CN114557694B

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Info

Publication number: CN114557694B
Application number: CN202210455230.1A
Authority: CN
Inventors: 刘仁材; 陈靖容; 周玉龙
Original assignee: Beijing Weiqiao Guoke New Energy Technology Research Institute Co ltd; University of Chinese Academy of Sciences
Current assignee: Beijing Weiqiao Guoke New Energy Technology Research Institute Co ltd; University of Chinese Academy of Sciences
Priority date: 2022-04-28
Filing date: 2022-04-28
Publication date: 2022-09-23
Anticipated expiration: 2042-04-28
Also published as: CN114557694A

Abstract

Translated fromChinese

本发明属于医学诊断仪器技术领域，具体涉及一种无创皮下组织液提取‑检测装置和提取‑检测方法，提取‑检测装置包括：可粘附衬底、第一电极组件和第二电极组件，第一电极组件包括提取/检测电极层，提取/检测电极层包括双电极；所述第二电极组件包括提取电极正极，用于与所述双电极中的一个电极配合，以通过反向离子电渗技术经皮提取皮下组织液；所述提取电极正极包覆所述提取/检测电极层，且提取电极正极沿提取/检测电极层被包覆的边缘延伸设置。本发明的提取‑检测装置能够提供更均匀电场的电极系统，能在低至0.1mA的工作电流下提取检测量的组织液样品，降低皮肤刺激和损伤等不适感；电极结构紧凑，测量准确度高。

The invention belongs to the technical field of medical diagnostic instruments, and in particular relates to a non-invasive subcutaneous tissue fluid extraction-detection device and extraction-detection method. The extraction-detection device comprises: an adhesive substrate, a first electrode assembly and a second electrode assembly, a first The electrode assembly includes an extraction/detection electrode layer, and the extraction/detection electrode layer includes double electrodes; the second electrode assembly includes an extraction electrode positive electrode for cooperating with one electrode of the double electrodes to pass reverse iontophoresis technology The subcutaneous tissue fluid is extracted percutaneously; the extraction electrode positive electrode covers the extraction/detection electrode layer, and the extraction electrode positive electrode extends along the coated edge of the extraction/detection electrode layer. The extraction-detection device of the present invention can provide an electrode system with a more uniform electric field, can extract a detected amount of tissue fluid samples at a working current as low as 0.1 mA, and reduce discomfort such as skin irritation and damage; the electrode structure is compact and the measurement accuracy is high .

Description

Translated fromChinese

一种无创皮下组织液提取-检测装置和提取-检测方法A non-invasive subcutaneous tissue fluid extraction-detection device and extraction-detection method

技术领域technical field

本发明属于医学诊断仪器技术领域，具体涉及一种无创皮下组织液提取-检测装置和提取-检测方法。The invention belongs to the technical field of medical diagnostic instruments, in particular to a non-invasive subcutaneous tissue fluid extraction-detection device and extraction-detection method.

背景技术Background technique

当今，组织液的提取-检测，仍广泛选用有创的检测仪，但因有创伤与疼痛感，所以病人仍尽可能逃避这类有创检测。因而，微创及无创测试仪就变成患者的盼望。Today, the extraction and detection of interstitial fluid still widely use invasive detectors, but due to trauma and pain, patients still avoid such invasive detection as much as possible. Therefore, minimally invasive and non-invasive testers have become the hope of patients.

无创组织液提取-检测，顾名思义就是指在不对人体皮肤组织造成损伤的情况下对皮下组织液进行提取和检测。现有的研究无创组织液检测的方法很多，可以大体分为光学法和电化学法两大类。其中光学法主要有近红外光谱法、偏振光旋光法、拉曼光谱法、荧光法、光学相干层析成像法等。电化学方法主要是利用人体其他体液与待测物值呈现的相干关系，例如，测量血糖值，可以测量唾液、泪液、汗液、ISF等体液中的葡萄糖含量，在经过与标准血糖值进行校准后建立数据模型，进而得出血糖值。Non-invasive tissue fluid extraction-detection, as the name suggests, refers to the extraction and detection of subcutaneous tissue fluid without causing damage to human skin tissue. There are many existing methods for non-invasive tissue fluid detection, which can be roughly divided into two categories: optical methods and electrochemical methods. The optical methods mainly include near-infrared spectroscopy, polarized light rotation, Raman spectroscopy, fluorescence, optical coherence tomography and so on. Electrochemical methods mainly use the coherent relationship between other body fluids in the human body and the value of the object to be measured. For example, to measure the blood sugar value, the glucose content in saliva, tears, sweat, ISF and other body fluids can be measured. After calibration with the standard blood sugar value A data model is established to obtain the blood glucose value.

本发明的发明人早期专利CN105954331B公开了一种用于生化分析的纸基电极检测平台及其制备方法，所述用于生化分析的纸基电极检测平台，以可降解纸材为基底材料，基底材料上印制碳电极，在碳电极表面固定电子传递介质和识别分子层，得到完全可降解的全新纸基电极检测平台。所制备的可降解的纸基电极检测平台通过电化学测试表明与其塑料基材电极具有同样良好的电化学性能。但如何基于该检测平台构建无创的提取装置与方法仍需要进一步研究。The inventor's early patent CN105954331B discloses a paper-based electrode detection platform for biochemical analysis and a preparation method thereof. The paper-based electrode detection platform for biochemical analysis uses degradable paper as the base material, and the base A carbon electrode is printed on the material, and an electron transfer medium and a recognition molecule layer are fixed on the surface of the carbon electrode, and a completely degradable new paper-based electrode detection platform is obtained. The prepared degradable paper-based electrode detection platform has the same good electrochemical performance as its plastic substrate electrode through electrochemical tests. However, how to construct a non-invasive extraction device and method based on the detection platform still needs further research.

同时，反离子渗透过程中，由于人体皮肤中取样组织间质液(ISF)待测物提取率一般与电流强度存在相关性，而ISF待测物提取率的提高可以有效地改善检测的准确性。目前ISF提取电流一般在0.3-0.5mA，才能实现准确检测；在该电流下进行长时间的提取会造成皮肤的刺激和损伤。At the same time, in the process of reverse ion osmosis, since the extraction rate of the analyte in the interstitial fluid (ISF) sampled from human skin is generally correlated with the current intensity, the improvement of the extraction rate of the ISF analyte can effectively improve the detection accuracy. . At present, the ISF extraction current is generally 0.3-0.5mA to achieve accurate detection; long-term extraction under this current will cause skin irritation and damage.

CN110455887B提供了一种检测微传感器，包括：至少一个检测单元及NFC模块；检测单元包括抽取电极、微流道和三电极阵列；抽取电极将含有待检测物质的汗液通过微流道传输至三电极阵列进行检测，得到待检测物质对应的响应电流；NFC模块用于将响应电流转化为调制信号。基于该检测微传感器，可无创检测血液中葡萄糖、乳酸、尿酸等生理参数的浓度。该检测微传感器需要两个检测电极与多个三电极配合使用，结构复杂，并且由于提取与检测位置相差较大，需要较高的提取电流。因此，如何构造更有效的进行ISF提取与检测，降低检测极限，避免皮肤损伤成为了目前探索的重点。CN110455887B provides a detection microsensor, comprising: at least one detection unit and an NFC module; the detection unit includes an extraction electrode, a microfluidic channel and a three-electrode array; the extraction electrode transmits sweat containing a substance to be detected to the three-electrode through the microfluidic channel The array performs detection to obtain the response current corresponding to the substance to be detected; the NFC module is used to convert the response current into a modulation signal. Based on the detection microsensor, the concentration of physiological parameters such as glucose, lactic acid, and uric acid in blood can be non-invasively detected. The detection micro-sensor requires two detection electrodes to be used in conjunction with a plurality of three electrodes, the structure is complex, and a higher extraction current is required due to the large difference between extraction and detection positions. Therefore, how to construct more effective ISF extraction and detection, reduce the detection limit, and avoid skin damage has become the focus of current exploration.

