CN109381750B - Anticoagulation conveniently-taken heart stent - Google Patents

Anticoagulation conveniently-taken heart stent Download PDF

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CN109381750B
CN109381750B CN201810436538.5A CN201810436538A CN109381750B CN 109381750 B CN109381750 B CN 109381750B CN 201810436538 A CN201810436538 A CN 201810436538A CN 109381750 B CN109381750 B CN 109381750B
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stent
agent
myricetin
copolymer
segment material
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CN109381750A (en
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张锋
祖晓麟
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/047—Other specific proteins or polypeptides not covered by A61L31/044 - A61L31/046
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06—Use of macromolecular materials
    • A61L33/12—Polypeptides, proteins or derivatives thereof, e.g. degradation products thereof
    • A61L33/128—Other specific proteins or polypeptides not covered by A61L33/122 - A61L33/126
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00—Products made by additive manufacturing
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/4009—Two or more macromolecular compounds not provided for in one single group of groups C08G18/42 - C08G18/64
    • C08G18/4018—Mixtures of compounds of group C08G18/42 with compounds of group C08G18/48
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C08G18/4236—Polycondensates having carboxylic or carbonic ester groups in the main chain containing only aliphatic groups
    • C08G18/4238—Polycondensates having carboxylic or carbonic ester groups in the main chain containing only aliphatic groups derived from dicarboxylic acids and dialcohols
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/48—Polyethers
    • C08G18/4825—Polyethers containing two hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
    • C08G18/76—Polyisocyanates or polyisothiocyanates cyclic aromatic
    • C08G18/7614—Polyisocyanates or polyisothiocyanates cyclic aromatic containing only one aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
    • C08G18/76—Polyisocyanates or polyisothiocyanates cyclic aromatic
    • C08G18/7657—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings
    • C08G18/7664—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings containing alkylene polyphenyl groups
    • C08G18/7671—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings containing alkylene polyphenyl groups containing only one alkylene bisphenyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents

Abstract

The invention aims to provide an anticoagulant heart stent convenient to take out, which overcomes the defect that the stent is softened by body temperature in the prior art. The prepared stent is heated to 43 ℃ to be extruded and deformed. When in use, the predetermined deformation is achieved by heating to 42 degrees celsius after delivery to the destination. Meanwhile, anticoagulant peptide is also attached to the stent, so that the stent can be effectively prevented from being blocked, and the service life is prolonged.

Description

Anticoagulation conveniently-taken heart stent
Technical Field
The invention relates to a medical product for interventional therapy, in particular to a long-acting heart stent easy to take out, and particularly relates to a heart stent prepared by 3D printing of a heat-sensitive material, which has better compatibility with blood, can effectively prevent secondary blockage and can reduce the restenosis rate of heart blood vessels after stent operation.
Background
The heart Stent (Stent), also known as coronary Stent, is a common medical instrument used in cardiac interventional surgery and has the function of dredging arterial vessels. The main material is stainless steel, nickel-titanium alloy or cobalt-chromium alloy. The earliest appeared in the 80 th 20 th century, and the development process of metal brackets, coated brackets and soluble brackets is experienced.
First generation metal stents. The initial challenge in developing a coronary stent was how to make it both tough and stiff. The stent is tough, so that the stent can pass through coronary arteries with indefinite directions and large branch angles; the hard stent can support the expanded narrow artery lumen so as not to retract.
The second generation of film coating bracket. Plating a layer of medicine film on the surface of the metal bracket. After the stent is implanted into a body, the medicine can be slowly released, scar tissues are inhibited from growing around the stent, and the coronary artery is kept unobstructed. For example, CN 206304160U discloses a cardiac stent with a nano-biological coating for effectively preventing secondary thrombus, which mainly comprises: the biological coating comprises a metal wire mesh, a knotted wire and a biological coating, wherein concave and convex points of every two transverse metal wire meshes are knotted and fixed by the knotted wire; the drawknot wires are in a plurality of arc shapes, and the arc-shaped parts of the drawknot wires are wrapped with biological coatings.
Third generation soluble scaffolds. The drug on the coated stent will eventually be exhausted, and by then the physician and patient will face the initial problem. The belgium scientist reported a new type of arterial stent at the beginning of the 21 st century. Unlike traditional stents, this stent can dissolve in vivo and be absorbed by the body. The novel stent can play a role in expanding blood vessels during arterial stenosis. When the acute phase is passed, the stent effect is completed and the blood vessel is reshaped, it can be dissolved and disappeared, so that the adverse effect of local inflammatory reaction can be avoided.
