CN116803440A - Drug-coated stent capable of rapidly promoting endothelialization and preventing restenosis in stent - Google Patents
Drug-coated stent capable of rapidly promoting endothelialization and preventing restenosis in stent Download PDFInfo
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- Materials For Medical Uses (AREA)
Abstract
The invention discloses a drug-coated stent capable of rapidly promoting endothelialization and preventing restenosis in the stent, which adopts magnesium alloy AZ31 as a cardiovascular stent substrate material; firstly, performing surface functionalization on a magnesium alloy substrate through an alkali process, and performing sanding, ultrasonic cleaning and drying to obtain hydroxylated AZ31; secondly, preparing spinning solution from human recombinant collagen III, an allo You Shan antibody, a VEGFR2 antibody and a polylactic acid-glycolic acid copolymer by taking hexafluoroisopropanol as a solvent, loading the spinning solution on the hydroxylated AZ31 surface by an electrostatic spinning technology, forming a layer of porous fiber film on the surface, covalently modifying folic acid on the polylactic acid coating surface by chemical grafting, and crosslinking PLGA in the fiber film with the hydroxylated AZ31 substrate by a glutaraldehyde steam crosslinking method to prepare the multifunctional drug coating/magnesium alloy AZ31 stent. The invention has reasonable design and good practical application value.
Description
Technical Field
The invention relates to the technical field of percutaneous coronary intervention treatment of coronary heart disease, in particular to a drug coated stent capable of rapidly promoting endothelialization and preventing restenosis in the stent.
Background
Percutaneous coronary intervention is an important means for treating coronary heart disease, but restenosis after operation is always a major problem affecting the therapeutic effect of percutaneous coronary intervention. Intracoronary stenting is a treatment means for restoring the smoothness of stenosed vessel through mechanical support of the stent, is the most effective method for treating arterial occlusion at present, but has a certain vascular adaptability reaction, wherein Endothelial Cell (ECs) injury is an initiating factor, and thrombus is easy to occur.
Implantation of a Bare Metal Stent (BMS) is safe for low-risk patients, but can cause inflammatory reaction in early intravascular stage, leading to a series of problems such as cell adhesion and proliferation, thrombus formation in the stent, etc., and restenosis rate of BMS is 15% -25%. In contrast, DES mechanically supports diseased vessels and acts on the vessel wall in contact with the stent due to the surface-loaded drug coating, so that the problems of elastic retraction, remodeling and intimal hyperplasia of the vessels can be solved, the occurrence rate of restenosis and the occurrence rate of postoperative thrombosis complications and major adverse events are reduced below 5%, but the effect is considered as a double-edged sword, and the potential risk of delayed re-endothelialization of damaged sites of the vessels and causing late-stage internal thrombosis of the stent exists; thus, promoting vascular endothelialization is a key measure for both reducing restenosis in stents and preventing late stent thrombosis.
At present, a metal bracket eluted by medicines is generally adopted clinically, the main material of the bracket is stainless steel, nickel-titanium alloy or cobalt-chromium alloy, an organic polymer coating is arranged on a metal surface, and medicines capable of regulating and controlling local inflammatory reaction and cell proliferation are loaded on the coating. The medicine mainly adopts CD34 antibody, but the main problems in actual use are: (1) thrombosis and restenosis problems due to permanent support and implantation of foreign bodies; (2) the drug coating inhibits intimal growth while interfering with endothelial functionalization and structural regeneration, with the potential risk of late thrombosis; (3) CD34 antibodies, because they are not fully specific for ECs, promote endothelialization in the short term to have an anti-stenting effect. In addition, the construction method of the metal stent eluted by the drug mainly adopts an immersion method, the drug only depends on physical adsorption on the surface of the stent, the interfacial binding force between the drug and a stent substrate is relatively weak, the drug has a falling problem, the drug coating on the surface of the stent after the implant has a 'burst release' problem, and the drug action time is too short.
