CN111773440A - Anticoagulation material based on enzyme-like catalytic reaction - Google Patents
Anticoagulation material based on enzyme-like catalytic reaction Download PDFInfo
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- CN111773440A CN111773440A CN202010440536.0A CN202010440536A CN111773440A CN 111773440 A CN111773440 A CN 111773440A CN 202010440536 A CN202010440536 A CN 202010440536A CN 111773440 A CN111773440 A CN 111773440A
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- anticoagulant
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- A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
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- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/0005—Use of materials characterised by their function or physical properties
- A61L33/0047—Enzymes, e.g. urokinase, streptokinase
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses an anticoagulation material, which is based on an enzyme-like catalytic reaction to generate nitric oxide, dinitrogen trioxide, nitric acid and/or other similar substances with anticoagulation function, thereby improving the anticoagulation effect of blood contacting the surface of a medical instrument or a medical material. The invention also discloses a related medical apparatus or medical material, a preparation method and application thereof. The blood contact medical device surface anticoagulant coating based on the generation of nitric oxide or the like through the enzyme-like catalytic reaction has an excellent service effect, and can solve the problems that the blood contact medical device has poor biocompatibility, the surface is easy to coagulate blood, and anticoagulant drugs with large side effects need to be matched, and the like for a long time.
Description
Technical Field
The invention relates to a biomedical engineering functional material, in particular to the technical field of a medical material with an anticoagulation effect, and specifically relates to an anticoagulation material based on an enzyme-like catalytic reaction.
Background
With the development of scientific technology, it has become common to implant medical devices, either temporarily or permanently, to treat various medical conditions. Especially applied to the medical implantation devices (such as cardiovascular stents, heart valves, artificial blood vessels, prostate stents, biliary stents, internal drug release catheters and the like) in the aspects of vascular systems, esophagus, trachea, colon, biliary tracts, urinary tracts and the like, greatly relieves the pain of human/animals, and improves the survival rate and the life quality. The support of introducing devices, such as balloon catheters, cannulas, is needed when implanting medical devices in the human or animal body; when toxin expelling is carried out in vitro, a filtering or purifying device is needed, such as a blood filter screen, a blood purifying apparatus and the like. These medical devices are generally well suited for their intended purpose, treating disease.
However, these medical devices still have some problems in practical use. For example, mechanical damage to the vessel wall may be caused when introducing the device into and through the vascular system of a patient. The site of injury causes the aggregation and adhesion of platelets and fibrin, which in turn forms a blood clot that narrows the blood vessel at the site of injury. In addition, if the medical device (e.g., bare metal vascular stent) is left in the patient for a long period of time, it often results in smooth muscle cells migrating to the surface thereof, which in turn produces neointimal hyperplasia, causing restenosis. Eventually leading to the patient's risk of various complications such as heart attack, pulmonary embolism, and stroke. To reduce these adverse effects, the medical device may be coated with a biocompatible coating. Wherein the coating may incorporate a bioactive material. When the disease is localized to a specific site (such as, but not limited to, in a blood vessel), the bioactive material can be applied directly to the specific site of the body using such coated surface modified medical devices for treatment of the disease. Theoretically, such topical administration is more effective than systemic administration. However, it has been found that the release rate, action time, etc. of the drug have a great influence on the therapeutic effect. Therefore, the problem of improving the biocompatibility of these medical devices is very challenging and needs to be solved, and the development of surface modification/coating technology for medical devices with excellent anticoagulant function is urgent.
Common methods for forming the surface coating of the medical device include spray coating, spin coating, dipping, static evaporation, vapor deposition, and electrostatic spinning, each of which has various features. In recent years, the development of 3D printing technology has also driven the development of new medical instruments, whereby desired surfaces can be directly obtained.
At present, many common medical instruments are made of metal materials. For example, nitinol is widely used for its excellent shape memory properties, but its electropositive surface and high free energy induce thrombus formation. Although heparin modification of the alloy surface can improve the biocompatibility, the method also brings other problems, such as rapid inactivation of heparin in physiological environment and reduction of the anticoagulant function of heparin due to the covalently linked structure. Therefore, recent research on surface modification of metal medical devices mainly focuses on constructing surface coatings, aiming at improving biocompatibility of metal devices by designing surface coatings with excellent anticoagulation function.
