CN110974809B

CN110974809B - Patterned hollow-structure graphene film drug carrier and application thereof

Info

Publication number: CN110974809B
Application number: CN201911274403.4A
Authority: CN
Inventors: 陈刚; 王国航; 栗国贝; 孙冰冰
Original assignee: Beijing Tianxinfu Medical Appliance Co Ltd
Current assignee: Beijing Tianxinfu Medical Appliance Co Ltd
Priority date: 2019-12-12
Filing date: 2019-12-12
Publication date: 2022-03-15
Anticipated expiration: 2039-12-12
Also published as: CN110974809A

Abstract

The invention discloses a graphene film drug carrier with a patterned hollow structure, which comprises a film made of graphene materials, wherein the surface of the film is provided with at least two drug-loading devices which are communicated in a hollow mode, and a groove is formed between every two adjacent drug-loading devices, so that groove-shaped patterns are formed on the surface of the film. The invention realizes the construction of the custom patterned hollow structure of the graphene material under the mesoscale, improves the precision to the micron level compared with the preparation method of the macroscopic scale, is not limited by the shape and the property of the template any more compared with the preparation method of the nanometer scale, can prepare the hollow structure material which is more widely applied, has wide space of the prepared cavity structure, can contain more medicaments, and is suitable for the storage, transportation and release of the medicaments.

Description

Patterned hollow-structure graphene film drug carrier and application thereof

Technical Field

The invention belongs to the technical field of biological materials, and particularly relates to a patterned hollow-structure graphene film drug carrier and application thereof.

Background

Graphene is a two-dimensional monoatomic layer material composed of carbon atoms arranged in a hexagonal structure. By sp between carbon atoms²The hybrid orbitals are mutually bonded, the C-C sigma bond in the planar sheet layer is one of the bonds with the highest strength in the material, the large pi bond between the sheet layers determines the formation of a delocalized electron network, and the special structure causes the uniqueness of the physicochemical properties of the material.

The graphene film material in the prior art can also be used as a drug carrier. The common drug surface loading method mainly comprises surface adsorption, covalent bonding, blending of the drug and a base material and the like, for example, CN105456233B adopts a layer-by-layer self-assembly technology to form a composite hybrid structure by electrostatically bonding an antibacterial peptide molecule and graphene oxide; CN103097288A adopts a gel film containing graphene sheets, which can be used as a drug carrier for controlling drug release. However, the graphene carrier in the scheme has a complex drug loading mode and small loading capacity, and is not easy to operate practically.

In contrast, in many studies and researches on graphene, it has been an interesting problem to construct a morphology of a graphene material. The hollow structure material has a special internal control cavity structure, presents the characteristics of low density and high specific surface area, has good material storage and transportation functions, and is an important functional material. By using different mechanisms and templates, various hollow structures can be obtained to realize different required applications. Due to the adjustable physicochemical property of the hollow structure, the hollow structure has considerable advantages in structure construction and energy storage and conversion technology, such as a fuel cell, a lithium ion battery, a hybrid super capacitor and the like. The application of the functional material with the hollow structure in various fields is continuously developed, including catalyst, cosmetics, medicine and gene transportation, hydrogen preparation and storage, and photoelectric energy fields, and the hollow structure plays an important role. CN105217605A provides a method for preparing patterned graphene, which comprises taking a container with a designed patterned groove structure as a reactor, spreading graphene powder dispersed in oleic acid and water in the container to form a thin film, and standing by shaking, ultrasound, heating, freezing, magnetizing, and the like. CN105139963A provides an electronic device, in which a conductive material such as graphene is adhered to the bottom of the trench of the resin layer to make patterning. Patent documents CN110467177A and document [1] also provide a two-sided three-dimensional graphene scaffold, which can be used for differentiation of nerve cells, but the preparation method is very complicated and cumbersome, and is not easy to operate, and the obtained graphene scaffold has a very thin wall thickness, only a single layer or a few layers of graphene are present, and the precision is too small, which undoubtedly increases the difficulty of practical application (1 [ rapid, biological research on neural progenitor cells by controllable graphene scaffold [ D ].2019.5 ]).