The mechanical damage can be weakened to the greatest extent by predicting the stress change in the stent implantation process, but can not be completely avoided, so that the damaged vascular endothelium can be repaired and recombined by reasonably controlling the quality and the performance of the stent, and the mechanical damage mainly depends on the construction of an ideal drug coating. The research shows that the ideal stent drug coating has the following requirements in terms of performance: (1) has the advantage of rapid capture of EPCs; (2) promoting proliferation and differentiation of vascular endothelial ECs; (3) lowering homocysteine (Hcy) levels in blood; (4) effectively inhibit inflammatory factors; (5) good blood compatibility; (6) has certain medicine slow release performance.
Antibody coated scaffolds are the predominant product of in vivo capture of cell endothelialization. The antibody CD31, CD34 and CD133 can attract the adhesion of endothelial cells, but the endothelialization promoting efficiency is lower, compared with the Vascular Endothelial Growth Factor (VEGF) mainly acts on the growth factor of vascular endothelial cells, has the functions of promoting the proliferation of endothelial cells, increasing the permeability of microvessels, inducing angiogenesis and the like, wherein the VEGFR2 antibody not only has higher specificity on the antigen on the surface of EPCs, but also promotes the proliferation and differentiation of vascular endothelial ECs cells, and an important influencing factor in the rapid endothelialization process of a stent, so that the EPCs are captured by targeting the antigen attracting the surface of endothelial progenitor cells through the antibody bound on the stent. The recombinant human collagen (Rhc-III) is closely related to the skin injury repair process and repair quality, has rich hydrophilic groups and good film forming property, can increase the adhesion and proliferation of fibroblasts under the trend guiding action, effectively improves the skin regeneration speed, shortens the wound healing time, and further recovers the skin barrier function, and the hydrolysate has certain biological activity.
The drug coating not only aims at the damaged endothelial repair function, but also combines with atherosclerosis pathological factors, and proper targeting components are introduced to further prevent and treat the focus area caused by stent implantation for timely and rapid treatment. Because low-density lipoprotein cholesterol and homocysteine (Hcy) are two important factors closely related to atherosclerosis, human proprotein convertase subtilisin kexin type 9 (PCSK 9) is an important inflammatory medium in the pathogenesis of atherosclerosis, and the alo You Shan is resistant to affecting the process of atherosclerosis by inhibiting inflammatory reaction while reducing lipid with high efficiency, so that vascular endothelial function is improved, coronary vulnerable plaque is stabilized and even plaque is reversed; studies have shown that folic acid is closely related to homocysteine. Intermediate products in methionine metabolic process, wherein 5-methyltetrahydrofolate, betaine and vitamin B are needed in metabolic process 6 Vitamin B 12 In the homocysteine and methionine conversion process, 5-methyltetrahydrofolate can provide a methyl donor, and the supplementation of folic acid can help reduce Hcy in blood plasma and enhance the HcyElasticity and compliance of the blood vessel. Therefore, the project proposes a novel drug coating for promoting rapid endothelialization of blood vessels after stent implantation.
Disclosure of Invention
The invention aims to provide a drug-coated stent for rapidly promoting endothelialization and preventing restenosis in the stent, in particular to a stent for loading folic acid, recombinant human collagen and an anti-VEGFR 2 antibody on a vascular stent. The anti-VEGFR-2 antibody can enable the damaged part of the blood vessel to rapidly capture EPCs, the recombinant human collagen can inhibit the deposition of thrombotic components at the damaged part of the blood vessel, and folic acid enhances the elasticity and the compliance of the blood vessel.
The invention is realized by adopting the following technical scheme:
a drug-coated stent capable of rapidly promoting endothelialization and preventing restenosis in the stent, which adopts magnesium alloy AZ31 as a cardiovascular stent substrate material; firstly, performing surface functionalization on a magnesium alloy substrate through an alkali process, and performing sanding, ultrasonic cleaning and drying to obtain hydroxylated AZ31; secondly, preparing spinning solution from human recombinant collagen III, an allo You Shan antibody, a VEGFR2 antibody and a polylactic acid-glycolic acid copolymer by taking hexafluoroisopropanol as a solvent, loading the spinning solution on the hydroxylated AZ31 surface by an electrostatic spinning technology, forming a layer of porous fiber film on the surface, covalently modifying folic acid on the polylactic acid coating surface by chemical grafting, and crosslinking PLGA in the fiber film with the hydroxylated AZ31 substrate by a glutaraldehyde steam crosslinking method to prepare the multifunctional drug coating/magnesium alloy AZ31 stent.
