxyl-terminated polydimethylsiloxane is reacted with LDI and micromolecular diol or diamine, organic tin or organic bismuth is used as a catalyst to form an organic silicon-polyurethane block copolymer consisting of the soft segment and the hard segment which are alternately arranged, and the organic silicon-polyurethane block copolymer can be further added as a stent film-coating material for improving the degradation performance of the stent.

Wherein the organotin and organobismuth are selected from commercially available medically acceptable catalysts such as: bismuth isooctanoate, bismuth laurate, bismuth neodecanoate, bismuth naphthenate, bismuth oxide, etc., preferably stannous octoate or bismuth octyldecanoate.

The controllable gradient degradation spiral film-coated stent can also comprise other hydrophobic polymer materials and hydrophilic polymer materials, wherein the hydrophobic polymer materials comprise: polylactic acid, polycaprolactone, poly-p-dioxanone and copolymers thereof (PPDO, PLA-PDO) poly-p-dioxanone (PPDO), polytrimethylene carbonate, polylactic acid-trimethylene carbonate copolymer, polycaprolactone-trimethylene carbonate copolymer, polyglycolic acid, polylactic acid-glycolic acid copolymer, polyetheretherketone, polyvinylpyrrolidone and/or polyethylene glycol, polylactone, poly-epsilon-decalactone, polylactide, polyglycolide, copolymers of polylactide and polyglycolide, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyhydroxybutyrate, polyhydroxyvalerate, polyhydroxybutyrate-co-valerate, poly (1, 4-dioxane-2, 3-dione), poly (1, 3-dioxane-2-one), Poly-p-dioxanone, polyanhydrides (such as polymaleic anhydride), polyhydroxymethacrylate, polycyanoacrylate, polycaprolactone dimethacrylate, poly-beta-maleic acid, polycaprolactone butylacrylate, multiblock polymers from oligopolycaprolactone diols and oligodioxanone diols, polyethylene glycol and polybutylene terephthalate)), polyneovalerolactone, polyglycolic acid trimethylcarbonate, polycaprolactone-glycolide, poly (gamma-ethylglutamate), poly (DTH-iminocarbonate), poly (DTE-co-DT-carbonate), poly (bisphenol A-iminocarbonate), polyorthoesters, polyglycolic acid trimethylcarbonate, polytrimethylcarbonate, polyiminocarbonate, poly (N-vinyl) -pyrrolidone, poly (N-vinyl-pyrrolidone), poly (N-vinyl-co-ethylene-butylene terephthalate), poly (N-butylene-co-ethylene-terephthalate), poly, Polyvinyl alcohol, polyester amide, glycolated polyester, polyphosphate, polyphosphazene, poly [ p-carboxyphenoxy) propane ], polyhydroxyvaleric acid, polyanhydride, polyethylene oxide-propylene oxide, flexible polyurethane, polyurethane with amino acid residues in the backbone, polyetherester (such as polyethylene oxide), polyolefin oxalate, polyorthoester, and copolymers thereof, preferably one of polylactic acid, polycaprolactone, polydioxanone and copolymers thereof (PPDO, PLA-PDO) Polydioxanone (PPDO), polytrimethylene carbonate, polylactic acid-trimethylene carbonate copolymer, polycaprolactone-trimethylene carbonate copolymer, polyglycolic acid, polylactic acid-glycolic acid copolymer, the viscosity average molecular weight of the biodegradable high polymer material is 500-1000000, so as to adjust the hardness of the material;

the hydrophilic polymer material comprises one of alginate, modified alginate, alginate degraded into hexosamine and N-acetylglucosamine, polyvinylpyrrolidone series, starch grafted acrylonitrile, starch grafted hydrophilic monomer, carrageenan, fibrinogen, fibrin, collagen, protein-containing polymer, polyamino acid, synthetic polyamino acid, zein, polyacrylate, vinyl acetate copolymer, modified polyvinyl alcohol, carboxymethyl cellulose, cellulose grafted acrylonitrile, cellulose grafted acrylate, cellulose xanthated grafted acrylate, cellulose grafted acrylamide and cellulose carboxymethyl-post-epichlorohydrin cross-linking; or one of a high molecular antibacterial water-absorbing material, polyamino acid, chitosan, polylysine and polyvinyl alcohol.

