WO2016061858A1 - Instrument médical contenant une protéine hcreg recombinée et procédé pour le préparer - Google Patents

Instrument médical contenant une protéine hcreg recombinée et procédé pour le préparer Download PDF

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WO2016061858A1
WO2016061858A1 PCT/CN2014/090824 CN2014090824W WO2016061858A1 WO 2016061858 A1 WO2016061858 A1 WO 2016061858A1 CN 2014090824 W CN2014090824 W CN 2014090824W WO 2016061858 A1 WO2016061858 A1 WO 2016061858A1
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hcreg
recombinant
protein
glycoprotein
medical device
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PCT/CN2014/090824
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Chinese (zh)
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韩雅玲
张娜
邓婕
闫承慧
孙鸣宇
陈永强
崔凯
蒲忠杰
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乐普（北京）医疗器械股份有限公司
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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
    • 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
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells

Definitions

  • the invention relates to the preparation of a bioengineered and bioengineered medical device, in particular to a medical device containing recombinant hCREG protein and a preparation method thereof. It belongs to the field of interventional medical devices for bioengineering and implanting.
  • Cardiovascular disease is a serious threat to human health. According to the WHO, the number of deaths due to cardiovascular disease is up to 30% of the total global deaths. Major interventions in the treatment of severe cardiovascular disease through cardiovascular interventional implantation, but interventional devices such as valves, occluders, stents, etc. are prone to thrombosis and neoplasms, and stenosis (RS) occurs, affecting successful surgery. The rate significantly reduces the benefit of surgery.
  • vascular endothelial injury and excessive proliferation/migration of Vascular smooth muscle cells are important sites of RS.
  • the cause of postoperative vascular restenosis is not fully understood.
  • vascular endothelial function damage is an important starting factor for RS.
  • vascular endothelial cells Ecs are not only monolayer cells on the surface of the intima, but also an organ with endocrine function, which ensures the integrity of the vascular endothelium structure is important for maintaining vascular homeostasis.
  • vascular smooth muscle cell proliferation inhibitors rapamycin and its analogs, Paclitaxel's drug-eluting stent (DES) is the most commonly used treatment for clinical prevention of restenosis.
  • DES Paclitaxel's drug-eluting stent
  • the protein-eluting stents studied at home and abroad mainly include: 1. Inflammatory response scaffolds after inhibiting vascular injury, including TNF- ⁇ antibody-loaded scaffolds, loaded cyclic RGD polypeptide scaffolds, etc.; 2. Vascular endothelium that accelerates endothelialization of blood vessels Growth factor (bFGF and VEGF) release scaffold; 3. Complement protein C release scaffold, etc., which inhibit local thrombosis by anticoagulation and maintaining normal blood coagulation balance.
  • bFGF and VEGF blood vessels Growth factor
  • CREG human repressor of E1A-stimulated genes
  • CREG belongs to a small molecular weight secreted glycoprotein, which is widely expressed in differentiated mature tissue cells, but has a low expression level in undifferentiated tissues such as embryonic stem cells and teratoma cells.
  • Veal et al. introduced the exogenous CREG gene into tumor cells cultured in vitro, and found that CREG gene expression can significantly inhibit tumor cell proliferation and induce differentiation; similarly, in the absence of specific inducer, the addition of tiller type
  • the CREG protein can induce the differentiation of ES cells and teratoma cells into neural cells in vitro.
  • the above studies suggest that CREG, as a small molecular weight secreted glycoprotein, can induce and maintain tissue or cell differentiation.
  • the researchers of the present invention successfully cloned the human CREG gene from the human internal thoracic artery VSMCs cultured in vitro using the mRNA differential display technology in 1999, and after several years of basic research confirmed:
  • CREG expression is highly correlated with proliferation and differentiation of VSMCs cultured in vitro, suggesting that CREG is involved in the regulation of VSMCs differentiation phenotype.