发明内容SUMMARY OF THE INVENTION

本发明的目的是为了克服现有组织液检测技术存在的皮肤刺激和损伤且采血疼痛、易感染的缺陷，提供一种无创皮下组织液提取-检测装置和提取-检测方法，该提取-检测装置的电极系统能够提供更均匀电场，能在低至0.1mA的工作电流下提取足够检测量的组织液样品，大大降低皮肤刺激和损伤等不适感，解决了采血疼痛、易感染、凝血障碍的问题；且，提供更简化的电极系统的同时获得高准确度的测量结果。The purpose of the present invention is to overcome the defects of skin irritation and damage, pain in blood collection, and susceptibility to infection in the existing interstitial fluid detection technology, and to provide a non-invasive subcutaneous tissue fluid extraction-detection device and extraction-detection method. The electrode of the extraction-detection device The system can provide a more uniform electric field, and can extract a sufficient amount of tissue fluid samples at a working current as low as 0.1mA, which greatly reduces discomfort such as skin irritation and damage, and solves the problems of blood collection pain, susceptibility to infection, and coagulation disorders; and, Provides a more simplified electrode system while obtaining highly accurate measurement results.

为了实现上述目的，第一方面，本发明提供了一种无创皮下组织液提取-检测装置，包括：In order to achieve the above object, in the first aspect, the present invention provides a non-invasive subcutaneous tissue fluid extraction-detection device, comprising:

可粘附衬底；Adhesive substrate;

第一电极组件，其设置在所述可粘附衬底上，其包括提取/检测电极层，所述提取/检测电极层包括双电极，用于通过电化学法检测被提取出来的皮下组织液中待测物的含量；The first electrode assembly, which is arranged on the adhesive substrate, includes an extraction/detection electrode layer, and the extraction/detection electrode layer includes a double electrode for detecting the extracted subcutaneous tissue fluid by an electrochemical method The content of the analyte;

第二电极组件，其设置在所述可粘附衬底上，其包括提取电极正极，用于与所述双电极中的一个电极配合，以通过反向离子电渗技术经皮提取皮下组织液；且所述提取电极正极包覆所述提取/检测电极层，且所述提取电极正极沿所述提取/检测电极层被包覆的边缘延伸设置。a second electrode assembly, disposed on the adherable substrate, comprising an extraction electrode positive electrode for cooperating with one electrode of the dual electrodes to percutaneously extract subcutaneous tissue fluid by reverse iontophoresis; And the extraction electrode positive electrode covers the extraction/detection electrode layer, and the extraction electrode positive electrode extends along the covered edge of the extraction/detection electrode layer.

在一些优选实施方式中，所述提取电极正极呈矩形或弧形，以进行所述包覆。In some preferred embodiments, the positive electrode of the extraction electrode is rectangular or arc-shaped for the coating.

在一些优选实施方式中，所述提取电极正极呈“匚”形。In some preferred embodiments, the positive electrode of the extraction electrode is in the shape of a "crown".

在一些优选实施方式中，所述提取电极正极与所述提取/检测电极层之间的最短距离在2-3mm。In some preferred embodiments, the shortest distance between the positive electrode of the extraction electrode and the extraction/detection electrode layer is 2-3 mm.

在一些优选实施方式中，在贴附侧所在平面上，所述提取电极正极的面积在0.5-10 cm²，优选在0.5-4 cm²，更优选在1-2 cm²。In some preferred embodiments, on the plane of the attached side, the positive electrode of the extraction electrode has an area of 0.5-10 cm² , preferably 0.5-4 cm² , more preferably 1-2 cm² .

在一些优选实施方式中，所述提取/检测电极层的面积为0.5-5 cm²，优选在0.5-2cm²，更优选在0.5-1 cm²。In some preferred embodiments, the extraction/detection electrode layer has an area of 0.5-5 cm² , preferably 0.5-2 cm² , more preferably 0.5-1 cm² .

在一些优选实施方式中，所述提取/检测电极层整体为矩形或弧形。In some preferred embodiments, the extraction/detection electrode layer is rectangular or arc-shaped as a whole.

在一些优选实施方式中，所述提取/检测电极层中的电极为玻碳电极或碳电极。In some preferred embodiments, the electrodes in the extraction/detection electrode layer are glassy carbon electrodes or carbon electrodes.

在一些优选实施方式中，所述双电极呈山脊形、蛇形、同心圆形或梳状叉指排布。In some preferred embodiments, the dual electrodes are arranged in a ridge-shaped, serpentine-shaped, concentric circular or comb-shaped interdigitated arrangement.

在一些优选实施方式中，所述双电极呈梳状叉指排布。In some preferred embodiments, the dual electrodes are arranged in a comb-like interdigital arrangement.

在一些优选实施方式中，所述双电极的梳状叉指部位所在平面满足：面积为40-60mm²。In some preferred embodiments, the plane where the comb-shaped interdigital parts of the double electrodes are located satisfies: the area is 40-60 mm² .

在一些优选实施方式中，所述双电极的梳状叉指部位所在平面满足：长为9-12mm，宽为3-6mm，叉指之间的间隔为0.1-0.5mm。In some preferred embodiments, the plane where the comb-shaped interdigital parts of the double electrodes are located satisfies: the length is 9-12 mm, the width is 3-6 mm, and the interval between the interdigital fingers is 0.1-0.5 mm.

在一些优选实施方式中，所述第一电极组件还包括：In some preferred embodiments, the first electrode assembly further comprises:

基底层，其设置在所述可粘附衬底上，且位于所述提取/检测电极层下方；a base layer disposed on the adherable substrate and below the extraction/detection electrode layer;

修饰涂层，其设置在所述提取/检测电极层上方且靠近皮肤，其包括电子传递介质和识别分子，所述电子传递介质和识别分子与待测物相适配。A modified coating, which is disposed above the extraction/detection electrode layer and close to the skin, includes an electron transfer medium and a recognition molecule, and the electron transfer medium and the recognition molecule are adapted to the analyte.

在一些优选实施方式中，所述提取-检测装置还包括：凝胶层，其设置在所述修饰涂层上方且靠近皮肤。In some preferred embodiments, the extraction-detection device further comprises: a gel layer disposed over the modification coating and adjacent to the skin.