Further preferably, the concentration of the solution in the composite spinning solution is 8-15 g/ml; wherein the concentration of the recombinant human collagen is 0.1-5 mg/ml, the mass ratio of folic acid to polylactic acid caprolactone is 1-40:100, and the concentration of the VEGFR-2 antibody is 0.001-1 mg/ml.
In order to realize the effect of multiple components of the drug coating, and the effective bonding on the surface of the stent, the rapid and durable drug effect is realized, so that the time in vivo after implantation is prolonged, and the drug slow-release layer is constructed on the surface of the stent by adopting a combination strategy of electrostatic spinning technology and chemical grafting through strong bonding. Constructing a degradable polylactic acid coating of a recombinant humanized collagen+ebo You Shan anti-VEGFR 2 antibody by adopting an electrostatic spinning method, and then covalently modifying folic acid on the surface of the polylactic acid coating by chemical grafting, wherein the construction method has the advantages that: (1) enhancing the interface bonding effect between the drug coating and the stent; (2) realizing the durable and controllable release of the medicine; (3) the drug loading is high. Compared with the soaking method and the spraying method, the method can not only protect the biological activity of the medicine or the factor to the greatest extent, but also enable the medicine or the factor to be controllably and continuously released through diffusion action, degradation mechanism and the like.
The invention has the following beneficial technical effects:
1. the invention prepares the vascular stent loaded with recombinant humanized collagen, folic acid, and an anti-VEGFR-2 antibody of Elol You Shan for the first time. On the basis of meeting the requirements of general vascular stents, the method further specifically promotes the capture, homing, proliferation and differentiation of EPCs, inhibits the excessive proliferation of intima, realizes the rapid endothelialization of blood vessels, and has good biocompatibility and compliance.
2. The concentration of the solution in the composite spinning solution is 8-15 g/ml (preferably 10-12 g/ml); wherein: the concentration of the recombinant human collagen III is 0.1-5 mg/ml (preferably 0.5-2 mg/ml), the mass ratio of folic acid to polylactic acid caprolactone is 1-40:100 (preferably 15-25:100), and the concentration of the VEGFR-2 antibody is 0.001-1 mg/ml (preferably 0.05-0.5 mg/ml).
3. The dynamic liquid electrostatic spinning method is adopted to realize that the functional medicine is loaded on the surface of the bare metal stent, and compared with a soaking method and a spraying method, the method can not only protect the biological activity of the medicine or the factor to the greatest extent, but also can enable the medicine or the factor to be controllably and continuously released through diffusion action, degradation mechanism and the like.
The invention has reasonable design and good practical application value.
Drawings
Fig. 1 shows a schematic diagram of the construction process of the multifunctional drug coating/magnesium alloy AZ31 stent.
Detailed Description
Specific embodiments of the present invention are described in detail below.
(1) Construction of multifunctional drug-coated vascular stent, structure and performance evaluation
(1) Constructing a drug-coated stent of VEGFR2 antibody, recombinant human collagen III, and allo You Shan anti-folic acid:
the magnesium alloy AZ31 is selected as a cardiovascular stent substrate material. Firstly, performing surface functionalization on a magnesium alloy substrate through an alkali process, cutting the magnesium alloy substrate into sheets with the thickness of 3mm, and performing sanding, ultrasonic cleaning and drying to obtain hydroxylated AZ31. Secondly, preparing spinning solution from human recombinant collagen III, an allo You Shan antibody, a VEGFR2 antibody and a polylactic acid-glycolic acid copolymer (PLGA) according to a certain proportion by taking hexafluoroisopropanol as a solvent, loading the spinning solution on the hydroxylated AZ31 surface by an electrostatic spinning technology, forming a layer of porous fiber film on the surface, covalently modifying folic acid on the polylactic acid coating (porous fiber film) surface by chemical grafting, and crosslinking PLGA in the fiber film with the hydroxylated AZ31 substrate by a glutaraldehyde steam crosslinking method to prepare the multifunctional drug coating/magnesium alloy AZ31 stent (shown in figure 1).
