CN111839811B - Antithrombotic/antitumor functional blood vessel covered stent and preparation method thereof - Google Patents
Antithrombotic/antitumor functional blood vessel covered stent and preparation method thereof Download PDFInfo
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- CN111839811B CN111839811B CN202010641008.1A CN202010641008A CN111839811B CN 111839811 B CN111839811 B CN 111839811B CN 202010641008 A CN202010641008 A CN 202010641008A CN 111839811 B CN111839811 B CN 111839811B
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- A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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Abstract
The invention discloses an anti-thrombus/anti-tumor functional blood vessel covered stent and a preparation method thereof. The anti-thrombosis drug is carried on the inner layer of the covering film through the inner layer, the anti-tumor drug is carried on the outer drug bag interlayer, the covalent crosslinking technology is utilized, the anti-thrombosis coating is carried out on the inner layer of the covering film, the inner layer of the covering film can be anti-thrombosis and rapid endothelialization, the treatment requirement of the intracavity repair operation on the aortic aneurysm is met, curcumin and metformin microspheres are carried on the outer cavity interlayer of the covering film, the anti-tumor treatment can be carried out on the aortic aneurysm, the long-term slow release of the drug is realized, the restenosis is effectively prevented, the growth of the tumor is inhibited, the risk of vascular rupture is reduced, and the anti-thrombosis coating film is particularly suitable for patients with abdominal aortic aneurysm.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and particularly relates to an anti-thrombus/anti-tumor functional blood vessel covered stent and a preparation method thereof.
Background
Aneurysms are persistent dilatations of the vessel wall caused by damage to the wall of the artery, a condition that often occurs in the aorta and the main arteries of the lower extremities. Vascular stent implantation is one of the effective ways of minimally invasive surgery for treating cardiovascular diseases, and has the advantages of small trauma, low risk, quick recovery and relatively low cost. The intravascular stent is an implantable medical device which can provide enough mechanical supporting force for blood vessels, keep the blood vessels unobstructed and complete the task of repairing the blood vessels on the premise of not causing local and systemic tissue damage.
Common vascular stents include bare stents, drug-coated stents, stent grafts, and the like. Such as: the utility model provides a metal, naked support of aorta, is the tubular network structure, has suitable radial support intensity and axial support intensity to and good bending compliance, can reduce the oppression to the vascular wall when arranging in human blood vessel. However, the bare stent only satisfies mechanical properties required during and after the operation, but has a rough surface, is prone to mechanical damage to blood vessels, has poor biocompatibility, releases heavy metal ions on the surface, and is prone to restenosis caused by intimal hyperplasia, thereby causing thrombosis. For another example: a medicine eluting stent is used for providing an expansion supporting force for cardiovascular of a patient in a percutaneous artery intervention stent operation, a medicine with the function of inhibiting smooth muscle proliferation is carried on the outer side of the stent, and a medicine layer with the function of accelerating vascular endothelialization is carried on the inner side surface of the stent. Compared with a metal bare stent, the drug eluting stent has the advantages that the surface drug can effectively inhibit intimal hyperplasia and prevent thrombus, but the drug loading is small, the drug release rate is high, the drug eluting stent does not have an anti-tumor function, and the treatment effect on diseases is poor. For another example: vascular stent-grafts, a type of stent commonly used in endoluminal exclusion procedures for the treatment of abdominal aortic aneurysms. The tectorial membrane stent is formed by covering a layer of biological polymeric membrane or internal stent graft on the surface of a metal stent, so that the tectorial membrane stent not only has the supporting function of a common stent, but also has the functions of isolating blood, reducing thrombosis and preventing tumor body from cracking through the obstruction of the membrane. The inner cavity of the covering film is coated with anticoagulant drugs, and the outer wall of the bracket is loaded with drugs for inhibiting the proliferation and migration of smooth muscle cells. The method for coating the medicine is ultrasonic spraying, and due to the fact that a plurality of factors affect the effect of ultrasonic atomization spraying equipment, for example: the method has too much limitation on the used medicament due to the viscosity of the liquid, the mixing degree of different components, the dynamic characteristics of the liquid and the like, so the method has great application difficulty. And the medicament coated by the method has the burst release phenomenon and has no obvious inhibition effect on the formation of thrombus. And the tectorial membrane stent does not have the dual functions of anti-tumor and anti-thrombus, so that the problems of poor biocompatibility, restenosis, vascular endothelial disqualification and the like are easy to occur in middle and long-term clinic, and secondary operation is needed when postoperative complications occur to 15-20 percent of patients after the operation.
Therefore, the invention provides an anti-thrombus/anti-tumor functional blood vessel covered stent and a preparation method thereof, and the anti-thrombus anti-restenosis blood vessel covered stent can inhibit tumor proliferation and can resist thrombus.
Disclosure of Invention
The invention aims to provide an antithrombotic/antitumor functional blood vessel covered stent and a preparation method thereof.