The construction of surface coatings is largely divided into two categories, one being supported and the other catalytic. The construction of supported coatings relies on the chemical and/or physical modification of the surface to directly modify or support exogenous anticoagulant drugs, with drug eluting coatings being of most interest. The drug eluting surface coating loads some exogenous anticoagulant drugs by growing polymer molecules with a certain thickness on the surface of the metal. After the metal instrument is intervened, the anticoagulant medicine in the surface coating is gradually released to play an anticoagulant function, so that the generation of thrombus is reduced, the neointimal hyperplasia is inhibited, and the incidence rate of restenosis is reduced. However, drug eluting coatings still suffer from several drawbacks. For example, the loading capacity of the exogenous anticoagulant drugs in the coating is very limited, the release rate cannot be effectively controlled, and the requirements of some medical instruments needing long-term service are difficult to meet; the monomer products released by many polymer coatings during degradation are prone to cause local over-acidity, which can cause local inflammation and subacute thrombosis; the released anticoagulant drugs can inhibit the migration and proliferation of endothelial cells and delay the re-endothelialization and repair process of blood vessels; after the medicine elution coating device such as a vascular stent is implanted, patients still need to take anti-platelet medicines such as aspirin, thienopyridine and the like for a long time. Therefore, it is still difficult for the supported coating to fully meet the actual clinical requirements. The catalytic coating is used as a new medical apparatus surface coating, does not depend on exogenous anticoagulant drugs, has excellent long-term service performance, has good application prospect and is widely concerned by researchers. At present, the catalytic coating constructed on the surface mainly catalyzes endogenous Nitric Oxide (NO) prodrugs to generate NO so as to realize the anticoagulation function of the stent coating. Nitric oxide synthase (eNOS) in human vascular endothelial cells is capable of catalyzing the oxidation of endogenous arginine to produce NO. NO released to the inner surface of the blood vessel has a good antiplatelet effect, so that the generation of blood coagulation is inhibited, and the smooth flow of blood in the blood vessel is ensured. Based on the inspiration, researchers design a series of catalytic coatings capable of catalyzing endogenous prodrugs to generate NO, and apply the catalytic coatings to the surface modification of the vascular stent, so that the anticoagulation effect and the long-term service performance of the metal vascular stent are improved. For example, Yang et al reported a 3, 3' -diselenodipropionic acid (SeDPA) modified functionalized coating (Zhilu Yang et al, Nitric oxide producing coating electrochemical ligation of an endothionium function for a multifunctional vacuum procedure.2015; 63: 80-92). SeDPA has catalytic activity similar to glutathione peroxidase, and can catalyze the decomposition of nitrosothiol (RSNO) to generate NO in the presence of glutathione. The released NO can inhibit the activation and aggregation of blood platelet, promote the proliferation of endothelial cell, inhibit the proliferation of smooth muscle cell and promote the vasodilation, and has excellent anticoagulant function. However, all of the endogenous catalytic coatings reported so far have some problems to be solved. For example, most of catalysts loaded on the surface of the catalytic coating are unstable small molecular compounds, and the catalytic activity is easily reduced or even inactivated due to structural change; most of the catalysts are selenium-containing or copper-containing compounds, and toxic free radicals are easily generated; the blood has low content of RSNO, and RSNO molecules are unstable and easy to decompose, so that the supply of RSNO is insufficient, and the amount of generated NO is small. Therefore, improving the stability of the supported catalyst in the catalytic coating, and selecting an endogenous or exogenous NO prodrug with sufficient stability is an important challenge for further development of catalytic anticoagulant coatings.
In recent years, biomimetic catalysis based on enzyme-like materials has received increasing attention. The enzyme-like material has the catalytic activity of natural enzyme-like, has the physical and chemical properties peculiar to artificial materials, has good stability, can be subjected to various surface functional modifications, can be prepared in large quantities, and has low production cost. Therefore, enzyme-like materials are a good alternative to natural enzymes. If an enzyme-like material with a natural eNOS catalytic function can be designed, loaded on the surface of a blood contact medical device or directly generated in situ in the forming process, and an endogenous or exogenous substrate which is sufficient and stable in blood is utilized to generate NO or an analogue, the problem of the surface coating of the current catalytic blood contact medical device can be solved, and the enzyme-like material is expected to be popularized to the practical clinical application.
Disclosure of Invention
The invention aims to provide an anticoagulant material with an excellent anticoagulant function. To achieve this object, the present invention provides an anticoagulant material loaded with and/or comprising and/or grown with an enzyme-like material. The enzyme-like material is capable of catalyzing endogenous substrates and/or exogenous supplemental substrates in the blood to continuously produce nitric oxide or the like at a localized site. Nitric oxide or the like released on the surface of a blood contact type medical device or medical material can inhibit the adhesion and activation of platelets and has an anticoagulation effect.