The preparation process of the scheme is complicated, the obtained graphene pattern is limited by the shape and properties of the template, the graphene film is difficult to separate from the template, and the operation difficulty is increased.

Disclosure of Invention

In order to solve the problems, the invention aims to provide a graphene film drug carrier with a patterned hollow structure, which can be used for loading drug particles rapidly and massively and is particularly suitable for repairing damaged peripheral nerves.

In one aspect, the invention provides a graphene film drug carrier with a patterned hollow structure, which comprises a film made of graphene materials, wherein the surface of the film is provided with at least two drug carrying devices which are communicated in a hollow mode, and a groove is formed between every two adjacent drug carrying devices, so that a groove-shaped pattern is formed on the surface of the film.

The medicine carrying device arranged on the surface of the film extends along the radial direction of the film body of the film, for example, the medicine carrying device extends along the length direction or the width direction of the rectangular film; the hollow and through structure of the medicine carrying device forms a large medicine carrying space, and can be used as a medicine carrying cavity for carrying, storing, transporting and releasing a large amount of medicines.

Preferably, the shape of the drug delivery device may be linear, in which case the groove-like pattern formed is also a linear pattern.

Above-mentioned graphite alkene film drug carrier when being applied to the restoration impaired nerve, should have the surface and the impaired nerve direct contact of medicine carrier with the graphite alkene film, so set up can make the prosthetic ability of nerve material no longer be subject to the influence of self material, effectively improved the regeneration repair efficiency of nerve repair material to impaired peripheral nerve. In addition, the groove-shaped pattern surface can induce the damaged nerve to grow along the linear direction, preferably, the medicine carrying device can extend to the edge position of the film body, on one hand, the guidance of the groove pattern surface can be further improved, on the other hand, the medicine carrying can be carried out at two ends simultaneously when the medicine is carried, the filling or the releasing of the medicine particles in the medicine carrying device is more convenient, and the carrying process is simplified.

In one embodiment, the film has two opposing surfaces, one of which has the drug delivery device and the pattern, and the other of which may be substantially smooth or slightly concave to the drug delivery device side. In another embodiment, the cross-sectional shape of the drug delivery device may be a regular geometric shape, such as a semi-circle, a rectangle, a triangle, a trapezoid, etc., preferably a rectangle.

Further, the medicine carrying device is formed by at least part of the thin film protruding along the height direction of the film body of the thin film. The medicine carrying device and the film are integrally arranged, the materials are the same and uniform, the arrangement is favorable for simplifying the preparation method, and meanwhile, the conductive efficiency of the graphene film is improved.

Further, the height of the drug-loaded device is 10-50 μm, preferably 15-40 μm, more preferably 20-30 μm, more preferably 20-25 μm, more preferably 20 μm.

Further, the width of the drug-loaded device is 20-100 μm, preferably 20-80 μm, more preferably 20-60 μm, more preferably 20-50 μm.

Further, the interval between two adjacent drug carrying devices is 5-200 μm, preferably 10-100 μm, more preferably 15-100 μm, more preferably 20-50 μm.

Wherein, the graphene film drug carrier of the drug carrying device with the size is adopted, besides a larger drug carrying space, the cavity structure is easier to form during preparation, and if the graphene film of the drug carrying device with larger size is prepared, the hollow structure is difficult to form under the same preparation method.

Further, the fine dimension of the pattern is 10 to 100. mu.m, preferably 20 to 50 μm, more preferably 20 to 30 μm. Preferably, the etching depth of the pattern is 20-50 μm, preferably 20 μm.

It is to be understood that the fine scale of the pattern described herein may be understood as a size range of each graphic unit in the pattern, for example, when the pattern is a plurality of grooves arranged in an orderly and repeated manner, the fine scale of the pattern is a size range of a width of one groove.