  • VSMCs showed high expression of CREG when cultured in vitro, and the expression of differentiated phenotypic markers increased at the same time. After stimulation with serum (ie, VSMCs exposure induced by intimal injury in vitro), the expression of CREG in VSMCs was significantly decreased.
  • differentiated phenotypic markers The expression of differentiated phenotypic markers was down-regulated; the use of retroviral vector to mediate the overexpression of exogenous CREG revealed that the proliferation of VSMCs cultured in vitro was significantly inhibited, and the cells showed a differentiated phenotype; conversely, through antisense RNA technology After inhibiting the expression of CREG in VSMCs, the differentiation ability of VSMCs was significantly decreased, and the proliferative ability and apoptosis ability were significantly increased.
  • CREG is involved in the maintenance of normal physiological functions of blood vessels, and its down-regulation may be one of the mechanisms of vascular pathological damage.
  • the expression of CREG in pathologically injured blood vessels found that CREG was abundantly expressed in the normal mammalian vascular wall and the expression intensity in vascular ECs was significantly higher than that in VSMCs.
  • CREG overexpression can promote endothelial cell migration and proliferation.
  • the expression of VEGF was increased.
  • the expression of CREG protein in the vascular wall was significantly down-regulated. The inhibitory effect of CREG protein expression was more significant in vascular ECs, suggesting that CREG is involved in the repair of vascular endothelium.
  • CREG overexpression is beneficial to reduce the incidence of RS after intervention.
  • CREG expression was negatively correlated with the proliferation of VSMCs in injured blood vessels.
  • CREG gene overexpression was detected by retrovirus and adenoviral vector, respectively, and rats and rabbits after balloon injury. Carotid neointimal formation is significantly inhibited, effectively reducing the occurrence of RS.
  • CREG protein is an important molecule for maintaining tissue and cell differentiation in mature organisms, and is induced in tumor cells. Differentiation and inhibition of vascular VSMCs dedifferentiation and promotion of endothelial function recovery have positive biological functions. Therefore, the inventors proposed to use CREG as an entry point to further explore the mechanism of RS after intervention and develop a new type of recombinant human E1A-stimulated genes (hCREG) bioprotein. Eluting the stent.
  • hCREG human E1A-stimulated genes
  • Protein glycosylation is an important means of post-translational modification of eukaryotic proteins. About 50% of proteins in organisms are glycosylated proteins, including enzymes, carrier proteins, hormones, toxins, various lectins and structural proteins. As a secreted glycoprotein, the correct glycosylation modification of the hCREG protein during its synthesis is a basic condition for its normal structure and function. Veal et al. found that CREG is a secreted glycoprotein that exerts its biological functions through autocrine and paracrine; Alessandra Di Bacco studies also confirmed that CREG-induced cell growth inhibition is dependent on M6P/IGF2R, while M6P/IGF2R preferentially binds to sugar.
  • the conjugated CREG binds only a small amount to the non-glycosylated CREG.
  • the above studies suggest that the successful acquisition of human hCREG glycoprotein is critical for the future clinical application of novel scaffolds, both in terms of biocompatibility, economic effectiveness, and maximization of effects.
  • the object of the present invention is to provide a medical device containing recombinant hCREG glycoprotein, wherein the recombinant hCREG glycoprotein distributed on the surface of the stent can be sustained to inhibit the proliferation of smooth muscle cells of the blood vessel wall, promote the re-endothelialization of blood vessels, and promote the healing of the damaged blood vessel wall. Prevent the occurrence of thrombosis in the stent and reduce the time for patients to take antithrombotic and platelet drugs after surgery.
  • Another object of the present invention is to provide a method of preparing a medical device comprising recombinant hCREG glycoprotein.
  • a further object of the present invention is to provide a blood vessel-eluting stent comprising recombinant hCREG glycoprotein for inhibiting proliferation of vascular wall smooth muscle cells and preventing and treating vascular restenosis.