Soluble cardiac stents, also known as bioabsorbable cardiac stents, are gradually degraded in the body and are made of biodegradable materials (e.g., poly (L-lactic acid), PLLA), which are degradable into polymers of carbon dioxide and water. Different from a metal stent, the stent can be dissolved in the body in about 2 years, and the anticoagulant drug is not needed to be taken for the whole life without influencing nuclear magnetic examination. The probability of reocclusion of the vessel is said to be 4%, which is less than the reocclusion rate of metal stents.
Other bioabsorbable metal stents made of magnesium, titanium, copper, silver, tantalum, zinc and/or silicon as component a and lithium, sodium, potassium, calcium, manganese and/or iron as component B are described in european patent EP0966979a 2. Stents made of zinc/titanium alloys having a weight percent of titanium of 0.1% to 1% and stents made of zinc/calcium alloys having a weight percent of zinc to calcium of 21: 1 are specifically provided as examples. This scaffold has the disadvantage that it dissolves too quickly and uncontrollably, so that some of them have decomposed after two weeks.
CN101837148B discloses a porous biodegradable stent and a preparation method thereof, which mainly comprises biodegradable polymers. The preparation method comprises the following steps: dissolving biodegradable polymer in organic solvent, stirring with soluble salt at normal temperature to obtain paste, pressing into semi-finished product in a mold, drying, removing organic solvent, desalting in pure water, and freeze drying.
The existing biodegradable stents generally disappear in vivo function gradually with the lapse of time, but in some patients, stents which can work for a longer time may be needed, or stents which can be non-invasively taken out at any time are the key direction of the current medical research.
Disclosure of Invention
The invention aims to provide a heart stent convenient for anticoagulation taking out, which can be taken out from an expansion state to a softening and shrinking state by providing a heat source or a light source according to needs. The prepared stent is heated to 40-45 ℃ to be extruded and deformed so as to be suitable for inserting into a surgical heart catheter, and then is rapidly cooled to room temperature and stored at 4 ℃ to maintain the extruded state. When used, the predetermined deformation is achieved by heating after delivery to the destination. Meanwhile, anticoagulant peptide is also attached to the stent, so that the stent can be effectively prevented from being blocked, and the service life is prolonged.
The invention also provides a preparation method of the thermosensitive heart stent, which comprises the following steps:
(1) preparation of thermosensitive memory material
The hard segment material is: 4, 4' -diphenylmethane diisocyanate and 2, 4-toluene diisocyanate.
The soft segment material is: polybutylene adipate and polypropylene glycol.
The preparation method comprises the steps of taking a hard segment material and a soft segment material as raw materials, preparing a copolymer X under the action of an organic bismuth catalyst DY-20, and carrying out cross-linking reaction on the copolymer X, cinnamamide and anticoagulant polypeptide A in sequence to prepare the thermosensitive memory material.
(2)3D prints intravascular stent
And (3) printing the heart stent by using the material obtained in the step (1) and adopting a Dimension Elite 3D printer at the temperature of 45 ℃.
Further, the molar ratio of the 4, 4' -diphenylmethane diisocyanate to the 2, 4-toluene diisocyanate is 1: 0.7.
The mass volume ratio of the hard segment material to the soft segment material is as follows: 1: 1-5: 1.
The mass volume ratio of the addition amounts of the hard segment material, the soft segment material and the organic bismuth catalyst DY-20 is 1-5: 0.5-2.5: 0.01-0.05.
The addition amount of the anticoagulant polypeptide A is 0.1-0.5% of the total weight of the copolymer X.
Further, the copolymer X and the cinnamamide are subjected to cross-linking reaction for 2 hours at the temperature of 60-65 ℃, the product and the anticoagulant polypeptide are subjected to continuous cross-linking reaction for 4 hours at the temperature of 55-60 ℃, and then the product and the anticoagulant polypeptide are subjected to concussion and uniform mixing for 10-15 hours at the temperature of 25 ℃.
More specifically, the anticoagulant polypeptide is a polypeptide with anticoagulant effect which is developed and obtained in the earlier stage of the applicant, and is specifically named as anticoagulant polypeptide or KNZJ-2 peptide: SVLIEILQESPPWFMKGMSMLMENDWSYGKHSHMWGI are provided.
