WO2014108087A1

WO2014108087A1 - Portable monitoring system for dynamically and continuously measuring analyte in body liquid

Info

Publication number: WO2014108087A1
Application number: PCT/CN2014/070413
Authority: WO
Inventors: 莫健伟; 邵敏玲; 郭旻; 杨轶颖; 李元光; 何伟
Original assignee: 北京怡成生物电子技术有限公司; 美国优西生物仪器公司
Priority date: 2013-01-09
Filing date: 2014-01-09
Publication date: 2014-07-17

Abstract

A portable monitoring system for dynamically and continuously measuring an analyte in body liquid, comprising: a close-fitting subsystem (31); the close-fitting subsystem (31) comprises a micro body liquid sampler and a micro biochip sequentially interconnected via a micro tube (7) to form a complete fluid pathway; the close-fitting subsystem further comprises a micro-fluidic pump(8), a close-fitting electronic instrument (11), a test calibrating chamber, and a waste liquid collector(10); the portable monitoring system further comprises: a compact and wearable electronic instrument (32), and/or, a data processing and transmitting terminal device(33). The portable monitoring system not only has a shorter preheating time and less pain during sampling and produces a more accurate result, but also requires fewer calibration points, is easy to operate, and has high sensitivity, especially in the hypoglycemia range.

Description

动态连续测定体液中分析物的便携式监测*** 本申请要求 2013年 1月 17日递交的申请号为 201310026915.5、发明名称为 "动态连续测定体液中分析物的便携式监测***" 及 2013 年 1 月 9 日递交的申请号为 201310008656.3、发明名称为 "微型体液采样器" 、 2013年 1 月 9 日递交的申请号为 201310007653.8、发明名称为 "用于体液中物质实时检测的微型生物芯片" 的中国专利申请的优先权，其全部内容通过引用结合在本申请中。技术领域 A portable monitoring system for dynamically and continuously measuring analytes in body fluids. This application claims the application number 201310026915.5, filed on January 17, 2013, entitled "Dynamic Continuous Measurement of Portable Monitoring Systems for Analytes in Body Fluids" and January 9, 2013 The Chinese patent application filed is 201310008656.3, the invention name is "micro-body fluid sampler", the application number submitted on January 9, 2013 is 201310007653.8, and the invention name is "micro-biochip for real-time detection of substances in body fluids". Priority is hereby incorporated by reference in its entirety. Technical field

本发明涉及临床样品监测***，特别是涉及一种用于体液中物质实时检测的便携式监测***。背景技术 The present invention relates to a clinical sample monitoring system, and more particularly to a portable monitoring system for real-time detection of substances in body fluids. Background technique

血糖的自我监测*** （SMBG) 例如血糖测试试纸条和血糖仪广泛地用于血糖的检测。现有的 SMBG主要局限是：不便、不适，间歇性的信息，而且获得此信息取决于病人取血及测试的主动性；在最好的情况下， SMBG提供每天 2、 4、或最多 10个数据点，这样测量最多次数达到 10次。但糖尿病人的血糖变化是连续和不可预知的，在一天 24小时的过程中，可高达六倍的变化！因此， SMBG的数据是不连续的，只提供一个估计的葡萄糖水平。但是，控制血糖涉及不断变化的***。连续血糖监测（CGM) 提供患者有关血糖水平随时间序列数据的实时信息，以及血糖变化的方向、速度和趋势。实时 CGM的临床结果表明 CGM显著地改善了糖尿病患者病情，如较低的 HbAlc值，减少血糖波动和低血糖发作时间，减少超出低血糖和高血糖范围的持续时间，并且降低了与糖尿病并发症相关的风险，提高病人的生活质量。 The Self-Monitoring System for Blood Sugar (SMBG) such as blood glucose test strips and blood glucose meters are widely used for blood glucose testing. The main limitations of the existing SMBG are: inconvenience, discomfort, intermittent information, and access to this information depends on the patient's blood sampling and testing initiative; in the best case, SMBG provides 2, 4, or up to 10 per day. Data points, so the maximum number of measurements is up to 10 times. However, the blood sugar changes in diabetics are continuous and unpredictable, and can vary up to six times in the course of 24 hours a day! Therefore, the SMBG data is discontinuous and only provides an estimated glucose level. However, controlling blood sugar involves a constantly changing system. Continuous Blood Glucose Monitoring (CGM) provides patients with real-time information about blood glucose levels over time series, as well as the direction, speed, and trends of blood glucose changes. The clinical results of real-time CGM indicate that CGM significantly improves the condition of diabetic patients, such as lower HbAlc values, reduces blood glucose fluctuations and hypoglycemic episodes, reduces duration beyond hypoglycemia and hyperglycemia, and reduces complications with diabetes Related risks improve the quality of life of patients.

目前，在 CGM市场上的主导产品是植入皮下的针型电化学传感器，例如 SEVEN® PLUS, Guardian® EAL-Time, FreeStyle Navigator, 可在体内工作数天，用完后，可由使用者更换。但是，它们必须多次定时例如 2、 6小时用 SMBG检测的数据来校准，以得到所需的准确读数。 Currently, the leading product in the CGM market is a needle-type electrochemical sensor implanted under the skin, such as SEVEN® PLUS, Guardian® EAL-Time, FreeStyle Navigator, which can be used in the body for several days. After use, it can be replaced by the user. However, they must be calibrated with SMBG-detected data for multiple timings, for example 2, 6 hours, to obtain the exact readings required.

植入皮下的针型电化学传感器具有以下缺陷： Needle-type electrochemical sensors implanted under the skin have the following drawbacks:

每个单独的数据点缺乏准确性，必须多次用 SMBG检测的数据来校准； Each individual data point lacks accuracy and must be calibrated multiple times with SMBG detected data;

预热时间较长，一般大于 2小时，而 FreeStyle Navigator为 10小时，使得它们在初始化的预热期没有用，使得它们很难应用于医院急诊室和重症监护病房（ICU) ；植入体内的传感器容易被体内物质迅速沉积 /粘附在植入部位，由疤痕组织形成厚厚的胶囊，包裹植入的传感器，严重影响它的性能，特别是准确性； Warm-up time is longer, usually more than 2 hours, and FreeStyle Navigator is 10 hours, making them at the beginning The preheating period of the initialization is useless, making them difficult to apply to hospital emergency rooms and intensive care units (ICUs); sensors implanted in the body are easily deposited/adhered to the implant site by the body material, forming thick from scar tissue Thick capsules, wrapped in implanted sensors, severely affect its performance, especially accuracy;

校准时疼痛和不便； Pain and inconvenience during calibration;

植入传感器时涉及疼痛及不便的操作：植入 13毫米长的传感器或用疼痛 22号针导入，以困难的 45度***；不容易取出植入的传感器； Implantation of the sensor involves painful and inconvenient operation: Implantation of a 13 mm long sensor or introduction with a painful 22 gauge needle, with a difficult 45 degree insertion; it is not easy to remove the implanted sensor;

正常组织中的氧气浓度比生理血糖水平低约 1个数量级，这会导致传感器响应的变化并降低响应线性的上限。 Oxygen concentrations in normal tissues are about one order of magnitude lower than physiological blood glucose levels, which can result in changes in sensor response and lower the upper limit of response linearity.