  • the present invention provides a coronary stent comprising a recombinant hCREG glycoprotein uniformly coated on the surface of a blood vessel eluting stent using recombinant hCREG glycoprotein.
  • the preparation method of the recombinant hCREG glycoprotein comprises the following steps:
  • RT-PCR technology was used to amplify the hCREG open reading frame of the stop-codon mutation, and the hCREG RT-PCR primer for terminating the mutation was as follows: the upstream primer was 5'-aa ggatcc atggccgggctatcccgc-3' (SEQ ID NO.1), the downstream primer is: 5'-gc gaattc Gcactgaactgtgacattataatattcttctgg-3' (SEQ ID NO. 2), in which the upper case letters represent the stop codon of the C/G mutation.
  • a recombinant human CREG protein expression vector pcDNA3.1-his/myc-hCREG with his tagged protein was constructed.
  • the recombinant hCREG protein amino acid sequence (SEQ ID NO. 3) is as follows:
  • the recombinant hCREG glycoprotein may be used in combination with one or more selected from the group consisting of immunosuppressive agents and anti-inflammatory drugs, anti-proliferative drugs, pro-endothelial drugs, and anti-cell migration drugs. , intercellular matrix regulators and other extracellular matrix proteins.
  • the anti-proliferative drugs include sirolimus, tacrolimus, irolimus, immunosuppressant ABT-578, dexamethasone, imidazoribin, rapamycin, paclitaxel and its derivatives, actinomycetes Vincristine and its derivatives, statins, 2-chlorodeoxyadenosine, ribozyme, bamastat, clopidogrel bromide, probucol, any one or more of them may be used.
  • the drug layer is composed of one or more drugs, and the drug layer and the recombinant hCREG glycoprotein are distributed in a layered structure, or the drug layer and the recombinant hCREG glycoprotein layer are respectively distributed on the two different surfaces of the stent lumen and the stent lumen. .
  • the medical device of the present invention has a metal material selected from the group consisting of titanium, cobalt, ruthenium, nickel-titanium alloy, nickel-titanium-niobium alloy, medical stainless steel, medical degradable alloy material such as aluminum-magnesium alloy, and polymer material, including Degradable or non-degradable materials, degradable materials such as PCL, PGA, PLLA, PCLA, PLGA, etc.
  • the medical device surface uniformly distributes micropores of 0.5 ⁇ m to 5 ⁇ m.
  • the size of the microwells determines the amount of protein/drug carried by the microporous drug/protein eluting scaffold.
  • the pore size of the microwell should be determined according to the width of the stent wire of the selected stent.
  • the stent performance parameters of the present invention are integrated to determine an acceptable range of apertures.
  • the recombinant hCREG or drug coating of the medical device does not contain a polymeric carrier that is directly distributed in the micropores of the surface or surface of the material.
  • the inner and outer surfaces of the material can be coated on one side or on both sides. Both the inner and outer sides can be coated with the same drug, or different drugs can be applied on both sides.
  • the method for preparing a medical device according to the present invention is produced by any method as follows:
  • the solvent used for recombinant hCREG is distilled water, physiological saline, borate buffer solution having a pH of 3.0-9.0, pH 8.0-10.0 carbonate buffer solution, pH 3.0-9.0 acetate buffer solution.
  • the concentration is 1-20% ethanol solution or the pH value is 3.0-9.0 phosphate buffer solution.
  • the concentration of recombinant hCREG is 0.01-1.6 mg/ml. Preferably it is 1.6 mg/ml.
  • the solvent of the drug is a paraffin, an olefin, an alcohol, an aldehyde, an amine, an ester, an ether, a ketone, an aromatic hydrocarbon, a hydrogenated hydrocarbon, a terpene olefin, a halogenated hydrocarbon, a heterocyclic compound, a nitrogen-containing compound, a sulfur-containing compound, or the like, which may preferably be used.
  • the method of electrostatic spraying or anodic polarization spraying or dip coating according to the present invention can be carried out by the method disclosed in CN101337093A.