More closely, the copolymer X is further coupled, if desired, with other active drugs, such as anti-inflammatory agents, cytostatic agents, cytotoxic agents, antiproliferative agents, antimicrotubulin agents, antiangiogenic agents, antirestenotic agents, antifungal agents, antineoplastic agents, anti-migratory agents, non-thrombotic and/or antithrombotic agents, examples of which are: abciximab, acemetacin (acemetacin), acetoxyvismitone b (acetylvirsmine b), aclarubicin (aclarubicin), ademetionine (ademetionine), doxorubicin (adriamycin), aescin (aescin), alfuroxime (affomosone), akagatrine (akageline), aldesleukin (aldesleukin), amiodarone (amidorone), aminoglutethimide (aminoglutethimide), angora 21353 cry (amsacrine), anakinra (anakinra), anastrozole (anastrozole), glaucosin (anakinine), aminopterin (aminopterin), antifungal agents (antifungics), antithrombotic agents (antithrombotics), apigenin (aristolocystin), apigenin (aristosin), gargin (aristolocin), gargin (atroviridin), gargin (aristomycin), aristomicin (aristomycin (5)3/4Aminic acid-All (aristoIactam-AII), Malus 53/4Ringing acid (aristolochic acid), ascomycin (ascomycin), asparaginase (ascoenzyme), aspirin (aspirin), atorvastatin (atorvastatin), auranofin (auranofin), azathioprine (azathioprine), azithromycin (azithromycin), fruit (baccatin), bafilomycin (bafilmycin), basiliximab (basiliximab), bendamustine (bendamustine), benzocaine (benzocaine), trabeculene (berberine), bivalenol (betalain), betulinic acid (betalainic acid), albuginestin (ascomycin), piceatannose (ascomycin), aspirin (aspargine), aspirin (aspirin), and a pharmaceutically acceptable salt thereof(bilobol), bispinosidine (bisparthenolidine), bleomycin (bleomycin), borrelidin (bombestatin), Boswellic acid (Boswellic acid) and derivatives thereof, brucea operculata (bruceanol) A, B and C, Asiatic root toxin A (bryophyllin A), busulfan (busufan), antithrombin (antithrombin), bivalirudin (bivalirudin), I beggar adhesin (cadherin), camptothecin (camptothecin), capecitabine (capecitabine), anthranoylphenoxyacetic acid, carboplatin (carmustine), carmustine (carmustine), celecoxib (ecoxib), cepharanthin (ceratin), cerivastatin (clavulanate), ciprofloxacin (ciprofloxacin) and ciprofloxacin (ciprofloxacin), ciprofloxacin (ciprofloxacin) inhibitors (ciprofloxacin), ciprofloxacin (ciprofloxacin) and clindamycin phosphate (ciprofloxacin), ciprofloxacin (ciprofloxacin) as well as a, Coderidin, type C natrium (C-typesolitary peptide, CNP), tsugeki A (cudraisoflavone A), curcumin (curcumin), cyclo acid amine (cyclophosphamide), cyclosporin A (ciclosporin A), cytarabine (cyclabine), dacarbazine (dacarbazine), daclizumab (daclizumab), dactinomycin (dactinomycin), aminobenzene mock (dapsone), daunorubicin (daunorubicin), diclofenac (diclofenac), 1, 11-dimethoxyferrugenon-6-one (1, 11-dimcthiophyllin-6-one), docetaxel (docetaxel), doxorubicin (doxocin), daunorubicin (epirubicin), epirubicin (epothilone), iumurarubicin (epothilone A), epothilone (fluvastatin), epirubicin (epothilone A), epirubicin (fluvastatin), epirubicin (fluvastatin (epothilone A), epirubicin (fluvastatin), epirubicin (fluvastatin (I (fluvastatin), epirubicin), fluvastatin (I (fluvastatin), epirubicin (fluvastatin (I), epirubicin), fluvastatin (I), epirubicin), fluvastatin (E, E, Fludarabine-5 '- dihydrogen salt (f ludarabine-5' -dihydrogenphenasphate), flurouracil (fluouracil), folomycin (folamycin), phosestrol (fosfestrol), gemcitabine (gemcitabine), li ralanine (ghakinoside), ginko (ginkgol), ginkgolic acid (ginkgolic acid), glycosidic la, 4-lightylcyclophosphamide, idarubicin (idarubicin), ifosfamide (iformide), josamycin (josamycin)Lapachol (Iapachol), lomustine (l mustine), lovastatin (l vastatin), melphalan (melphalan), midecamycin (midecamycin), mitoxantrone (mitoxantrone), nimustine (nimustine), pitavastatin (pitavastatin), pravastatin (pravastatin), procarbazine (procarbazine), mitomycin (mitomycin), methoprene (methotrexate), bortexine (merteprin), thiopterosin (thioguanine), oxazido (oxalifolin), irinotecan (topotecan), lepturene (hydoxyurea (hydxycarb), miltefosine (itoxin), pentraxin (itoxin), oxyphenicol (oxyphenicol), oxyphenbutazone (oxyphenicol), oxyphenicol (e), oxyphenicol (oxyphenicol), oxyphenicol (e), oxyphenicol (e), oxyphenicol (e), oxyphenicol (e), oxyphenicol (oxyphenicol), oxyphenicol (e), oxyphenicol (e), the inhibitors (e), the inhibitors of estrogen-2-S (e), the inhibitors of estrogen-S (e), the inhibitors of estradiol-2-S (e), the inhibitors of estradiol-2-S (e), the inhibitors of estradiol-S (e), the inhibitors of estradiol-2-iso (e), the inhibitors of estradiol-2-iso (e), the inhibitors of estradiol-S (e), the inhibitors of the (e), the estrogen-S (e), the inhibitors of the estrogen-iso (e), the estrogen-2-iso (e), the (e), the inhibitors of estradiol-iso (phospho (e), theThe compounds are useful as inhibitors of the enzyme receptors of the group consisting of tricarbon oxide (MCS) and macrocyclic oligomers thereof, mofetil (mofebutazone), clonazelate (lnazolac), lidocaine (Iidocaine), ketoprofen (ketoprofen), mefenamic acid (mefenamic acid), piroxicam (piroxicam), meloxicam (meloxicam), penicillamine (penicillamine), chloroquine (hydroxychlorequine), disodium aurothioate (sodiumuthylacetate), oxazirociprole (oxacepiropiroctone), β -sitosterol (β -sitosterol), mecticaine (myrtecaine), polidocanol (polidocanol), nonivamide (nonivamide), levogramicin (Iomehol), rose acetylide (acetylide), hepsin (hepcidin), thrombospondin (hepsin), heparin (hepsin), thrombospondin (hepsin), heparin-arginine (hepsin), heparin (hepsin), heparin-arginine (hepcidin), inhibitors of the enzyme receptors of the group consisting of the enzyme receptors of the heparin, penicillin, fibrinogen (VEGF, fibrinogen, the enzyme receptors of the group consisting of the enzyme receptors of the protein (VEGF, the enzyme receptors of the protein (paclobulin, the enzyme receptors of the factor (paclobulin, the group), heparin, the protein (angiotensin), heparin, factor (angiotensin), heparin, factor (angiotensin), heparin, angiotensin (angiotensin), heparin, factor (angiotensin), heparin, factor (angiotensin), heparin, angiotensin (angiotensin), heparin, factor (angiotensin), heparin, angiotensin (angiotensin), heparin, angiotensin (1), heparin, angiotensin (angiotensin), heparin (1), heparin, angiotensin (angiotensin), heparin, angiotensin (angiotensin), heparin (angiotensin), heparin, angiotensin (angiotensin), heparin), angiotensin (angiotensin), and (angiotensin), and (angiotensin), and (angiotensin), angiotensin (angiotensin), heparin), angiotensin (1), and (angiotensin), angiotensin (angiotensin), and (angiotensin), angiotensin (topril, cilazapril, lisinopril (lisinopril), enalapril (enalapril), losartan (lsartan)), thioproteinase inhibitor (thioproteinase inhibitor), prostacyclin (prostacyclin), vapreolide (vapreoprost), interferon α, β and Y, histamine antagonist, serotonin blocker (serotoninbacker), apoptosis inhibitor (apoptosis inhibitor), apoptosis regulator (such as p65, NF-. kappa.B or Bcl-xL antisense oligonucleotide), halofuginone (halofuginone), nifedipine (nifedipine), tocotrienol (tocophenol), tranilast (tranilast), molimine (momidomycin), picrocaine (epirubicin), epirubicin (epirubicin), piclorane (epirubicin), picloratadine (neomycin), piclorane (neomycin), picloratadine (isoproquinone (isoproxacin), piclorasone), picloratadine (isopropyl alcohol), piclorasone (isopropyl alcohol), picloran (isopropyl alcohol), isopropyl alcohol (isopropyl alcohol), isopropyl alcohol (isopropyl alcohol), isopropyl alcohol (isopropyl alcohol), isopropyl alcohol (isopropyl alcohol), isopropyl alcohol (isopropyl alcohol), isopropyl alcohol (isopropyl alcohol), isopropyl alcohol (isopropyl alcohol), isopropyl alcohol (isopropyl alcohol), isopropyl alcohol (isopropyl,