The concentration of the solution in the composite spinning solution is 8-15 g/ml; wherein: the concentration of the recombinant human collagen III is 0.1-5 mg/ml, the mass ratio of folic acid to polylactic acid caprolactone is 1-40:100, and the concentration of the VEGFR-2 antibody is 0.001-1 mg/ml.
The invention constructs a degradable polylactic acid coating of recombinant human collagen +Elo You Shan anti +VEGFR2 antibody by adopting an electrostatic spinning method, and then covalently modifies folic acid on the surface of the polylactic acid coating by chemical grafting, and the construction method has the advantages that: 1) Enhancing the interface bonding effect between the drug coating and the stent; 2) Realizing the durable and controllable release of the medicine; 3) The drug loading is high. Compared with the soaking method and the spraying method, the method can not only protect the biological activity of the medicine or the factor to the greatest extent, but also enable the medicine or the factor to be controllably and continuously released through diffusion action, degradation mechanism and the like.
In practical application, structural regulation and control of the fiber film are realized by examining the influence rules of technological parameters such as the proportion of each component of the spinning solution, the spinning speed, the spinning voltage, the spinning temperature, the spinning humidity, the consumption of the cross-linking agent and the like on the structure and the performance of the spinning film.
(2) Testing and characterizing the microscopic morphology, molecular structure and slow release performance of the drug coating film:
a. the microscopic morphology of the drug coating film was examined using a Scanning Electron Microscope (SEM).
b. The molecular structure of the drug coating film was analyzed by 1H-NMR and Fourier infrared diffraction (FTIR).
c. The structure and activity of the coating film proteins were detected by round dichroism.
d. PLGA degradation and drug release rates were determined in combination with Gel Permeation Chromatography (GPC).
(3) Testing and characterizing the structure, physical and chemical properties and biochemical properties of the drug coating stent:
a. and testing the mechanical properties of the bracket by adopting a universal mechanical testing machine, wherein the mechanical properties comprise indexes such as extrusion resistance, radial supporting force, radial resilience force, axial shrinkage, fatigue resistance, flexibility and the like.
b. Platelet adhesion was evaluated by SEM observation of platelet growth.
c. And (5) evaluating hemolytic performance and cytotoxicity test of the scaffold by using an enzyme-labeled instrument.
d. Cell scratch-wound healing experiments are adopted, primary Porcine Coronary Artery Endothelial Cells (PCAECs) are used as culture objects, and the cell migration speed is calculated by combining with image J image processing software.
e. The looping test of the blood vessels was evaluated using an inverted microscope.
f. The phase structure change of the magnesium alloy substrate was evaluated by X-ray diffraction (XRD).
g. The change in hydrophilicity of the stent drug coating before and after was evaluated using a contact angle meter.
(2) Research on restenosis effect of drug-coated stent on blood vessel after stent implantation
(1) Preparation of pig coronary artery stenosis animal model/in-stent restenosis animal model:
(2) grouping of experimental animals:
after the establishment of the coronary artery stenosis model, 18 vital signs are randomly selected to be stable, the coronary artery stenosis pig model is subjected to stent implantation in two groups, and the two groups are divided into an experimental group and a control group, wherein the control group is implanted with a magnesium alloy AZ31 bare metal stent, the experimental group is implanted with a drug coating/a magnesium alloy AZ31 stent (VEGFR 2 antibody+recombinant human collagen III+Elo You Shan anti-folic acid), the control group is 6, and the experimental group is 12. The experimental groups were divided into 1 month group (4), 2 month group (4) and 3 month group (4) according to the time of sacrifice, and the control group was sacrificed 1 month after operation.