第二方面，本发明还提供一种无创皮下组织液提取-检测方法，采用第一方面所述的提取-检测装置进行检测，包括以下步骤：In the second aspect, the present invention also provides a non-invasive subcutaneous tissue fluid extraction-detection method, using the extraction-detection device described in the first aspect for detection, comprising the following steps:

将所述提取-检测装置的检测区域面向受试者皮肤，通过可粘附衬底将所述第一电极组件和第二电极组件贴附于受试者待测皮肤区域；The detection area of the extraction-detection device faces the subject's skin, and the first electrode assembly and the second electrode assembly are attached to the subject's skin area to be measured through an adhesive substrate;

将双电极中的一个电极作为负极，与提取电极正极组合，进行反离子电渗提取，使得皮下组织液中待测物提取到皮肤表面并富集在所述提取/检测电极层区域；One of the double electrodes is used as a negative electrode, combined with the positive electrode of the extraction electrode, and reverse iontophoresis extraction is performed, so that the substance to be tested in the subcutaneous tissue fluid is extracted to the skin surface and enriched in the region of the extraction/detection electrode layer;

在所述电渗提取完成后，以双电极中的一个电极作为工作电极，另一个电极作为对电极，对所述电渗提取得到的提取液进行电化学检测。After the electroosmotic extraction is completed, one electrode of the double electrodes is used as a working electrode, and the other electrode is used as a counter electrode, and the extraction solution obtained by the electroosmotic extraction is electrochemically detected.

本发明的发明人研究发现，反离子电渗透有两种机制：一是主动迁移，带电离子与外加电场的直接相互作用，经皮肤附属物通路直接导出到皮肤表面的电极区域；二是被动迁移，带电离子载流子带动中性分子定向流动。钠离子是组织液中的多数载流子，这些钠离子的定性迁移产生了一种溶剂流，将中性分子如葡萄糖夹带其中，经皮肤附属物通路间接导出到皮肤表面的电极区域，因此电场分布尤为重要，尤其是如何将促渗液富集且集中于检测电极，是一重要问题。The inventors of the present invention have found that there are two mechanisms for reverse ion electroosmosis: one is active migration, the direct interaction of charged ions with an applied electric field, and is directly exported to the electrode area on the skin surface through the skin appendage pathway; the other is passive migration , charged ion carriers drive the directional flow of neutral molecules. Sodium ions are the majority carriers in interstitial fluid, and the qualitative migration of these sodium ions generates a solvent flow that entrains neutral molecules such as glucose, which is indirectly exported through the skin appendage pathway to the electrode area on the skin surface, thus the electric field distribution. It is particularly important, especially how to enrich and concentrate the permeate on the detection electrode, which is an important issue.

本发明通过上述技术方案，特别的设置包括双电极的提取/检测电极层及包覆该提取/检测电极层的提取电极正极形成原位提取与检测促渗电场，通过将促渗电场分布在提取/检测电极层上，确保促渗液（即含待测物的组织液）集中于提取/检测电极层，使得本发明具有如下优势：Through the above technical solutions, the present invention specially sets up an extraction/detection electrode layer including a double electrode and an extraction electrode positive electrode covering the extraction/detection electrode layer to form an in-situ extraction and detection permeation-promoting electric field. On the detection electrode layer, it is ensured that the permeation-promoting liquid (that is, the tissue fluid containing the test substance) is concentrated on the extraction/detection electrode layer, so that the present invention has the following advantages:

（1）本发明设置的上述包覆结构，能够使得提取与检测可以在同一位置实施，且提取功能与电化学检测功能互不干扰，实现了极低电流(低至0.1mA)条件下的高效促渗，大大降低皮肤刺激和损伤等不适感。同时，由于促渗液富集在提取/检测电极层上，能获得高准确度的检测结果。(1) The above-mentioned coating structure provided by the present invention can enable extraction and detection to be performed at the same location, and the extraction function and the electrochemical detection function do not interfere with each other, achieving high efficiency under extremely low current (as low as 0.1 mA) conditions. Promotes penetration and greatly reduces discomfort such as skin irritation and damage. At the same time, since the permeation-promoting liquid is enriched on the extraction/detection electrode layer, high-accuracy detection results can be obtained.

（2）相对于传统检测装置（普遍采用两个电极作为提取电极，结合三电极作为检测电极），本发明结构简单，能够在省略参比电极的情况下，利用双电极即可实现待测物的高准确度检测。具体的，本发明提取时双电极中的一个作为提取电极负极，在对提取后的组织液中待测物含量进行检测的过程中，以人体作为等势电位，该电位基本不发生变化，所以在检测的整个过程中对电极的电位不漂移，故可以省略参比电极，采用双电极测量复杂的结果以及能进行定量的分析电化学反应，获得高准确度的测量结果。(2) Compared with the traditional detection device (two electrodes are generally used as extraction electrodes, combined with three electrodes as detection electrodes), the present invention has a simple structure, and can realize the object to be tested by using two electrodes without omitting the reference electrode. high-accuracy detection. Specifically, during extraction in the present invention, one of the double electrodes is used as the negative electrode of the extraction electrode. In the process of detecting the content of the analyte in the extracted tissue fluid, the human body is used as the equipotential potential, and the potential basically does not change. During the whole detection process, the potential of the counter electrode does not drift, so the reference electrode can be omitted, and the double electrode is used to measure complex results and quantitatively analyze the electrochemical reaction to obtain high-accuracy measurement results.

（3）使用范围广，可用于组织液中人体无创生化指标(可以是血糖，钠、氨或其他金属离子，乳酸，皮酯醇等)的实时检测，解决了采血疼痛、易感染等缺陷；适用于健康人体及患者的自我、实时、原位检测，具有无创无痛、安全便携、准确稳定、价格低廉等优势。(3) It has a wide range of applications and can be used for real-time detection of non-invasive biochemical indicators of the human body (can be blood sugar, sodium, ammonia or other metal ions, lactic acid, cortisol, etc.) It has the advantages of non-invasive and painless, safe and portable, accurate and stable, and low price for self, real-time, in-situ detection of healthy human body and patients.

附图说明Description of drawings

为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。In order to illustrate the technical solutions of the embodiments of the present invention more clearly, the following briefly introduces the accompanying drawings used in the embodiments. It should be understood that the following drawings only show some embodiments of the present invention, and therefore do not It should be regarded as a limitation of the scope, and for those of ordinary skill in the art, other related drawings can also be obtained according to these drawings without any creative effort.

图1是本发明无创皮下组织液提取-检测装置的一种实施方式的结构示意图。FIG. 1 is a schematic structural diagram of an embodiment of the non-invasive subcutaneous tissue fluid extraction-detection device of the present invention.

图2是图1贴附在皮肤上的使用状态图。Fig. 2 is a use state diagram of Fig. 1 attached to the skin.

图3是图1中提取电极正极和双电极配合的一种实施方式的结构示意图。FIG. 3 is a schematic structural diagram of an embodiment of the combination of the positive electrode of the extraction electrode and the double electrode in FIG. 1 .

图4是图3的结构的电场分布仿真图。FIG. 4 is an electric field distribution simulation diagram of the structure of FIG. 3 .

图5是双电极呈山脊形排布的结构示意图。FIG. 5 is a schematic diagram of the structure of double electrodes arranged in a ridge shape.

图6是双电极呈蛇形排布的结构示意图。FIG. 6 is a schematic view of the structure of double electrodes arranged in a serpentine shape.

图7是双电极呈同心圆形排布的结构示意图。FIG. 7 is a schematic view of the structure of double electrodes arranged in a concentric circle.

图8是图3的结构中梳状叉指部分的尺寸示意图；其中A是指梳状叉指部分。FIG. 8 is a schematic view of the size of the interdigitated portion of the comb in the structure of FIG. 3 ; wherein A refers to the interdigitated portion of the comb.