The invention relates to a controllable gradient degradation spiral tectorial membrane stent, wherein a degradable magnesium alloy material is selected from materials refined by various chemical elements harmless to human bodies, and specifically comprises one or two combinations of high-purity magnesium (the purity is more than 99.0%), magnesium-iron alloy (the weight percentage is 1: 0.01-10), magnesium-zinc alloy (the weight percentage is 1: 0.01-1), magnesium-calcium alloy (the weight percentage is 1: 0.01-1) and magnesium-aluminum alloy (the weight percentage is 1: 0.01-0.1), preferably high-purity magnesium and magnesium-zinc alloy (the weight percentage is preferably 1: 0.01-0.1), for example: Mg-Nd-Zn-Zr, Mg-Zn-Mn, Mg-Zn-Zr, Mg-Zn-Mn-Se-Cu and Mg-Zn binary alloy.

The invention relates to a controllable gradient degradation spiral tectorial membrane stent, one of the preparation methods is as follows:

(1) preparing gradient degradable magnesium wires: completely soaking round or flat magnesium wires (the width is 0.1-2mm, the thickness is 0.1-0.5mm) with the length of 1 meter in a dipotassium hydrogen phosphate aqueous solution containing phytic acid with a certain concentration or a hydrofluoric acid solution with the thickness of 5-30%, lifting for 1-10cm every 1-10 minutes to form a gradient passivation protective film, marking one end with short passivation time as a B end, and marking one end with long passivation time as an A end.

(2) Coiling the treated degradable magnesium alloy wire material in the step (1) to prepare a spiral pattern (a single-strand spiral or a reverse multi-strand spiral) (shown in figures 1 and 2), dissolving the degradable medical polyurethane material or the composite material in an organic solvent (one or two selected from heptane, decane, tetrahydrofuran, isoamyl acetate, hexane, dichloromethane, trichloromethane, cyclohexanone and dimethylformamide) to prepare a coating material (the concentration of the material is 5-50%), and uniformly spraying the coating material on the surface of the stent through an electrostatic spinning nozzle in the process of continuously rotating the step (1) to prepare the coated composite stent, wherein the thickness of the coated composite stent is (0.001-1mm, preferably 0.01-0.5 mm).

(3) The hydrophilic material is dissolved in water to prepare the required concentration, and the hydrophilic material is dipped or evenly sprayed on the surface of the bracket to prepare the water-soluble coating which is convenient for a clinician to place and use.

The second preparation method of the controllable gradient degradation spiral tectorial membrane stent is as follows:

(1) preparing gradient degradable magnesium wires: completely soaking round or flat magnesium wires (the width is 0.1-2mm, the thickness is 0.1-0.5mm) with the length of 1 meter in a dipotassium hydrogen phosphate aqueous solution containing phytic acid with a certain concentration or a hydrofluoric acid solution with the thickness of 5-30%, lifting for 1-10cm every 1-10 minutes to form a gradient passivation protective film, marking one end with short passivation time as a B end, and marking one end with long passivation time as an A end.

(2) Coiling the treated degradable magnesium alloy wire material in the step (1) to form a spiral pattern (single-strand spiral or reverse multi-strand spiral) (shown in figures 1 and 2), threading the wire material by using a tetrafluoro or metal rod, fixing the magnesium wire spiral in a special corrugated pipe manufacturing grinding tool according to the processing technology for manufacturing the corrugated pipe, extruding the degradable medical polyurethane material by using a small pipe extruder to form a film-coated composite stent with the thickness of (0.001-1mm, preferably 0.1-0.5 mm).

(3) The hydrophilic material is dissolved in water to prepare the required concentration, and the hydrophilic material is dipped or evenly sprayed on the surface of the bracket to prepare the water-soluble coating which is convenient for a clinician to place and use.

The covered stent of the invention can also be processed by the following processes:

when preparing the blood vessel stent, on the treated surface of the naked stent, the anticoagulation component is fixed by crosslinking by a crosslinking agent such as glutaraldehyde, the anticoagulation component can be hirudin, heparan sulfate and derivatives thereof such as complete desulfation, N-reacetylated heparin desulfation and N-reacetylated heparin, and an anticoagulation coating which can not activate blood coagulation is prepared;

the method is characterized in that a corrosion-resistant nontoxic conversion coating is formed on the surface of the degradable magnesium alloy through passivation, and commonly used methods comprise a phosphate conversion coating method, a phytic acid conversion coating method, a rare earth salt conversion coating method and an organic matter conversion coating method, or fluorination treatment is carried out on the surface of a bare support, and the specific method comprises the following steps:

polishing an untreated biodegradable magnesium alloy bracket, completely soaking the bracket in 5-25g/L dipotassium hydrogen phosphate aqueous solution containing 0.5-1.5g/L phytic acid at the temperature of 40-70 ℃, and lifting the bracket for a certain distance every a certain time minute according to the requirement of degradation time to form a gradient passivation protective film.

