CN110664439B - Microneedle capable of extracting skin tissue fluid and preparation method thereof - Google Patents
Microneedle capable of extracting skin tissue fluid and preparation method thereof Download PDFInfo
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Abstract
本发明公开了一种可提取皮肤组织液的微针及其制备方法，所述微针包括相互贯穿的多孔网络骨架及在该骨架内外表面修饰的亲水性聚合物层。制备方法具体是先配制聚合物和致孔剂的混合溶液，然后将它们填入微针模具中，然后除去其中的致孔剂，即可得到具有相互贯穿的多孔网络骨架，最后在多孔网络骨架内外表面修饰亲水性聚合物层。本发明通过对该微针所采用的亲水性聚合物层的厚度、微针的孔隙率、孔径以及相应制备方法的整体工艺流程设计进行改进，得到可提取皮肤组织液的微针。本发明提供的微针生物相容性好，提取皮肤组织液的速度快，无需外加负压装置，不会引起明显疼痛感和皮肤感染，无需专业人员操作。
The invention discloses a microneedle capable of extracting skin tissue fluid and a preparation method thereof. The microneedle comprises an interpenetrating porous network skeleton and a hydrophilic polymer layer modified on the inner and outer surfaces of the skeleton. The preparation method is to prepare a mixed solution of polymer and porogen first, then fill them into the microneedle mold, and then remove the porogen in it, so as to obtain a porous network skeleton with interpenetration, and finally in the porous network skeleton. The inner and outer surfaces are modified with hydrophilic polymer layers. The invention obtains a microneedle capable of extracting skin tissue fluid by improving the thickness of the hydrophilic polymer layer used in the microneedle, the porosity and pore size of the microneedle and the overall process design of the corresponding preparation method. The microneedle provided by the invention has good biocompatibility, fast extraction of skin tissue fluid, no need for external negative pressure device, no obvious pain and no skin infection, and no professional operation is required.
Description
Technical Field
The invention belongs to the field of biomedical polymer materials, and particularly relates to a microneedle capable of extracting skin tissue fluid and a preparation method thereof.
Background
In disease treatment and monitoring of physical conditions, timely diagnosis plays an important role. The extraction of a body fluid sample is the primary and critical step in a timely diagnosis. Blood is often used for timely diagnosis because it is rich in metabolites. However, the blood sampling needs to pierce the skin and penetrate the dermal layer rich in nerve cells, which causes problems such as pain and skin irritation.
The skin tissue fluid has similar components to blood, and the composition of the skin tissue fluid changes with the change of the plasma composition, so the skin tissue fluid can be used for sample extraction instead of blood. Generally, the skin tissue fluid can be extracted by a suction tube technology and a microtubule insertion technology, but the procedures are complicated and easily cause discomfort of patients, so a simple, convenient, minimally invasive and painless tissue fluid extraction method is urgently needed.
Microneedles are a micro-scale three-dimensional array structure, and have been widely researched and paid attention to due to their advantages of safety, no pain, and the like. Microneedles are used for both transdermal drug delivery and interstitial fluid extraction. Hollow microneedles made of metal, glass, silicon, etc. are often used for extracting skin tissue fluid, but the preparation process of the microneedles is complicated, the preparation cost is high, an additional negative pressure device is required, and the preparation materials are brittle and have a risk of fracture, so that the application of the microneedles is limited. Therefore, a safe microneedle for skin tissue fluid extraction, which has a simple preparation method, a low preparation cost, a simple structure and a certain toughness, is urgently needed.
Disclosure of Invention
In view of the above-mentioned drawbacks or needs for improvement in the prior art, it is an object of the present invention to provide a microneedle capable of extracting skin tissue fluid and a method for manufacturing the same, in which the microneedle capable of extracting skin tissue fluid is obtained by improving the thickness of a hydrophilic polymer layer used for the microneedle, the porosity and pore size of the microneedle, and the overall process flow design of the corresponding manufacturing method. The microneedle provided by the invention has good biocompatibility, high speed of extracting skin tissue fluid, no need of an external negative pressure device, no obvious pain and skin infection, and no need of professional operation; in addition, the invention can extract more tissue fluid by regulating and controlling the porosity, the pore diameter and other aspects of the porous network structure in the polymer micro-needle, and is very suitable for the practical application of skin tissue fluid extraction.