Figure BSA0000163501590000071
Indomethacin (indomethacin), naproxen (naproxen), phenylbutazone (phenylbutazone) and other antiviral agents such as acyclovir (acyclovir), ganciclovir (ganciclovir) and zidovudine (zidovudine), clotrimazole (clotrimazole), flucycloxuron (flucytosine), griseofulvin (griseofulvin), ketoconazole (ketoconazole), miconazole (miconazole), nystatin (chrystatin), terbinafine (terbinafine), antiprotozoal agents such as chloroquine (chloroquine), mefloquine (mefloquine)Quinine (quinine), other natural types (such as hippocampal I beggar protein (hippophae scutellarin), myristyl alcohol-C21-angelate (moringenol-C21 _ angelate), 14-dehydrogenistin (14-dehydroagosticin), euphorbia (agroskerin), macrotoxin (agosticin), 17-phytin (17-hydroxygrostaphin), sapodilactone (ovandiolide), 4, 7-oxocyclodicarisperidone (4, 7-oxolancholanoisomiclic acid), echinoid (charinoid) B7, B2, B3 and B7, Tubei (tubellosidine), anticholine glycoside C (ascophylloside A), myricetin A-D), cineole (cineole A-D), cineole (angiosperm A), cineole (angiosperm injection), cineole A-D), cineole (dihydrochrysoidine A-D), cineole (angiosperm A-dihydrochrysoidine), myricetin (A-4, phytochrome), myricetin (4-A), myricetin (dihydrochrysin), myricetin A-D), myricetin (dihydrocaritin A), myricetin (7-D), myricetin A-4, myricetin (dihydrocaritin A), myricetin A-4, myricetin (dihydrocaritin A), myricetin A-D) and (dihydrocaritin A-D), myricetin (dihydrocaritin A), myricetin (dihydrocarin (7-D), myricetin (dihydrocarin A), myricetin A-D), myricetin A), myricetin (dihydrocarin A), myricetin A-D), myricetin (7-D), myricetin (dihydrocarin and (dihydrocarin A), myricetin (dihydrocarin and (dihydrocarin A), myricetin A), myricetin and (dihydrocarin A), myricetin (dihydrocarin (7-D), myricetin (dihydrocarin, myricetin A), myricetin (7-D), myricetin (dihydrocarin and (7) and (dihydrocarin (7-D), myricetin A), myricetin (7-D), myricetin (dihydrocarin A) and (dihydrocarin (7) and (7-D), myricetin (dihydrocarin, myricetin (7) and (dihydrocarin, myricetin (dihydrocarin) and (dihydrocarin, myricetin A), myricetin (dihydrocarin, myricetin and (dihydrocarin) and (dihydrocarin (7) and (7-D), myricetin (vitamin A), myricetin (7-D), myricetin A) and (vitamin A), myricetin (dihydrocarin A), myricetin A) and (7-D), myricetin A) and (vitamin A) and (dihydrocarin, myricetin A), myricetin (dihydrocarin (vitamin A) and (dihydrocarin (vitamin A), myricetin (vitamin AKalopanax (Iiriodenine), bispinosidine (bisparthenolidine), oxybupronin (oxoshinsine), periploside a (periplocoside a), ursolic acid (ursolic acid), deoxyspergualin (deoxyspergualin), nonagroside (psyrubibin), cymoxatoxin a (ricin a), sanguinarine (sanguinarine), manwu wheatic acid (manwu wort acid), methylmargariside (methylorbifolin), chromone of rutaceae (spathalila), stringoplalin (diphyllin), mansonine (mansonine), rennin (dihydrosaxorubicin), dihydrouramustine (dihydrouramustine), dihydrouramustine (hydrabamine), hydrabamine (hydrabamine), syringoplane (oxyphenocarpine), syringine (clavine), syzygin (clavine), dihydrouramustine (clavine), dihydrouramusareolide (clavine), syringine (clavine), clavine (clavine), clavine (clavine ), clavine (clavine, clav, Somatostatin (somatotatin), tacrolimus (tacrolimus), roxithromycin (roxithromycin), oleandomycin (troleandomycin), simvastatin (simvastatin), rosuvastatin (rosuvastatin), vinca yezoensis (vinblastatine), vincristine (vincristine), vindesine (vindesine), teniposide (teniposide), vinorelbine (vinorelbine), tre\\ 24976, amine (trofosfamide), treosulfan (treosulfan), temozolomide (temozolomide), thiotepa (thiotepa), tretinoin (tretinoin), spiramycin (spiramycin), umbelliferone (umbelliferone), desacetylretinide (desazamide A), tyisismine A and B ().