另一个商用但不是普通消费产品的 CGM是 GlucoDay, 应用微透析的原理，将有透析膜的一个约 25mm长小导管手术植入皮下组织，通过透析液将体内的血糖带到体外，用位于体外的葡萄糖传感器测量透析液中的葡萄糖，并换算成体内的血糖浓度。这个系统的局限性：手术植入透析导管； ***点的局部组织损伤和炎症造成信号漂移；由于葡萄糖在体内组织和透析液之间的平衡需要时间，导致较长的滞后时间，而且这与透析液流量有关。 Another CGM that is commercial but not a general consumer product is GlucoDay. Applying the principle of microdialysis, a small 25 mm long catheter with a dialysis membrane is surgically implanted into the subcutaneous tissue, and the blood glucose in the body is brought to the outside by dialysate. The glucose sensor measures glucose in the dialysate and converts it to blood glucose levels in the body. Limitations of this system: surgical implantation of dialysis catheters; local tissue damage at the insertion site and inflammation cause signal drift; due to the balance of glucose in the body tissue and dialysate takes time, resulting in longer lag times, and this is dialysis Liquid flow related.

另外的一些体外***，将从体内抽取的血液的一小部分通过多个泵送到体外的葡萄糖传感器，进行血糖的测定；同时，将抽取的血液的绝大部分通过清洗装置清洗后送回体内。这样的***是非常复杂和危险的，并且价格昂贵，使它难以应用在必需快速设置或简陋的工作环境中，如家庭医疗保健或急诊室。发明内容 In other in vitro systems, a small portion of the blood drawn from the body is pumped to the glucose sensor outside the body for blood glucose measurement; at the same time, most of the extracted blood is washed by the cleaning device and returned to the body. . Such a system is very complex and dangerous, and expensive, making it difficult to apply in a work environment that requires quick setup or a simple work, such as a home healthcare or emergency room. Summary of the invention

为了解决现有技术的上述不足，本发明目的是提供一种动态连续测定体液中分析物的便携式监测***，所便携式监测***的技术方案如下。 In order to solve the above-mentioned deficiencies of the prior art, it is an object of the present invention to provide a portable monitoring system for dynamically and continuously measuring analytes in body fluids. The technical solution of the portable monitoring system is as follows.

一种动态连续测定体液中分析物的便携式监测***，其包括： A portable monitoring system for dynamically and continuously measuring analytes in body fluids, comprising:

贴身亚***，所述贴身亚***包括通过微导管依次相互连接贯通、组成一个完整流体通路的微型体液采样器和微型生物芯片，其中： The body sub-system includes a micro-body sampler and a micro-biochip that are sequentially connected to each other through a microcatheter to form a complete fluid passage, wherein:

微型体液采样器，其由微针、微针固定器、和微针固定贴士组成；当取样时，按压微针固定器，推动固定的微针剌入皮肤中，由贴在皮肤上的微针固定贴士固定；剌入皮肤中的微针管，用于连续抽取体液； A micro-body fluid sampler consisting of a micro-needle, a micro-needle holder, and a micro-needle fixing tip; when sampling, pressing the micro-needle holder to push the fixed micro-needle into the skin, by sticking to the skin Needle fixing tips; micro-needle tube that is inserted into the skin for continuous extraction of body fluids;

微型生物芯片，其由流通型微流体芯片和薄膜生物传感器组装而成； a micro biochip assembled from a flow-through microfluidic chip and a thin film biosensor;

流通型微流体芯片包括：依次相互连通，组成一个完整流体通路的流体入口，微孔和 /或微型通道，检测室，微通道，流体出口；例如，流体入口可以与微孔或微型通道连通，或者流体入口也可以连通微孔再由微孔连通微型通道，微型通道例如可以是蛇形通道； The flow-through microfluidic chip comprises: a fluid inlet that sequentially communicates with each other to form a complete fluid passage, the micropore And/or microchannels, detection chambers, microchannels, fluid outlets; for example, the fluid inlet may be in communication with the micropores or microchannels, or the fluid inlet may also be connected to the microholes and the microchannels may be connected to the microchannels, such as a snake Shaped channel

薄膜生物传感器包括：工作电极，对电极，参比电极，用于将多个电极与微型生物芯片外仪器连接的接触垫，连接电极与接触垫的连线，连接体液的穿透孔，具有与电极匹配的绝缘层图案开孔的电极绝缘层； The thin film biosensor comprises: a working electrode, a counter electrode, a reference electrode, a contact pad for connecting a plurality of electrodes to the micro biochip device, a connection line connecting the electrode and the contact pad, and a penetration hole connecting the body fluid, having Electrode matching insulating layer pattern opening electrode insulating layer;

在检测室中以串联和 /或并联形式，嵌入一种或多种薄膜生物传感器，使得嵌入的薄膜生物传感器的表面总是与流经的体液接触，连续监测体液中的物质。 One or more thin film biosensors are embedded in the detection chamber in series and/or in parallel such that the surface of the embedded membrane biosensor is always in contact with the body fluid flowing through to continuously monitor the contents of the body fluid.

在一种实施方式中，所述贴身亚***还可以包括： In an embodiment, the personal sub-system may further include:

微流体泵，微流体泵可位于微型体液采样器与微型生物芯片之间，或紧接在微型生物芯片之后；提供可控的动力，将吸取的体液流过微型生物芯片。 The microfluidic pump, the microfluidic pump can be located between the micro-body fluid sampler and the micro-biochip, or immediately after the micro-biochip; providing controlled power to flow the bodily fluid through the micro-biochip.

贴身式电子仪，通过传感器接口和微流体泵接口，分别与微型生物芯片和微流体泵连接；当启动所述贴身式电子仪，驱动微流体泵和薄膜生物传感器，体液就会连续或间断地从剌入皮肤的微针管中抽取，流过流通型微流体芯片并与嵌入的薄膜生物传感器中的电极组接触，产生待测分析物的检测信号。 The body-mounted electronic instrument is connected to the micro biochip and the microfluidic pump through the sensor interface and the microfluidic pump interface respectively; when the intimate electronic device is activated, the microfluidic pump and the thin film biosensor are driven, the body fluid is continuously or intermittently It is drawn from the microneedle tube that has penetrated the skin, flows through the flow-through microfluidic chip and contacts the electrode group in the embedded thin film biosensor to generate a detection signal of the analyte to be tested.

测试校准室和废液收集器，其中测试校准室固定设置在贴身亚***内或者在校准时加入到贴身亚***中；在测定体液中分析物时，体液进入废液收集器，校准时，体液进入测试校准室；测试校准室位于微型体液采样器与微型生物芯片之间，或与废液收集器并行地紧接在微流体泵之后。 Test the calibration chamber and the waste collector, wherein the test calibration chamber is fixed in the body sub-system or added to the body sub-system during calibration; when measuring the analyte in the body fluid, the body fluid enters the waste collector, when calibrating, body fluid Enter the test calibration chamber; the test calibration chamber is located between the micro-body fluid sampler and the micro-biochip, or immediately after the microfluidic pump in parallel with the waste collector.