The invention has a technical scheme that:
an anti-thrombus/anti-tumor functional vascular covered stent comprises a metal stent and a covered membrane,
the metal bracket is divided into a first straight pipe part, a first transition part and a first bifurcation part which are connected into an integral structure, the first transition part is provided with a first pipe end and a first bifurcation end and a second bifurcation end which correspond to the first pipe end, the first bifurcation part is provided with a first supporting leg and a second supporting leg, the first pipe end is connected with the first straight pipe part, the first bifurcation end is connected with the first supporting leg, the second bifurcation end is connected with the second supporting leg,
the film is coated on the metal bracket and is divided into a second straight pipe part, a second transition part and a second bifurcation part, the second straight pipe part, the second transition part and the second bifurcation part are connected into an integral structure, the second transition part is provided with a second pipe end and a third bifurcation end and a fourth bifurcation end corresponding to the second pipe end, the second bifurcation part is provided with a third supporting leg and a fourth supporting leg, the second pipe end is connected with the second straight pipe part, the third bifurcation end is connected with the third supporting leg, the fourth bifurcation end is connected with the fourth supporting leg, the second straight pipe part coats the first straight pipe part, the top end of the first straight pipe part is exposed out of the second straight pipe part, the second transition part coats the first transition part, the third supporting leg coats the first supporting leg, and the bottom end of the first supporting leg is exposed out of the third supporting leg, the fourth supporting leg covers the second supporting leg, the bottom end of the second supporting leg is exposed out of the fourth supporting leg,
the second straight pipe part is provided with a medicine bag interlayer, and the top end of the second straight pipe part is exposed out of the medicine bag interlayer.
Further, the metal support is formed by weaving nickel-titanium alloy wires, the nickel content in the nickel-titanium alloy wires is 8% -15%, the fineness range is 0.1-0.5mm, the expansion rate is greater than 20%, the metal support is of a mesh structure, the weaving angle is 30-75 degrees, the diameter of the first straight pipe part is 10-30mm, and the diameters of the first support leg and the second support leg are both 5-15 mm; the pitch length is 3-12 mm; the metal coverage rate is 10% -60%; the radial supporting force is 0.3-1.5N; the longitudinal short shrinkage rate is 15-50%; the elastic retraction rate is 0.5-5%.
Furthermore, the coating film is prepared by using warp and weft yarn materials as raw materials and adopting a weaving method, wherein the warp and weft yarn materials are synthetic fibers or natural fibers, when the synthetic fibers are selected, the single-yarn fineness is 10-50D, the multifilament is 10-50D, and the complex number is 12-72 f; when natural fibers are selected, for example, 10-50D is adopted for silk, 10-50D is adopted for mature fibers, the complex number is 12-72f, the basic tissue of the coating is any one or combination of more of plain weave, twill, satin, double plain weave, honeycomb weave, crepe weave or small jacquard weave, the warp density of the coating is 3000 pieces/10 cm, the weft density is 300 pieces/10 cm, and the thickness of the coating is 0.05-0.2 mm; the cross-section water permeability is 4.19-8.75 mL/(cm)2Min); the surface hydrophilic angle is 30-75 degrees; the radial tensile strength is 30-120 MPa; the longitudinal tensile strength is 50-200 MPa; the bursting strength of the probe is 20-100 MPa.
Furthermore, the synthetic fiber is any one or more of polyester monofilament, polyester multifilament, spandex monofilament, spandex multifilament, acrylic monofilament and acrylic multifilament, and the natural fiber is any one or combination of silk, spider silk and chitosan silk.
The other technical scheme of the invention is as follows:
a preparation method of an anti-thrombus/anti-tumor functional vascular graft stent comprises the following steps:
(1) the inner layer carries antithrombotic drugs: fixing the reverse side of a coating on a metal stent by using a covalent crosslinking technology, exposing the inner surface of the coating, and performing low-temperature plasma treatment on the surface of the coating to be coated by taking the inner surface of the coating as the surface of the coating to be coated so as to generate an etching trace and introduce amino; preparing MES buffer solution, adding heparin sodium, uniformly dissolving to obtain heparin coating solution, and coating the surface to be coated with the coating with the heparin coating solution to obtain a coated film with a coating; introducing diamino polyethylene glycol as a connecting molecule, introducing ethyl carbodiimide hydrochloride and N-hydroxysuccinimide as a carboxyl activating agent, uniformly mixing, incubating the coated film with the coating at normal temperature in a shaking way, incubating the coated film with the coating stably, and washing with distilled water; preparing cytokine solutions with different concentrations for composite coating, and after repeating the coating operation for multiple times, placing the coated film with the coating in a refrigerator at 4 ℃ for 8-24h to form a stable antithrombotic drug coating on the inner surface of the coated film;
(2) the outer layer is loaded with anti-tumor drugs: mixing curcumin dissolved by PEG and metformin dissolved by deionization with a fibroin solution by using a PEG emulsification-precipitation technology, and preparing fibroin-carried metformin and curcumin-carrying microspheres by the steps of incubation, centrifugation, washing and ultrasonic dispersion; fixing the front surface of the coating on the metal stent, and loading the drug-loaded microspheres into a drug sac interlayer to obtain the anti-thrombus/anti-tumor functional vascular coating stent.