In order to achieve the above objects, according to one aspect of the present invention, a microneedle capable of extracting skin tissue fluid, the microneedle comprising a substrate and a needle tip on the substrate, wherein the microneedle comprises a skeleton having a porous network penetrating each other therein and hydrophilic polymer layers modified on inner and outer surfaces of the skeleton.
In a further preferred aspect of the present invention, the hydrophilic polymer layer has a thickness of 20 to 800 nm.
Further preferably, the microneedle has a porosity of 40% to 90%, and the diameter of the microneedle is 2 to 50000 nm.
As another aspect of the present invention, there is provided a method for preparing a microneedle capable of extracting skin tissue fluid, comprising the steps of:
(1) preparing a mixed solution of a polymer and a pore-foaming agent;
(2) filling the mixed solution obtained in the step (1) into a microneedle mould;
(3) removing the pore-foaming agent doped in the microneedle obtained in the step (2) to obtain an interpenetrating microneedle porous network skeleton;
(4) and (4) modifying a hydrophilic polymer layer on the inner surface and the outer surface of the porous network skeleton obtained in the step (3) to obtain the microneedle capable of extracting skin tissue fluid.
As a further preferred aspect of the present invention, in the step (1), the polymer is one or a blend of more of polyacrylonitrile, polylactic acid-glycolic acid copolymer, polyvinylidene fluoride, polyarylsulfone, polyethersulfone, cellulose acetate, polyimide, polyetherimide, polyamide, polyetheretherketone, polycarbonate, polytetrafluoroethylene, polyvinyl chloride, polymethacrylic acid, polyethyleneimine, polyvinylpyridine, isotactic propylene, cellulose ester, polystyrene, polybutadiene, polyphenylene oxide, polyurethane, brominated polyphenylene oxide, polyvinyl alcohol, and fibroin, or a copolymer composed of the above polymers;
the polymer in step (1) is more hydrophobic than the hydrophilic polymer in step (4).
As a further preferred aspect of the present invention, in step (1), the porogen is one or a mixture of several of an organic solvent, water, a polymer and inorganic particles;
in the step (3), the polymer constituting the skeleton of the porous network of the microneedle is not removed when the porogen is removed.
In a further preferred embodiment of the present invention, in the step (4), the hydrophilic polymer is one or a mixture of several of poly (4-vinylpyridine), poly (2-vinylpyridine), polyethylene oxide, polyethylene glycol, polyacrylic acid, chitosan, hyaluronic acid, sodium alginate, and carboxymethyl cellulose.
As a further preferred aspect of the present invention, in the step (4), the thickness of the hydrophilic polymer layer is 20 to 800 nm.
According to still another aspect of the present invention, there is provided a use of the above-mentioned microneedle capable of extracting skin tissue fluid for the preparation of a preparation for extracting skin tissue fluid or blood.
According to another aspect of the present invention, there is provided a use of the above microneedle capable of extracting skin tissue fluid in preparation of a preparation for glucose detection, cholesterol detection, and tumor marker early detection.
Compared with the prior art, the microneedle has the advantages that the microneedle is designed to be internally provided with the mutually-penetrated porous network structure, the mutually-communicated pore structures are utilized, and the polymer is adopted as the microneedle material, so that the porosity and the pore diameter of the microneedle can be flexibly adjusted, and the microneedle has a good water absorption effect on the basis of keeping the microneedle insoluble in water. The invention preferably adopts one or a mixture of more of polyacrylonitrile, polylactic acid-glycolic acid copolymer, polyvinylidene fluoride, polyarylsulfone, polyethersulfone, cellulose acetate, polyimide, polyetherimide, polyamide, polyether ether ketone, polycarbonate, polytetrafluoroethylene, polyvinyl chloride, polyacrylic acid, polymethacrylic acid, polyethyleneimine, polyvinylpyridine, polyethylene glycol, poly isotactic propylene, cellulose ester, polystyrene, polybutadiene, polyphenyl ether, polyurethane, brominated polyphenyl ether, polyvinyl alcohol, sodium alginate, poly (4-vinylpyridine), poly (2-vinylpyridine), polyethylene oxide and fibroin or a copolymer formed by the polymers to form a porous network structure framework of the microneedle and a hydrophilic layer on the surface of the porous framework (the hydrophilic layer polymer has better hydrophilicity than that of the polymer of the porous network framework structure), the porosity of the microneedle is controlled to be 40% -90%, the pore diameter is controlled to be 2-50000nm, and the integral hydrophilic effect of the microneedle can be further ensured.