在一种实施方式中，所述便携式监测***还可以包括： In an embodiment, the portable monitoring system may further include:

紧凑型佩带式电子仪和 /或数据处理和传输终端设备，所述紧凑型佩带式电子仪或所述数据处理和传输终端设备直接实时、无线传输地接收贴身亚***产生的待测分析物的检测或校准信号，然后进行数据的存储、分析处理、和显示分析物的生理结果；或者所述数据处理和传输终端设备通过无线或有线传输方式接收所述紧凑型佩带式电子仪的显示分析物的生理结果，并能将测试结果传输到互联网上存储，与其他人分享。 a compact wearable electronic device and/or a data processing and transmission terminal device, the compact wearable electronic device or the data processing and transmission terminal device receiving the analyte to be tested generated by the body sub-system directly in real time and wirelessly Detecting or calibrating the signal, then performing data storage, analyzing processing, and displaying physiological results of the analyte; or the data processing and transmission terminal device receiving the display analyte of the compact wearable electronic device by wireless or wired transmission Physiological results, and can transfer test results to the Internet for storage and sharing with others.

数据处理和传输终端设备可以进行数据的长期存储、结果的分析处理及显示。例如，一个月内血糖浓度随时间的变化图；超过血糖阈值的时间。另外，数据处理和传输终端设备可上传数据到互联网上加密的个人 "云" 中，与授权人分享，例如医生、家属、挚友，提供便捷、多方面、长期的个人健康信息，便于诊断、治疗、疾病管理。数据处理和传输终端设备可以是手机、电脑、或其它便携式设备。 The data processing and transmission terminal device can perform long-term storage of data, analysis processing and display of results. For example, a graph of changes in blood glucose concentration over time in one month; a time that exceeds the blood glucose threshold. In addition, data processing and transmission terminal devices can upload data to an encrypted "cloud" on the Internet and share it with authorized persons, such as doctors, homes. The genus and friends provide convenient, multi-faceted and long-term personal health information for diagnosis, treatment and disease management. The data processing and transmission terminal device can be a cell phone, a computer, or other portable device.

在一种实施方式中，所述述微针固定器包括在底部具有孔的凸起插头，在侧面的流体出口，微针固定器内的流体通道，和微针固定器主体；所述微针固定贴士包括：微针固定贴士主体中的凹入插座，凹入插座中的孔，在凹入插座周围的凸缘；所述微针固定器的凸起插头位于微针固定器的底部，所述凸起插头的底部孔用于容纳微针，微针密封地固定在凸起插头的底部孔中，并且伸出凸起插头；所述微针在微针体中具有将所述微针固定器的流体出口与体液连通的孔；所述微针固定贴士的孔和凹入插座分别与所述微针和所述微针固定器的凸起插头在位置、尺寸和几何形状上匹配。 In one embodiment, the microneedle holder includes a raised plug having a hole at the bottom, a fluid outlet at the side, a fluid passage in the microneedle holder, and a microneedle holder body; the microneedle Fixing tips include: a recessed socket in the microneedle fixing tip body, a hole recessed into the socket, a flange around the recessed socket; a raised plug of the microneedle holder at the bottom of the microneedle holder a bottom hole of the protruding plug for receiving the microneedle, the microneedle is sealingly fixed in the bottom hole of the protruding plug, and protruding the protruding plug; the microneedle has the micro in the microneedle body a hole in the fluid outlet of the needle holder communicating with the body fluid; the hole and the recessed socket of the microneedle fixing tip are respectively in position, size and geometry with the protruding pin of the microneedle and the microneedle holder match.

在一种实施方式中，所述微针固定器中凸起插头的底部具有多个孔所述微针固定贴士的凹入插座中具有多个孔，多个所述微针密封地固定在凸起插头的底部多个孔中，所述微针固定贴士内凹入插座和多个孔分别与所述凸起插头和多个微针在位置、尺寸和几何形状上匹配。 In one embodiment, the bottom of the protruding plug in the microneedle holder has a plurality of holes. The recessed socket of the microneedle fixing tip has a plurality of holes, and the plurality of micro pins are sealingly fixed In the plurality of holes in the bottom of the raised plug, the microneedle fixing tips are recessed into the socket and the plurality of holes are respectively matched in position, size and geometry with the raised plug and the plurality of microneedles.

在一种实施方式中，在微针固定器中具有用于聚集来自多个微针的多个流体流动路径进入到一个路径中的通道。 In one embodiment, there is a channel in the microneedle holder for collecting a plurality of fluid flow paths from the plurality of microneedles into one path.

在一种实施方式中，微型体液采样器面积小于 5 c ²，高度小于 10 。 In one embodiment, the micro-body fluid sampler has an area of less than 5 c ² and a height of less than 10.

在一种实施方式中，所述微针的外径优选地小于 380 。 In one embodiment, the outer diameter of the microneedles is preferably less than 380.

在一种实施方式中，微针伸出凸起插头的长度通常小于 10 ，优选地小于 5 ，和更优选地小于 3 _; 当微型体液采样器用于取样血糖样品时，微针伸出凸起插头的长度优选地小于 5 。 In one embodiment, the length of the microneedle protruding projection plug is typically less than 10, preferably less than 5, and more preferably less than 3 _; when the micro-body sampler is used to sample a blood glucose sample, the microneedle protrudes from the raised plug The length is preferably less than 5.

在一种实施方式中，通过调节伸出微针固定器凸起插头的长度来控制微针剌入体内深度，通过穿入皮肤中不同的深度来取样不同体液，例如可以取样组织液、血液、或者组织液和血液的混合物。 In one embodiment, the microneedle is controlled to penetrate the depth of the body by adjusting the length of the protruding pin of the protruding microneedle holder, and different body fluids are sampled by penetrating into different depths in the skin, for example, tissue fluid, blood, or A mixture of tissue fluid and blood.

在一种实施方式中，微针可以以不同角度***体内，优选地角度为 90度。 In one embodiment, the microneedles can be inserted into the body at different angles, preferably at an angle of 90 degrees.

在一种实施方式中，微针穿入体内并留在体内进行采样，例如进行长时间采样，对皮肤及皮下组织只有微创或几乎无创，这样极大地减少了身体对进入体内微针的反应。 In one embodiment, the microneedles penetrate into the body and remain in the body for sampling, such as long-term sampling, which is minimally invasive or almost non-invasive to the skin and subcutaneous tissue, which greatly reduces the body's response to microneedle entry into the body. .

在一种实施方式中，微针可以由任何生物兼容性并且有机械强度的材料制成，例如由不锈钢、钛及钛合金、硅及其化合物、钨合金、塑料、陶瓷等等制成；微针可以从市场上购买，例如皮下注射器针头、 Kumetrix' s硅微针等等。 In one embodiment, the microneedles can be made of any biocompatible and mechanically strong material, such as stainless steel, titanium and titanium alloys, silicon and its compounds, tungsten alloys, plastics, ceramics, and the like; Needles are commercially available, such as hypodermic syringe needles, Kumetrix's silicon microneedles, and the like.

在一种实施方式中，微针固定器内的流体通道和在侧面的流体出口形状和大小可以根据需要进行选择，优选地是它们直径小于 400 μιη 流体通道长度小于 20 mm。 In one embodiment, the fluid passages in the microneedle holder and the fluid outlets on the sides may be of a shape and size Selection is made as needed, preferably with a diameter of less than 400 μηη and a fluid channel length of less than 20 mm.