In one embodiment, the anticoagulant material is loaded and/or contains and/or grows an enzyme-like material on the whole, part or surface of a base material capable of being used for blood contact.
In one embodiment, the anticoagulant material is a coating or surface. Preferably, the surface is a surface of a medical device.
In one embodiment, the anticoagulant material is applied as a coating to the surface of the medical device.
In another embodiment, the anticoagulant material is used as one of a medical device or a material for manufacturing an outer layer of a medical device, and the surface of the medical device is obtained to contain the anticoagulant material.
In one embodiment, the effective anticoagulant molecules catalytically produced by the enzyme-like material of the present invention are NO and/or its analogs, and these small molecules can activate cyclic adenylase and cyclic guanosinase, upregulate the cyclization of adenosine and guanosine, and inhibit the adhesion and activation of platelets on blood contact surfaces, thereby achieving an anticoagulant effect. Preferably, the anticoagulant material disclosed by the invention can catalyze endogenous and/or exogenous substrates to generate nitric oxide, dinitrogen trioxide, nitric acid and/or other substances with anticoagulant function by loading and/or containing and/or growing enzyme-like materials to realize the anticoagulant function; preferably nitric oxide is generated.
In one embodiment, the substrate of the invention is capable of producing NO and/or its analogs by catalytic reaction, either endogenous or exogenous. The endogenous substances are substances existing in human bodies/animal bodies and include, but are not limited to, nitrosothiols, arginine, nitrate, nitrite and the like. The exogenous substance is a substance which is supplemented into the human body/animal body by injection, oral administration and the like, and includes but is not limited to guanidinoacetic acid, hydroxylamine, sodium nitroprusside, azide, metformin, hydroxyurea, glyceryl trinitrate, spermine, diazeniumdiolate, nitrosamine and the like. Preferably, the substrate of the invention comprises one or a combination of several of nitrosothiols, guanidinoacetic acid, hydroxylamine, sodium nitroprusside, arginine, azide, metformin, nitrate, nitrite, hydroxyurea, glyceryl trinitrate, spermine, diazeniumdiolate and/or nitrosamines.
In one embodiment, the enzyme-like material is an enzyme-like material capable of mimicking peroxidase-like activity, oxidase-like activity, and/or nitrite-like reductase activity.
In one embodiment, the enzyme-like material is a carbon material (C) doped with both a metal element (M) and a nitrogen element (N) having a natural-like enzyme catalytic activity; the enzyme-like material is preferably M-N-C; preferably, M is a transition metal element; more preferably, M is selected from iron (Fe), cobalt (Co), nickel (Ni), manganese (Mn), copper (Cu), ruthenium (Ru), rhodium (Rh), palladium (Pd), platinum (Pt), iridium (Ir), titanium (Ti), vanadium (V), chromium (Cr), zinc (Zn), gold (Au) or a combination of one or more of the above elements.
The conditions for the catalytic reaction of M-N-C in the present invention are mainly based on the substrate concentration, pH and temperature. The concentration of the catalytic substrate is 0-10 millimoles per liter, preferably the highest concentration allowed by normal physiological conditions or pharmacokinetic display. The reaction pH is from pH 0 to pH 14, preferably from pH 5 to pH 8, more preferably from pH 7.0 to 7.8.
In one embodiment, the base material comprises one or a combination of several of the following materials:
i) a metal; preferably stainless steel, tantalum, titanium, nickel titanium alloys, gold, platinum, inconel, iridium, silver, tungsten and/or other biocompatible metals, and/or alloys of any of the foregoing;
ii) a biocompatible polymer; preferably carbon fibers, cellulose acetate, cellulose nitrate, silicone, polyethylene terephthalate, polyurethane, polyamide, polyester, polyorthoester, polyanhydride, polyethersulfone, polycarbonate, polypropylene, high molecular weight polyethylene, polytetrafluoroethylene, and/or other biocompatible polymers, and/or mixtures or copolymers thereof;
iii) a biodegradable polymer; preferably polylactic acid, polyglycolic acid or copolymers of the two, polyanhydrides, polycaprolactones, polyhydroxybutyrate valerate and/or other biodegradable polymers, and/or mixtures or copolymers thereof; and/or
iv) a biological agent; preferably proteins, extracellular matrix components, collagen, fibrin and/or other biological agents, and/or mixtures thereof.
In one embodiment, the coating or surface is a coating or surface of a biodegradable polymeric material, a coating or surface of a biologically inert polymeric material, a coating or surface of a metal or alloy, a coating or surface of a carbon material, a coating or surface of another non-metallic material, or a coating or surface formed during a molding process.