Preferred active agents are paclitaxel and derivatives thereof (such as 6-alpha-hydroxy-paclitaxel), or sarcodictyin and other taxanes, sirolimus, everolimus, sirolimus a9(biolimus a9), pimecrolimus (pimecrolimus), zotarolimus (zotarolimus), tacrolimus, erythromycin, midecamycin, josamycin and triazolopyrimidine.
Particular preference is given to paclitaxel
Figure BSA0000163501590000091
And all derivatives of paclitaxel (such as 6- α -hydroxy-paclitaxel), as well as sirolimus and its derivatives.
The glass transition temperature of the thermosensitive heart stent prepared by the invention is 42-44 ℃.
Specifically, the using method of the heart stent comprises the steps of heating the printed heart stent to 43 ℃, extruding and deforming, inserting the heart stent into a surgical heart catheter, cooling and fixing, heating the stent after guiding the heart stent to the position of the heart stent, and recovering the memory shape to perform functions.
The invention has the beneficial effects
The intravascular stent prepared by the invention is convenient to use, has a good glass transition temperature, prevents the defect that the stent is softened when reaching the glass transition temperature under the condition of 37 ℃ of a human body, and has good safety because the temperature of 42 ℃ is generally difficult to reach by the human body. In addition, the anticoagulant polypeptide implanted in the stent can well decompose blood plaques attached to the stent, so that the stent is prevented from being further blocked, and the service life is prolonged.
Detailed Description
The technical solution of the present invention is further illustrated by the following examples. Reaction conditions not indicated in the examples are in principle carried out by means of experimental methods customary in the art, and the reagents or apparatus used are also customary in the art, and the description of the examples is not intended to limit the scope of the invention.
EXAMPLE 1 preparation of thermosensitive memory-type Material containing anticoagulant Polypeptides
4, 4' -diphenylmethane diisocyanate and 2, 4-toluene diisocyanate are mixed according to the molar ratio of 1: 0.7, 5.0g of the mixture is mixed with 2.5mL of poly (butylene adipate) and polypropylene glycol according to the molar ratio of 1: l, and the mixture reacts for 40min in 50mL of DMSO under the oxygen-free condition at 70-75 ℃ in the presence of 50 mu l of organic bismuth catalyst DY-20 and under the protection of nitrogen. Then, dissolving 15.5mg of crosslinked cinnamamide in 1mL of DMSO, adding the solution into a reaction system, and reacting for 2h at 65 ℃; dissolving 90mg of anticoagulant polypeptide (shown in SEQ ID NO: 1, obtained by adopting a conventional artificial synthesis mode in the field) by adopting 2mLDMSO, adding the solution into a system, and oscillating and uniformly mixing the solution at 60 ℃ for 4h to continuously generate crosslinking; followed by reaction at 25 ℃ for 15 h. The polymerization was then terminated by the addition of 1mL of methanol. And (3) removing the catalyst and low molecular weight residues involved by a conventional precipitation washing process, and drying in vacuum to obtain 5.9g of the thermosensitive memory material containing the anticoagulant polypeptide.
Example 2 preparation of thermosensitive memory type material containing clopidogrel
4, 4' -diphenylmethane diisocyanate and 2, 4-toluene diisocyanate were mixed according to a molar ratio of 1: 0.7, 5.0g of the mixture was mixed with 2.5mL of polybutylene adipate and polypropylene glycol according to a molar ratio of 1: 1, and the mixture was reacted in 50mL of DMSO for 40min at 70 ℃ to 75 ℃ in the absence of oxygen in the presence of 50. mu.l of an organic bismuth catalyst DY-20 and under the protection of nitrogen. Then, dissolving 15.5mg of crosslinked cinnamamide in 1mL of DMSO, adding the solution into a reaction system, and reacting for 2h at 65 ℃; dissolving 100mg of clopidogrel base by using 2mL of DMSO, adding the solution into a system, and shaking and uniformly mixing the solution at 65 ℃ for 4 hours to continuously generate crosslinking; followed by reaction at 20 ℃ for 10 h. The polymerization was then terminated by the addition of 1mL of methanol. Through the conventional precipitation washing process, the participated catalyst and low molecular weight residues are removed, and 5.7g of the thermosensitive memory material containing clopidogrel alkali is obtained after vacuum drying.