在一种实施方式中，用于辅助微针进入并固定在体内的微针固定器凸起插头可以使用任何合适的形状和大小，优选地为直径小于 8 的凸出的圆锥体。 In one embodiment, the microneedle holder boss plug for assisting the microneedle to enter and be secured within the body can be of any suitable shape and size, preferably a convex cone having a diameter of less than 8.

在一种实施方式中，微针固定器尺寸与固定微针的数量有关，当是单个微针时，微针固定器的面积优选地小于 3 c ²。 In one embodiment, the micro-needle holder fixed size and number of microneedles relevant when a single microneedle is, the area of the micro-needle holder is preferably less than 3 c ^2.

在一种实施方式中，微针固定器可以由可用于医疗设备的材料制成，例如由塑料、橡胶、金属、陶瓷等制成。塑料可以是 PE、 PP、 POM、 PTFE、 PES、 PSU、 PEEK、 In one embodiment, the microneedle holder can be made of materials that can be used in medical devices, such as plastic, rubber, metal, ceramic, and the like. Plastics can be PE, PP, POM, PTFE, PES, PSU, PEEK,

PC、 PU、和医疗级 PVC等等；橡胶可以是硅橡胶等等；金属可以是不锈钢、钛、钛合金、铝、铝合金等等。 PC, PU, and medical grade PVC, etc.; rubber may be silicone rubber, etc.; metal may be stainless steel, titanium, titanium alloy, aluminum, aluminum alloy, and the like.

在一种实施方式中，微针固定器可采用机械加工或模具制造的方法进行制造。 In one embodiment, the microneedle holder can be fabricated by mechanical or mold manufacturing methods.

在一种实施方式中，微针固定贴士内用于辅助微针进入并固定在体内的凹入插座是直径小于 10 凹入的圆锥腔。 In one embodiment, the recessed socket in the microneedle fixing tip for assisting the microneedle to enter and secure within the body is a conical cavity having a diameter of less than 10 recesses.

在一种实施方式中，微针固定贴士尺寸与固定微针的数量有关，当是单个微针时，微针固定贴士的面积优选地小于 5 c ²。 In one embodiment, the microneedle tips fixed number of fixed size and For microneedles, the microneedles when is a single, fixed area of the tips the microneedles is preferably less than 5 c ^2.

在一种实施方式中，微针固定贴士底面有带胶的宽边，用于将整个体液采样器固定在采样处皮肤表面，进行采样，例如进行长时间采样。 In one embodiment, the microneedle fixing tips have a wide side with a glue for fixing the entire body fluid sampler to the skin surface of the sampling site for sampling, for example, for long time sampling.

在一种实施方式中，微针固定贴士还可以包括：贴在凸缘底部上的医用粘合剂。在一种实施方式中，贴在凸缘底部上的医用粘合剂是创可贴式的胶。 In one embodiment, the microneedle fixing tips may further include: a medical adhesive attached to the bottom of the flange. In one embodiment, the medical adhesive applied to the bottom of the flange is a band-aid glue.

在一种实施方式中，微针固定贴士的材料是对皮肤无剌激的医用材料，例如塑料和橡胶，塑料可以是 PE、 PTFE、 PES、 PU、医疗级 PVC等等；橡胶可以是硅橡胶等等。 In one embodiment, the microneedle fixing material is a medical material that is not irritating to the skin, such as plastic and rubber, the plastic may be PE, PTFE, PES, PU, medical grade PVC, etc.; the rubber may be silicon Rubber and so on.

在一种实施方式中，微针固定贴士可采用机械加工或模具制造的方法进行制造。在一种实施方式中，整个微型体液采样器固定在采样处皮肤表面，进行采样，例如进行长时间采样。 In one embodiment, the microneedle fixing tips can be fabricated by mechanical processing or mold manufacturing. In one embodiment, the entire micro-body fluid sampler is attached to the surface of the skin at the sampling site for sampling, for example, for long periods of sampling.

在一种实施方式中，微针固定器流体出口可以直接连接至微流体泵。 In one embodiment, the microneedle holder fluid outlet can be directly connected to the microfluidic pump.

在一种实施方式中，微针固定器流体出口可以通过生物芯片，然后连接至微流体泵。 In one embodiment, the microneedle holder fluid outlet can pass through a biochip and then be coupled to a microfluidic pump.

在一种实施方式中，在流通型微流体芯片和薄膜生物传感器之间，放入具有与薄膜生物传感器匹配的图案开孔的薄层双面胶进行组装。 In one embodiment, a thin layer of double-sided tape having a pattern opening that matches the film biosensor is placed between the flow-through microfluidic chip and the thin film biosensor for assembly.

在一种实施方式中，微导管分别固定在流体入口和流体出口中，固定在流体入口的微导管将流体入口与连续监测体液中物质的分析***中的体液采样器连接，固定在流体出口的微导管将流体出口与微流体泵连接，使连接通道的死体积最小。 In one embodiment, the microcatheters are respectively fixed in the fluid inlet and the fluid outlet, and the microcatheter fixed at the fluid inlet connects the fluid inlet with the body fluid sampler in the analysis system for continuously monitoring the substance in the body fluid, and is fixed to the fluid The outlet microcatheter connects the fluid outlet to the microfluidic pump to minimize the dead volume of the connecting channel.

在一种实施方式中，流通型微流体芯片包括两个以上的检测室，在薄膜生物传感器中具有与检测室数量相匹配的工作电极；每个工作电极可以制备成不同的生物传感器，用于连续实时地检测多种不同的分析物。 In one embodiment, the flow-through microfluidic chip comprises more than two detection chambers having working electrodes in the membrane biosensor that match the number of detection chambers; each of the working electrodes can be prepared as a different biosensor for Continuous detection of multiple different analytes in real time.

在一种实施方式中，流通型微流体芯片的面积小于 5 c ²，高度小于 2 。 In one embodiment, the flow-through microfluidic chip has an area of less than 5 c ² and a height of less than two.

在一种实施方式中，微孔小于 400 ; 当流速小于 10 μ/ / ηώι流速，微孔小于 In one embodiment, the micropores are less than 400; when the flow rate is less than 10 μ/ /ηηι flow rate, the micropores are smaller than

\50 μιη。 \50 μιη.

在一种实施方式中，蛇形通道宽度小于 600 μ^，长度小于 10 。 In one embodiment, the serpentine channel has a width of less than 600 μ^ and a length of less than 10.

在一种实施方式中，体液中物质可以是血糖、乳酸、氧气、 pH值、血细胞比容、电解质其中之一或任意组合。 In one embodiment, the substance in the body fluid may be one or any combination of blood glucose, lactic acid, oxygen, pH, hematocrit, electrolyte.

在一种实施方式中，微导管直径小于 600 μ^。微导管由可用于医疗设备的材料制成，诸如，塑料、橡胶、金属；塑料可以是 PE、 PTFE、 PES、 PEEK, PU、或医疗级 PVC; 橡胶可以是硅橡胶；金属可以是不锈钢或钛合金。微导管引导微流体导应去的地方诸如检测室，与芯片外部件诸如体液采样器和微流体泵连接。微导管可以是长方形或圆形；尺寸小于 3000 μ?«。 In one embodiment, the microcatheter has a diameter of less than 600 μ^. The microcatheter is made of materials that can be used in medical equipment, such as plastic, rubber, metal; plastic can be PE, PTFE, PES, PEEK, PU, or medical grade PVC; rubber can be silicone rubber; metal can be stainless steel or titanium alloy. The microcatheter directs the microfluidic guide to a location such as a detection chamber, and is coupled to off-chip components such as a body fluid sampler and a microfluidic pump. The microcatheter can be rectangular or circular; the size is less than 3000 μ?«.