Further, in the step (1), the concentration of the MES buffer solution is 0.1-0.5mol/L, the pH value is 4-8, the mass concentration of heparin in the MES solution is 1%, and the concentration of ethyl carbodiimide hydrochloride is as follows: n-hydroxysuccinimide: the mass ratio of the heparin sodium is 7.5:12.5:1, the volume concentrations of the cytokine solutions with different concentrations are in the range of 1-8%, and the coating operation is carried out for 2-5 times.
Further, in the step (2), the mass concentration of the PEG is 10-75%, the mass ratio of the curcumin to the PEG is 1:50, and the mass ratio of the metformin to the fibroin is 1: 50.
The other technical scheme of the invention is as follows:
a preparation method of an anti-thrombus/anti-tumor functional vascular graft stent comprises the following steps:
(1) carrying a coating on the inner surface and the outer surface: fixing the reverse side of a coating film, exposing the inner surface of the coating film, dissolving heparin in 1-15% of silk fibroin solution by mass, wherein the mass ratio of the heparin to the silk fibroin is 1:50, then soaking the coating in the mixed solution, fully stirring and taking out, finally treating the taken out sample by water vapor (50-80 ℃) and drying; adding 0.1-0.8g of aliphatic polyester hydrogel into a PBS solution, heating the mixture to 50-80 ℃, stirring until the mixture is completely dissolved, then cooling to 5-20 ℃ to form a transparent polymer, adding metformin with the mass concentration of 1-10% into the aliphatic polyester hydrogel at 5-20 ℃, filling the mixture to the outer surface of a covering membrane at room temperature, rapidly heating after sealing two ends to enable the polymer solution to be aggregated into a gel state, incubating for 8-24h, flushing the inner cavity of a graft with PBS at room temperature, washing off excessive metformin, ensuring the smoothness in the stent, and obtaining the anti-thrombus/anti-tumor functional vascular covering membrane stent.
The other technical scheme of the invention is as follows:
a preparation method of an anti-thrombus/anti-tumor functional vascular graft stent comprises the following steps:
(1) carrying a coating on the inner surface and the outer surface: fixing the reverse side of the coating film, exposing the inner surface of the coating film to the outside, soaking the coating film in a heparin sodium solution with the mass concentration of 1-10% for 5-30min, then washing with distilled water to obtain heparin coating, then soaking the heparin coating in a mixed solution of acetic acid and chitosan with the substance quantity ratio of 3:1 for 5-30min, rinsing again, repeating the above operations for 2-5 times to finally obtain a stable chitosan/heparin coating intravascular stent combined through electrostatic attraction, exposing the outer surface of the coating, electrostatically attracting metformin/silk fibroin microspheres on the surface of the coating, the method comprises the steps of mixing 1-15% of silk fibroin solution and 10-50% of PEG in a volume ratio of 1:1, and then adding the mixture of the two components in a mass ratio of 1:50, mixing, standing, centrifuging and cleaning to prepare the metformin silk fibroin microsphere with the diameter of about 0.2-2 mu m, introducing some active groups to the fiber surface by etching the fabric surface by adopting a low-temperature plasma technology, and performing electrostatic combination on the active groups and the microsphere to obtain the antithrombotic/antitumor functional vascular graft stent.
Further, before the step (1), the method further comprises the following steps:
(1) weaving the metal stent: weaving a single nickel-titanium alloy wire to obtain a tubular stent, and carrying out high-temperature shaping on the tubular stent to ensure that the tubular stent is cylindrical, the alloy wires at two ends of the tubular stent are arc-shaped, the diameter of the nickel-titanium alloy wire is 0.1-0.5mm, and the weaving angle is 30-75 degrees; the metal coverage rate is 10% -60%; the radial supporting force is 0.3-1.5N;
(2) preparing a coating film: the warp and weft yarn materials are used as raw materials, the warp density is 300-3000 pieces/10 cm, the weft density is 300-3000 pieces/10 cm, the fineness of the warp yarn is 10-50D monofilament, the fineness of the weft yarn is 10-50D/12-72f multifilament, a covering film is prepared by a weaving method, and the thickness of the covering film is 0.05-0.2 mm.