In one embodiment, the material of the coating or surface comprises one or a combination of several of the following materials:
i) a polymer; preferably Polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA), polyvinylpyrrolidone (PVP), biodegradable Polyurethane (PU), Polyhydroxyalkanoate (PHA) and/or polylactic acid (PLA); and/or
ii) a biopolymer; starch, cellulose, hyaluronic acid, collagen, albumin and/or gelatin are preferred.
In one embodiment, the anticoagulant material further comprises a bioactive material; the bioactive material is preferably a medicament for adjuvant treatment or prevention of diseases; preferably, the bioactive material comprises an anti-tumour, anti-inflammatory, anti-platelet, anti-coagulant substance, anti-thrombin, antibiotic, anti-allergic and/or anti-oxidant substance; preferably, the anti-tumor substance comprises paclitaxel, methotrexate and/or vincristine; preferably, the anti-inflammatory substance comprises aspirin and/or indomethacin; preferably, the antiplatelet agent comprises prostacyclin, clopidogrel and/or prasugrel; preferably, the anticoagulant substance comprises dicoumarol and/or warfarin; preferably, the antithrombin substance comprises heparin sodium and/or argatroban; preferably, the antibiotic comprises methicillin, cefazolin, roxithromycin and/or azithromycin; preferably, the antiallergic agent comprises diphenhydramine, promethazine and/or chlorpheniramine; preferably, the antioxidant substance comprises vitamin C and/or vitamin E.
In one embodiment, the method for synthesizing the enzyme-like material is at least one method selected from a solvothermal method, a high-temperature solid-phase method, a coprecipitation method and a vapor deposition method.
In one embodiment, the enzyme-like material is supported by and/or comprised in and/or grown in the anticoagulant material by at least one method selected from the group consisting of in situ growth, spray coating, spin coating, dipping, static evaporation, chemical ligation, electrospinning, 3D printing techniques.
Preferably, the method for synthesizing the enzyme-like material uses a solvent; the solvent is preferably a liquid substance compatible with the polymer and capable of dissolving the polymer at the required concentration; preferably, the solvent comprises at least one of dimethyl sulfoxide, chloroform, dichloroethane, acetone, water, xylene, methanol, ethanol, 1-propanol, tetrahydrofuran, dimethylformamide, dimethylacetamide, cyclohexanone, ethyl acetate, isopropanol and/or toluene.
The invention also provides a medical appliance or a medical material which carries and/or contains and/or grows an enzyme-like material.
In one embodiment, the enzyme-like material is any of the enzyme-like materials described previously herein.
In one embodiment, the medical device or medical material is loaded with and/or contains and/or grows any of the anticoagulant materials described previously herein.
In one embodiment, the enzyme-like material or the anticoagulant material forms an entirety, portion, or surface of the medical device or medical material.
In one embodiment, the anticoagulant material is a coating or surface. Preferably, the surface is a surface of a medical device.
In one embodiment, the medical device or medical material is a cardiovascular stent, an intravascular catheter, a balloon catheter, a pacing electrode, a heart valve, an artificial blood vessel, a blood purification-type device, an artificial joint, an artificial organ, an intracorporeal drug delivery catheter, a urinary catheter, an artificial arteriovenous fistula, a ventricular assist device, a cardiac or tissue repair material, a prostate stent, a biliary stent, or a blood filter.
The invention also provides a preparation method of the medical appliance or the medical material, which is to load and/or contain and/or grow the enzyme-like material on the whole, part or surface of the medical appliance or the medical material.
In one embodiment, the enzyme-like material is any of the enzyme-like materials described previously herein.
In one embodiment, the preparation method comprises the steps of: mixing the enzyme-like material with a material for forming a coating, and forming a film on the surface of a medical instrument or a medical material; preferably, the material for forming the coating layer is a material having good biocompatibility.
In one embodiment, the preparation method comprises the steps of: mixing the enzyme-like material with a material for molding, and directly molding by a molding technology to obtain the surface of a medical instrument or a medical material; preferably, the molding technique is 3D printing, and the material for molding is a 3D printing raw material.
In one embodiment, the preparation method comprises the steps of: the enzyme-like material is directly synthesized on the surface of medical instruments or medical materials.
In one embodiment, the method of making further comprises the step of synthesizing the enzyme-like material; preferably, the enzyme-like material may be synthesized from precursors of metal oxides and carbon; more preferably, the metal oxide is iron oxide; more preferably, the precursor of carbon is guanine.