在一种实施方式中，流通型微流体芯片可由用于微机械加工和生物兼容性的材料制成，例如，塑料、硅、玻璃、金属、或陶瓷，塑料可以是 PMMA、 PAA、 PS、 PC、 PE、 PP、 PET、或 PDMS，金属可以是不锈钢、或钛合金。 In one embodiment, the flow-through microfluidic chip can be made of materials for micromachining and biocompatibility, such as plastic, silicon, glass, metal, or ceramic, and the plastic can be PMMA, PAA, PS, PC. , PE, PP, PET, or PDMS, the metal can be stainless steel, or titanium alloy.

在一种实施方式中，流通型微流体芯片可以通过激光蚀刻、化学蚀刻、等离子刻蚀、模具制造等的方法制备。激光蚀刻适合于上述所有的材料。可选用的激光： CO 光（10.6 μ?« ) ，红外激光（1064nm) ，绿激光 (532nm)， UV激光（355nm) ；不同材料及不同的加工精度，选用不同的激光器来加工。化学蚀刻适合于金属、硅、和玻璃。模具制造适合于大量制造。 In one embodiment, the flow-through microfluidic chip can be prepared by a method of laser etching, chemical etching, plasma etching, mold manufacturing, or the like. Laser etching is suitable for all of the above materials. Optional laser: CO light (10.6 μ?«), infrared laser (1064nm), green laser (532nm), UV laser (355nm); different materials and different processing precision, different lasers are used for processing. Chemical etching is suitable for metals, silicon, and glass. Mold making is suitable for mass production.

在一种实施方式中，通过激光蚀刻的方法在塑料上加工制备用于测量血糖的流通型微流体芯片。还可以通过注塑的方法在塑料上加工制备用于测量血糖的流通型微流体芯片。 In one embodiment, a flow-through microfluidic chip for measuring blood glucose is prepared by processing on a plastic by laser etching. It is also possible to process a flow-through microfluidic chip for measuring blood sugar by injection molding on a plastic.

在一种实施方式中，薄膜生物传感器的电极材料可以是 Au、 Pt、 Pd、 R 、 Ru、 Ag、 Ni、 C等等。电极可以通过溅射法、化学气相沉积、等离子体气相沉积、或丝网印刷等方法进行制备。薄膜生物传感器的载体材料可以是用塑料、硅、玻璃、陶瓷。塑料可以是 PI、 PEI、 PSE、 PES、 PVC、 PET、或 PP。薄膜生物传感器中绝缘层材料可以是 PMMA、 PL PEI、 SU8、 Si0₂ 或 >S₃N₄。 In one embodiment, the electrode material of the thin film biosensor may be Au, Pt, Pd, R, Ru, Ag, Ni, C, or the like. The electrode can be prepared by a sputtering method, chemical vapor deposition, plasma vapor deposition, or screen printing. The carrier material of the thin film biosensor can be made of plastic, silicon, glass, ceramic. The plastic can be PI, PEI, PSE, PES, PVC, PET, or PP. The insulating layer material in the thin film biosensor may be PMMA, PL PEI, SU8, Si0 ₂ or >S ₃ N ₄ .

在一种实施方式中，工作电极是直径小于 1.5 m 的圆形单电极，或微电极阵列；制备工作电极的材料可以是 Pt、 Pd、 R 、或 Ru，优选地是 Rh。工作电极可以通过溅射法、化学气相沉积、等离子体气相沉积或电镀的方法制备。 In one embodiment, the working electrode is a circular single electrode having a diameter of less than 1.5 m, or a microelectrode array; the material for preparing the working electrode may be Pt, Pd, R, or Ru, preferably Rh. The working electrode can be prepared by a sputtering method, a chemical vapor deposition, a plasma vapor deposition or an electroplating method.

在一种实施方式中，参比电极是尺寸小于 3 ²的任何几何图形，优选地为环绕工作电极的环形带。制备参比电极的材料可以是 Ag或 Ag/AgCl。参比电极可以通过溅射法、化学气相沉积、等离子体气相沉积或电镀的方法制备。当参比电极的材料为 Ag 时，是通过氧化将 Ag转化成为 Ag/AgCl。例如，在 HC1中，通过恒电流氧化 Ag成为 Ag/AgCL In one embodiment, the reference electrode is any geometric shape having a size less than 3 ² , preferably an endless belt surrounding the working electrode. The material for preparing the reference electrode may be Ag or Ag/AgCl. The reference electrode can be prepared by a sputtering method, a chemical vapor deposition, a plasma vapor deposition or an electroplating method. When the material of the reference electrode is Ag, Ag is converted to Ag/AgCl by oxidation. For example, in HC1, Ag is oxidized by constant current to become Ag/AgCL.

在一种实施方式中，对电极是尺寸小于 3 ²的任何几何图形，优选地为环绕工作电极的环形带。制备对电极的材料可以是 Au、 Pt、 Pd、 R 、 Ru、或〔。 In one embodiment, the counter electrode is any geometric shape having a size of less than 3 ² , preferably an endless belt surrounding the working electrode. The material for preparing the counter electrode may be Au, Pt, Pd, R, Ru, or [.

在一种实施方式中，可以将多种生物敏感膜和其它不同功能膜固定在薄膜生物传感器工作电极上。在薄膜生物传感器上可以有敏感膜、消除干扰的膜、扩散控制的膜或生物兼容性的膜。 In one embodiment, a plurality of bio-sensitive membranes and other different functional membranes can be immobilized on the membrane biosensor working electrode. There may be sensitive membranes, interference-eliminating membranes, diffusion-controlled membranes or biocompatible membranes on the membrane biosensor.

在一种实施方式中，敏感膜中可以含有用于血糖检测的葡萄糖氧化酶或葡萄糖脱氢酶，或用于乳酸检测的乳酸氧化酶或乳酸脱氢酶，牛血清白蛋白，全氟磺酸，纤维素；或包含介质，例如用于血糖检测的二甲基二茂铁。优选地是在工作电极上固定葡萄糖氧化酶，制成检测血糖的薄膜生物传感器。 In one embodiment, the sensitive membrane may contain glucose oxidase or glucose dehydrogenase for blood glucose detection, or lactate oxidase or lactate dehydrogenase for lactate detection, bovine serum albumin, perfluorosulfonic acid , cellulose; or a medium, such as dimethyl ferrocene for blood glucose testing. Preferably, glucose oxidase is immobilized on the working electrode to form a thin film biosensor for detecting blood sugar.

在一种实施方式中，消除干扰的膜可以是纤维素、全氟磺酸、聚碳酸酯、聚氨酯、或电聚合苯二胺。 In one embodiment, the interference-eliminating film can be cellulose, perfluorosulfonic acid, polycarbonate, polyurethane, or electropolymerized phenylenediamine.