The invention provides an anti-thrombus/anti-tumor functional blood vessel covered stent and a preparation method thereof, and the stent has the advantages that:
(1) if the structure utilizes a special weaving technology, stent tectorial membranes with different pipe diameters and different structures can be designed and prepared;
(2) the prepared stent covering film has the advantages of high strength, low permeability, ultra-thin and the like, and can meet the treatment requirement of the intracavity repair operation on the abdominal aortic aneurysm;
(3) an anti-thrombus coating is carried out on the inner layer of the coating by utilizing a covalent crosslinking technology, so that the inner layer of the coating can resist thrombus and quickly endothelialize;
(4) curcumin and metformin microspheres are carried on the interlayer of the cavity at the outer layer of the covering film, so that the anti-tumor treatment can be carried out on AAA, and the long-term slow release of the medicament is realized;
(5) can effectively prevent restenosis, inhibit tumor growth, and reduce risk of blood vessel rupture, and is especially suitable for patients with abdominal aortic aneurysm.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without inventive exercise. Wherein,
FIG. 1 is a schematic structural diagram of an anti-thrombus/anti-tumor functional vascular stent graft according to the present invention;
wherein, 1 is a metal bracket, 11 is a first straight pipe part, 12 is a first support leg, 13 is a second support leg, 2 is a coating film, 21 is a second straight pipe part, 22 is a second transition part, 23 is a second bifurcation part, 24 is a third support leg, 25 is a fourth support leg, and 3 is a medicine sac interlayer.
FIG. 2 is a scanning electron microscope image of different warp and weft density fabrics of the coating of the anti-thrombus/anti-tumor functional blood vessel coating stent, wherein (1) is 1100 multiplied by 700 roots/10 cm, (2) is 1300 multiplied by 700 roots/10 cm, and (3) is 1500 multiplied by 700 roots/10 cm;
FIG. 3 is a schematic diagram showing the mechanical strength of the coated fabric in example 1 of the anti-thrombus/anti-tumor functional vascular graft stent of the present invention;
FIG. 4 is a schematic diagram showing the surface contact angle and water permeability of the coated fabric in example 1 of the anti-thrombus/anti-tumor functional vascular graft stent of the present invention;
FIG. 5 is a schematic diagram of the anticoagulant index activated partial thromboplastin time APTT and prothrombin time PT of a sample before and after the coated fabric heparin coating in example 1 of the antithrombotic/antitumor functional vascular graft stent of the present invention;
FIG. 6 is a schematic diagram showing the in vitro release rate of heparin after drug loading of the coated fabric in example 1, of an antithrombotic/antitumor functional stent of the present invention;
fig. 7 is a schematic diagram of the activity of vascular smooth muscle cells in the leaching solution of the heparin coating sample after the coated fabric is loaded with the drug according to the anti-thrombus/anti-tumor functional vascular coated stent of the present invention in example 1.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in further detail below.
Referring to fig. 1, fig. 1 is a schematic structural diagram of an anti-thrombus/anti-tumor functional vascular graft stent according to the present invention. As shown in figure 1, the anti-thrombus/anti-tumor functional vascular covered stent is composed of a metal stent 1 and fabric covered membranes 2 which are respectively loaded with drugs inside and outside, wherein the metal stent 1 is woven by nickel-titanium alloy wires with excellent characteristics of wear resistance, corrosion resistance, high damping, superelasticity and the like. Wherein, the nickel content in the nickel-titanium alloy wire is 8 percent to 15 percent, the fineness range is 0.1 mm to 0.5mm, and the expansion ratio is more than 20 percent. The metal bracket 1 is of a mesh structure, and the weaving angles are respectively 30-75 degrees; the diameter of the first straight pipe part 11 of the metal bracket 1 is 10-30mm, and the diameter of the first supporting leg 12 and the diameter of the second supporting leg 13 are 5-15 mm; the pitch length is 3-12 mm; the metal coverage rate is 10% -60%; the radial supporting force reaches 0.3-1.5N; the longitudinal short shrinkage rate is 15-50%; the elastic retraction rate is 0.5-5%. The film 2 is prepared by a weaving method and is composed of a second straight pipe part 21, a second transition part 22, a second branch part 23, a third supporting leg 24 and a fourth supporting leg 25. The outer layer of the second straight tube part 21 is provided with a anther sac interlayer 3, and a double-layer 'binding structure' design method with different warp and weft densities is adopted for loading silk fibroin/anti-tumor drug microspheres to realize a long-acting drug slow release function. The fabric warp and weft yarn material is one or a combination of several of synthetic fibers such as polyester monofilament, polyester multifilament, spandex monofilament, spandex multifilament, acrylic monofilament, acrylic multifilament and the like and natural fibers such as raw silk, boiled silk and the like. The synthetic fiber monofilament has fineness of 10-50D, multifilament of 10-50D, and complex number of 12-72 f. The raw silk in the natural fiber is 10-50D, the cooked silk is 10D-50D,the complex numbers are 12-72 f. The base weave of the covering film 2 may be selected from one or any combination of plain weave, twill weave, satin weave, rib weave, honeycomb weave, crepe weave, jacquard weave, and the like. The warp density of the coating film 2 is 300-3000 pieces/10 cm, the weft density is 300-3000 pieces/10 cm, and as shown in figure 2, the thicknesses of the three coating films 2 are 0.05-0.2 mm; the cross-section water permeability is 4.19-8.75 mL/(cm)2Min); the surface hydrophilic angle is 30-75 degrees, which proves that the hydrophilic coating has good hydrophilicity; the radial tensile strength is 30-120 MPa; the longitudinal tensile strength is 50-200 MPa; the bursting strength of the probe is 20-100MPa, and the whole probe shows good mechanical properties.