  • the medical device according to the present invention may be one or more medical devices in a medical device such as a heart valve, a cardiac occluder, a blood vessel stent, an artificial blood vessel, a catheter, a pacemaker, a pacemaker derivation, and a defibrillator.
  • a medical device such as a heart valve, a cardiac occluder, a blood vessel stent, an artificial blood vessel, a catheter, a pacemaker, a pacemaker derivation, and a defibrillator.
  • a medical device such as a heart valve, a cardiac occluder, a blood vessel stent, an artificial blood vessel, a catheter, a pacemaker, a pacemaker derivation, and a defibrillator.
  • the invention inhibits the proliferation of vascular wall smooth muscle cells through the sustained release of recombinant hCREG distributed on the surface of the stent, promotes revascularization of blood vessels, promotes healing of damaged blood vessel walls, prevents the occurrence of thrombus in the stent, and reduces antithrombotic and platelet administration in patients after surgery.
  • the time of the drug is the time of the drug.
  • protein/drug-eluting stents generally use polymers as carriers, but after long-term clinical trials, the disadvantages of polymers as carriers are gradually being discovered.
  • the use of a polymer as a carrier increases the wall thickness of the stent and affects the passability.
  • the polymer carrier generally has a low drug loading amount, which satisfies the therapeutic concentration alone, and the release mechanism is surface desorption, which is difficult to overcome the serious phenomenon of sudden release.
  • the polymer carrier remains on the surface of the stent, thereby causing late allergy. And inflammation, which will be an important cause of late thrombosis.
  • the invention adopts the carrierless coating technology, can avoid the allergic and inflammatory reaction brought by the carrier, and becomes a bare stent after the drug is released, which leads to lower possibility of late thrombosis and inflammation and high safety.
  • the stent mechanically supports the vessel for a period of time after intervention and prevents restenosis by means of the eluted drug. After the stent is slowly degraded and completely absorbed by the tissue, the occurrence of late stent thrombosis should be reduced, without long-term antiplatelet drug treatment, no worries.
  • Figure 1 shows the electrophoretic analysis of the purified recombinant wild-type CREG-myc/his fusion protein obtained in the present invention, showing that the protein purity is above 95%.
  • 2 is an in vitro elution curve of a recombinant hCREG glycoprotein eluting stent of the present invention, the abscissa is the time of release, and the ordinate is the residual percentage of recombinant hCREG glycoprotein on the scaffold.
  • Figure 3 shows that HE staining showed a significant thickening of the intima of the bare metal stent group at 4 weeks.
  • Metal is a bare metal stent group
  • SRL is a rapamycin eluting stent group
  • CREG is a recombinant hCREG eluting stent group.
  • Figure 4 shows that CD31 staining showed a marked increase in the degree of endothelialization in the recombinant hCREG group at 4 weeks.
  • Metal bare metal stent group, SRL rapamycin eluting stent group, CREG: recombinant hCREG eluting stent group.
  • Figure 5 is an electron micrograph of the stent of the present invention.
  • Figure A shows the electron micrograph of the nano-microporous bare stent
  • Figure B shows the electron micrograph of the recombinant hCREG glycoprotein eluting stent.
  • the hCREG RT-PCR primers for blocking the mutation of the mutation are as follows: the upstream primer is 5'-aa ggatccatggccgggctatcccgc-3' (SEQ ID NO.1), and the downstream primer is: 5'-gc gaattc Gcactgaactgtgacattataatattcttctgg-3' (SEQ ID NO. 2), where the uppercase letters represent the termination password for the C/G mutation.
  • a recombinant human CREG protein expression vector pcDNA3.1-his/myc-hCREG with his tagged protein was constructed.
  • the recombinant hCREG protein amino acid sequence (SEQ ID NO. 3) is as follows:
  • nanometer microporous bare metal stent adopts the nano microporous bare metal stent of Lepu (Beijing) Medical Instrument Co., Ltd., which is based on the 316L stainless steel bare metal stent and adopts the general electrochemical corrosion method.