在一种实施方式中，扩散控制的膜可以是全氟磺酸、聚碳酸酯、聚氨酯、或聚四氟乙烯。 In one embodiment, the diffusion controlled membrane can be perfluorosulfonic acid, polycarbonate, polyurethane, or polytetrafluoroethylene.

在一种实施方式中，生物兼容性的膜可以是全氟磺酸、聚碳酸酯、聚氨酯、聚四氟乙烯、聚乙二醇、聚环氧乙烷、或肝素。 In one embodiment, the biocompatible film can be perfluorosulfonic acid, polycarbonate, polyurethane, polytetrafluoroethylene, polyethylene glycol, polyethylene oxide, or heparin.

在一种实施方式中，全氟磺酸、聚碳酸酯、聚氨酯、或聚四氟乙烯可以具有多重功能。 In one embodiment, perfluorosulfonic acid, polycarbonate, polyurethane, or polytetrafluoroethylene can have multiple functions.

在一种实施方式中，可以用温敏式分配器将一定体积例如小于 1 μ/的膜溶液精准地放置在所需的位置并覆盖所需的区域，例如，只覆盖工作电极的表面，形成很薄的膜；或用电聚合方法***所需的生物酶例如 GOx; 或用浸涂方法固定非敏感膜的其它膜。 In one embodiment, a temperature sensitive dispenser can be used to accurately place a volume of a film solution, for example less than 1 μ/, in a desired location and cover the desired area, for example, covering only the surface of the working electrode. A very thin film; or an electropolymerization method to insert a desired biological enzyme such as GOx; or a dip coating method to fix other films of the non-sensitive film.

在一种实施方式中，在组装流通型微流体芯片和生物薄膜传感器中，使用双面胶，双面胶可以是很薄的压敏胶，例如小于 350μΜ。在双面胶上加工有图案的开孔，让有些地方不要被胶覆盖；将有图案的双面胶按设计精确地置于在流通型微流体芯片和生物薄膜传感器之间。例如，让检测室 /传感器、流通口不会被胶遮挡；并且，检测室 /传感器、流通口定位放置；另外，可在通型微流体生物芯片和生物薄膜传感器上加其它设置，帮助定位组装。组装时，在通型微流体生物芯片和生物薄膜传感器之间加一定的压力或温度，固定。 In one embodiment, in assembling a flow-through microfluidic chip and a biofilm sensor, a double-sided tape is used, The double-sided tape can be a very thin pressure sensitive adhesive, for example less than 350 μΜ. A patterned opening is formed in the double-sided tape so that some areas are not covered by the glue; the patterned double-sided tape is accurately placed between the flow-through microfluidic chip and the biofilm sensor. For example, the detection chamber/sensor and the flow port are not blocked by the glue; and the detection chamber/sensor and the flow port are positioned; in addition, other settings can be added to the through-type microfluidic biochip and the biofilm sensor to help locate the assembly. . When assembled, apply a certain pressure or temperature between the pass-through microfluidic biochip and the biofilm sensor to fix it.

在一种实施方式中，在组装流通型微流体芯片和生物薄膜传感器中，使用适当粘度的 UV胶，采用盖印（stamping ) 方法，将很薄有图案的 UV胶精确地转移到流通型微流体芯片上设定的位置。将生物薄膜传感器按设计精确地盖在流通型微流体芯片上；例如，让检测室 /传感器、流通口定位放置，可在通型微流体生物芯片和生物薄膜传感器加其它设置，帮助定位组装。组装时，加压、 UV光照固化 UV胶，固定。 In one embodiment, in assembling a flow-through microfluidic chip and a biofilm sensor, a very thin patterned UV glue is accurately transferred to a flow-through type using a UV glue of a suitable viscosity using a stamping method. The position set on the fluid chip. The biofilm sensor is precisely designed to cover the flow-through microfluidic chip; for example, by positioning the detection chamber/sensor and the flow port, other settings can be added to the integrated microfluidic biochip and biofilm sensor to aid in positioning assembly. When assembled, the UV glue is cured by pressure and UV light and fixed.

在一种实施方式中，在组装流通型微流体芯片和生物薄膜传感器中，使用超声波焊接或激光焊接，该方法较适合于至少焊接的一面是塑料。将和生物薄膜传感器按设计精确地盖在流通型微流体芯片上。例如，让检测室 /传感器、流通口定位放置，可在生物芯片和生物传感器加其它设置，帮助定位组装。组装时，加压，施加适合的超声波频率，固定。 In one embodiment, ultrasonic welding or laser welding is used in assembling the flow-through microfluidic chip and biofilm sensor, and the method is more suitable for at least one side of the solder being plastic. The biofilm sensor will be accurately placed on the flow-through microfluidic chip as designed. For example, by positioning the chamber/sensor and flow port, you can add other settings to the biochip and biosensor to help locate the assembly. When assembling, pressurize, apply a suitable ultrasonic frequency, and fix it.

在一种实施方式中，微流体泵的面积小于 5 cm²，高度小于 10 mm , 微小的尺寸，使其容易与监测***的其它部件整合为一体；该泵死体积很小，容易快速更新采集的体液。结合生物芯片的微流体控流线路，控制流速，让体液按适当的流速流经***，例如，流速小于 10 μ〃ηώι，在一天 24小时内采集的体液小于 14.4 m/。另外，控制微流体泵，使采集的体液根据具体的应用要求，连续或间歇地流过嵌入生物芯片的生物传感器，以达到对不同时间点的体液，在对应时间点测定体液中分析物的信号，最终得到实时反映分析物浓度随时间变化的曲线。微流体泵可位于体液采样器与生物芯片之间，或紧接在生物芯片之后。 In one embodiment, the microfluidic pump has an area of less than 5 cm ² and a height of less than 10 mm, and the small size makes it easy to integrate with other components of the monitoring system; the pump has a small dead volume and is easy to update and collect quickly. Body fluids. In combination with the microfluidic flow control circuit of the biochip, the flow rate is controlled so that the body fluid flows through the system at an appropriate flow rate, for example, the flow rate is less than 10 μ〃ηώ, and the body fluid collected within 24 hours a day is less than 14.4 m/. In addition, the microfluidic pump is controlled so that the collected body fluid flows continuously or intermittently through the biosensor embedded in the biochip according to specific application requirements to achieve body fluid at different time points, and the signal of the analyte in the body fluid is measured at the corresponding time point. Finally, a curve reflecting the concentration of the analyte over time is obtained in real time. The microfluidic pump can be located between the body fluid sampler and the biochip, or immediately after the biochip.