The invention also provides a method for preparing the anticoagulant coating or surface on the surface of the medical appliance or the medical material, which is to load and/or contain and/or grow the enzyme-like material on the surface of the medical appliance or the medical material.
In one embodiment, the enzyme-like material is any of the enzyme-like materials described previously herein.
In one embodiment, the method comprises the steps of: mixing the enzyme-like material with a material for forming a coating, and forming a film on the surface of a medical instrument or a medical material; preferably, the material for forming the coating layer is a material having good biocompatibility.
In one embodiment, the method comprises the steps of: mixing the enzyme-like material with a material for molding, and directly molding by a molding technology to obtain the surface of a medical instrument or a medical material; preferably, the molding technique is 3D printing, and the material for molding is a 3D printing raw material.
In one embodiment, the method comprises the steps of: the enzyme-like material is directly synthesized on the surface of medical instruments or medical materials.
In one embodiment, the method further comprises the step of synthesizing the enzyme-like material; preferably, the enzyme-like material is synthesized from precursors of metal oxides and carbon; more preferably, the metal oxide is iron oxide; more preferably, the precursor of carbon is guanine.
The invention also provides application of the enzyme-like material in preparation of an anticoagulation material, an anticoagulation coating or surface, a medical device or a medical material.
In one embodiment, the enzyme-like material is any of the enzyme-like materials described previously herein.
The invention also provides the application of the enzyme-like material or the anticoagulation coating or surface containing the enzyme-like material or the medical appliance or medical material containing the enzyme-like material in anticoagulation.
In one embodiment, the enzyme-like material is any of the enzyme-like materials described previously herein.
The anticoagulation surface coating prepared by the invention can be a catalytic coating, and anticoagulation molecules are generated through a chemical reaction catalyzed by a catalyst loaded on the coating, so that the anticoagulation function is realized.
The beneficial effects of the invention comprise the following aspects: (1) the related endogenous or exogenous catalytic substrate is a micromolecule with stable structure, so that side effects caused by spontaneous decomposition are avoided, and the utilization rate of the substrate is improved; (2) the catalytic reaction for generating Nitric Oxide (NO) and/or the like only occurs on the surface of the coating, and has good selectivity; (3) the coating can continuously catalyze and generate Nitric Oxide (NO) and/or analogues thereof to exert an anticoagulation effect, so that excellent long-term service performance of the coating is ensured; (4) the surface coating prepared by the invention has an excellent anticoagulation function, is suitable for surface modification of various blood contact type medical instruments, can improve the biocompatibility and blood compatibility of the medical instrument, and reduces adverse reactions such as thrombus caused by coagulation when the medical instrument is in contact with blood; (5) the anticoagulant material based on nitric oxide or the like generated by enzyme-like catalytic reaction has excellent service effect, and can solve the problems that blood contacts medical instruments for a long time, the biocompatibility is poor, the surface is easy to coagulate blood, anticoagulant drugs with large side effects need to be matched, and the like.
Drawings
FIG. 1A Material science characterization of Fe-N-C class enzyme materials. A) Transmission electron microscopy of Fe-N-C. B) Powder X-ray diffraction pattern of Fe-N-C. C) An X-ray photoelectron spectrum of Fe-N-C. D) A high-resolution X-ray photoelectron spectrum of a 2p orbit of a metal Fe element in Fe-N-C.
FIG. 2 is an evaluation of the antiplatelet performance of Fe-N-C loaded blood contact medical device surface coatings. A) And detecting an absorption spectrogram of NO molecules generated by the oxidation of the Fe-N-C-loaded coating catalyzed substrate by the Griess reagent. B) The Fe-N-C loaded coating catalyzes the substrate oxidation to generate statistics of the concentration of NO molecules as a function of time. C) Scanning electron microscope picture of pure polycaprolactone coating surface. D) Scanning electron microscope pictures of the coating surface after incubation of the pure polycaprolactone coating with platelet rich plasma for 2 hours. E) Scanning electron microscope pictures of the surface of the Fe-N-C loaded coating. F) Scanning electron microscopy pictures of the coating surface after 2 hours incubation of the Fe-N-C loaded coating with platelet rich plasma.
FIG. 3 is a graph showing absorption spectra of NO molecules generated by detecting Fe-N-C spray coating with different concentrations by Griess reagent.
Detailed Description
Unless otherwise defined, all terms used herein have the meanings commonly used in the art, and all reagents used therein are commercially available in the art.
The term "enzyme-like material" in the present invention refers to an artificial material having a natural-like enzyme catalytic activity and having its own specific physicochemical properties. The enzyme-like material may preferably be M-N-C.