In the preparation process of the microneedle, the pore-foaming agent can be adopted, the pore-foaming agent and the polymer material are molded together, and then the pore-foaming agent component in the microneedle is removed by a method which can only dissolve the pore-foaming agent and has no negative influence on the polymer base material, so that the microneedle with the internal porous network structure penetrating through each other is formed. By adjusting the proportion of the polymer and the pore-forming agent and the size of the pore-forming agent, the microneedle with the interconnected porous network structure can be obtained, and the microneedle especially suitable for extracting skin tissue fluid can be obtained. The microneedle can be especially a polymer microneedle, and the polymer microneedle with a porous structure is prepared by selecting a polymer with high mechanical strength, good toughness and good biocompatibility and can be used for quickly extracting interstitial fluid. The polymer used in the invention has good biocompatibility, no stimulation to skin and low cost. Compared with a hollow metal microneedle, the polymer microneedle with the porous structure has the advantages of good toughness, no fracture risk, no additional device and simple structure. The polymer microneedle with the porous structure prepared by the preparation method of the porous polymer microneedle provided by the invention has a larger cavity, can extract more tissue fluid, and is suitable for practical application of skin tissue fluid extraction.
Some documents in the prior art also prepare microneedles with porous structures, but the pinholes are not communicated, so that the effect of the invention cannot be achieved; the method specifically comprises the steps of controlling the ratio of the polymer to the pore-foaming agent to regulate the porosity (40-90%), and controlling the size of the pore-foaming agent to regulate the pore size (2-50000 nm), so that the pore structures are communicated.
In general, compared with the prior art, the above technical solution provided by the present invention can achieve the following beneficial effects:
(1) the material for preparing the porous polymer microneedle has good biocompatibility, no stimulation to skin, wide source and low cost.
(2) Compared with hollow metal microneedles, the porous polymer microneedles provided by the invention have the advantages of good toughness, no fracture risk, no additional device and simple structure.
(3) Compared with the traditional method, the preparation method of the porous polymer microneedle provided by the invention has the advantages of simple process, mild condition, low cost and controllable pore structure, size and distribution.
(4) The porous polymer microneedle with the hydrophilic coating has good hydrophilicity, can quickly extract skin tissue fluid and is used for detecting glucose, tumor markers and the like.
Drawings
In FIG. 1, (a), (b) and (c) are respectively a microscope photograph of a cellulose acetate porous microneedle, a scanning electron microscope photograph of the tip surface and a cross section.
Fig. 2 is a microscope image of a porous cellulose acetate microneedle extracting skin tissue fluid.
FIG. 3 is a confocal microscope of mice after skin prick with porous cellulose acetate loaded with sodium fluorescein solution.
Fig. 4 is a result of comparing blood glucose values of rats with three different blood glucose models measured by microneedle extraction of skin tissue fluid with values measured by a commercial blood glucose meter.
Fig. 5 is a schematic view of a porous network structure of a microneedle according to the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1
Firstly, obtaining a Polydimethylsiloxane (PDMS) female die by a micro-needle male die through a reverse replication method, then, dropwise adding a dimethyl sulfoxide solution of 25% (w/w) cellulose acetate with a molecular weight of 10KDa and a mass fraction of 25% (w/w) onto the female die (a pore-forming agent is solvent dimethyl sulfoxide), ultrasonically treating for 1 hour, placing the mixture into ultrapure water at 25 ℃ to enable a polymer to undergo phase separation, and carrying out freeze drying after stripping to obtain porous micro-needles (the diameter of the bottom edge is 210 mu m, the height is 600 mu m, and the array is 10 x 10, wherein the parameters are all shown in the following examples) with the aperture of 1500nm and the porosity of 57% (mercury porosimetry). Then subjecting the microneedle to iso-O2Performing ion treatment, alternately soaking in 1mg/mL chitosan and hyaluronic acid solution to obtain a hydrophilic layer with the thickness of 20nm, cleaning with pure water, and air drying, wherein the mass of water extracted from the agarose hydrogel by the microneedle within 10min is 0.8 mg.