在一种实施方式中，废液收集器面积小于 5 cm²，高度小于 10 mm ; 内含超高吸水性材料，减少所需体积，例如 5 c ²的废液收集器可以吸收约 27 /或更多的水。测试校准室可以直接固定在贴身亚***内；或者可以根据需要在校准时才引人测试校准室，这样可以减小贴身亚***的体积。在无需校准时，废液收集器的开关是打开的，同时测试校准室的开关是关闭的。按照设定的校准时间或具体需求，打开测试校准室的开关，同时关闭废液收集器的开关，使采集的体液流入测试校准室；校准完成后，立即打开废液收集器的开关同时关闭测试校准室的开关，因此校准时，无需另外取样，实现了无痛校准。在校准时，有手动校准和自动校准两种方式，在手动校准时，手动导入须校准分析物的检测条例如血糖试纸条；在自动校准时，自动地导入须校准分析物的检测条。例如，在手动校准时，使用小于 0.5 m 直径的导管，可将体液滴到血糖试纸条的*** 位；在自动校准时，可使用 Bayer BREEZE 2血糖测试盒类的试纸条组件。测试校准室可位于体液采样器与生物芯片之间，或与废液收集器并行地紧接在微流体泵之后。 In one embodiment, the waste collector has an area of less than 5 cm ² and a height of less than 10 mm; contains an ultra-high water-absorbent material to reduce the required volume, for example, a 5 c ² waste collector can absorb about 27 / or More water. The test calibration chamber can be directly attached to the body sub-system; or the calibration chamber can be introduced at the time of calibration as needed to reduce the volume of the sub-system. When calibration is not required, the waste collector switch is turned on and the test calibration chamber switch is turned off. Open the switch of the test calibration room according to the set calibration time or specific requirements, and close the switch of the waste collector to make the collected body fluid flow into the test calibration room. After the calibration is completed, immediately open the waste liquid. The collector's switch also turns off the switch in the test calibration chamber, so no additional sampling is required for calibration, resulting in a painless calibration. In the calibration, there are two methods: manual calibration and automatic calibration. In the manual calibration, manually introduce the detection strip of the analyte to be calibrated, such as a blood glucose test strip. In the automatic calibration, the test strip of the analyte to be calibrated is automatically introduced. For example, in manual calibration, a catheter with a diameter of less than 0.5 m can be used to drop the body onto the examination site of the blood glucose test strip; in the case of automatic calibration, the test strip assembly of the Bayer BREEZE 2 blood glucose test kit can be used. The test calibration chamber can be located between the body fluid sampler and the biochip, or immediately after the microfluidic pump in parallel with the waste collector.

在一种实施方式中，贴身式电子仪控制传感器和微流体泵以及进行处理，通过无线传输将信号传输到佩戴式电子仪。贴身式电子仪可以由电池供电，与皮肤接触部分，应对皮肤无剌激、符合医用标准，并易于贴身放置。 In one embodiment, the body-mounted electronic control sensor and microfluidic pump are processed and processed to transmit signals to the wearable electronic device via wireless transmission. The on-body electronics can be powered by batteries, in contact with the skin, should be non-irritating to the skin, meet medical standards, and be easily placed close to the body.

在一种实施方式中，紧凑型佩带式电子仪进行信号处理和储存，并无线或有线传输信号到数据处理和传输终端设备。紧凑型佩带式电子仪中可输入校准值，显示分析物的生理结果例如血糖的浓度；预测并显示分析物的变化趋势、方向和速率，超过设定阈值范围的报警；可以由电池供电。 In one embodiment, the compact wearable electronic device performs signal processing and storage and transmits signals wirelessly or by wire to data processing and transmission terminal equipment. The compact wearable electronics can be entered with calibration values that show the physiological results of the analyte, such as the concentration of blood glucose; predict and display the trend, direction and rate of the analyte, alarms that exceed the set threshold range; can be battery powered.

在本发明中使用微型体液采样器，其用手指力将单针或多针剌入到皮肤中，从身体中以合适流速抽取合适量的体液，结合微流体泵用于体液中分析物的连续监测，特别适合应用于体液中的血糖连续监测。本发明的微型体液采样器结构紧凑、容易使用；本发明的微型体液采样器在大气压力下使用，取样时，一方面死体积小、结果可靠和准确，另一方面时间延迟非常短，可以用于连续监测，并且取样后不需要将抽取的体液送回到身体中。 In the present invention, a micro-body sampler is used, which uses a finger force to pry a single needle or a multi-needle into the skin, extracts a suitable amount of body fluid from the body at a suitable flow rate, and combines the microfluidic pump for continuous analysis of the analyte in the body fluid. Monitoring, especially suitable for continuous monitoring of blood glucose in body fluids. The micro body fluid sampler of the invention is compact and easy to use; the micro body fluid sampler of the invention is used under atmospheric pressure, and when sampling, the dead volume is small, the result is reliable and accurate, and on the other hand, the time delay is very short, and can be used. Continuous monitoring, and the sampled body fluid does not need to be returned to the body after sampling.

在本发明的微型生物芯片中，检测室不同的尺寸和几何形状、位置及布局，可以用于并联或串联地嵌入各种尺寸和几何形状的薄膜生物传感器；检测室不同的尺寸和几何形状确保嵌入的生物传感器的表面总是与流经的体液接触。嵌入在微生物芯片中检测室的薄膜生物传感器能够同时连续 /间歇地监测体液中的单种或多种分析物。 In the micro biochip of the present invention, the different sizes and geometries, positions and layouts of the detection chambers can be used to insert thin film biosensors of various sizes and geometries in parallel or in series; different sizes and geometries of the detection chamber ensure The surface of the embedded biosensor is always in contact with the body fluid flowing through it. A thin film biosensor embedded in a detection chamber in a microbial chip is capable of simultaneously/intermittently monitoring single or multiple analytes in body fluids.

本发明的流通型微流体芯片的各种几何形状和表面，允许体液在微流体生物芯片中流通顺利并且死体积最小，无气泡。微流体线路的各种尺寸和几何形状，允许***以不同的速率采取不同量的体液，调整到适当的速率，就避免了采取大量的体液而将采取的体液送回体内的非常危险的情况。 The various geometries and surfaces of the flow-through microfluidic chips of the present invention allow for the smooth flow of body fluids in the microfluidic biochip with minimal dead volume and no bubbles. The various sizes and geometries of microfluidic circuits allow the system to take different amounts of body fluid at different rates, adjusting to an appropriate rate, avoiding the very dangerous situation of taking large amounts of body fluids and returning bodily fluids to the body.

本发明的流通型微流体芯片具有不同的尺寸和几何形状的入口和出口通道，用于连接与微型生物芯片连接的器件例如采样器和微流体泵，并让连接的死体积最小。本发明的流通型微流体芯片的总体积非常小，例如，小于 15微升，这样允许在短的时间之内，例如小于 15分钟，以连续或间歇的速率，例如缓慢速率，更新所有在微型生物芯片内的流体。这样可以保证，每隔几分钟，每一次的测量数据都是来源于新鲜采取的体液中的检测分析物，而不是旧体液中的该分析物。 The flow-through microfluidic chip of the present invention has inlet and outlet channels of different sizes and geometries for connecting devices coupled to the microbiochip, such as samplers and microfluidic pumps, and minimizing the dead volume of the connection. The total volume of the flow-through microfluidic chip of the present invention is very small, for example, less than 15 microliters, which allows for a short period of time, For example, less than 15 minutes, all fluids within the microbiochip are updated at a continuous or intermittent rate, such as a slow rate. This ensures that every few minutes, each measurement is derived from the analyte in the freshly taken body fluid, not the analyte in the old body fluid.