The term "M-N-C" in the invention refers to a carbon material (C) doped with a metal element (M) and a nitrogen element (N) with natural enzyme catalytic activity. Wherein the metal element M may be a transition metal element; m includes, but is not limited to, iron (Fe), cobalt (Co), nickel (Ni), manganese (Mn), copper (Cu), ruthenium (Ru), rhodium (Rh), palladium (Pd), platinum (Pt), iridium (Ir), titanium (Ti), vanadium (V), chromium (Cr), zinc (Zn), gold (Au), and the like, as well as combinations of one or more of the foregoing elements. The natural enzyme catalytic reaction activity simulated by the method comprises but is not limited to peroxidase-like enzyme activity, oxidase-like enzyme activity, nitrite reductase-like enzyme activity and the like.
The term "carbon precursor" as used herein refers to a raw material that forms a carbon material after high temperature processing. The precursor of carbon may preferably be guanine.
The term "medical device" as used herein refers to instruments, devices, implements, in vitro diagnostic reagents and calibrators, materials, and other similar or related items used directly or indirectly on humans or animals. Preferably, the medical device is a cardiovascular stent, an intravascular catheter, a balloon catheter, a pacing electrode, a heart valve, an artificial blood vessel, a blood purification device, an artificial joint, an artificial organ, an intracorporeal drug release catheter, a urinary catheter, an artificial arteriovenous catheter, a ventricular assist device, a heart or tissue repair material, a prostate stent, a biliary stent or a blood filter.
The technical contents of the present invention will be described in detail below with reference to specific embodiments and the accompanying drawings. The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention.
Example 1
A two-step method is adopted to construct a coating on the surface of a medical appliance loaded with Fe-N-C, the first step is to synthesize the enzyme-like material Fe-N-C, the second step is to uniformly mix the Fe-N-C with a material which has good biocompatibility and can form the coating, and a film is formed on the surface of the medical appliance.
The synthesis of Fe-N-C adopts the following steps: and (3) putting equal amounts of iron oxide particles and guanine serving as a carbon precursor into an agate mortar for grinding, and uniformly mixing. And putting the obtained mixture into a high-temperature tube furnace, and performing high-temperature carbonization under the protection of inert gas. Wherein the temperature is 900 ℃, and the high-temperature treatment time is 3 hours. The carbonized product was taken out and immersed in an acid solution to remove the template and other impurities. The residual solid product is obtained by high-speed centrifugal separation and washed by ultrapure water for several times until the washing liquid is neutral and no free metallic iron ions remain. And (3) drying the washed product in a drying box at 60 ℃ to obtain Fe-N-C.
The obtained Fe-N-C enzyme material is characterized, and the result is shown in figure 1. The transmission electron microscope picture of fig. 1A shows that the finally obtained material is a thin shell structure. The powder X-ray diffraction results of fig. 1B confirm that the material contains only pure carbon components and no other crystalline phases. X-ray photoelectron spectroscopy analysis of fig. 1C showed that the resulting material in the example contained mainly C, N, O, Fe four elements. Further analysis of the 2p orbitals of Fe revealed that the Fe element in the material was mainly present in the form of divalent Fe ions (fig. 1D).
Based on the synthesized Fe-N-C material, the surface coating of the medical appliance loaded with Fe-N-C is constructed by a solvent volatilization method, and the process is as follows: dispersing polycaprolactone with the molecular weight of 15 ten thousand and Fe-N-C in a tetrahydrofuran solvent, and uniformly mixing, wherein the final concentration of the polycaprolactone is 40mg/ml, and the final concentration of the Fe-N-C is 2 mg/ml. Immersing a medical 316L stainless steel sheet in the mixed solution, and depositing a polymer coating loaded with Fe-N-C on the surface of the sheet by means of solvent volatilization.
The anticoagulant function of the prepared Fe-N-C loaded medical device surface coating is evaluated. First, to verify the ability of the coating to catalyze the generation of nitric oxide, 1 cm × 1 cm of the coating was immersed in PBS buffer at pH 7.4, 1 mmol/l of substrate arginine was added, and the concentration of NO in the solution was measured every ten minutes using Griess's reagent, the results of which are shown in fig. 2A and 2B. As can be seen from fig. 2A, in the presence of arginine, the product NO of arginine oxidation catalyzed by the coating can be detected by Griess reagent; the detection signal of the absorption peak of the Griess reagent at 550 nm is gradually enhanced along with the prolonging of the reaction time (note: the absorption peak at 0 min in the figure is the background signal of the detection system, and when NO exists, the A liquid and the B liquid in the Griess reagent can spontaneously generate weak reaction, namely the background signal, when the A liquid and the B liquid are mixed, the similar situation exists in figure 3). Fig. 2B further shows that the coating catalyzes rapidly, producing over 1 micromole per liter of NO molecules in half an hour, sufficient to provide excellent antiplatelet effects.