In the fine scale range described above, the pattern has a pattern cell size that matches the size of most cells; at the same time, the size range also defines the pattern precision (i.e. the minimum size of the pattern unit, such as the width of one groove with the minimum size in the groove-like pattern), so that the pattern precision which can be realized in the fine scale range is far smaller than the precision of manual operation by human, i.e. can not be implemented by hand; in addition, under the fine scale of the range, the gravity effect of the graphene film material is far smaller than the interface effect and can be ignored.

Further, the thickness of the film is 8 to 12 μm, preferably 10 μm. Wherein, the film thickness is understood to be the thickness of the film body from the bottom of the groove to the other surface of the film.

Furthermore, the material of the film is selected from reduced graphene oxide. The reduced graphene oxide is beneficial to enhancing the mechanical strength of the obtained graphene film, and the film breakage and damage caused by insufficient mechanical strength are avoided.

Further, the sheet diameter of the reduced graphene oxide is 2-100 μm, and preferably, the raw material for preparing the graphene thin film is graphene oxide with the sheet diameter of 2-100 μm.

In one embodiment, the above drug carrier can be prepared by the following method: preparing a graphene oxide film with the thickness of 10 microns by using a suction filtration method by taking 2mg/ml graphene oxide dispersion liquid with the sheet diameter of 2 microns as a raw material; preparing a silica gel template with a micron-scale patterned surface by using a reverse mold method, flatly paving the dried graphene oxide film on the wetted silica gel template, standing, airing and forming; and reducing the formed graphene oxide film by using a reducing solution prepared from a hydrogen iodide solution and absolute ethyl alcohol, taking the film down, and cleaning to obtain the graphene film with the patterned hollow structure.

The preparation method realizes the controllable custom pattern manufacturing of the graphene film under the mesoscopic scale by utilizing the surface interface effect, and is simple and easy to operate.

Preferably, the graphene film drug carrier can be directly coated on the damaged peripheral nerve for use.

Wherein, above-mentioned graphene film drug carrier can restore impaired nerve under multiple use scene, for example, can the exclusive use, can use after the medicine carrying, can add and lead to the use of constant current, also can use after the medicine carrying and the electric current simultaneously, impaired nerve can be restoreed under graphite alkene, pattern, medicine, electric conductivity multiple action this moment, has improved repair efficiency greatly.

In another aspect, the invention provides a method for carrying a drug by using the graphene film drug carrier with the patterned hollow structure, which comprises the following steps: and immersing the graphene film drug carrier into a liquid containing a drug, and repeatedly vacuumizing and drying.

In one embodiment, the drug loading method specifically comprises the following steps: dispersing the desired drug in a volatile solvent in which the drug is insoluble to form a suspension dispersion. And immersing the prepared graphene film with the hollow structure into the medicine dispersion liquid, replacing the dispersion liquid with air in the cavity by adopting a vacuumizing method, taking out the film and drying, and leaving the medicine in the cavity. This process is repeated to substantially fill the cavity with the drug. Preferably, the vacuum pumping is maintained for 10 minutes at-0.8 atmosphere, and the mixture is taken out and dried in an oven at 60 ℃ for 15 minutes and repeated for 5 times.

Further, the drug comprises drug particles having a diameter of 0.1 to 5 μm, preferably, the drug particles have a diameter of 0.6 to 4 μm. Alternatively, the drug that can be loaded into the pack includes nerve growth factors such as NGF, NT-3, NT-4, BDNF, and the like.

On the other hand, the invention also provides application of the graphene film drug carrier with the patterned hollow structure in preparation of a nerve repair material, wherein the nerve repair material comprises a catheter and a stent.

Furthermore, electrodes are additionally arranged at two ends of the patterned hollow-structure graphene film drug carrier. In one embodiment, electrodes can be directly added to two ends of the graphene film; in another embodiment, the graphene film may be made into a nerve conduit, and additional electrode channels are provided at two ends of the nerve conduit for external electrodes, preferably, the additional electrode channels may be a section of tube wall of the tube body extending along two ends of the tube body, so as to apply electrical stimulation to the nerve conduit, promote nerve growth, and also be used for overlapping and fixing with nerves.