Examples 2 to 5
The pore size and the porosity of the microneedle can be further regulated and controlled by adjusting the mass percentage of the cellulose acetate in the dimethyl sulfoxide solution, and the hydrophilic capability of the microneedle can be regulated by regulating the thickness of the hydrophilic layer. In addition, other polymers can be used to replace cellulose acetate to form the micro-needle corresponding to the polymer material, and the pore size and porosity of the micro-needle can be adjusted by controlling the ratio of the polymer to the pore-forming agent.
Examples 2-5 can be adjusted based on example 1, and the parameters of the microneedles in examples 2-5 are shown in the following table:
example 6
Firstly, preparing a PDMS female die by a micro-template method; then, adding polyether sulfone and calcium oxide with the size of 2 mu m into N, N-dimethylformamide according to the mass ratio of 3:7 to prepare a solution, dropwise adding the solution onto a PDMS female die, and ultrasonically promoting the solution to enter a die; heating and drying N, N-dimethylformamide, and stripping to obtain solid substance containing calcium oxidePolyether sulfone microneedles; the resulting solid microneedles are placed in 10-4Removing the calcium oxide nano particles in a mol/L dilute nitric acid solution to obtain the porous polyether sulfone microneedle with the aperture of 2000nm and the porosity of 65%. Then subjecting the microneedle to iso-O2Performing ion treatment, alternately soaking in 1mg/mL chitosan and polyacrylic acid solution to obtain a hydrophilic layer with the thickness of 20nm, cleaning with pure water, and air drying, wherein the mass of water extracted from the agarose hydrogel by the microneedle within 10min is 0.2 mg.
Example 7
Firstly, preparing a PDMS female die by a micro-template method; then, adding cellulose acetate and polyethylene glycol into dimethyl sulfoxide according to the mass ratio of 1:1 to prepare a solution, dropwise adding the solution onto a PDMS female die, and centrifuging to promote the solution to enter a die; freeze-drying to remove dimethyl sulfoxide, and stripping to obtain solid cellulose acetate microneedle containing polyethylene glycol; and (3) placing the obtained solid microneedle in pure water, and removing polyethylene glycol to obtain the porous cellulose acetate microneedle with the pore diameter of 200nm and the porosity of 52%. Then subjecting the microneedle to iso-O2Performing ion treatment, alternately soaking in 1mg/mL chitosan and polyacrylic acid solution to obtain a 20nm hydrophilic layer, cleaning with pure water, and air drying, wherein the mass of water extracted from the agarose hydrogel within 10min by the microneedle is 1.0 mg.
Effect verification:
example 8
Porous microneedles prepared using the method of example 1 were loaded with rhodamine B, inserted into pre-prepared, de-haired, flat fresh mouse skin, and the mouse skin was observed under a fluorescent microscope after a period of time.
Under the observation of an optical microscope, the skin surface of the acted mouse has obvious holes, and the rest skin is intact, which shows that the porous polymer micro-needle can effectively pierce the epidermis of the mouse. Similarly, under a fluorescence microscope, the skin surface of the acted mouse has obvious green fluorescence, and other parts of the acted mouse show black, which indicates that the green fluorescence is formed by rhodamine B at holes left by the porous polymer microneedle after the porous polymer microneedle pierces the skin, and indicates that the porous polymer microneedle can effectively pierce the skin.
Example 9
The porous cellulose acetate microneedles prepared in example 1 were inserted into the skin of a previously prepared unhaired mouse, pulled out after 15 minutes, and the ability of the microneedles to take up interstitial fluid was judged by weighing the mass change of the microneedles before and after insertion into the skin of the mouse. The microneedles inserted into the skin of the mice after being pulled out were immersed in 500 μ L of ultrapure water, and the concentrations of glucose and cholesterol in the interstitial fluid extracted by the microneedles were calculated by measuring the concentrations of glucose and cholesterol in the ultrapure water solution.