(3) CT examination and stenosis measurement and general observation:
a. the coronary lumen area, the inner spring plate surrounding area, the outer spring plate surrounding area, the neointima area, the area restenosis percentage, and the incidence of restenosis within the stent were determined using CT measurements.
b. Measuring the stenosis degree after the establishment of a stenosis animal model by using CT: the stenosis animal model was sacrificed 4 weeks after establishment, the stenosis rate was measured by CT scan, frozen sections were fixed with 4% paraformaldehyde solution, HE staining and MASSN staining were performed, and the vessel reconstruction was observed.
c. The stenoses of stent placement were determined using CT: CT detection is carried out on the experimental rabbits in the experimental group and the control group before death, and the stenosis degree of the lumen is measured. The experimental groups were tested for dead forward CT at 1 month, 2 months, and 3 months, respectively, and measure the stenosis rate at the most severe lumen stenosis. Control pigs were sacrificed 1 month post-surgery and were pre-mortem to measure the stenosis rate at the narrowest lumen site under CT.
d. General observations: including heart rate, blood pressure, weight and behavioral status, compare heart rate, blood pressure and changes thereof before stent placement and immediately before termination of the experiment. The changes in behavior and weight before and after stent placement and between the different groups were compared.
(4) Monitoring of vascular segment response after stent implantation
a. Measuring the haemorheology index: and 5ml of heparin is taken for anticoagulation detection of the viscosity shear rate of whole blood, the erythrocyte aggregation index and the like.
b. Measurement of plasma endothelin content: 2ml of the mixture is poured into a test tube containing 30ul of 10% EDTA-Na2 and 10ul of aprotinin for anticoagulation, centrifugal separation is carried out, and the upper plasma is frozen in dry ice for testing.
(5) Evaluation of important organ function and pathological injury
a. The biochemical indexes of blood are analyzed, and the influence on the liver and kidney functions is mainly analyzed.
b. The myocardial, lung, stomach, small intestine, large intestine, liver and kidney tissues were sectioned and HE stained, and the pathological changes, lesion types and lesion ranges thereof were observed and compared.
c. Analyzing the whole blood cell count result, and analyzing whether hemolysis exists or not by combining with blood biochemical indexes.
Finally, it should be noted that the above-mentioned embodiments are merely for illustrating the technical solution of the present invention and not for limiting the same, and although the detailed description is given with reference to the embodiments of the present invention, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted without departing from the spirit and scope of the technical solution of the present invention, and it should be covered by the scope of the claims of the present invention.
Claims (2)
1. A drug-coated stent for rapid endothelialization prevention of restenosis in the stent, comprising: selecting magnesium alloy AZ31 as a cardiovascular stent substrate material; firstly, performing surface functionalization on a magnesium alloy substrate through an alkali process, and performing sanding, ultrasonic cleaning and drying to obtain hydroxylated AZ31; secondly, preparing spinning solution from human recombinant collagen III, an allo You Shan antibody, a VEGFR2 antibody and a polylactic acid-glycolic acid copolymer by taking hexafluoroisopropanol as a solvent, loading the spinning solution on the hydroxylated AZ31 surface by an electrostatic spinning technology, forming a layer of porous fiber film on the surface, covalently modifying folic acid on the polylactic acid coating surface by chemical grafting, and crosslinking PLGA in the fiber film with the hydroxylated AZ31 substrate by a glutaraldehyde steam crosslinking method to prepare the multifunctional drug coating/magnesium alloy AZ31 stent.
2. A rapid endothelialization-promoting, stent of drug coatings for preventing restenosis within stents according to claim 1, wherein: the concentration of the solution in the composite spinning solution is 8-15 g/ml;
wherein: the concentration of the recombinant human collagen III is 0.1-5 mg/ml, the mass ratio of folic acid to polylactic acid caprolactone is 1-40:100, and the concentration of the VEGFR-2 antibody is 0.001-1 mg/ml.
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