The invention relates to a coating 2 which carries medicine on the inner and outer surfaces respectively, the technical process is as follows:
(1) the inner layer carries antithrombotic drugs: fixing the fabric reverse side of the film 2 of the metal bracket 1 by using a self-made mould by using a covalent crosslinking technology, and carrying out low-temperature plasma treatment on the inner surface (the surface to be coated) of the film 2 to generate etching traces and introduce amino; preparing MES buffer solution with certain concentration and pH value of 4-8, adding a certain amount of heparin sodium, uniformly dissolving to obtain heparin coating solution, and performing coating treatment on the inner layer of the coated film; introducing a certain concentration of bisaminopolyethylene glycol (di-NH)2PEG) is used as a connecting molecule, ethyl carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) with certain concentration are introduced as carboxyl activating agents, the mixture is uniformly mixed, the mixture is incubated at normal temperature in a shaking way, and a sample is rinsed by distilled water after being incubated stably; and then preparing cytokine solutions with different concentrations for composite coating, repeating the coating operation for multiple times, and then placing the sample in a refrigerator at 4 ℃ for a period of time to form a stable antithrombotic drug coating on the inner surface of the coating.
(2) The outer layer is loaded with anti-tumor drugs: changing the hydrophilic and hydrophobic environment of the solution by utilizing the high hydrophilicity of the PEG, inducing the structural change of the fibroin molecules and inducing the self-assembly process; mixing the curcumin dissolved by PEG and the metformin dissolved by pure water with a fibroin solution with a proper concentration by using a PEG emulsification-precipitation technology, and preparing the fibroin drug-carrying metformin and curcumin drug-carrying microspheres by the steps of incubation, centrifugation, washing, ultrasonic dispersion and the like; the drug-loaded microspheres are loaded in the outer drug bag interlayer 3 of the coating film 2 of the metal stent 1, the structure adopts a double-layer 'binding tissue' design with different warp and weft densities, the defects of low drug-loaded amount and short slow release time of the conventional electrostatic binding coating microspheres can be overcome, and the long-acting slow release function of the anti-tumor drug is realized.
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are further described below. The invention is not limited to the embodiments listed but also comprises any other known variations within the scope of the invention as claimed.
First, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
The present invention is described in detail by using the schematic structural diagrams, etc., and for convenience of illustration, the schematic diagrams are not enlarged partially according to the general scale when describing the embodiments of the present invention, and the schematic diagrams are only examples, which should not limit the scope of the present invention. In addition, the actual fabrication process should include three-dimensional space of length, width and depth.
Example 1
As shown in fig. 1, the present embodiment shows a method for preparing an anti-thrombus/anti-tumor functional vascular graft stent:
(1) weaving of the metal stent 1: firstly, weaving a tubular stent on a prefabricated mould by adopting a single nickel-titanium alloy wire. And then the woven metal bracket 1 is shaped at high temperature, and the woven bracket can be taken down from the die. The metal support 1 is cylindrical, and the alloy wires at the two ends of the metal support 1 are arc-shaped, so that the blood vessel is prevented from being punctured and damaged. In the invention, the diameter of the nickel-titanium alloy wire is 0.1-0.5mm, and the weaving angle is 30-75 degrees; the metal coverage rate is 15-60%; the radial supporting force is 0.2-2.0N.
(2) Preparation of film-covered 2 fabric: the fabric coating 2 is prepared by a weaving method, the thickness of the coating 2 is 0.05-0.2mm, the warp and weft materials of the coating 2 are medical polyester filaments, the warp density is 3000 filaments/cm, the weft density is 3000 filaments/cm, the warp fineness is 10-50D monofilament, the weft fineness is 10-50D/12-72f multifilament, and the fabric weave is plain weave.
(3) Inner drug-loaded coating of film 2: fixing the reverse side of the coating film by using a self-made mold, carrying out low-temperature plasma treatment on the surface to be coated of the coating film (the inner surface of the coating film 2) to generate nicks on the surface of the coating film, introducing amino groups, and carrying out closed storage on the fabric after the treatment is finished. Preparing MES buffer solution with certain concentration and pH of 4-8, dissolving heparin sodium in MES solution, and introducing di-NH2PEG is used as a connecting molecule of heparin and fabric, ethyl carbodiimide hydrochloride (EDC) with the concentration of 0.3-3.0% and N-hydroxysuccinimide (NHS) are added as carboxyl activating agents, the mixture is uniformly mixed, the inner layer of the coating film 2 is coated, the mixture is subjected to vibration incubation for 1-3h at normal temperature in a dark place, after the incubation is stable, the mixture is washed for 2-5 times by distilled water, then matrix cell derived factor (SDF-1 alpha) with the concentration of 1-8% is used for composite coating, after the coating is dried, secondary coating is carried out, after the repeated operation for 2-5 times, the sample is placed in a refrigerator with the temperature of 4 ℃ for 8-24h, and a stable antithrombotic coating is formed on the inner surface of the coating film.