By comparing the mass of the porous polymer microneedle before and after being inserted into the skin of a mouse, the mass of the microneedle after being inserted into the skin of the mouse is increased by 1.4mg compared with that before the microneedle is inserted into the skin of the mouse, so that the microneedle absorbs 1.4mg of liquid from the skin, and the microneedle can be used for extracting skin tissue liquid. The concentration of glucose and cholesterol in the skin tissue fluid extracted by the microneedle is calculated to be 4.0mmol/L and 2.5mmol/L respectively by calculating the concentration of glucose and cholesterol in the microneedle leachate, which indicates that the microneedle has the capability of extracting the skin tissue fluid.
Therefore, the microneedle capable of extracting the skin tissue fluid can be used for preparing a preparation for extracting the skin tissue fluid or blood, and further can be used for preparing a preparation for detecting glucose, cholesterol and tumor markers in early stage.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (3)
1. The preparation method of the microneedle capable of extracting the skin tissue fluid is characterized in that the microneedle capable of extracting the skin tissue fluid comprises a substrate and a needle point positioned on the substrate, wherein the microneedle comprises a porous network skeleton which is internally provided with a plurality of mutually penetrated pores and a hydrophilic polymer layer which is modified on the outer surface of the skeleton; the thickness of the hydrophilic polymer layer is 20-800 nm; the porosity of the microneedle is 40% -90%, and the pore diameter of the microneedle is 2-50000 nm; the microneedle can extract skin tissue fluid without an additional negative pressure device;
the preparation method comprises the following steps:
(1) preparing a mixed solution of a polymer and a pore-foaming agent;
(2) filling the mixed solution obtained in the step (1) into a microneedle mould;
(3) removing the pore-foaming agent doped in the microneedle obtained in the step (2) to obtain an interpenetrating microneedle porous network skeleton;
(4) modifying a hydrophilic polymer layer on the outer surface of the porous network skeleton obtained in the step (3) to obtain a microneedle capable of extracting skin tissue fluid; wherein, the outer surface of the porous network skeleton is modified with a hydrophilic polymer layer, specifically, the porous network skeleton is firstly modified with O2Plasma treatment, and then alternately soaking in chitosan and hyaluronic acid solutions, or alternately soaking in chitosan and polyacrylic acid solutions, to obtain a hydrophilic polymer layer.
2. A method for preparing microneedles capable of extracting skin tissue fluid according to claim 1, wherein in the step (1), the polymer is one or more of polyacrylonitrile, polylactic acid-glycolic acid copolymer, polyvinylidene fluoride, polyarylsulfone, polyethersulfone, cellulose acetate, polyimide, polyetherimide, polyamide, polyetheretherketone, polycarbonate, polytetrafluoroethylene, polyvinyl chloride, polymethacrylic acid, polyethyleneimine, polyvinylpyridine, poly-isotactic propylene, cellulose ester, polystyrene, polybutadiene, polyphenylene oxide, polyurethane, brominated polyphenylene oxide, polyvinyl alcohol, fibroin, or a copolymer of the above polymers;
the polymer in step (1) is more hydrophobic than the hydrophilic polymer in step (4).
3. A method for preparing microneedles capable of extracting skin tissue fluid according to claim 1, wherein in the step (1), the pore-forming agent is one or a mixture of organic solvent, water, polymer and inorganic particles;
in the step (3), the polymer constituting the skeleton of the porous network of the microneedle is not removed when the porogen is removed.
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| CN111345853B (en) * | 2020-03-06 | 2022-07-15 | 华中科技大学同济医学院附属协和医院 | A sampling rod capable of collecting throat swabs and preparation method thereof |
| CN112842333A (en) * | 2020-12-31 | 2021-05-28 | 华中科技大学 | Visual glucose concentration detection microneedle patch, preparation method and application |
| CN114081538B (en) * | 2021-11-12 | 2023-09-15 | 江西中医药大学 | Microneedle device for skin tissue fluid puncture |
| CN114129503A (en) * | 2021-11-19 | 2022-03-04 | 烟台魔技纳米科技有限公司 | Preparation method of porous microneedle with adjustable pore size |
| CN115089862B (en) * | 2022-06-09 | 2023-11-28 | 中国科学院理化技术研究所 | Hydrogel microneedle patch based on three-dimensional framework structure and preparation method and application thereof |
| CN116807520A (en) * | 2023-06-28 | 2023-09-29 | 南方医科大学 | Method for minimally invasive extraction of tissue fluid without damage and pain |
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