Next, the coating was further verified and evaluated for anti-platelet effect. Fresh blood was drawn from the auricular vein of a new zealand white rabbit and placed in a blood collection tube containing 3.8% by mass of sodium citrate. The obtained blood was centrifuged at 1500 rpm for 15 minutes in a centrifuge to obtain a supernatant as platelet-rich plasma, which was taken out for use. 60 microliters of platelet rich plasma containing the catalytic substrate was applied to the surface of the coating and incubated at 37 ℃ for 2 hours. After incubation, the coating was washed with physiological saline, incubated with 60. mu.l of 2.5% glutaraldehyde for 1 hour, and washed with physiological saline. Finally, four kinds of alcohol of 50%, 75%, 90% and 100% are used for gradient dehydration in sequence. After drying, the surface of the coating is sprayed with gold for characterization and analysis by a scanning electron microscope. The prepared Fe-N-C-loaded medical device surface coating and the simple polycaprolactone coating serving as a control were subjected to the above treatment and characterization, and the results are shown in FIGS. 2C to 2F.
From the characterization results of the scanning electron microscope, it can be seen that the pure polycaprolactone coating has no anticoagulation function, and platelets are adsorbed and activated on the coating surface in a large amount (fig. 2C and 2D). For the coating loaded with Fe-N-C, because the coating can catalyze and generate NO to play a role in resisting platelets, the surface of the coating is hardly adsorbed and aggregated by platelets (figures 2E and 2F), and a good anticoagulation effect is shown.
Example 2
The surface coating of the Fe-N-C-loaded medical apparatus and instrument is constructed by a two-step method, the enzyme-like material Fe-N-C is synthesized by the same method as that in the embodiment 1 in the first step, and the surface coating of the Fe-N-C-loaded heart stent is constructed by a spraying method in the second step.
The coating was built up as follows:
dispersing a polylactic acid-glycolic acid copolymer with the molecular weight of 15 ten thousand and Fe-N-C in a dichloromethane solvent, wherein the final concentration of the polylactic acid-glycolic acid copolymer is 10 milligrams per milliliter, and the final concentration of the Fe-N-C is 0 or 0.25 or 0.5 or 1.0 milligrams per milliliter. Uniformly mixing the Fe-N-C material and a dichloromethane solution of polylactic acid-glycolic acid copolymer in a magnetic stirring mode for 12 hours. And spraying the mixed solution on the surface of the heart stent by using an ultrasonic spraying machine, and volatilizing the solvent at room temperature to form a surface coating.
Next, the effect of catalyzing and generating NO by the heart stent modified by the Fe-N-C coating is examined. The four coating modified heart scaffolds were immersed in 200. mu.l of the reaction solution, and incubated at 37 ℃ for 30 minutes in the absence of light. The reaction solution was a phosphate buffer solution of pH 7.4, and hydroxyurea was added as a substrate at a concentration of 1 mmol per liter. As shown in the Griess test results of FIG. 3, three Fe-N-C coating modified heart stents were able to catalyze the oxidation of hydroxyurea, a substrate, to produce NO. Wherein, the Fe-N-C coating modified heart stent prepared under the condition that the final concentration of Fe-N-C is 1.0 milligram per milliliter has the best effect of catalyzing the generation of NO. This indicates that increasing the Fe-N-C loading increases the anticoagulant effect of the coating.
Example 3
In addition to the construction of Fe-N-C bearing medical device surface coatings using the methods of examples 1 and 2, other methods that enable the loading and/or inclusion and/or growth of enzyme-like materials on or in the medical device surface can be used to prepare the medical devices of the present invention. The following examples are listed exemplarily (but not exclusively) in this embodiment:
(1) and constructing the surface of the medical appliance containing Fe-N-C by adopting a molding technology. Specifically, a polymer heart scaffold containing Fe-N-C can be directly constructed by adopting a 3D printing technology, and the Fe-N-C is added into a polymer for 3D printing to create a high-performance functional composite material. The specific process is as follows:
target anatomical assessment is performed in a cardiac catheter workstation using both Optical Coherence Tomography (OCT) and intravascular ultrasound (IVUS) imaging modalities to find atypical vessel geometries, the stent being designed based on the vessel shape obtained in the imaging modality. After the polycaprolactone is melted, the Fe-N-C synthesized according to the method in the embodiment 1 is added, the mixture is uniformly mixed, and the designed stent and the surface thereof are obtained by adopting Fused Deposition Modeling (FDM) and combining a 3-axis 3D printing technology.