  • the surface of the stainless steel bare metal stent forms micropores with a micropore size between 0.5 ⁇ m and 5 ⁇ m.
  • the surface of the coronary stent of the present embodiment is uniformly distributed with recombinant hCREG glycoprotein and rapamycin drugs.
  • the rapamycin drug is distributed on the outer layer of the stent, and the lumen distribution in the stent is Recombinant hCREG glycoprotein.
  • a scaffold equipped with micropores the scaffold is made of 316L medical stainless steel matrix, and the surface is evenly arranged with micropores of about 500 nm.
  • rapamycin drug scaffold a 1% concentration of rapamycin drug was formulated with an acetone solution. The inner surface of the stent is protected, and the rapamycin drug is sprayed on the outer surface of the stent.
  • Preparation of recombinant hCREG protein eluting scaffold The recombinant hCREG glycoprotein was immobilized into the inner lumen of the scaffold by the physical adsorption principle of micropores.
  • the solvent was prepared in a sodium carbonate buffer solution with a pH of 9.6 (0.05 mol/l), and the naked bare stent was loaded with recombinant hCREG glycoprotein solution (1.6 mg/ml), and the adsorption was terminated 48 hours after the soaking, and the vacuum drying machine at -55 ° C was used. Freeze in the middle.
  • the drug protein combined with the stent combines the advantages of the drug stent and the protein scaffold for treating severe vascular stenosis, and simultaneously achieves the effects of inhibiting intimal hyperplasia and accelerating vascular endothelialization, and reducing the dose and period of taking antithrombotic drugs, which is superior to The effect of a simple drug stent or a simple protein scaffold.
  • the surface of the coronary stent of the present embodiment is uniformly distributed with recombinant hCREG glycoprotein, rapamycin and paclitaxel.
  • the rapamycin and paclitaxel drugs are distributed on the outer surface of the stent, and the recombinant hCREG glycoprotein is distributed in the lumen of the stent.
  • a scaffold equipped with micropores the scaffold is made of 316L medical stainless steel matrix, and the surface is evenly arranged with micropores of about 500 nm.
  • Preparation of a three-sided rapamycin drug scaffold protecting the inner surface of the scaffold, spraying rapamycin and paclitaxel on the outer surface of the scaffold, the drug concentration is 1%, and the drug solvent is between tetrahydrofuran, rapamycin and paclitaxel
  • the mass ratio is 1:1.
  • recombinant hCREG protein eluting scaffold drug on the outer surface, protein on the inner surface:
  • the recombinant hCREG glycoprotein was immobilized into the inner lumen of the scaffold by the physical adsorption principle of micropores.
  • the solvent was used in a sodium carbonate buffer solution with a pH of 9.6 (0.05 mol/l), so that the naked bare stent was loaded with recombinant hCREG glycoprotein solution (1.0 mg/ml), 48 hours after soaking.
  • the adsorption was terminated after the time and lyophilized in a vacuum dryer at -55 °C.
  • the dual drug protein combined stent can inhibit angiogenesis and promote the repair of vascular endothelial cells, and is effective for treating severe cardiovascular stenosis.
  • a fully degradable polymer scaffold from Beijing Lepu Medical was used to uniformly distribute recombinant hCREG glycoprotein on its surface.
  • the drug is distributed on the outer surface of the stent, and the recombinant hCREG glycoprotein is distributed in the lumen of the stent.
  • the surface of the degradable polymer scaffold is free of micropores.
  • Preparation of three-sided rapamycin drug stent precise concentration of 1% rapamycin drug in acetone solution to protect the inner surface of the stent and spray rapamycin on the outer surface.
  • a recombinant hCREG glycoprotein eluting scaffold was prepared: the solvent was a sodium carbonate buffer solution having a pH of 9.6 (0.05 mol/l), and the concentration of the recombinant hCREG glycoprotein solution was 0.01 mg/ml.