The invention has the beneficial effects that:

1. the invention realizes the construction of the custom patterned hollow structure of the graphene material under the mesoscale, improves the precision to the micron level compared with the preparation method of the macroscopic scale, is not limited by the shape and the property of the template any more compared with the preparation method of the nanometer scale, can prepare the hollow structure material which is more widely applied, has wide space of the prepared cavity structure, can contain more medicaments, and is suitable for the storage, transportation and release of the medicaments.

2. The graphene film drug carrier provided by the invention can be used for loading a large amount of drugs rapidly, and the loading method is simple and easy to implement; in addition, the graphene film drug carrier provided by the invention does not use a high-temperature and high-pressure environment or a high-risk chemical reagent during preparation, is simple to operate, has the advantages of economic raw materials, good forming effect, high structure precision, customizable patterns and corresponding hollow structures, and wider application, and is particularly suitable for nerve repair.

Drawings

The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the application and together with the description serve to explain the application and not to limit the application. In the drawings:

fig. 1 is a Scanning Electron Microscope (SEM) image of the surface of a patterned hollow structure graphene film drug carrier prepared in example 2 when the drug carrier is not loaded with a drug;

FIG. 2 is an enlarged view of a portion of FIG. 1;

fig. 3 is a Scanning Electron Microscope (SEM) image of a cross-section of the patterned hollow structure graphene thin film drug carrier prepared in example 2 when the drug carrier is not loaded with a drug;

fig. 4 is a Scanning Electron Microscope (SEM) image of the patterned hollow structure graphene film drug carrier prepared in example 2 after being loaded with a drug;

fig. 5 is a Scanning Electron Microscope (SEM) image of the patterned hollow structure graphene film drug carrier prepared in example 3 after loading with a drug.

Detailed Description

In order to more clearly explain the overall concept of the present application, the following detailed description is given by way of example. In the following description, numerous specific details are set forth in order to provide a more thorough understanding of the present application. It will be apparent, however, to one skilled in the art, that the present application may be practiced without one or more of these specific details. In other instances, well-known features of the art have not been described in order to avoid obscuring the present application.

Unless otherwise specified, the reagents and devices in the following examples were commercially available, wherein the graphene oxide dispersion was obtained from Nanjing Xiapong nanomaterial science and technology Co., Ltd; scanning electron microscopes available from FEI corporation of america under the model Quanta 250 FEG; the plasma cleaning instrument is provided by Saott (Beijing) science and technology Limited and has the model of SAOT-5L.

Example 1: preparation of graphene oxide film

Using 2mg/ml graphene oxide dispersion as an example, the sheet size is 2 μm thin layer graphene oxide, and the thin film preparation steps are as follows:

(1) according to 0.8ml/cm²The application ratio of (1) is that 10ml of dispersion liquid is filtered on a filter membrane with the diameter of 4 cm;

(2) filtering with 0.45 μm cellulose acetate water filter membrane under-0.8 atmosphere for about 8 hr;

(3) taking down the filter membrane with the graphene oxide film, and naturally and completely airing at room temperature;

(4) and stripping the graphene oxide film from the filter membrane.

Example 2: preparation method of micropatterned hollow-structure graphene film drug carrier

(1) Manufacturing a groove-shaped pattern silicon wafer which is arranged in parallel, wherein the specification size of the groove pattern is 50 micrometers in width, 50 micrometers in interval and 20 micrometers in depth, manufacturing a polydimethylsiloxane silica gel template by utilizing the silicon wafer reverse mould, processing the surface of the pattern of the silica gel template by using a plasma cleaner, and processing for 90s at 150W power;

(2) wetting the surface of the silica gel pattern with pure water, then flatly paving the dried graphene oxide film prepared in the embodiment 1, standing and airing;

(3) preparing a reducing solution by using a 47% hydrogen iodide solution and absolute ethyl alcohol, coating the reducing solution on the surface of the graphene oxide film, and standing for 7 hours in a dark place;

(4) polystyrene balls with the diameter of 4 mu m are used as simulated medicine particles to prepare suspension;

(5) and (3) immersing the hollow graphene film into the suspension dispersion liquid, vacuumizing to 0.8 atmosphere, maintaining for 10 minutes, taking out the film from the 60-DEG C oven, drying for 15 minutes, and repeating for 5 times.