Polishing an untreated biodegradable magnesium alloy bracket, soaking in 10-40% hydrofluoric acid by mass percent for 10-120min, and lifting for a certain distance every a certain time minute according to the requirement of degradation time to form a gradient passivation protective film. .

According to the clinical treatment requirement, the controllable gradient degradation spiral tectorial membrane stent can be added with polypeptide, protein and active ingredients which are sold or disclosed in the market and comprise antiproliferative, anti-migration, antiangiogenesis, anti-inflammation, cytostatic, cytotoxic or antithrombotic drugs with physiological activity into the polyurethane material. Examples are as follows: such as sirolimus, everolimus, pimecrolimus, melphalan, ifosfamide, trofosfamide, chlorambucil, bendamustine, somatostatin, tacrolimus, roxithromycin, daunomycin, ascomycin, bafilomycin, sirolimus, cyclophosphamide, estramustine, dacarbazine, ethosuximycin, midecamycin, josamycin, canavalin, clarithromycin, oleandomycin, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, nimustine, carmustine, busulfan, procarbazine, trooshusuo, temozolomide, setipide, doxorubicin, aclarubicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin C, dactinomycin, methotrexate, fludarabine-5' -dihydrophosphate, Cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, phyllomycin, cerivastatin, simvastatin, lovastatin, fluvastatin, amsacrine, irinotecan, topotecan, hydroxyurea, miltefosine, pentostatin, aldesleukin, retinoic acid, asparaginase, perlapase, anastrozole, exemestane, letrozole, formestane, aminoglutethimide, bromocriptine, ergoline, ergocrine, ergosoxin, ergocornine, ergotamine, ergocristine, ergocristinine, ergometridine, gemcitabine, ergotamine, ergocristinine, ergometridine, and simvastatin, Ergonitrile, lisuride, ergosterol, lysergic acid, doxorubicin, azithromycin, spiramycin, ciprofloxacin, 8-alpha-ergoline, dimethylergoline, ergoline, 1-allyllisuride, 1-allylterguride, ergoamide, diethylamine lysergate, isolysergic acid diethylamine, mesulergine, thalidomide, (5-isoquinolinesulfonyl) homopiperazine, cyclosporine, smooth muscle cell proliferation inhibitor 2 omega, benzyl ergoate, methylergonovine, dimethylargocristine, pergolide, profezuride and terguride, celecoxib, epothilone A and B, mitoxantrone, azathioprine, phenolate, antisense-myc, antisense B-myc, betulinic acid, camptothecin, papaverst, melanocyte-stimulating hormone, melanophore-stimulating hormone, and other growth hormone, Active protein C, interleukin 1-beta-inhibitor, beta-lapachone, podophyllotoxin, betulin, 2-ethylhydrazine of podophyllic acid, molastatin, polyethylene glycol interferon alpha-2 b, legrostin, filgrastim, dacarbazine, basiliximab, daclizumab, selectin, cholesterol ester transfer protein inhibitor, cadherin, cytokine inhibitor, cyclooxygenase-2 inhibitor, thymosin alpha-1, fumaric acid and its esters, calcipotriol, tacalcitol, lapachol, nuclear factor kB, angiopeptin, ciprofloxacin, fluoxetine, monoclonal antibody for inhibiting muscle cell proliferation, bovine basic fibroblast growth factor antagonist, probucol, prostaglandin, 1, 11-dimethoxycoumarin-6-one, 1-hydroxy-11-methoxycoumarin-6-one, beta-lapachol, beta-ethylhydrazine, mogroside, polyethylene glycol, or polyethylene glycol, Scopoletin, colchicine, nitric oxide donors, tamoxifen, fosfestrol, medroxyprogesterone, estradiol cypionate, estradiol benzoate, tranilast, verapamil, staurosporine, beta-estradiol, alpha-estradiol, estriol, estrone, ethinylestradiol, tyrosine kinase inhibitors, cyclosporine A, paclitaxel and derivatives thereof, synthetic and naturally derived three-carbon dioxide macrocyclic oligomers and derivatives thereof, monobenzophenone, acetanilide, diclofenac, clonazethazole, dapsone, anthranoyl-phenoxy-acetic acid, lidocaine, ketoprofen, mefenamic acid, tumstatin, avastin, hydroxychloroquine, auranofin, sodium thiometalate, oxaciclovir, celecoxib, beta-sitosterol, ademetin, muginine, polyethylene glycol monododecaneether, levodione, and/or levofloxacin, Vanillylnonanamide, levomenthanol, benzocaine, aescin, alitatene, colchicine, cytochalasin A-E, indocinocin (indoxacine), nocodazole, piroxicam, meloxicam, chloroquine phosphate, penicillamine, S100 