EXAMPLE 3 preparation of drug-free thermosensitive memory Material
4, 4' -diphenylmethane diisocyanate and 2, 4-toluene diisocyanate were mixed according to a molar ratio of 1: 0.7, 5.0g of the mixture was mixed with 2.5mL of polybutylene adipate and polypropylene glycol according to a molar ratio of 1: 1, and the mixture was reacted in 50mL of DMSO for 40min at 70 ℃ to 75 ℃ in the absence of oxygen in the presence of 50. mu.l of an organic bismuth catalyst DY-20 and under the protection of nitrogen. The polymerization was then terminated by the addition of 1mL of methanol. The catalyst and low molecular weight residues were removed by a conventional precipitation washing process, and dried under vacuum to obtain 6.1g of a thermosensitive memory material.
EXAMPLE 4 preparation of scaffolds
The thermosensitive memory material prepared in the examples 1-3 is prepared into coarse fibers with the diameter of 2mm through an extruder, and then a Dimension Elite 3D printer is adopted to print and obtain the heart stent under the condition of the filament outlet temperature of 45 ℃, wherein the heart stent is respectively named as a polypeptide stent, a drug stent and a blank stent.
The three stents were tested and found to have deformation initiation temperatures of 42.0 degrees celsius.
Example 5 establishment of animal model and application experiment of scaffold
First, establishment of animal model
Clean grade adult male C57BL/6J (22) mice. The average weight was 25g, which was provided by the animal center of the Shanghai academy of sciences of China. Animals were anesthetized by intraperitoneal injection of 1% sodium pentobarbital (50mg/kg) and a median incision was made in the neck of the mouse, about 2cm long, and the common carotid artery was isolated and exposed, according to the methods of the prior art. At the left common carotid artery branch, the blood flow is blocked by complete ligation. Animals did not die during 4 weeks of recovery. The total artery at the ligation part of two ligated mice is taken by anesthesia, fixed by fixative for 24h, dehydrated conventionally and embedded by paraffin, and ultrathin section is carried out by Leitz microtome, HE staining is carried out on conventional cases, inflammatory cells infiltrate 100% at the part, the artery is obviously narrow, and the reduction of the lumen reaches 90%. The method shows that the blood vessel reconstruction and the reduction of the blood vessel cavity area caused by the blood vessel diameter and the neointima formation are caused by the changed blood vessel shearing force, thereby realizing the establishment of the blood vessel restenosis model.
The three stents prepared in example 4 were respectively stored in a catheter under compression, and introduced into a mouse vascular stenosis, and the stents were restored to their pre-deformation states by local heating at 43 ℃. After culturing the mice introduced into the scaffolds and the blank control mice for 1 month, the scaffolds were removed, the residual blood remnants on the surfaces were carefully washed away, and the condition of platelets adhering to the surfaces of the scaffolds was observed by using a scanning electron microscope. The detection shows that the surface of the stent prepared by the anticoagulant peptide has almost no platelet adhesion; the average number of platelets attached to the drug stent is 102/cm2While the mean number of platelets attached to the placebo stent was 653/cm2This fully states that the use ofBesides safe use, the scaffold with the polypeptide also has a good effect of resisting surface coagulation, so that the service time of the scaffold is prolonged.
Effect of the Polypeptides described in example 6 on clotting time in mice
1) Preparation of sample solution
Diluting clopidogrel with normal saline into liquid medicine with required concentration (dosage is 4mg/kg) just before use of the positive control group; diluting the polypeptide group with physiological saline to obtain medicinal liquid with desired concentration (dosage of 4mg/kg) immediately before use; the drug was administered into the tail vein of each group at a volume of 10 ml/kg.
2) Experimental procedure
Taking 24 healthy ICR mice with the weight of 20-25 g and half of each sex, randomly dividing the mice into 3 groups according to the weight, and dividing each group into 8 mice, namely a model control group, a positive control group and a polypeptide group. The tail vein of each group is administrated, the volume is 10ml/kg, 1 time/d, 4 days are continuously administrated, after 15min of the last administration (2 hours after the last administration of the positive control group), a glass capillary tube is inserted into the eye socket of the mouse to enable blood to flow out automatically, the 1 st drop of blood is wiped off by a dry cotton ball, then blood drops are respectively dripped at the two ends of the cleaning glass slide, the diameter of the blood drops is 5-10 mm, and timing is started immediately. After that, every 30s, the blood is stirred by a dry needle for 1 time until the needle can pick up fibrin fiber, namely the blood coagulation time, and the blood I is dripped for final retesting. The model control group is given with physiological saline with equal volume, and the positive control group is given with clopidogrel.
3) Statistical treatment
Excel software was used to process the data. All data are expressed as standard deviations on the mean, and comparisons between groups are made using the t test, with the results shown in Table 1.
TABLE 1 Effect of groups on clotting time in mice
Group of N tBlood coagulation/S
Model control group 8 258±25.8
Positive control group 8 513±37.2
Polypeptide group 8 589±32.7
The statistical method comprises the following steps: t-test P is less than O.05, and P is more than 0.05 compared with the model control group and compared with the positive control group.
The results show that: the positive control clopidogrel group and the polypeptide group can obviously prolong the blood coagulation time in a mouse body under the same concentration, and can judge that the clopidogrel group and the polypeptide group have the antithrombotic effect. And the positive group and the sample group with the same dosage have significant difference compared with the blank group. Therefore, the anticoagulant polypeptide can effectively prolong the blood coagulation time of the mouse.
The above embodiments are merely exemplary, and it should not be understood that the present invention is limited thereto, and those skilled in the art can make modifications and changes without departing from the spirit and the principle of the present invention.
Figure ISB0000178134000000011

Claims (4)

1. An anticoagulant polypeptide for cardiac stenting, comprising: the amino acid sequence is shown as SEQ ID NO: 1 is shown.
2. A heart stent is prepared by the following steps: the adopted hard segment materials are as follows: 4, 4' -diphenylmethane diisocyanate and 2, 4-toluene diisocyanate; the soft segment material is: polybutylene adipate and polypropylene glycol;
(1) taking a hard segment material and a soft segment material as raw materials, preparing a copolymer X under the action of an organic bismuth catalyst DY-20, wherein the copolymer X is sequentially mixed with cinnamamide and SEQ ID NO: 1, performing a cross-linking reaction on the anticoagulant polypeptide to prepare a thermosensitive memory material;
(2)3D printing of the vascular stent: printing the heart stent by using the material obtained in the step (1) through a 3D printer at 45 ℃;
wherein the mass volume ratio of the hard segment material to the soft segment material is as follows: 2: 1;
the mol ratio of the 4, 4' -diphenylmethane diisocyanate to the 2, 4-toluene diisocyanate is 1: 0.7; the addition amount of the anticoagulant polypeptide is 0.1-0.5% of the total weight of the copolymer X.
3. The cardiac stent of claim 2, further comprising at least one of an anti-inflammatory agent, cytostatic agent, cytotoxic agent, antiproliferative agent, antimicrotubulin agent, antiangiogenic agent, antirestenotic agent, antifungal agent, antineoplastic agent, anti-migratory agent, non-thrombotic or antithrombotic agent.
4. A method of making the heart scaffold of claim 2, comprising the steps of:
(1) preparation of thermosensitive memory material
The hard segment material is: 4, 4' -diphenylmethane diisocyanate and 2, 4-toluene diisocyanate;
the soft segment material is: polybutylene adipate and polypropylene glycol;
taking a hard segment material and a soft segment material as raw materials, preparing a copolymer X under the action of an organic bismuth catalyst DY-20, wherein the copolymer X is sequentially mixed with cinnamamide and SEQ ID NO: 1, performing a cross-linking reaction on the anticoagulant polypeptide to prepare a thermosensitive memory material;
(2)3D prints intravascular stent
And (3) printing the heart stent by using the material obtained in the step (1) through a 3D printer at the temperature of 45 ℃.
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CN1634613A (en) * 2004-09-29 2005-07-06 上海交通大学 Plant source alcohol soluble protein and its preparation method
CN106366285A (en) * 2016-09-09 2017-02-01 福州维亚生物科技有限公司 Method for preparing and using vascular stent

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US8778376B2 (en) * 2006-06-09 2014-07-15 Advanced Cardiovascular Systems, Inc. Copolymer comprising elastin pentapeptide block and hydrophilic block, and medical device and method of treating
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CN1634613A (en) * 2004-09-29 2005-07-06 上海交通大学 Plant source alcohol soluble protein and its preparation method
CN106366285A (en) * 2016-09-09 2017-02-01 福州维亚生物科技有限公司 Method for preparing and using vascular stent

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