图9是本发明提取-检测装置对不同浓度NaCl溶液测试开路电位响应曲线图。FIG. 9 is a graph showing the open-circuit potential response curve of the extraction-detection device of the present invention to different concentrations of NaCl solutions.

附图标记说明Description of reference numerals

101-提取电极正极导线，102-提取电极正极，103-可粘附衬底，104-提取/检测电极层，105-夹持固定部，106-第一电极导线，107-第二电极导线，108-修饰涂层，109-双电极，200-皮肤。101-Extraction electrode positive lead, 102-Extraction electrode positive lead, 103-Adhesive substrate, 104-Extraction/detection electrode layer, 105-Clamping and fixing part, 106-First electrode lead, 107-Second electrode lead, 108 - Modified coating, 109 - Dual electrode, 200 - Skin.

具体实施方式Detailed ways

在本文中所披露的范围的端点和任何值都不限于该精确的范围或值，这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说，各个范围的端点值之间、各个范围的端点值和单独的点值之间，以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围，这些数值范围应被视为在本文中具体公开。The endpoints of ranges and any values disclosed herein are not limited to the precise ranges or values, which are to be understood to encompass values proximate to those ranges or values. For ranges of values, the endpoints of each range, the endpoints of each range and the individual point values, and the individual point values can be combined with each other to yield one or more new ranges of values that Ranges should be considered as specifically disclosed herein.

第一方面，本发明提供了一种无创皮下组织液提取-检测装置，如图1所示，包括：可粘附衬底103、第一电极组件和第二电极组件，第一电极组件和第二电极组件分别设置在所述可粘附衬底上。In a first aspect, the present invention provides a non-invasive subcutaneous tissue fluid extraction-detection device, as shown in FIG. 1 , comprising: anadhesive substrate 103, a first electrode assembly and a second electrode assembly, the first electrode assembly and the second electrode assembly Electrode assemblies are respectively disposed on the adhereable substrates.

其中，所述第一电极组件包括提取/检测电极层104，所述提取/检测电极层104包括双电极109，用于通过电化学法检测被提取出来的皮下组织液中待测物的含量。The first electrode assembly includes an extraction/detection electrode layer 104, and the extraction/detection electrode layer 104 includes adouble electrode 109 for electrochemically detecting the content of the analyte in the extracted subcutaneous tissue fluid.

本发明所述提取/检测电极层104是指既可以作为提取用电极层，又可以作为检测电极层。The extraction/detection electrode layer 104 in the present invention refers to both an extraction electrode layer and a detection electrode layer.

其中，所述第二电极组件包括提取电极正极102，用于与所述双电极109中的一个电极配合，以通过反向离子电渗技术经皮提取皮下组织液；且所述提取电极正极102包覆所述提取/检测电极层104，且所述提取电极正极102沿所述提取/检测电极层104被包覆的边缘延伸设置。Wherein, the second electrode assembly includes an extraction electrodepositive electrode 102, which is used to cooperate with one electrode in thedual electrodes 109 to percutaneously extract subcutaneous tissue fluid by reverse iontophoresis technology; and the extraction electrodepositive electrode 102 contains The extraction/detection electrode layer 104 is covered, and the extraction electrodepositive electrode 102 extends along the covered edge of the extraction/detection electrode layer 104 .

应当理解的是，“所述提取/检测电极层104包括双电极109”是指，提取/检测电极层104至少包括两个电极（也即双电极109），还可以包括两个以上电极。It should be understood that "the extraction/detection electrode layer 104 includesdouble electrodes 109" means that the extraction/detection electrode layer 104 includes at least two electrodes (ie, double electrodes 109), and may also include more than two electrodes.

本发明的上述提取-检测装置，能够提供更均匀电场，能在低至0.1mA的工作电流下提取足够检测量的组织液样品，可以在仅有双电极109的情况下即可实现待测物的高准确度电化学检测。The above-mentioned extraction-detection device of the present invention can provide a more uniform electric field, can extract a sufficient detection amount of tissue fluid samples at a working current as low as 0.1 mA, and can realize the detection of the object to be tested with only thedouble electrodes 109. High-accuracy electrochemical detection.

“所述提取电极正极102包覆所述提取/检测电极层104”是指，提取电极正极102可以包覆整个提取/检测电极层104，也可以包覆部分提取/检测电极层104。"The extraction electrodepositive electrode 102 covers the extraction/detection electrode layer 104" means that the extraction electrodepositive electrode 102 may cover the entire extraction/detection electrode layer 104, or may cover part of the extraction/detection electrode layer 104.

“所述提取电极正极102沿所述提取/检测电极层104被包覆的边缘延伸设置”是指，在沿提取/检测电极层104被包覆的边缘方向上，提取电极正极102的包覆部分是连续的、不间断的，如图1所示的“匚”型结构。"The extraction electrodepositive electrode 102 is extended along the coated edge of the extraction/detection electrode layer 104" refers to the coating of the extraction electrodepositive electrode 102 along the coated edge direction of the extraction/detection electrode layer 104. Parts are continuous and uninterrupted, as shown in Fig.

应当理解的是，所述提取-检测装置使用时，所述第一电极组件和第二电极组件均贴附于人体体表待测皮肤200，如图2所示，并通过可粘附衬底103固定。It should be understood that, when the extraction-detection device is in use, the first electrode assembly and the second electrode assembly are both attached to the skin to be tested 200 on the surface of the human body, as shown in FIG. 103 fixed.

本发明所述可粘附衬底103可以是柔性高分子胶带，例如PET或者其他塑料、树脂材料，只要能将第一电极组件和第二电极组件固定贴附在皮肤200表面即可，例如胳膊、手背等裸露的待测表皮处。Theadhesive substrate 103 of the present invention can be a flexible polymer tape, such as PET or other plastics, resin materials, as long as the first electrode assembly and the second electrode assembly can be fixedly attached to the surface of theskin 200, such as an arm , the back of the hand and other exposed epidermis to be tested.

本发明中，所述提取电极正极102可以使用柔性贴片电极。In the present invention, thepositive electrode 102 of the extraction electrode may use a flexible patch electrode.

在一些优选实施方式中，所述提取电极正极102呈矩形或弧形，以进行所述包覆。所述提取电极正极102可以由一个矩形或弧形结构组成，也可以由多个矩形或弧形结构呈矩阵的方式排布而成，或是其他延伸形式。所述矩形包括正方形、长方形、“匚”型或一边具有缺口的长方形、正方形；所述弧形包括封边或不封边的圆形、封边或不封边的椭圆形结构。In some preferred embodiments, the extraction electrodepositive electrode 102 is rectangular or arc-shaped for the coating. The extraction electrodepositive electrode 102 may be composed of a rectangular or arc-shaped structure, or may be composed of a plurality of rectangular or arc-shaped structures arranged in a matrix, or other extended forms. The rectangle includes a square, a rectangle, a "scratch" type or a rectangle with a notch on one side, a square; the arc includes a circle with or without an edge, and an ellipse with a sealed or unsealed edge.

在一些具体实施方式中，所述提取电极正极102以“匚”形外包（如图1所示）的方式将提取/检测电极层104包覆。In some specific embodiments, the extraction electrodepositive electrode 102 wraps the extraction/detection electrode layer 104 in a "trap"-shaped outer covering (as shown in FIG. 1 ).