protein, surfactin, vitronectin receptor antagonists, azelastine, guanidyl cyclase stimulators, tissue inhibitors of metalloproteinases 1 and 2, free nucleic acids, nucleic acids incorporating viral transmitters, deoxyribonucleic acid and ribonucleic acid fragments, plasminogen activator inhibitor 1, plasminogen activator inhibitor 2, antisense oligonucleotides, vascular endothelial growth factor inhibitors, insulin-like growth factor 1, active agents from the antibiotic group, penicillins, antithrombotic agents, desulphated and N-re-acetylated heparins, tissue activators, plasminogen/IIIa platelet membrane receptor, plasminogen, Factor Xa inhibitor antibodies, heparin, hirudin, r-hirudin, D-phenylalanine-proline-arginine-chloromone (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone), acetylcholinesterase inhibitors, thiol protease inhibitors, prostacyclin, vapreotide, interferons alpha, beta and gamma, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis modulators, protamine, the sodium salt of 2-methylthiazolidine-2, 4-dicarboxylic acid, prourokinase, streptokinase, warfarin and urokinase, vasodilators, platelet-derived growth factor antagonists, bromoclopiquinone, nifedipine, tocopherol, vitamin B1, B2, B6 and B12, folic acid, molsidomine, tea polyphenols, epicatechin gallate, epicatechin, catechin gallate, heparin, hirudin, gamma-L-arginine-L-arginine methyl ketone, acetylcholinesterase inhibitors, thiol protease inhibitors, prostacyclin antagonists, serotonin antagonists, inhibitors, Gallocatechin gallate, leflunomide, anakinra, etanercept, procainamide, retinoic acid, quinidine, pyributiamine, flecainide, propafenone, sotalol, amiodarone, naturally or synthetically obtained steroids, fuscoporinol, marquel A, sulfasalazine, etoposide, triamcinolone, epirubicin, funoloside, methoprimisulin, maguenin, hydrocortisone acetate, betamethasone, dexamethasone, non-steroidal anti-inflammatory substances, antimycotic drugs, antiprotozoal agents, natural terpenoids, 4, 7-oxocyclododecanedioic acid, echinocandine B1, B2, B3 and B7, eupolyphagaside, brucol A, B and C, brucin N and P, isodeoxycholic acid, pulegorin A and B, Glycophylline A, B, C and D, Isodon amethystoides A and B, nitidine chloride, 12-beta-hydroxy pregnene-3, 20-dione, longitannin extract B, daylily amethystolide C, pseudoleptinotarne, Isodon amethystolide A and B, Taxol A and B, rolidinol), triptolide, ursolic acid, nardostachylic acid A, Iridehyde, maytansinol, Guanqiyan grapheme A, magaponin, Convolvulin, aristolic acid, aminopterin, hydroxylamine pterin, anemonin, protoanemonin, berberine, Chebuergenin chloride, carvotoxin, menispermine, cudrania tricuspidata, Curcuma longa, dihydronitine, ginkgol, bilobol, ginkgol, neobilobovate, and the like, as well as salts, hydrates, solvates, enantiomers, racemic compounds, isomeric mixtures, and the like of the above-mentioned agents, Mixtures of diastereomers, and mixtures thereof.

The gradient-controllable degradable spiral tectorial membrane stent can be used for various in-vivo pipeline stents, and specifically comprises the following components: a blood vessel, a vein, an esophagus, a biliary tract, a trachea, a bronchus, a small intestine, a large intestine, a urethra, a ureter or other ducts close to the passage of a tubular body, in particular a vascular stent, a tracheal stent, a bronchial stent, a urethral stent, an esophageal stent, a biliary stent, a ureteral stent (double J-tube), a ureter stenosis stent, a stent for a small intestine, a stent for a large intestine, a laryngeal implant, a bypass catheter or an ileostomy.

The spiral tectorial membrane stent capable of being degraded in a controllable gradient can be added with one or two of contrast agents, such as zirconium dioxide, barium sulfate, iodine preparation and the like which can be used for developing in vivo.

Drawings

FIG. 1 is a schematic view of a single-helix magnesium alloy stent;

FIG. 2 is a schematic view of a bifilar helical magnesium alloy stent;

FIG. 3 is a schematic view of a multi-strand helical magnesium alloy stent;

fig. 4 is a schematic view of a degradable ureteral stent;

fig. 5 is a partial enlarged schematic view of a degradable ureteral stent.

The specific embodiment is as follows: