WO2019062326A1 - 一种类皮肤的超薄柔性葡萄糖测量传感器及其制备方法 - Google Patents
一种类皮肤的超薄柔性葡萄糖测量传感器及其制备方法 Download PDFInfo
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- G01N27/3271—Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood
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- the invention relates to biosensor technology, in particular to a skin-like ultra-thin flexible glucose measuring sensor and a preparation method thereof.
- Glucose is a major component of carbohydrates in animals and plants, so the quantitative determination of glucose plays an important role in biochemistry, clinical chemistry and food analysis.
- Clark's oxygen electrode analysis method made it possible to perform non-destructive measurement of the partial pressure of oxygen in living tissues, thereby opening up the field of research on biosensors.
- glucose sensors Over the past 50 years, the research and development of biosensors by researchers in various countries have made glucose sensors useful in food analysis, fermentation control, clinical testing and many other aspects. This paper gives a brief overview of the classification, principle and development of glucose biosensors.
- Glucose sensor is the most researched and commercialized biosensor in the field of biosensors. It is composed of glucose oxidase (GOD) and cured at the oxygen electrode.
- GOD glucose oxidase
- the enzyme has high selectivity, high affinity, and can catalyze the substrate reaction under mild conditions, so it is selected as the biologically active substance of choice in biosensors. Since the enzyme sensor is constructed by a combination of an immobilized enzyme and an electrochemical device (electrode), it is also called an enzyme electrode.
- the GOD is immobilized on a membrane that is permeable to glucose and oxygen, and then fixed to the front end of the oxygen electrode.
- glucose is present in the solution, glucose is oxidized by GOD when passing through the immobilized enzyme membrane. Oxygen is consumed during the reaction, and this consumption can be measured by an oxygen electrode, so that the glucose content can be checked by this.
- changes in the partial pressure of oxygen in the atmosphere can cause changes in the concentration of dissolved oxygen in the solution, thereby affecting the accuracy of the determination. This is a problem to be solved when the enzyme electrode glucose biosensor is applied.
- the classical glucose oxidase sensor uses a hydrogen peroxide electrode as a base electrode to detect the amount of H2O2 produced, thereby detecting the glucose content in the serum.
- the advantage is that the glucose concentration has an equivalent relationship with the produced H2O2 and is not affected by changes in the oxygen concentration in the blood.
- a biosensor using hydrogen peroxide as a base electrode is the earliest biosensor.
- glucose sensors Since the birth of the first biosensor in 1962, glucose sensors have played an important role in all stages of the development of biosensors. In terms of commercialization, the application of glucose biosensors is unmatched by any other biosensor. Now, the annual output of enzyme electrodes for blood glucose testing has reached billions. In the fermentation industry, glucose sensors have also been widely used in raw material analysis and remote control. In the field of research, compared with other biosensors, the proportion of papers published by glucose sensors has always been the highest. In recent years, research reports on nanobiosensors and DNA biosensors have increased rapidly, but the proportion of glucose biosensors reported throughout the sensor research has not changed significantly. This is because the research of many new biosensors is related to glucose sensors.
- the present invention proposes a skin type ultra-thin flexible glucose measuring sensor and a preparation method thereof for detecting the concentration of glucose present on the skin surface.
- the skin-like ultra-thin flexible glucose measuring sensor of the present invention comprises: a flexible film substrate, an insulating support layer, a bonding layer, a counter electrode, a working electrode, and a chitosan film to which glucose oxidase is immobilized; wherein a turn is formed on the substrate
- the printing layer forms an insulating support layer on the transfer layer, forms a bonding layer on the insulating support layer, forms a conductive layer on the bonding layer, and etches the conductive layer on the surface to the upper surface of the insulating support layer to form a pair on the conductive layer.
- the pattern of the electrode and the pattern of the working electrode are insulated between the pattern of the electrode and the pattern of the working electrode, a Prussian blue film is formed on the pattern of the working electrode, and the pattern of the working electrode and the Prussian blue film formed thereon constitute the working electrode,
- the pattern of the electrode serves as a counter electrode; a chitosan film in which glucose oxidase is immobilized is formed on the working electrode; the insulating support layer, the bonding layer, the counter electrode, the working electrode, and the chitosan film immobilized with glucose oxidase constitute a multilayer Structure; the multilayer structure is peeled off from the transfer layer and transferred onto the flexible film substrate; the counter electrode and the working electrode are respectively connected to the electrification by wires A workstation or measuring circuit; a chitosan film immobilized with glucose oxidase is attached to the surface of the skin, glucose on the surface of the skin generates hydrogen peroxide under the action of glucose oxidase, and hydrogen per
- the amount of free electrons produced is proportional to the concentration of glucose
- free electrons are transmitted to the electrochemical workstation through the Prussian blue film or the measuring circuit forms the reaction current, and the electrochemical workstation measures the current generated by the reaction in the measurement mode or using the measuring circuit. Thereby obtaining the concentration of glucose.
- the counter electrode and the working electrode have a thickness of 100 nm to 1 cm, and the counter electrode and the working electrode have bendability and folding characteristics.
- the thickness of the counter electrode and the working electrode of the present invention is small, and it is easy to fit the glucose measuring sensor to the skin, thereby ensuring that the working electrode can closely adhere to the skin surface.
- the shape of the working electrode and the counter electrode is a planar electrode, a finger electrode or a wire electrode.
- the filament electrode refers to a metal wire of the working electrode and the counter electrode, respectively, or an organic material filament which is surface-plated, electrochemically deposited, vapor-deposited, and magnetron-sputtered with a conductive material layer.
- the counter electrode and the working electrode of the present invention have transferable characteristics, that is, the multilayer structure can be peeled off from the surface of the substrate to form a separate thin film electrode, and the insulating support layer can be used when the thin film electrode and the measuring circuit are bonded together.
- the effect of insulation prevents mutual interference, and the insulating support layer can serve as a support layer.
- the conductive layer with a thickness of nanometer is used as a support to form an independent flexible film.
- the adhesive layer and the insulating support layer have strong adhesion, and the conductive layer
- the bonding layer has strong adhesion, and the conductive layer and the insulating layer can be closely adhered together by the action of the bonding layer, thereby reducing the probability of the surface conductive layer of the electrode falling off.
- the insulating support layer is one of Polyimide (PI), Polyethylene terephthalate (PET), and Polyvinyl Alcohol (PVA). It is prepared by spin coating or scratching, or is adhered to the surface of the transfer layer by using an off-the-shelf film insulating material to deposit the subsequent bonding layer and conductive layer.
- the thickness of the insulating support layer is ⁇ 1 cm.
- the bonding layer is made of Cr or Pt and has a thickness of ⁇ 0.5 cm.
- the conductive layer is obtained by electroplating, electrochemical deposition, vapor deposition or magnetron sputtering; the material of the conductive layer is one of Au, Cu, Al, Ag and ITO. Electrodeposition can be improved by forming a nano-scale microstructure on the surface of the conductive layer by surface etching.
- the preparation of the Prussian blue film is carried out by connecting the pattern of the working electrode to the electrochemical workstation, and the pattern of the working electrode is immersed in a mixed solution of KCl, K 3 [Fe(CN) 6 ], FeCl 3 and HCl on the pattern of the working electrode. Electrochemical deposition is performed to form a Prussian blue film; or Prussian blue is made into an ink solution, and ink is dropped on the surface of the electrode by printing, printing, spin coating, and dripping, and a Prussian blue film can be obtained after the ink is dried.
- the nano-scale Prussian blue film was obtained by short-term potentiostatic deposition.
- the Prussian blue film has obvious oxidation-reduction potential under the electrochemical cyclic volt-ampere characteristic test. Larger, and the scan curve is stable after multiple scans.
- the Prussian blue film obtained after electrochemical deposition was subjected to cyclic voltammetry scanning in an electrochemical workstation, heated to a Prussian blue film for drying, and subjected to constant potential activation at a low potential, and then subjected to cyclic voltammetry scanning again.
- Cyclic voltammetric scanning after electrochemical deposition can cause the Prussian blue film to undergo redox reaction at different potentials, stabilize the deposited Prussian blue film, release internal cracks and defects, and heat the film to the interior of the Prussian blue film after drying.
- the structure becomes dense, the moisture between the pores is removed, and the low potential constant potential activation is performed again to increase the reactivity of the Prussian blue film near the low potential and enhance the surface measurement effect of glucose.
- the thickness of the Prussian blue film is ⁇ 10 ⁇ m.
- the working electrode is connected to the electrochemical workstation or measuring circuit via an anisotropic conductive film ACF flexible wire.
- the flexible ACF wire is a wire composed of a conductive metal particle based on a polymer.
- the cross section is flat, the thickness is small, the flexibility is good, and the flexible work of the Prussian blue film can be electrochemically deposited by heating and pressing.
- the surface of the electrode is connected without causing excessive increase in the height of the working electrode, and the characteristic of flexibility and low elastic modulus reduces the stress concentration at the junction of the flexible wire and the working electrode, preventing the bending deformation of the flexible wire or the flexible working electrode. Causes electrode cracking and wire debonding.
- the metal columnar wire is connected to the working electrode on which the Prussian blue film is electrochemically deposited by means of silver glue bonding and soldering, and is connected to an electrochemical workstation or a measuring circuit.
- a chitosan membrane immobilized with glucose oxidase is formed on the surface of the working electrode, and glycerin is added to the chitosan solution in which glucose oxidase is immobilized to increase the toughness of the chitosan membrane formed after the chitosan solution is dried, thereby preventing It broke.
- Another object of the present invention is to provide a method of preparing a skin-like ultra-thin flexible glucose measuring sensor.
- the preparation method of the skin-like ultra-thin flexible glucose measuring sensor of the invention comprises the following steps:
- the insulating support layer, the bonding layer, the counter electrode, the working electrode and the chitosan film immobilized with glucose oxidase form a multilayer structure, and the multilayer structure is peeled off from the transfer layer and transferred onto the flexible film substrate;
- the counter electrode and the working electrode are respectively connected to the electrochemical workstation or the measuring circuit through a wire;
- the chitosan membrane immobilized with glucose oxidase is adhered to the surface of the skin, and glucose on the surface of the skin generates hydrogen peroxide under the action of glucose oxidase. Hydrogen peroxide reacts with the Prussian blue film to form water and free electrons. The amount of free electrons produced is proportional to the concentration of glucose.
- the free electrons are transferred to the electrochemical workstation through the Prussian blue film or the measuring circuit is used to form the reaction current.
- the electrochemical workstation measures the current generated by the reaction in the measurement mode or by using a measuring circuit. The concentration of glucose is obtained.
- the substrate is washed with a cleaning agent and heated and dried on a hot plate to obtain a substrate.
- step 6 the surface etches the conductive layer to form a pattern of the counter electrode and the working electrode, and specifically includes the following steps:
- step 7 a Prussian blue film is formed on the pattern of the working electrode by electrochemical deposition; or an ink solution is prepared by using Prussian blue, and the ink is dropped on the electrode surface by printing, printing, spin coating or dripping. After the ink is dried, a Prussian blue film is obtained.
- the Prussian blue film is formed by electrochemical deposition, and specifically includes the following steps:
- the preparation method of the chitosan solution immobilized with glucose oxidase comprises the following steps:
- the invention prepares a nano-scale pattern of a counter electrode and a working electrode on an ultra-thin flexible insulating support layer and a bonding layer, forms a Prussian blue film on the pattern of the working electrode, and forms a glucose oxidase immobilized on the Prussian blue film.
- the chitosan film is adhered to the surface of the skin.
- Glucose generates hydrogen peroxide under the action of glucose oxidase. Hydrogen peroxide reacts with the Prussian blue film to form water and free electrons, and the reaction current is measured to obtain the concentration of glucose.
- the sensor of the invention has the characteristics of ultra-thin flexibility, can be attached to any surface of the human skin surface, and non-invasively and accurately measure the concentration of glucose present on the skin surface without affecting the movement and normal life of the human body, thereby realizing diabetes Non-invasive monitoring of patient blood glucose.
- Figure 1 is a cross-sectional view showing one embodiment of a skin-like ultrathin flexible glucose measuring sensor of the present invention
- FIG. 2 is a schematic view of the counter electrode and the working electrode of the skin-like ultra-thin flexible glucose measuring sensor of the present invention.
- the skin-like ultra-thin flexible glucose measuring sensor of the present embodiment comprises: a flexible film substrate, an insulating support layer 1, a bonding layer 2, a counter electrode 4, a working electrode, and a shell-shaped particle immobilized with glucose oxidase.
- a sugar film 6 wherein a transfer layer is formed on the substrate, an insulating support layer 1 is formed on the transfer layer, a bonding layer 2 is formed on the insulating support layer, and a conductive layer is formed on the adhesive layer 2;
- the layer forms a pattern of the counter electrode and the pattern 3 of the working electrode, a Prussian blue film 5 is formed on the pattern 3 of the working electrode, the pattern 3 of the working electrode and the Prussian blue film 5 formed thereon constitute a working electrode, and the counter electrode pattern serves as a counter electrode 4; forming a chitosan film 5 immobilized with glucose oxidase on the working electrode; an insulating support layer, a bonding layer, a counter electrode, a working electrode, and a chitosan film immobilized with glucose oxidase to form a multilayer structure; The structure is peeled off from the transfer layer and transferred onto a flexible film substrate.
- the counter electrode and the working electrode have various shapes, a rectangular shape, an interdigitated shape, and a filament shape.
- the substrate is a silicon wafer
- the transfer layer is polymethyl methacrylate PMMA
- the insulating support layer is PI
- the bonding layer is Pt
- the conductive layer is gold.
- the insulating support layer, the bonding layer, the counter electrode, the working electrode and the chitosan film immobilized with glucose oxidase form a multilayer structure, and the multilayer structure is peeled off from the transfer layer and transferred onto the flexible film substrate;
- the counter electrode and the working electrode are respectively connected to the electrochemical workstation or the measuring circuit by wires.
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Abstract
一种类皮肤的超薄柔性葡萄糖测量传感器及其制备方法，在超薄柔性的绝缘支持层(1)和粘结层(2)上制备纳米级的对电极(4)和工作电极的图案(3)，在工作电极的图案上形成普鲁士蓝薄膜(5)，在普鲁士蓝薄膜上形成固定了葡萄糖氧化酶的壳聚糖膜(6)，粘附在皮肤表面，葡萄糖在葡萄糖氧化酶的作用下产生过氧化氢，过氧化氢与普鲁士蓝薄膜发生催化反应，生成水和自由电子，测量反应电流，从而得到葡萄糖的浓度。该传感器具有超薄柔性的特点，能够贴附在人体皮肤表面的任何位置，在不影响人体运动和正常生活的情况下，无创、准确测量皮肤表面存在的葡萄糖的浓度，实现对糖尿病病人血糖的无创监测。
Description
本发明涉及生物传感器技术，具体涉及一种类皮肤的超薄柔性葡萄糖测量传感器及其制备方法。
葡萄糖是动物和植物体内碳水化合物的主要组成部分，因此葡萄糖的定量测定在生物化学、临床化学和食品分析中都占有很重要的位置。1954年Clark的氧电极分析方法使活体组织氧分压的无损测量成为可能，由此打开了生物传感器这一研究领域。50多年来各国科研人员对生物传感器的研究和发展使得葡萄糖传感器在食品分析、发酵控制、临床检验等诸多方面得到应用并发挥了重要的作用。本文对葡萄糖生物传感器的分类、原理及发展概况等作一简要概述。葡萄糖传感器是生物传感器领域研究最多、商品化最早的生物传感器，为葡萄糖氧化酶(glucose oxidase，GOD)经固化后于氧电极组成成。酶具有高选择性，高亲和力，在较温和条件下也能对底物反应起催化作用，因此被选为生物传感器中首选的生物活性物质。酶传感器因为多由固定化酶和电化学装置(电极)组合构建而成，所以又称为酶电极(enzyme electrode)。将GOD固定在能透过葡萄糖和氧的薄膜上，然后固定在氧电极的前端，当溶液中存在着葡萄糖时，葡萄糖在通过固定化酶膜时被GOD氧化。在反应发生过程中需要消耗氧气，而这种消耗量可用氧电极测定到，因此能够以此检查葡萄糖含量。但是大气中氧气分压的变化，会导致溶液中溶解氧浓度产生变化，从而影响测定的准确性，这是酶电极葡萄糖生物传感器在应用时要解决的问题。
经典葡萄糖氧化酶传感器是采用过氧化氢电极作为基础电极，通过检测H2O2的产生量，进而检测血清中的葡萄糖含量。其优点是，葡萄糖浓度与产生的H2O2有当量关系，不受血液中氧浓度变化的影响。采用过氧化氢作为基础电极的生物传感器是最早的生物传感器。
从1962年第一个生物传感器的诞生开始，葡萄糖传感器在整个生物传感器发展过程中的各个阶段都占有重要的地位。在商品化方面，葡萄糖生物传感器的应用是其它任何生物传感器所不能比拟的，现在全世界每年用于血糖测试的酶电极产量已达到数十亿支。在发酵工业中，葡萄糖传感器也已广泛应用于原料分析和远程控制等。在研究领域，与其他生物传感器相比，葡萄糖传感器发表论文的比例一直占据首位。近年来，纳米生物传感器及DNA生物传感器的研究报道迅速增加，但葡萄糖生物传感器在整个传感器研究报道的比例没有大的变 化。这是因为许多新型生物传感器的研究同葡萄糖传感器有关。
发明内容
针对以上现有技术中存在的问题，本发明提出了一种类皮肤的超薄柔性葡萄糖测量传感器及其制备方法，用于检测皮肤表面存在的葡萄糖浓度。
本发明的一个目的在于提出一种类皮肤的超薄柔性葡萄糖测量传感器。
本发明的类皮肤的超薄柔性葡萄糖测量传感器包括：柔性薄膜基底、绝缘支持层、粘结层、对电极、工作电极和固定了葡萄糖氧化酶的壳聚糖膜；其中，在基板上形成转印层，在转印层上形成绝缘支持层，在绝缘支持层上形成粘结层，在粘结层上形成导电层；表面刻蚀导电层至绝缘支持层的上表面，在导电层形成对电极的图案和工作电极的图案，对电极的图案和工作电极的图案之间绝缘，在工作电极的图案上形成普鲁士蓝薄膜，工作电极的图案及其上形成的普鲁士蓝薄膜构成工作电极，对电极的图案作为对电极；在工作电极上形成固定了葡萄糖氧化酶的壳聚糖膜；绝缘支持层、粘结层、对电极、工作电极和固定了葡萄糖氧化酶的壳聚糖膜构成多层结构；多层结构从转印层上剥离，转印到柔性薄膜基底上；对电极和工作电极分别通过导线连接至电化学工作站或者测量电路；固定了葡萄糖氧化酶的壳聚糖膜粘贴在皮肤表面，皮肤表面的葡萄糖在葡萄糖氧化酶的作用下产生过氧化氢，过氧化氢与积普鲁士蓝薄膜发生催化反应，生成水和自由电子，自由电子产生的数量与葡萄糖的浓度成正比，自由电子通过普鲁士蓝薄膜传递到电化学工作站或者测量电路形成反应电流，电化学工作站在测量模式下或者采用测量电路测量反应产生的电流，从而得到葡萄糖的浓度。
对电极和工作电极的厚度为100nm～1cm，对电极和工作电极具有可弯曲和折叠的特性。本发明的对电极和工作电极的厚度小，易于将葡萄糖测量传感器与皮肤贴合，保证了工作电极能够与皮肤表面紧密贴合。工作电极和对电极的形状为平面电极、插指电极或丝状电极。丝状电极是指工作电极和对电极分别为一根金属丝，或者表面电镀、电化学沉积、气相沉积、磁控溅射了导电物质层的有机物材料细丝。
本发明的对电极和工作电极具有可转印的特性，即能够将多层结构从基板表面上剥离下来，形成一个独立的薄膜电极，绝缘支持层能够在薄膜电极和测量电路贴合时起到绝缘的效果，防止互通干扰，同时绝缘支持层能够作为支撑层，将厚度为纳米级的导电层作为支撑成为独立的柔性薄膜，粘结层和绝缘支持层具有很强的粘附力，导电层和粘结层具有很强的粘附力，通过粘结层的作用能够将导电层和绝缘层紧密黏附在一起，降低电极的表面导电层脱落的几率。
绝缘支持层采用聚酰亚胺(Polyimide，PI)、聚对苯二甲酸乙二醇酯(Polyethylene terephthalate，PET)和聚乙烯醇(Polyvinyl Alcohol，PVA)中的一种。通过旋涂或者刮膜的方式制备，或者使用现成的薄膜绝缘材料粘贴固定在转印层的表面，进行后续粘结层和导电层的沉积。绝缘支持层的厚度≤1cm。
粘结层采用Cr或Pt，厚度≤0.5cm。通过电镀、电化学沉积、气相沉积或磁控溅射的方式得到导电层；导电层的材料为Au、Cu、Al、Ag和ITO中的一种。通过表面刻蚀的方式在导电层表面形成纳米尺度的微结构，能够提高电化学。
普鲁士蓝薄膜的制备采用将工作电极的图案连接至电化学工作站，工作电极的图案沉浸在KCl、K
3[Fe(CN)
6]、FeCl
3和HCl的混合溶液中，在工作电极的图案上进行电化学沉积，从而形成普鲁士蓝薄膜；或者将普鲁士蓝制成墨水溶液，利用打印、印刷、旋涂、滴涂将墨水滴在电极表面，待墨水干燥后也可以得到普鲁士蓝薄膜。利用短时间的恒电位沉积的方式得到纳米级的普鲁士蓝薄膜，得益于具有表面微结构的薄膜柔性的导电层，普鲁士蓝薄膜在电化学循环伏安特性检验下氧化还原电位明显，幅值较大，而且多圈扫描后扫描曲线稳定。电化学沉积后得到的普鲁士蓝薄膜在电化学工作站中进行循环伏安扫描，加热至普鲁士蓝薄膜干燥，在低电位下进行恒电位活化后，再次进行循环伏安扫描。电化学沉积后的循环伏安扫描能够使普鲁士蓝薄膜在不同的电位下发生氧化还原反应，使沉积后的普鲁士蓝薄膜变得稳定，释放内部裂纹和缺陷，加热薄膜至干燥后普鲁士蓝薄膜内部结构变的致密，去除孔隙间的水分，再次进行低电位恒电位活化后提高普鲁士蓝薄膜在低电位附近的反应活性，增强葡萄糖的体表测量效果。普鲁士蓝薄膜的厚度≤10μm。
工作电极通过各向异性导电薄膜ACF柔性导线与电化学工作站或者测量电路连接。柔性ACF导线为以聚合物为基材的导电金属颗粒构成的导线，横截面为扁平状，厚度较小，柔性好，能够通过加热加压的方式与电化学沉积了普鲁士蓝薄膜的柔性的工作电极表面连接，不会引起工作电极高度增加过多，同时柔性、低弹性模量的特性减小了柔性导线与工作电极连接处的应力集中，防止因为柔性导线或者柔性的工作电极的弯曲变形而引起电极破裂和导线脱粘。或者通过银胶粘接、焊锡焊接的方式将金属柱状导线与电化学沉积了普鲁士蓝薄膜的工作电极连接在一起，并与电化学工作站或者测量电路相连。
工作电极的表面形成固定了葡萄糖氧化酶的壳聚糖膜，固定了葡萄糖氧化酶的壳聚糖溶液中添加了丙三醇，提高壳聚糖溶液干燥后形成的壳聚糖膜的韧性，防止其发生破裂。
本发明的另一个目的在于提供一种类皮肤的超薄柔性葡萄糖测量传感器的制备方法。
本发明的类皮肤的超薄柔性葡萄糖测量传感器的制备方法，包括以下步骤：
1)提供洁净干燥的基板；
2)在基板上旋涂转印层；
3)在转印层上通过旋涂或者刮膜的方式，或者使用现成的薄膜绝缘材料粘贴固定在转印层的表面，制备绝缘支持层；
4)在绝缘支持层上溅射粘结层；
5)在粘结层上电镀、电化学沉积、气相沉积或磁控溅射的方式制备导电层；
6)表面刻蚀导电层至绝缘支持层的上表面，在导电层形成对电极的图案和工作电极的图案，对电极的图案和工作电极的图案之间绝缘；
7)在工作电极的图案上形成普鲁士蓝薄膜，工作电极的图案及其上形成的普鲁士蓝薄膜构成工作电极，对电极的图案作为对电极；
8)在工作电极上滴加固定了葡萄糖氧化酶的壳聚糖溶液，溶液蒸干后形成固定了葡萄糖氧化酶的壳聚糖膜；
9)绝缘支持层、粘结层、对电极、工作电极和固定了葡萄糖氧化酶的壳聚糖膜构成多层结构，将多层结构从转印层上剥离，转印到柔性薄膜基底上；
10)对电极和工作电极分别通过导线连接至电化学工作站或者测量电路；
11)固定了葡萄糖氧化酶的壳聚糖膜粘贴在皮肤表面，皮肤表面的葡萄糖在葡萄糖氧化酶的作用下产生过氧化氢，过氧化氢与积普鲁士蓝薄膜发生催化反应，生成水和自由电子，自由电子产生的数量与葡萄糖的浓度成正比，自由电子通过普鲁士蓝薄膜传递到电化学工作站或者采用测量电路形成反应电流，电化学工作站在测量模式下或者采用测量电路测量反应产生的电流，从而得到葡萄糖的浓度。
其中，在步骤1)中，采用清洗剂清洗基板，并在加热板上加热烘干，得到基板。
在步骤6)中，表面刻蚀导电层形成对电极和工作电极的图案，具体包括以下步骤：
a)在导电层上旋涂光刻胶；
b)采用掩膜在光刻机下对光刻胶进行曝光；
c)在显影液中显影；
d)在刻蚀液中刻蚀导电层，从而形成对电极的图案和工作电极的图案。
在步骤7)中，在工作电极的图案上形成普鲁士蓝薄膜，采用电化学沉积的方式；或者采用将普鲁士蓝制成墨水溶液，采用打印、印刷、旋涂或滴涂将墨水滴在电极表面，待墨水干燥后得到普鲁士蓝薄膜。
采用电化学沉积的方式形成普鲁士蓝薄膜，具体包括以下步骤：
a)将工作电极的图案通过导线连接至电化学工作站；
b)将工作电极的图案沉浸在电化学沉积溶液中；
c)利用恒电位沉积的方式得到纳米级的普鲁士蓝薄膜；
d)电化学沉积后得到的普鲁士蓝薄膜在电化学工作站中进行循环伏安扫描；
e)加热至普鲁士蓝薄膜干燥；
f)在低电位下进行恒电位活化后，再次进行循环伏安扫描。在步骤8)中，固定了葡萄糖氧化酶的壳聚糖溶液的制备方法，包括以下步骤：
a)将壳聚糖粉末和醋酸溶解在去离子水中，并添加一定量的丙三醇形成壳聚糖溶液，丙三醇的体积浓度为3％～10％；
b)将葡萄糖氧化酶溶解在壳聚糖溶液中；
c)将从黑曲霉中提炼得到的葡萄糖氧化酶粉末溶解在去离子水中形成酶的水溶液；
d)按照一定的比例将壳聚糖溶液和酶的水溶液混合均匀形成固定了葡萄糖氧化酶的壳聚糖溶液，壳聚糖溶液与酶的水溶液的体积比为0.5:1～2:1。
本发明的优点：
本发明在超薄柔性的绝缘支持层和粘结层上制备纳米级的对电极和工作电极的图案，在工作电极的图案上形成普鲁士蓝薄膜，在普鲁士蓝薄膜上形成固定了葡萄糖氧化酶的壳聚糖膜，粘贴在皮肤表面，葡萄糖在葡萄糖氧化酶的作用下产生过氧化氢，过氧化氢与积普鲁士蓝薄膜发生催化反应，生成水和自由电子，测量反应电流，从而得到葡萄糖的浓度；本发明的传感器具有超薄柔性的特点，能够贴附在人体皮肤表面的任何位置，在不影响人体运动和正常生活的情况下，无创、准确测量皮肤表面存在的葡萄糖的浓度，实现对糖尿病病人血糖的无创监测。
图1为本发明的类皮肤的超薄柔性葡萄糖测量传感器的一个实施例的剖面图；
图2为本发明的类皮肤的超薄柔性葡萄糖测量传感器的对电极和工作电极的示意图。
下面结合附图，通过具体实施例，进一步阐述本发明。
如图1所示，本实施例的类皮肤的超薄柔性葡萄糖测量传感器包括：柔性薄膜基底、绝缘支持层1、粘结层2、对电极4、工作电极以及固定了葡萄糖氧化酶的壳聚糖膜6；其中，在基板上形成转印层，在转印层上形成绝缘支持层1，在绝缘支持层上形成粘结层2，在粘结层2上形成导电层；表面刻蚀导电层形成对电极的图案和工作电极的图案3，在工作电极的图案3上形成普鲁士蓝薄膜5，工作电极的图案3及其上形成的普鲁士蓝薄膜5构成工作电极，对电极图案作为对电极4；在工作电极上形成固定了葡萄糖氧化酶的壳聚糖膜5；绝缘支 持层、粘结层、对电极、工作电极和固定了葡萄糖氧化酶的壳聚糖膜构成多层结构；多层结构从转印层上剥离，转印到柔性薄膜基底上。
如图2所示，对电极和工作电极具有多种形状，矩形、叉指形以及丝状。
在本实施例中，基板为硅片，转印层为聚甲基丙烯酸甲酯PMMA，绝缘支持层为PI，粘结层为Pt，导电层为金。
本实施例的类皮肤的超薄柔性葡萄糖测量传感器的制备方法，包括以下步骤：
1)采用丙酮、异丙醇和去离子水清洗硅片，在加热板上加热烘干，作为基板；
2)在硅片上旋涂PMMA形成转印层；
3)在转印层上通过旋涂PI形成绝缘支持层，固化；
4)在绝缘支持层上溅射铬形成粘结层；
5)在粘结层溅射金形成导电层；
6)表面刻蚀导电层形成对电极和工作电极的图案：
a)在导电层上旋涂光刻胶；
b)使用掩膜在光刻机下对光刻胶进行曝光；
c)在显影液中显影；
d)在刻蚀液中刻蚀导电层，从而形成对电极和工作电极的图案；
7)在工作电极的图案上形成普鲁士蓝薄膜，工作电极的图案及其上形成的普鲁士蓝薄膜构成工作电极，对电极图案作为对电极：
a)将工作电极的图案通过导线连接至电化学工作站；
b)将工作电极的图案沉浸在KCl、K
3[Fe(CN)
6]、FeCl
3和HCl的混合溶液中；
c)利用恒电位沉积的方式得到纳米级的普鲁士蓝薄膜；
d)电化学沉积后得到的普鲁士蓝薄膜在电化学工作站中进行循环伏安扫描；
e)加热至普鲁士蓝薄膜干燥；
f)在低电位下进行恒电位活化后，再次进行循环伏安扫描；
8)在工作电极上滴加固定了葡萄糖氧化酶的壳聚糖溶液，溶液蒸干后形成固定了葡萄糖氧化酶的壳聚糖膜：
a)将壳聚糖粉末和醋酸溶解在去离子水中，并添加体积浓度为8％的丙三醇形成壳聚糖溶液；
b)将葡萄糖氧化酶溶解在壳聚糖溶液中；
c)将从黑曲霉中提炼得到的葡萄糖氧化酶粉末溶解在去离子水中形成酶的水溶液；
d)按照体积比1:1将壳聚糖溶液和酶的水溶液混合均匀形成固定了葡萄糖氧化酶的 壳聚糖溶液；
9)绝缘支持层、粘结层、对电极、工作电极和固定了葡萄糖氧化酶的壳聚糖膜构成多层结构，将多层结构从转印层上剥离，转印到柔性薄膜基底上；
10)对电极和工作电极分别通过导线连接至电化学工作站或者测量电路。
最后需要注意的是，公布实施例的目的在于帮助进一步理解本发明，但是本领域的技术人员可以理解：在不脱离本发明及所附的权利要求的精神和范围内，各种替换和修改都是可能的。因此，本发明不应局限于实施例所公开的内容，本发明要求保护的范围以权利要求书界定的范围为准。
Claims (10)
- 一种类皮肤的超薄柔性葡萄糖测量传感器，其特征在于，所述葡萄糖测量传感器包括：柔性薄膜基底、绝缘支持层、粘结层、对电极、工作电极和固定了葡萄糖氧化酶的壳聚糖膜；其中，在基板上形成转印层，在转印层上形成绝缘支持层，在绝缘支持层上形成粘结层，在粘结层上形成导电层；表面刻蚀导电层至绝缘支持层的上表面，在导电层形成对电极的图案和工作电极的图案，对电极的图案和工作电极的图案之间绝缘，在工作电极的图案上形成普鲁士蓝薄膜，工作电极的图案及其上形成的普鲁士蓝薄膜构成工作电极，对电极的图案作为对电极；在工作电极上形成固定了葡萄糖氧化酶的壳聚糖膜；绝缘支持层、粘结层、对电极、工作电极和固定了葡萄糖氧化酶的壳聚糖膜构成多层结构；多层结构从转印层上剥离，转印到柔性薄膜基底上；对电极和工作电极分别通过导线连接至电化学工作站或者测量电路；固定了葡萄糖氧化酶的壳聚糖膜粘贴在皮肤表面，皮肤表面的葡萄糖在葡萄糖氧化酶的作用下产生过氧化氢，过氧化氢与积普鲁士蓝薄膜发生催化反应，生成水和自由电子，自由电子产生的数量与葡萄糖的浓度成正比，自由电子通过普鲁士蓝薄膜传递到电化学工作站或者测量电路形成反应电流，电化学工作站在测量模式下或者采用测量电路测量反应产生的电流，从而得到葡萄糖的浓度。
- 如权利要求1所述的葡萄糖测量传感器，其特征在于，所述对电极和工作电极的厚度为100nm～1cm；工作电极和对电极的形状为平面电极、插指电极或丝状电极。
- 如权利要求1所述的葡萄糖测量传感器，其特征在于，所述绝缘支持层采用聚酰亚胺、聚对苯二甲酸乙二醇酯和聚乙烯醇中的一种；所述粘结层采用Cr或Pt。
- 如权利要求1所述的葡萄糖测量传感器，其特征在于，所述工作电极通过各向异性导电薄膜ACF柔性导线与电化学工作站或者测量电路连接。
- 一种类皮肤的超薄柔性葡萄糖测量传感器的制备方法，其特征在于，所述制备方法包括以下步骤：1)提供洁净干燥的基板；2)在基板上旋涂转印层；3)在转印层上通过旋涂或者刮膜的方式，或者使用现成的薄膜绝缘材料粘贴固定在转印层的表面，制备绝缘支持层；4)在绝缘支持层上溅射粘结层；5)在粘结层上电镀、电化学沉积、气相沉积或磁控溅射的方式制备导电层；6)表面刻蚀导电层至绝缘支持层的上表面，在导电层形成对电极的图案和工作电极的图 案，对电极的图案和工作电极的图案之间绝缘；7)在工作电极的图案上形成普鲁士蓝薄膜，工作电极的图案及其上形成的普鲁士蓝薄膜构成工作电极，对电极的图案作为对电极；8)在工作电极上滴加固定了葡萄糖氧化酶的壳聚糖溶液，溶液蒸干后形成固定了葡萄糖氧化酶的壳聚糖膜；9)绝缘支持层、粘结层、对电极、工作电极和固定了葡萄糖氧化酶的壳聚糖膜构成多层结构，将多层结构从转印层上剥离，转印到柔性薄膜基底上；10)对电极和工作电极分别通过导线连接至电化学工作站或者测量电路；11)固定了葡萄糖氧化酶的壳聚糖膜粘贴在皮肤表面，皮肤表面的葡萄糖在葡萄糖氧化酶的作用下产生过氧化氢，过氧化氢与积普鲁士蓝薄膜发生催化反应，生成水和自由电子，自由电子产生的数量与葡萄糖的浓度成正比，自由电子通过普鲁士蓝薄膜传递到电化学工作站或者采用测量电路形成反应电流，电化学工作站在测量模式下或者采用测量电路测量反应产生的电流，从而得到葡萄糖的浓度。
- 如权利要求5所述的制备方法，其特征在于，在步骤6)中，表面刻蚀导电层形成对电极和工作电极的图案，具体包括以下步骤：a)在导电层上旋涂光刻胶；b)使用掩膜在光刻机下对光刻胶进行曝光；c)在显影液中显影；d)在刻蚀液中刻蚀导电层，从而形成对电极的图案和工作电极的图案。
- 如权利要求5所述的制备方法，其特征在于，在步骤7)中，采用电化学沉积的方式，在工作电极的图案上形成普鲁士蓝薄膜；或者采用将普鲁士蓝制成墨水溶液，利用打印、印刷、旋涂、滴涂将墨水滴在电极表面，待墨水干燥后得到普鲁士蓝薄膜。
- 如权利要求7所述的制备方法，其特征在于，采用电化学沉积的方式形成普鲁士蓝薄膜，具体包括以下步骤：a)将工作电极的图案通过导线连接至电化学工作站；b)将工作电极的图案沉浸在电化学沉积溶液中；c)利用恒电位沉积的方式得到纳米级的普鲁士蓝薄膜；d)电化学沉积后得到的普鲁士蓝薄膜在电化学工作站中进行循环伏安扫描；e)加热至普鲁士蓝薄膜干燥；f)在低电位下进行恒电位活化后，再次进行循环伏安扫描。
- 如权利要求5所述的制备方法，其特征在于，在步骤8)中，固定了葡萄糖氧化酶的壳聚 糖溶液的制备方法，包括以下步骤：a)将壳聚糖粉末和醋酸溶解在去离子水中，并添加丙三醇形成壳聚糖溶液；b)将葡萄糖氧化酶溶解在壳聚糖溶液中；c)将从黑曲霉中提炼得到的葡萄糖氧化酶粉末溶解在去离子水中形成酶的水溶液；d)将壳聚糖溶液和酶的水溶液混合均匀形成固定了葡萄糖氧化酶的壳聚糖溶液。
- 如权利要求9所述的制备方法，其特征在于，丙三醇的体积浓度为3％～10％；壳聚糖溶液与酶的水溶液的体积比为0.5:1～2:1。
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