(4) Coating 2, outer drug-loaded coating: dissolving a certain amount of curcumin in 10-75% PEG solution, dissolving a certain amount of metformin in pure water, changing the hydrophilic and hydrophobic environment of the fibroin solution by utilizing the high hydrophilicity of PEG by using a PEG emulsification-precipitation technology, inducing the fibroin molecular structure to change and generate self-assembly, and preparing the drug-loaded microspheres. Uniformly mixing the PEG solution containing the curcumin and the fibroin solution containing the metformin, incubating for 24h in a dark place, centrifuging for 10min, washing with distilled water, performing ultrasonic dispersion again, repeating the steps for 2-5 times, and preparing the drug-loaded microspheres. The drug-loaded microspheres are loaded in the outer drug bag interlayer 3 of the coating film 2 of the metal stent 1, so that the long-acting and slow-release effect of the drug can be achieved.
The anti-thrombus/anti-tumor functional vascular graft stent has the following specific properties:
referring to fig. 3, fig. 3 is a schematic view of the mechanical strength of the coated fabric in example 1 of the anti-thrombus/anti-tumor functional vascular graft stent of the present invention. As shown in FIG. 3, the characterization results of the samples show that the coated fabric subjected to antithrombotic and antitumor treatment has no obvious difference from the untreated radial tensile strength, longitudinal tensile strength and probe bursting strength, and the two treatments do not influence the mechanical properties of the coated fabric.
Referring to fig. 4, fig. 4 is a schematic diagram illustrating the surface contact angle and water permeability of the coated fabric of the anti-thrombus/anti-tumor functional vascular graft stent of the present invention in example 1. As shown in fig. 4, the results of the characterization of the samples show that the coated fabric treated with antithrombotic and antitumor treatments has a reduced surface contact angle and a reduced water permeability compared to the untreated fabric. This shows that the treated fabric has good hydrophilicity and can play a good role in preventing leakage.
Referring to fig. 5, fig. 5 is a schematic diagram of the anticoagulant index activated partial thromboplastin time APTT and prothrombin time PT of the sample before and after the coated fabric heparin coating according to the present invention. As shown in FIG. 5, the characterization results of the samples show that the anticoagulation index activated partial thromboplastin time of the samples after being coated with heparin is increased from 33.2s to 124s, which indicates that the anticoagulation performance is improved to a certain extent.
Referring to fig. 6, fig. 6 is a schematic diagram of the in vitro release rate of heparin of the coated fabric with antithrombotic/antitumor functions according to the present invention after loading drugs thereon in example 1. As shown in FIG. 6, the sample characterization result shows that the release rate of heparin subjected to low-temperature plasma treatment and chemical crosslinking reaches 60% in vitro at 144h, and the release rate is slow after 144h, which indicates that heparin can be slowly released in vitro.
Referring to fig. 7, fig. 7 is a schematic diagram of the activity of vascular smooth muscle cells of an anti-thrombus/anti-tumor functional vascular graft scaffold in the leaching solution of the heparin coating sample after the coated fabric is loaded with drugs in example 1. As shown in FIG. 7, the samples before and after heparin coating were examined for the presence of inhibition of smooth muscle cells using human vascular smooth muscle cells. The sample characterization results show that the cell viability of the sample after heparin coating is lower, while the cell viability of the blank control group is higher.
Example 2
As shown in fig. 1, the present embodiment shows a method for preparing an anti-thrombus/anti-tumor functional vascular graft stent:
(1) weaving of the metal stent 1: the diameter of the nickel-titanium alloy wire is 0.1-0.5mm, and the weaving angles are 30-75 degrees respectively; the metal coverage rate is 15-60%; the radial supporting force is 0.2-2.0N; the longitudinal short shrinkage rate is 10-45%; the elastic retraction rate is 1-5%.
(2) Preparation of film-covered 2 fabric: the coating 2 is prepared by a weaving method, the thickness of the coating 2 is 0.05-0.2mm, the warp and weft materials of the coating 2 are medical polyester filaments, the warp density is 500-2500 pieces/cm, the weft density is 500-2500 pieces/cm, the fineness of the warp is 15-50D monofilament, the fineness of the weft is 15-50D/12-48f multifilament, and the fabric tissue is twill.