Example 3: preparation method of graphene film drug carrier with micropatterned hollow structure

(3) preparing a reducing solution by using a hydrogen iodide solution and absolute ethyl alcohol, coating the reducing solution on the surface of the graphene oxide film, and standing for 7 hours in a dark place;

(4) polystyrene balls with the diameter of 600nm are used as simulated medicine particles to prepare turbid liquid;

Example 4: preparation method of micropatterned hollow-structure graphene film drug carrier

(1) Manufacturing a groove-shaped pattern silicon wafer which is arranged in parallel, wherein the specification size of the groove pattern is 20 micrometers in width, 20 micrometers in interval and 20 micrometers in depth, manufacturing a polydimethylsiloxane silica gel template by utilizing the silicon wafer reverse mould, processing the surface of the pattern of the silica gel template by using a plasma cleaner, and processing for 90s at 150W power;

Example 5: preparation method of graphene film drug carrier with micropatterned hollow structure

The surface morphology and the cross-sectional morphologies before and after drug loading of the graphene film drug carrier prepared in example 2 are shown in fig. 1-4, and SEM pictures show that the graphene film provided by the invention has a patterned drug loading device with a hollow through structure on the surface, and can be used for loading drug particles.

Meanwhile, the loading condition of the graphene film obtained by comparing examples 1 to 5 after loading the drug is found that the film with a small hollow structure is easier to store the drug and is not easy to scatter, but is not easy to fill the large-particle drug; the large hollow structure can accommodate larger drug particles, but at the same time is easily scattered. Therefore, in practical use, the proper structural size can be selected according to the situation.

The above description is only an example of the present application and is not intended to limit the present application. Various modifications and changes may occur to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the scope of the claims of the present application.

Claims

1. The graphene film drug carrier with the patterned hollow structure is characterized by comprising a film made of graphene materials, wherein the surface of the film is provided with at least two drug carrying devices which are hollow and communicated, and a groove is formed between every two adjacent drug carrying devices, so that a groove-shaped pattern is formed on the surface of the film;

the medicine carrying device is formed by at least partially protruding the film along the height direction of the film body; the height of the medicine carrying device is 10-50 mu m, and the width of the medicine carrying device is 20-100 mu m;

the thickness of the film is 8-12 μm; the thin film is made of reduced graphene oxide, and the sheet diameter of the reduced graphene oxide is 2-100 mu m.

2. The drug carrier of claim 1, wherein the interval between two adjacent drug carrying devices is 5-200 μm.

3. The drug carrier of claim 1, wherein the fine dimension of the pattern is 10-100 μm.

4. The drug carrier of claim 1, wherein the fine dimension of the pattern is 20-50 μm.

5. The drug carrier of claim 1, wherein the fine dimension of the pattern is 20-30 μm.

6. A method for drug loading using the graphene thin film drug carrier of the patterned hollow structure of any one of claims 1-5, comprising: and immersing the graphene film drug carrier into a liquid containing a drug, and repeatedly vacuumizing and drying.

7. The method of claim 6, wherein the drug comprises drug particles having a diameter of 0.1-5 μm.

8. Use of a graphene film drug carrier of a patterned hollow structure according to any one of claims 1 to 5 in the preparation of a nerve repair material comprising a nerve scaffold.

9. The use according to claim 8, wherein electrodes are applied to both ends of the patterned hollow structured graphene film drug carrier.