本发明中，所述提取电极正极102和提取/检测电极层104之间的包覆区域的尺寸，可以根据检测效果（如检测准确度，工作电流或电压等的低成本）优化。在一些优选实施方式中，所述提取电极正极102与所述提取/检测电极层104之间的最短距离在2-3mm。该优选方案下，所述提取电极正极102与所述提取/检测电极层104的包覆结构尺寸，更利于促渗液的富集和电化学检测。In the present invention, the size of the coating area between the extraction electrodepositive electrode 102 and the extraction/detection electrode layer 104 can be optimized according to the detection effect (eg detection accuracy, low cost of operating current or voltage, etc.). In some preferred embodiments, the shortest distance between the extraction electrodepositive electrode 102 and the extraction/detection electrode layer 104 is 2-3 mm. In this preferred solution, the size of the coating structure of the extraction electrodepositive electrode 102 and the extraction/detection electrode layer 104 is more conducive to the enrichment and electrochemical detection of the permeation-promoting liquid.

“所述提取电极正极102与所述提取/检测电极层104之间的最短距离”是指提取电极正极102的包覆边缘，与提取/检测电极层104被包覆边缘之间的最短距离，包括在长度方向上的最短距离、在宽度方向上的最短距离（如图3所示，长度方向和宽度方向上的距离均为2.5mm），或在弧形延伸方向上的最短距离，总之取各个方向上的最小值。"The shortest distance between the extraction electrodepositive electrode 102 and the extraction/detection electrode layer 104" refers to the shortest distance between the coated edge of the extraction electrodepositive electrode 102 and the coated edge of the extraction/detection electrode layer 104, Including the shortest distance in the length direction, the shortest distance in the width direction (as shown in Figure 3, the distance in the length direction and the width direction are both 2.5mm), or the shortest distance in the arc extension direction, whichever minimum value in all directions.

本发明中，所述提取电极正极102的面积根据受试者检测区域面积而定。在一些优选实施方式中，在贴附侧所在平面上，所述提取电极正极102的面积在0.5-10 cm²，优选在0.5-4 cm²，更优选在1-2 cm²。该优选方案下，更利于促渗液的富集和电化学检测，且能够避免皮肤损伤。In the present invention, the area of thepositive electrode 102 of the extraction electrode is determined according to the area of the detection area of the subject. In some preferred embodiments, on the plane of the attached side, the area of thepositive electrode 102 of the extraction electrode is 0.5-10 cm² , preferably 0.5-4 cm² , more preferably 1-2 cm² . Under this preferred solution, the enrichment and electrochemical detection of the permeation-promoting liquid are more favorable, and skin damage can be avoided.

所述“在贴附侧所在平面上，所述提取电极正极102的面积”是指所述提取电极正极102贴附在皮肤200的区域的表面积。The “area of thepositive electrode 102 of the extraction electrode on the plane of the attached side” refers to the surface area of the area where thepositive electrode 102 of the extraction electrode is attached to theskin 200 .

本发明所述提取/检测电极层104的面积根据受试者检测区域面积而定，且受限于提取电极正极102面积。在一些优选实施方式中，所述提取/检测电极层104的面积为0.5-5cm²，优选在0.5-2 cm²，更优选在0.5-1 cm²。该优选方案下，更利于促渗液的富集和电化学检测。The area of the extraction/detection electrode layer 104 in the present invention is determined according to the area of the detection area of the subject, and is limited by the area of thepositive electrode 102 of the extraction electrode. In some preferred embodiments, the extraction/detection electrode layer 104 has an area of 0.5-5 cm² , preferably 0.5-2 cm² , more preferably 0.5-1 cm² . Under this preferred solution, the enrichment and electrochemical detection of the permeation-promoting liquid are more favorable.

“所述提取/检测电极层104的面积”是指提取/检测电极层104的有效面积，有效面积是指提取/检测电极层104中与皮肤接触的电极面积，其在加载电流后该电极面积处会产生皮下电场。例如对于具有梳状叉指结构的提取/检测电极层104，提取/检测电极层104的有效面积是指可产生皮下电场的梳状叉指部分的面积，而非叉指部分只起到导电的作用。"The area of the extraction/detection electrode layer 104" refers to the effective area of the extraction/detection electrode layer 104, and the effective area refers to the area of the electrode in the extraction/detection electrode layer 104 in contact with the skin, which is the area of the electrode after the current is loaded A subcutaneous electric field is generated. For example, for the extraction/detection electrode layer 104 with a comb-like interdigitated structure, the effective area of the extraction/detection electrode layer 104 refers to the area of the interdigitated portion of the interdigital comb that can generate the subcutaneous electric field, while the non-interdigital portion only acts as a conductive effect.

本发明所述提取/检测电极层104的整体形貌与所述提取电极正极102相匹配，以形成所述包覆。在一些优选实施方式中，所述提取/检测电极层104整体为矩形或弧形。所述矩形例如可以为正方形或长方形。所述弧形例如可以为椭圆形、圆形或半圆形等。The overall morphology of the extraction/detection electrode layer 104 of the present invention matches the extraction electrodepositive electrode 102 to form the coating. In some preferred embodiments, the extraction/detection electrode layer 104 is rectangular or arc-shaped as a whole. The rectangle can be, for example, a square or a rectangle. The arc shape can be, for example, an ellipse, a circle or a semi-circle, or the like.

所述提取/检测电极层104中的电极材料包括但不限于碳、金属电极或高分子导电材料。在一些优选实施方式中，所述提取/检测电极层104中的电极为玻碳电极或碳电极。Electrode materials in the extraction/detection electrode layer 104 include but are not limited to carbon, metal electrodes or polymer conductive materials. In some preferred embodiments, the electrodes in the extraction/detection electrode layer 104 are glassy carbon electrodes or carbon electrodes.

本领域技术人员可以根据需求选择提取/检测电极层104的制备方法，优选所述提取/检测电极层104通过丝网印刷制备得到。应用丝网印刷技术来印制提取/检测电极层104，具有设计灵活、成本低和可批量制作的优点。Those skilled in the art can select the preparation method of the extraction/detection electrode layer 104 according to the requirements. Preferably, the extraction/detection electrode layer 104 is prepared by screen printing. Applying the screen printing technology to print the extraction/detection electrode layer 104 has the advantages of flexible design, low cost and mass production.

在一些优选实施方式中，所述双电极109呈山脊形、蛇形、同心圆形或梳状叉指排布。山脊形是指双电极109排布至少部分轮廓类似山脊，例如可以如图5所示。蛇形是指双电极109排布至少部分轮廓类似蛇形，例如可以如图6所示。同心圆形是指双电极109中的两个电极为同心圆，其中一个电极包覆另一个电极，例如可以如图7所示。梳状叉指排布是指双电极109中两个电极的含梳状结构，且梳状结构相互啮合，形成叉指形状，例如可以如图3和图8所示。In some preferred embodiments, thedouble electrodes 109 are arranged in a ridge shape, a serpentine shape, a concentric circle or a comb-like interdigital arrangement. Ridge-shaped means that thedouble electrodes 109 are arranged at least partially in outline like a ridge, for example, as shown in FIG. 5 . The serpentine shape means that thedouble electrodes 109 are arranged at least partially in a serpentine shape, for example, as shown in FIG. 6 . Concentric circles means that the two electrodes in thedouble electrode 109 are concentric circles, and one electrode covers the other electrode, for example, as shown in FIG. 7 . The comb-like interdigitated arrangement refers to a comb-like structure of two electrodes in thedouble electrode 109 , and the comb-like structures mesh with each other to form an interdigitated shape, for example, as shown in FIG. 3 and FIG. 8 .

在一些优选实施方式中，所述双电极109呈梳状叉指排布。该优选方案，采用梳状叉指结构设计，能够最大程度上保证双电极109的有效面积，使得双电极109具有足够良好的电化学性质，更利于促渗液的富集和电化学检测。In some preferred embodiments, thedouble electrodes 109 are arranged in a comb-like interdigital arrangement. This preferred solution adopts a comb-like interdigital structure design, which can ensure the effective area of thedouble electrodes 109 to the greatest extent, so that thedouble electrodes 109 have sufficiently good electrochemical properties, which is more conducive to the enrichment and electrochemical detection of the permeation-promoting liquid.

在一些优选实施方式中，所述提取电极正极102以“匚”形包覆双电极109，且所述双电极109呈梳状叉指排布。该优选方案，在进行反离子电渗时，所述提取-检测装置的电场分布仿真图如图4所示，可以看出，其能获得最佳的促渗电场并集中于双电极109，且电场更均匀，更稳定。In some preferred embodiments, thepositive electrode 102 of the extraction electrode covers thedouble electrodes 109 in a "tuck" shape, and thedouble electrodes 109 are arranged in a comb-like interdigital arrangement. In this preferred solution, when reverse iontophoresis is performed, the electric field distribution simulation diagram of the extraction-detection device is shown in FIG. The electric field is more uniform and stable.

在一些优选实施方式中，所述双电极109的梳状叉指部位所在平面满足：面积为40-60mm²。In some preferred embodiments, the plane where the interdigitated portions of the comb-shaped electrodes of thedouble electrodes 109 are located satisfies: the area is 40-60 mm² .

“所述双电极109的梳状叉指部位所在平面”是指如图8所示的A部分。"The plane where the interdigitated parts of thedouble electrodes 109 are located" refers to part A as shown in FIG. 8 .

在一些优选实施方式中，所述双电极109的梳状叉指部位所在平面满足：长为9-12mm，宽为3-6mm，叉指之间的间隔为0.1-0.5mm。In some preferred embodiments, the plane of the comb-shaped interdigital portion of thedouble electrode 109 satisfies: the length is 9-12 mm, the width is 3-6 mm, and the interval between the interdigital fingers is 0.1-0.5 mm.

“所述双电极109的梳状叉指部位所在平面的长和宽以及叉指之间的间隔”是指如图8所示的A部分的长和宽以及叉指之间的间隔，在图8的一种具体实施方式中，长为10.50mm，宽为4.8mm，叉指之间的间隔为0.3mm。"The length and width of the plane where the comb-shaped interdigitated portion of thedouble electrode 109 is located and the interval between the interdigital fingers" refers to the length and width of part A as shown in FIG. 8 and the interval between the interdigitated fingers. In a specific embodiment of 8, the length is 10.50mm, the width is 4.8mm, and the interval between the interdigital fingers is 0.3mm.

本领域技术人员可以根据第一电极组件的支撑、固定或连接等需求，以及提取、检测识别需求，在所述第一电极组件中设置相应的部件或特定层。所述检测识别需求例如，与针对皮下组织液中待测物对应的电子传递和识别分子，以进行电化学检测。Those skilled in the art can set corresponding components or specific layers in the first electrode assembly according to requirements such as support, fixation or connection of the first electrode assembly, as well as extraction, detection and identification requirements. The detection and identification requirements are, for example, electron transfer and identification molecules corresponding to the analyte in the subcutaneous tissue fluid for electrochemical detection.

在一些优选实施方式中，如图1所示，所述第一电极组件还包括：In some preferred embodiments, as shown in FIG. 1 , the first electrode assembly further includes:

基底层，其设置在所述可粘附衬底103上，且位于所述提取/检测电极层104下方；a base layer, which is disposed on theadherable substrate 103 and under the extraction/detection electrode layer 104;

修饰涂层108，其设置在所述提取/检测电极层104上方且靠近皮肤200，其包括电子传递介质和识别分子，所述电子传递介质和识别分子与待测物相适配。Adecorative coating 108, which is disposed above the extraction/detection electrode layer 104 and close to theskin 200, includes electron transfer mediators and recognition molecules that are adapted to the analyte.

所述基底层优选采用柔性材料，更优选采用多孔结构的材料，可以是可降解高分子，也可以是不可分解高分子，例如可以包括但不限于纤维素纸、PET、纳米金和碳纳米管材料。优选地，上述基底层为纸基材，其亲疏水性保证了基材与提取/检测电极层104之间的黏附性。The base layer is preferably a flexible material, more preferably a material with a porous structure, which can be a degradable polymer or a non-decomposable polymer, such as but not limited to cellulose paper, PET, nano-gold and carbon nanotubes. Material. Preferably, the above-mentioned base layer is a paper base material, and its hydrophilicity and hydrophobicity ensures the adhesion between the base material and the extraction/detection electrode layer 104 .

在一些具体实施方式中，所述修饰涂层108中的电子传递介质和识别分子可以分为两个层，即电子传递介质层和识别分子层。更优选地，所述电子传递介质层位于所述提取/检测电极层104和识别分子层之间。本领域技术人员可以采用现有的方法制备得到所述电子传递介质层和识别分子层，例如可以采用其对应溶液喷涂干燥得到。在一些实施方式中，对于待测物为葡萄糖，电子转移介质层可以是铁氰化钾溶液喷涂干燥得到，葡萄糖氧化酶层可以是活性在1000U/mL到1,000,000U/mL之间的葡萄糖氧化酶溶液喷涂干燥得到。In some specific embodiments, the electron transport medium and the recognition molecule in the modifiedcoating 108 can be divided into two layers, namely, the electron transport medium layer and the recognition molecule layer. More preferably, the electron transport medium layer is located between the extraction/detection electrode layer 104 and the recognition molecule layer. Those skilled in the art can prepare the electron transport medium layer and the recognition molecule layer by using the existing methods, for example, they can be obtained by spraying and drying their corresponding solutions. In some embodiments, when the analyte is glucose, the electron transfer medium layer can be obtained by spraying and drying a potassium ferricyanide solution, and the glucose oxidase layer can be a glucose oxidase with an activity between 1000 U/mL and 1,000,000 U/mL. The solution was spray-dried.

在另一些具体实施方式中，所述修饰涂层108中的电子传递介质和识别分子不分层，可以为混合层，也可实现其相应功能。不分层时，例如所述电子传递介质和识别分子可以与导电浆料结合，然后涂覆在提取/检测电极层104上。In some other specific embodiments, the electron transfer medium and the recognition molecule in themodification coating 108 are not layered, and can be mixed layers, and can also achieve their corresponding functions. When not layered, for example, the electron transport media and recognition molecules can be combined with a conductive paste and then coated on the extraction/detection electrode layer 104 .

本领域技术人员可以根据组织液待测物选用对应的电子传递介质和识别分子，以实现电化学检测。例如，在葡萄糖电化学检测中，电子传递介质和识别分子分别可以为铁氰化钾和葡萄糖氧化酶(GOx)。Those skilled in the art can select corresponding electron transfer media and recognition molecules according to the tissue fluid to be tested, so as to realize electrochemical detection. For example, in the electrochemical detection of glucose, the electron transport mediator and recognition molecule can be potassium ferricyanide and glucose oxidase (GOx), respectively.

在本发明的一些优选实施方式中，所述第一电极组件为纤维素纸基柔性电极，以靠近皮肤200为内，其由外到内依次包括防水层、纤维素纸基、碳材质的提取/检测电极层104、铁氰化钾、葡萄糖氧化酶(GOx)、水凝胶，水凝胶贴近皮肤200。In some preferred embodiments of the present invention, the first electrode assembly is a cellulose paper-based flexible electrode, with close to theskin 200 as the inside, which sequentially includes a waterproof layer, a cellulose paper-based, and a carbon material extraction layer from outside to inside. /Detection electrode layer 104 , potassium ferricyanide, glucose oxidase (GOx), hydrogel, and the hydrogel is close to theskin 200 .

优选采用丝网印刷的方法印制纸基碳电极，用点胶机喷液印刷的方法在碳电极工作区域固定电子传递介质和识别分子。在一种具体实施方式中，纸电极的电子转移速率常数为k_s=1.78×10^-3 cm/s，表明其具有良好的电子转移能力。Preferably, the paper-based carbon electrode is printed by screen printing, and the electron transfer medium and the recognition molecule are fixed in the working area of the carbon electrode by the liquid-jet printing method of a glue dispenser. In a specific embodiment, the electron transfer rate constant of the paper electrode is k_s =1.78×10⁻³ cm/s, indicating that it has a good electron transfer capability.

本发明中，本领域技术人员还可以根据固定需要、反向离子电渗技术需要、电化学法检测需要以及增加舒适性等需求，在所述提取-检测装置中选择使用一些配件。例如，如图1和图2所示，所述提取-检测装置还包括夹持固定部105和电极导线；所述夹持固定部105用于夹持并固定所述第一电极组件，且与所述可粘附衬底103连接，本领域技术人员可以根据需求选用其具体结构，如可以采用图1所示的夹持结构，其含有金属接头，用于将双电极109和双电极109导线连接；所述电极导线用于形成回路和传导电流信号，包括提取电极正极导线101、双电极109导线，所述提取电极正极导线101与提取电极正极102连接，所述双电极109导线包括第一电极导线106和第二电极导线107，以与双电极109中每个电极对应连接。再例如，为了增加舒适性，在所述第一电极组件上设置一层水胶。所述水胶的材料本领域技术人员可以根据需求选用。In the present invention, those skilled in the art can also select and use some accessories in the extraction-detection device according to the requirements of fixation, reverse iontophoresis, electrochemical detection, and comfort. For example, as shown in FIG. 1 and FIG. 2 , the extraction-detection device further includes a clamping and fixingpart 105 and an electrode lead; the clamping and fixingpart 105 is used for clamping and fixing the first electrode assembly, and is connected with the first electrode assembly. Theadherable substrate 103 is connected, and those skilled in the art can choose its specific structure according to the needs, for example, the clamping structure shown in FIG. connection; the electrode lead is used to form a loop and conduct current signals, including an extraction electrodepositive lead 101 and adouble electrode 109 lead, the extraction electrodepositive lead 101 is connected to the extraction electrode positive 102, and thedouble electrode 109 lead includes a first Theelectrode lead 106 and thesecond electrode lead 107 are connected to each electrode in thedouble electrode 109 correspondingly. For another example, in order to increase comfort, a layer of water glue is arranged on the first electrode assembly. The material of the water glue can be selected by those skilled in the art according to requirements.

在一些优选实施方式中，所述提取-检测装置还包括：凝胶层，其设置在所述修饰涂层108上方且靠近皮肤200。所述凝胶层优选采用水凝胶。In some preferred embodiments, the extraction-detection device further comprises: a gel layer disposed over themodification coating 108 and adjacent to theskin 200 . The gel layer is preferably a hydrogel.

本发明所述提取-检测装置还包括电流源和电化学检测机构，以实现反离子电渗和电化学检测。在进行反离子电渗时，将提取电极正极导线101与所述电流源的正极连接，将双电极109导线中的任一导线与所述电流源的负极连接，以进行提取工作，组织液中的待测物分子随离子流集中在第一电极组件的提取/检测电极层104区域（参见图4）。在进行电化学检测时，断开电流源，将双电极109导线分别外接电化学分析仪器。The extraction-detection device of the present invention further comprises a current source and an electrochemical detection mechanism, so as to realize reverse iontophoresis and electrochemical detection. When performing reverse iontophoresis, thepositive electrode lead 101 of the extraction electrode is connected to the positive electrode of the current source, and any lead wire of thedouble electrode 109 is connected to the negative electrode of the current source to perform the extraction work. The analyte molecules are concentrated in the region of the extraction/detection electrode layer 104 of the first electrode assembly along with the ion current (see FIG. 4 ). When performing electrochemical detection, the current source is disconnected, and the leads of thedouble electrodes 109 are respectively connected to an electrochemical analyzer.

本发明提供的提取-检测装置可以用于皮下组织液中人体无创生化指标(可以是血糖，钠、氨或其他金属离子，乳酸，皮酯醇等)的实时检测，且低工作电流即可获取足够的检测量，检测结果与传统必须的三电极系统准确度相当，或甚至更优。另外，本发明仅需置换不同修饰涂层108，即可转变成不同的ISF生化指标无创传感器；解决了采血疼痛、易感染等缺陷；适用于健康人体及糖尿病患者的自我、实时、原位检测，具有无创无痛、安全便携、准确稳定、价格低廉等优势。The extraction-detection device provided by the present invention can be used for real-time detection of non-invasive biochemical indicators of human body (can be blood sugar, sodium, ammonia or other metal ions, lactic acid, cortisol, etc.) in subcutaneous tissue fluid, and low operating current can obtain sufficient The accuracy of the detection results is comparable to or even better than that of the traditional necessary three-electrode system. In addition, the present invention only needs to replace different modifiedcoatings 108, and then it can be transformed into a non-invasive sensor of different ISF biochemical indicators; it solves the defects of blood collection pain, susceptibility to infection, etc.; it is suitable for self, real-time, in-situ detection of healthy human body and diabetic patients It has the advantages of non-invasive and painless, safe and portable, accurate and stable, and low price.

本发明的提取-检测装置作为一种提取与检测复用的电极装置，在材料上具备好的生物兼容性，不会引起皮肤过敏等不良反应；在结构上具有很好的柔性，与皮肤贴合的紧凑；在功能上具备稳定的电化学特性，灵敏度大，检测极限低；在制作上简单，可以大大降低成本；可以实现一次性检测使用，更安全，避免交叉感染。The extraction-detection device of the present invention, as a multiplexed electrode device for extraction and detection, has good biocompatibility in material and will not cause adverse reactions such as skin allergy; It is compact and functional; it has stable electrochemical properties, high sensitivity, and low detection limit; it is simple in production, which can greatly reduce costs; it can be used for one-time detection, which is safer and avoids cross-infection.

将所述提取-检测装置的检测区域面向受试者皮肤200，通过可粘附衬底103将所述第一电极组件和第二电极组件贴附于受试者待测皮肤200区域；The detection area of the extraction-detection device faces the subject'sskin 200, and the first electrode assembly and the second electrode assembly are attached to the subject'sskin 200 area to be measured through theadhesive substrate 103;

将双电极109中的一个电极作为负极，与提取电极正极102组合，进行反离子电渗提取，使得皮下组织液中待测物提取到皮肤200表面并富集在所述提取/检测电极层104区域；One electrode in thedouble electrode 109 is used as the negative electrode, and combined with thepositive electrode 102 of the extraction electrode to perform reverse iontophoresis extraction, so that the analyte in the subcutaneous tissue fluid is extracted to the surface of theskin 200 and enriched in the area of the extraction/detection electrode layer 104 ;

在所述电渗提取完成后，以双电极109中的一个电极作为工作电极，另一个电极作为对电极，对所述电渗提取得到的提取液进行电化学检测。After the electroosmotic extraction is completed, one electrode of thedual electrodes 109 is used as a working electrode, and the other electrode is used as a counter electrode, and electrochemical detection is performed on the extraction solution obtained by the electroosmotic extraction.

在所述提取的过程中，本领域技术人员可以观察提取过程中的提取电流、提取电压、电极表面含水量的变化，保证提取过程在安全范围内运行，并保存检测数据。During the extraction process, those skilled in the art can observe the extraction current, extraction voltage, and changes in the water content of the electrode surface during the extraction process to ensure that the extraction process operates within a safe range and save the detection data.

本领域技术人员可以在所述电化学检测后，根据输出的检测信号，通过读取电化学的电流信号，根据现有的方法计算得出待测物的浓度。After the electrochemical detection, those skilled in the art can calculate the concentration of the analyte by reading the electrochemical current signal according to the output detection signal according to the existing method.

下面结合具体实施例对本发明进行进一步阐述。The present invention will be further described below with reference to specific embodiments.

实施例1Example 1

一种无创皮下组织液提取-检测装置，如图1所示，包括可粘附衬底103、第一电极组件、第二电极组件、电流源（图中未显示）和电化学检测分析装置（图中未显示），第二电极组件包括“匚”形的提取电极正极102、提取电极正极导线101，第一电极组件包括依次设置的纤维纸、碳电极层、铁氰化钾层、葡萄糖氧化酶层、凝胶层的纸基柔性生物电极，凝胶层贴近皮肤200。碳电极层呈梳状叉指排布，如图8所示。梳状叉指型碳电极层是有利于提取电场均匀化。本实施例的电极采用以纤维纸为基底，用丝网印刷的方式制备高导电碳电极，来降低电子进入电极的阻抗。其次，纤维素具有良好的生物相容性，不会引起皮肤过敏等不良反应。纤维纸，表面平整，与碳浆有良好的黏附性，加上纸特有的纤维疏松的孔洞，使得印制在纸基上的厚膜电极更加稳定。A non-invasive subcutaneous tissue fluid extraction-detection device, as shown in Figure 1, includes anadherent substrate 103, a first electrode assembly, a second electrode assembly, a current source (not shown in the figure) and an electrochemical detection and analysis device (Figure 1). (not shown in the figure), the second electrode assembly includes an extraction electrodepositive electrode 102 and an extraction electrodepositive electrode lead 101 in the shape of a “tuck”, and the first electrode assembly includes a fiber paper, a carbon electrode layer, a potassium ferricyanide layer, and a glucose oxidase that are arranged in sequence. A paper-based flexible bioelectrode with a layer and a gel layer, and the gel layer is close to theskin 200 . The carbon electrode layers are arranged in a comb-like interdigital arrangement, as shown in Figure 8. The comb-like interdigitated carbon electrode layer is conducive to the uniformity of the extraction electric field. The electrode of this embodiment uses fiber paper as a base to prepare a highly conductive carbon electrode by screen printing, so as to reduce the resistance of electrons entering the electrode. Secondly, cellulose has good biocompatibility and will not cause adverse reactions such as skin allergies. Fiber paper, with smooth surface, has good adhesion with carbon pulp, and the unique porous pores of paper make the thick film electrode printed on the paper base more stable.

将提取电极正极导线101与电流源的正极连接，将双电极109中的一个电极与电流源的负极连接，进行反离子电渗提取，使得皮下组织液提取到皮肤200表面并富集在所述提取/检测电极层104区域，其中提取电流为0.1mA。Connect thepositive electrode lead 101 of the extraction electrode to the positive electrode of the current source, connect one electrode of thedouble electrodes 109 to the negative electrode of the current source, and perform reverse iontophoresis extraction, so that the subcutaneous tissue fluid is extracted to the surface of theskin 200 and enriched in the extraction. /Detection electrode layer 104 area, where the extraction current is 0.1 mA.

在提取完成后，断开电流源，以双电极109中的一个电极作为工作电极，另一个电极作为对电极，将第一电极导线106和第二电极导线107分别作为工作电极和对电极的接线，外接电化学分析仪器，测量皮下组织液中钠离子的开路电位。本实施例的提取-检测装置对不同浓度NaCl溶液测试开路电位响应曲线图如图9所示。从图9中可以看出，随提取时间的不同，本实施例的提取-检测装置能够对不同浓度的钠离子具有稳定且高灵敏度的响应，说明了本装置具有优越的检测性能。After the extraction is completed, the current source is disconnected, one electrode of thedouble electrodes 109 is used as the working electrode, the other electrode is used as the counter electrode, and thefirst electrode lead 106 and thesecond electrode lead 107 are used as the connection between the working electrode and the counter electrode, respectively. , an external electrochemical analyzer to measure the open circuit potential of sodium ions in the subcutaneous tissue fluid. Figure 9 shows the open-circuit potential response curve of the extraction-detection device of the present embodiment to the test of NaCl solutions with different concentrations. It can be seen from FIG. 9 that the extraction-detection device of this embodiment can have stable and high-sensitivity responses to different concentrations of sodium ions with different extraction times, indicating that the device has superior detection performance.

并通过本实施例的提取-检测装置对皮下组织液中的葡萄糖进行检测，结果表明，在提取电流为0.1mA条件下，在1-8mM葡萄糖浓度范围内，灵敏度为1.057μA/mm，在8-18 mM葡萄糖浓度范围内，灵敏度为0.292μA/mm。检测极限为0.39mM (S/N=3)。And the glucose in the subcutaneous tissue fluid is detected by the extraction-detection device of this embodiment. The results show that under the condition of extraction current of 0.1mA, in the range of 1-8mM glucose concentration, the sensitivity is 1.057μA/mm, and the sensitivity is 1.057μA/mm at 8- The sensitivity was 0.292 μA/mm over the 18 mM glucose concentration range. The detection limit was 0.39mM (S/N=3).

通过上述实施例可以看出，本发明的提取-检测装置能够在较低的提取电流下，产生更加均匀磁场，从而进行高效提取，实现提取足够量的提取液。It can be seen from the above embodiments that the extraction-detection device of the present invention can generate a more uniform magnetic field at a lower extraction current, so as to perform efficient extraction and achieve extraction of a sufficient amount of extraction liquid.

以上详细描述了本发明的优选实施方式，但是，本发明并不限于此。在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，包括各个技术特征以任何其它的合适方式进行组合，这些简单变型和组合同样应当视为本发明所公开的内容，均属于本发明的保护范围。The preferred embodiments of the present invention have been described above in detail, however, the present invention is not limited thereto. Within the scope of the technical concept of the present invention, a variety of simple modifications can be made to the technical solutions of the present invention, including the combination of various technical features in any other suitable manner. These simple modifications and combinations should also be regarded as the content disclosed in the present invention. All belong to the protection scope of the present invention.