(3) Carrying a coating on the inner surface and the outer surface: coating the film 2 with antithrombotic coating, dissolving heparin in 1-15% silk fibroin solution, soaking the sample in the mixed solution, stirring, taking out, treating the sample with water vapor (50-80 deg.C), and drying. To achieve an anti-tumor effect, metformin is used as a drug. The method comprises adding 0.1-0.8g of aliphatic polyester hydrogel into PBS solution, heating the mixture to 50-80 deg.C, stirring to dissolve completely, and cooling to 5-20 deg.C to obtain transparent polymer. Adding metformin into aliphatic polyester hydrogel at 5-20 deg.C, filling the mixture onto the outer surface of the film at room temperature, sealing the two ends, and rapidly heating to make the polymer solution aggregate into gel state. Incubate for 8-24h, rinse the graft lumen with PBS at room temperature, wash away excess metformin, and ensure patency in the stent.
Example 3
As shown in fig. 1, the present embodiment shows an anti-thrombus/anti-tumor functional vascular graft stent.
(1) Weaving of the metal stent 1: the diameter of the nickel-titanium alloy wire is 0.1-0.5mm, and the weaving angles are 30-75 degrees respectively; the metal coverage rate is 15-60%; the radial supporting force is 0.2-2.0N; the longitudinal short shrinkage rate is 10-45%; the elastic retraction rate is 1-5%.
(2) Preparation of film-covered 2 fabric: the thickness of the covering film 2 is 0.05-0.2mm, the warp and weft materials of the covering film 2 are medical spandex filaments, the warp density is 500-3000 pieces/cm, the weft density is 500-3000 pieces/cm, the fineness of the warp yarn is 15-50D monofilament, the fineness of the weft yarn is 15-50D/12-48f multifilament, and the fabric tissue is satin.
(3) Carrying a coating on the inner surface and the outer surface: the method for antithrombotic treatment of the intravascular stent prepared by the invention comprises the following steps: soaking the support in heparin sodium salt water for 5-30min, washing with distilled water, soaking the heparin support in mixed solution of acetic acid and chitosan for 5-30min, and rinsing again. Repeating the above operation for 2-5 times to obtain a stable chitosan/heparin coated vascular stent combined by electrostatic attraction. In order to achieve the anti-tumor effect, the metformin/silk fibroin microsphere can be electrostatically attracted on the surface of the coating, and the method comprises the steps of mixing silk fibroin with a certain concentration, PEG with a concentration of 10-50% and metformin, standing, centrifuging and cleaning to prepare the metformin silk fibroin microsphere, wherein the diameter of the microsphere is about 0.2-2 mu m. The low-temperature plasma technology is adopted, the surface of the fabric is etched, active groups are introduced to the surface of the fiber, and the active groups are electrostatically combined with the microspheres to endow the intravascular stent with a long-acting drug slow-release function, so that the tumor is treated.
Table 1 shows the performance indexes of the anti-thrombotic/anti-tumor functional vascular stent graft in example 1, example 2 and example 3:
TABLE 1
As can be seen from Table 1, the braiding angle of the metal stent is 60-70 degrees; pitch length6.6-7.9 mm; the metal coverage rate reaches 30-35%; the radial supporting force of the metal bracket reaches 0.66-0.94N; the longitudinal short shrinkage rate is 25-33%; the elastic retraction rate is 1.56-2.33%; the thickness of the inner membrane layer is 0.09-0.12 mm; the longitudinal tensile strength reaches 100-120 MPa; the radial tensile strength reaches 94-97 MPa; the bursting strength of the probe reaches 40.5-43 MPa; the water permeability of the cross section is less than 6.75 mL/(cm)2Min); the surface contact angle is 41-58 degrees; the drug loading rate of the antithrombotic drug reaches 15.6 percent; the drug loading rate of the anti-tumor drug reaches 8.5 percent; the release rate of the antithrombotic drug reaches 65% in 144h, and slowly increases after 144 h; the release rate of the antitumor drug reaches 60 percent in 144 h.
In conclusion, the invention discloses an anti-thrombus/anti-tumor functional blood vessel covered stent and a preparation method thereof, which have the advantages of high strength, low permeability, ultra-thinness and the like and can meet the treatment requirement of an endoluminal repair operation on abdominal aortic aneurysm; has the function of long-acting drug slow release, can inhibit tumor proliferation, resist thrombus and prevent restenosis.
It should be noted that the above-mentioned embodiments are only for illustrating the technical solutions of the present invention and not for limiting, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, which should be covered by the claims of the present invention.
Claims (4)
1. A preparation method of an anti-thrombus/anti-tumor functional vascular graft stent is characterized by comprising the following steps:
(1) the inner layer carries antithrombotic drugs: fixing the reverse side of a coating on a metal stent by using a covalent crosslinking technology, exposing the inner surface of the coating, and performing low-temperature plasma treatment on the surface of the coating to be coated by taking the inner surface of the coating as the surface of the coating to be coated so as to generate an etching trace and introduce amino; preparing MES buffer solution, adding heparin sodium, uniformly dissolving to obtain heparin coating solution, and coating the surface to be coated with the coating with the heparin coating solution to obtain a coated film with a coating; introducing diamino polyethylene glycol as a connecting molecule, introducing ethyl carbodiimide hydrochloride and N-hydroxysuccinimide as a carboxyl activating agent, uniformly mixing, incubating the coated film with the coating at normal temperature in a shaking way, incubating the coated film with the coating stably, and washing with distilled water; preparing cytokine solutions with different concentrations for composite coating, and after repeating the coating operation for multiple times, placing the coated film with the coating in a refrigerator at 4 ℃ for 8-24h to form a stable antithrombotic drug coating on the inner surface of the coated film;
(2) the outer layer is loaded with anti-tumor drugs: mixing curcumin dissolved by PEG and metformin dissolved by deionized water with a fibroin solution by using a PEG emulsification-precipitation technology, and preparing fibroin-carried metformin and curcumin-carried drug-carrying microspheres by incubation, centrifugation, washing and ultrasonic dispersion; fixing the front side of the coating on the metal stent, and loading the drug-loaded microspheres into the interlayer of the drug bag to obtain the anti-thrombus/anti-tumor functional vascular coating stent;
the anti-thrombus/anti-tumor functional vascular covered stent comprises a metal stent and a covered membrane,
the metal bracket is divided into a first straight pipe part, a first transition part and a first bifurcation part which are connected into an integral structure, the first transition part is provided with a first pipe end and a first bifurcation end and a second bifurcation end which correspond to the first pipe end, the first bifurcation part is provided with a first supporting leg and a second supporting leg, the first pipe end is connected with the first straight pipe part, the first bifurcation end is connected with the first supporting leg, the second bifurcation end is connected with the second supporting leg,
the film is coated on the outer surface of the metal stent, the medicine bag interlayer is arranged on the outer layer of the film, the film is divided into a second straight pipe part, a second transition part and a second bifurcation part, the second straight pipe part, the second transition part and the second bifurcation part are connected into an integral structure, the second transition part is provided with a second pipe end and a third bifurcation end and a fourth bifurcation end which correspond to the second pipe end, the second bifurcation part is provided with a third supporting leg and a fourth supporting leg, the second pipe end is connected with the second straight pipe part, the third bifurcation end is connected with the third supporting leg, the fourth bifurcation end is connected with the fourth supporting leg, the second straight pipe part is coated on the first straight pipe part, the top end of the first straight pipe part is exposed out of the second straight pipe part, the second transition part is coated on the first transition part, and the third supporting leg is coated on the first supporting leg, the bottom end of the first supporting leg is exposed out of the third supporting leg, the fourth supporting leg covers the second supporting leg, and the bottom end of the second supporting leg is exposed out of the fourth supporting leg,
the second straight pipe part is provided with a medicine bag interlayer, and the top end of the second straight pipe part is exposed out of the medicine bag interlayer.
2. The method for preparing the anti-thrombus/anti-tumor functional vascular graft stent according to claim 1, wherein the method comprises the following steps: the concentration of the MES buffer solution in the step (1) is 0.1-0.5mol/L, the pH value is 4-8, the mass concentration of heparin in the MES buffer solution is 1%, and the content of ethyl carbodiimide hydrochloride is as follows: n-hydroxysuccinimide: the mass ratio of the heparin sodium is 7.5:12.5:1, the volume concentrations of the cytokine solutions with different concentrations are in the range of 1-8%, and the coating operation is carried out for 2-5 times.
3. The method for preparing the anti-thrombus/anti-tumor functional vascular graft stent according to claim 1, wherein the method comprises the following steps: in the step (2), the mass concentration of the PEG is 10-75%, and the curcumin are mixed
The mass ratio of PEG is 1:50, and the mass ratio of metformin to fibroin is 1: 50.
4. The method for preparing an anti-thrombotic/anti-tumor functional vascular graft according to any one of claims 1 to 3, wherein: before the step (1), the method further comprises the following steps:
(1) weaving the metal stent: weaving a single nickel-titanium alloy wire to obtain a tubular stent, and carrying out high-temperature shaping on the tubular stent to ensure that the tubular stent is cylindrical, the alloy wires at two ends of the tubular stent are arc-shaped, the diameter of the nickel-titanium alloy wire is 0.1-0.5mm, and the weaving angle is 30-75 degrees; the metal coverage rate is 10% -60%; the radial supporting force is 0.3-1.5N;
(2) preparing a coating film: the warp and weft yarn materials are used as raw materials, the warp density is 300-3000 pieces/10 cm, the weft density is 300-3000 pieces/10 cm, the fineness of the warp yarn is 10-50D monofilament, the fineness of the weft yarn is 10-50D/12-72f multifilament, a covering film is prepared by a weaving method, and the thickness of the covering film is 0.05-0.2 mm.
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