  • the hCREG glycoprotein was fixed to the lumen of the stent by ultrasonic stereo spraying.
  • the fully degradable drug protein combined stent of the present embodiment can inhibit angiogenesis and vascular endothelial cell repair, and can be completely absorbed, can be used for treating severe cardiovascular stenosis, can reduce the dosage of antithrombotic drugs, and accelerate the healing. The effect is better.
  • Test Example 1 Biological efficacy evaluation of recombinant hCREG glycoprotein eluting stent
  • the study subjects selected healthy pigs cultivated in the fine seed farm of Shenyang Agricultural University, male, male, 9-10 months old, weighing 30-40 kg.
  • the right femoral artery was punctured, and the guide wire was delivered through the puncture needle.
  • the 6F femoral sheath was sent along the wire, and the heparin was given 200 U/kg through the sheath.
  • the 6F right coronary guiding catheter was delivered through the sheath to perform left and right coronary angiography.
  • HE Hematoxylin-eosin
  • EEL cross-sectional area the external elastic lamina area
  • IEL cross-sectional area the inner elastic lamina area
  • the scoring method is as follows:
  • the damage integral of the vessel section is the average of the individual metal rod integrals.
  • the inflammation score was calculated according to the number of granulocytes around the stent metal column, 0 points: no inflammatory cells; 1 point: 1-10; 2 points: 11-20; 3 points > 20, the inflammation integral of the blood vessel section was a single metal column The average of the rod integrals. See Table 1 for details.
  • the neointimal thickness of the CREG group was significantly smaller than that of the METALL group and the SRL group.
  • the degree of intimal hyperplasia at the attachment of the stent wire was significantly higher than that of the stent-free wire.
  • the intimal hyperplasia of the bare stent group was significant and the stent was completely covered.
  • the surface has a thickness several times that of the original medium film.
  • the inner elastic plates of the three groups are complete, and there is only slight compression deformation at the contact with the stent wire, and the membrane also shows signs of compression.
  • the recombinant hCREG glycoprotein containing the recombinant hCREG glycoprotein of the invention can be used in combination with a plurality of drugs, and the recombinant hCREG glycoprotein carried by the device can be sustained by the device after being implanted into the human body. Release to inhibit the proliferation of vascular smooth muscle cells, and promote the re-endothelialization of the blood vessel wall, so that the damaged blood vessel wall can heal quickly, thereby preventing the occurrence of thrombosis in the lumen of medical devices, and reducing the time for patients to take antithrombotic and platelet drugs after surgery.
  • the medical device of the invention adopts the carrier-free coating technology, can avoid the allergic and inflammatory reaction brought by the carrier, and becomes a bare stent after the drug is released, which leads to lower possibility of late thrombosis and inflammation and high safety.

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Abstract

L'invention concerne un instrument médical contenant une protéine hCREG recombinée, dont une surface est uniformément recouverte de la glycoprotéine hCREG recombinée. Dans l'instrument médical, la glycoprotéine hCREG recombinée peut être utilisée en combinaison avec une pluralité de médicaments. Après implantation de l'instrument médical dans un corps humain, la glycoprotéine hCREG recombinée portée par l'instrument est sujette à une libération prolongée pour réduire la prolifération de cellules musculaires lisses vasculaires (CMLV), et pour faciliter la re-endothélialisation de la paroi vasculaire, de telle sorte que paroi vasculaire lésée guérisse rapidement, en empêchant ainsi une thrombose intraluminale de l'instrument médical, et en réduisant la durée de prise de médicaments antithrombotiques et antiplaquettaires par le patient après l'opération.
PCT/CN2014/090824 2014-10-21 2014-11-11 Instrument médical contenant une protéine hcreg recombinée et procédé pour le préparer WO2016061858A1 (fr)

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CN106421750A (zh) * 2016-09-18 2017-02-22 中国人民解放军沈阳军区总医院 一种重组hCREG糖蛋白的新用途及其在冠脉支架上的应用

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