The 3D printing technology used in this embodiment can be personalized, and relevant parameters of the stent are determined according to the actual condition of the patient, the stent model used in the experiment in this embodiment is a stent with closed diamond cells, and the following parameters are determined according to the condition of the patient: the inner diameter of the stent is 4 mm, the thickness of the stent wall is 0.2 mm, the number of circumferential holes is 8, the width of the hinge is 0.8 mm, and the total length is 20 mm. In the printing process, the temperature of the nozzle is controlled to be 220 ℃, the temperature of the bed layer is controlled to be 25 ℃, and the printing speed is controlled to be 300 millimeters per minute. After printing was completed, the stent was sterilized in 70% ethanol solution for 12 hours, washed twice with Phosphate Buffered Saline (PBS), and sterilized under an ultraviolet lamp for 30 minutes.
(2) The Fe-N-C loaded medical instrument surface coating is constructed by adopting a one-step method, the synthesis of the material is directly set to occur on the required surface, and the Fe-N-C covered medical instrument surface coating is obtained in one step. The specific process is as follows:
medical 316L stainless steel and a precursor guanine of carbon are uniformly mixed and placed in an alumina crucible. Then the mixture is transferred into a high-temperature tube furnace and carbonized at high temperature of 700 ℃ for 3 hours under the protection of inert gas. After cooling to room temperature, the instrument was taken out and immersed in an acid solution to remove impurities. After removing impurities, taking out the instrument, and washing the instrument for multiple times by using ultrapure water until the washing liquid is neutral and no metal ion remains. And (3) drying the washed instrument in a vacuum drying oven at 60 ℃ to obtain the surface of the metal medical instrument with the Fe-N-C growing in situ.
Several schemes can successfully construct the blood contact type medical appliance surface coating with excellent anticoagulation function.
Finally, it should be noted that: the above embodiments are only used for illustrating the technical solutions of the present invention, and are not limited thereto; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. An anticoagulant material, wherein said anticoagulant material is loaded with and/or comprises and/or grows an enzyme-like material.
2. The anticoagulant material of claim 1, wherein the enzyme-like material is an enzyme-like material capable of mimicking peroxidase-like activity, oxidase-like activity, and/or nitrite reductase-like activity.
3. The anticoagulant material according to claim 1 or 2, wherein the enzyme-like material is a carbon material (C) doped with both a metal element (M) and a nitrogen element (N) having a natural enzyme-like catalytic activity; the enzyme-like material is preferably M-N-C; preferably, M is a transition metal element; more preferably, M is selected from iron (Fe), cobalt (Co), nickel (Ni), manganese (Mn), copper (Cu), ruthenium (Ru), rhodium (Rh), palladium (Pd), platinum (Pt), iridium (Ir), titanium (Ti), vanadium (V), chromium (Cr), zinc (Zn), gold (Au) or a combination of one or more of the above elements.
4. A medical device or medical material, wherein the medical device or medical material is loaded with and/or comprises and/or grows an enzyme-like material.
5. The medical device or material according to claim 4, wherein the enzyme-like material is an enzyme-like material according to any one of claims 1 to 3.
6. The method for producing a medical device or a medical material according to claim 4 or 5, wherein the enzyme-like material is supported on and/or contained in and/or grown on the whole, part or surface of the medical device or the medical material.
7. The method of manufacturing according to claim 6, comprising the steps of:
a) mixing the enzyme-like material with a material for forming a coating, and forming a film on the surface of a medical instrument or a medical material; preferably, the material for forming the coating is a material having good biocompatibility; or
b) Mixing the enzyme-like material with a material for molding, and directly molding by a molding technology to obtain the surface of a medical instrument or a medical material; preferably, the molding technique is 3D printing, and the material for molding is a 3D printing raw material; or
c) The enzyme-like material is directly synthesized on the surface of medical instruments or medical materials.
8. A method for preparing an anticoagulant coating or surface on the surface of a medical device or a medical material, which is characterized in that an enzyme-like material is loaded on and/or contained in and/or grown on the surface of the medical device or the medical material.
9. Use of an enzyme-like material for the preparation of an anticoagulant material or an anticoagulant coating or surface or a medical device or a medical material.
10. Use of an enzyme-like material or an anticoagulant coating or surface comprising an enzyme-like material or a medical device or medical material comprising an enzyme-like material in anticoagulation.
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