在本发明的微型生物芯片中，嵌入在流通型的微生物芯片中薄膜生物传感器具有快的响应。薄膜生物传感器的电极是平面和毫米尺寸，可允许负载更多的酶和蛋白质在生物传感器表面，产生具有较大信号的更稳定的生物传感器。圆形的工作电极表面，可更精确和方便地将膜层固定在电极表面的限定范围内。用过氧化物催化剂例如铑做工作电极材料，可以增加检测信号密度和降低工作电位，减少 /消除体液中共存的尿酸、对乙酰氨基酚、抗坏血酸等对于检测的干扰。使用不可浸出的过氧化物催化剂例如铑，使得过氧化氢的测定，例如血糖、乳酸经各自氧化酶作用产生的过氧化氢，没有浸出物质，导致电极信号更稳定，适合于同时连续监测体液中多种物质。使用多层的生物传感器膜，可将干扰降至最低，延展检测的动态范围，提高生物传感器的使用寿命和生物相容性，适合于连续监测体液中的物质。 In the micro biochip of the present invention, the thin film biosensor embedded in the flow-through microbial chip has a fast response. The electrodes of the thin-film biosensor are planar and millimeter-sized, allowing more enzymes and proteins to be loaded on the surface of the biosensor to produce a more stable biosensor with a larger signal. The circular working electrode surface allows the film layer to be more precisely and conveniently fixed within the defined range of the electrode surface. The use of a peroxide catalyst such as ruthenium as a working electrode material can increase the detection signal density and lower the operating potential, and reduce/eliminate the interference of detection of uric acid, acetaminophen, ascorbic acid, etc. coexisting in body fluids. The use of non-leaching peroxide catalysts such as hydrazine, the determination of hydrogen peroxide, such as blood sugar, lactic acid by the action of the respective oxidase hydrogen peroxide, no leaching substances, resulting in more stable electrode signal, suitable for continuous monitoring of body fluids A variety of substances. The use of multi-layer biosensor membranes minimizes interference, extends the dynamic range of detection, improves biosensor life and biocompatibility, and is suitable for continuous monitoring of substances in body fluids.

在本发明的微型生物芯片中，薄膜生物传感器还可以包括：用于***仪器插口的凸出块。 In the micro biochip of the present invention, the thin film biosensor may further include: a protruding block for inserting into the instrument socket.

本发明的微型生物芯片是体外生物传感器，一方面减少了传感器缺氧的问题，扩大了传感器动态响应范围；另一方面，无体内对植入传感器的响应，极大地减少了传感器性能衰减和信号漂移的问题，因此只需较少的校准点。 The micro biochip of the invention is an in vitro biosensor, which reduces the problem of sensor hypoxia and expands the dynamic response range of the sensor; on the other hand, no in vivo response to the implanted sensor, greatly reducing sensor performance attenuation and signal Drift problems, so fewer calibration points are needed.

本发明的微型生物芯片中，以并联或串联方式，在同一个电极基板上集成排列的多种不同类型的工作电极，可同时连续监测多种分析物，例如血糖、乳酸等；以并联或串联方式，在同一个电极基板上集成排列的多个同类型的工作电极，可同时连续监测一种分析物，例如，用二个葡萄糖工作电极检测葡萄糖，以减少单个工作电极失效的风险，并极大地增加测定的可靠性；在薄膜生物传感器中几个工作电极共享相同的参比电极和对电极。本发明的微型生物芯片中，对电极和参比电极可以是同一个电极。 In the micro biochip of the present invention, a plurality of different types of working electrodes arranged in parallel or in series on the same electrode substrate can continuously monitor a plurality of analytes, such as blood glucose, lactic acid, etc.; in parallel or in series In this way, multiple working electrodes of the same type are arranged on the same electrode substrate, and one analyte can be continuously monitored at the same time, for example, two glucose working electrodes are used to detect glucose, so as to reduce the risk of failure of a single working electrode. Earth increases the reliability of the assay; several working electrodes share the same reference and counter electrodes in the thin film biosensor. In the micro biochip of the present invention, the counter electrode and the reference electrode may be the same electrode.

综上，本发明各实施例中的动态连续测定体液中分析物的便携式监测***，可具有以下优点的一种或多种： In summary, the portable monitoring system for dynamically and continuously measuring analytes in body fluids in various embodiments of the present invention may have one or more of the following advantages:

更短的预热时间，例如，使用未稀释体液的体外 CGM; Shorter warm-up time, for example, in vitro CGM using undiluted body fluids;

更准确的结果，例如，使用体外 CGM传感器，没有植入体内的传感器问题；需要更少的校准点，例如，使用体外 CGM，只需一点校准； More accurate results, for example, using in vitro CGM sensors, no sensor problems implanted in the body; fewer calibration points are required, for example, using in vitro CGM, with a little calibration;

无痛，甚至可自动校准；取样时疼痛感降低、操作简单，例如，取样时，使用方便的***和取出的微针；本发明实施例可根据具体的应用要求采集体液，然后按适当的流速连续或间歇地流过嵌入生物芯片的生物传感器，使其没有必要将提取液返回体内； Painless, even automatic calibration; The pain is reduced during the sampling, and the operation is simple. For example, when sampling, convenient insertion and removal of the microneedle are used; in the embodiment of the invention, the body fluid can be collected according to the specific application requirements, and then the embedded organism can be continuously or intermittently flowed at an appropriate flow rate. The biosensor of the chip makes it unnecessary to return the extract to the body;

本发明实施例可使用快速响应的薄膜传感器，可嵌入在一个微型生物芯片的微流体流通线路中； Embodiments of the present invention may use a fast response thin film sensor that can be embedded in a microfluidic flow line of a micro biochip;

本发明实施例的监测***灵敏度高，特别是在低血糖范围。附图说明 The monitoring system of the embodiments of the present invention is highly sensitive, particularly in the low blood glucose range. DRAWINGS

为了更清楚地说明本申请实施例中的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请中记载的一些实施例，对于本领域普通技术人员来说，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它的附图。 In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings to be used in the embodiments will be briefly described below. Obviously, the drawings in the following description are only some embodiments described in the present application. Other drawings may also be obtained from those of ordinary skill in the art in light of the inventive work.

图 1是本申请实施例中动态连续测定体液中分析物的便携式监测***原理图；图 2是本申请实施例中动态连续测定体液中分析物的监测***贴身亚***部件分解及展开示意图； 1 is a schematic diagram of a portable monitoring system for dynamically and continuously measuring an analyte in a body fluid in an embodiment of the present application; FIG. 2 is a schematic diagram showing the decomposition and expansion of a sub-system component of a monitoring system for an analyte in a dynamic continuous measurement of a body fluid in an embodiment of the present application;

图 3是本申请实施例中动态连续测定体液中分析物的监测***贴身亚***部件组装示意图； 3 is a schematic view showing the assembly of the sub-system components of the monitoring system of the analyte in the dynamic continuous measurement of the body fluid in the embodiment of the present application;

图 4是本申请实施例中动态连续测定体液中分析物的监测***传感器信号校准示意图； 4 is a schematic diagram of calibration of a sensor signal of a monitoring system for dynamically and continuously measuring an analyte in a body fluid in an embodiment of the present application;

图 5是本申请实施例中单微针微型体液采样器的拆分和组装结构示意图； 5 is a schematic view showing the disassembly and assembly structure of a single microneedle micro body fluid sampler in the embodiment of the present application;

图 6是本申请实施例中单微针微型体液采样器的拆分和组装结构示意图沿 A-A和 B- B线的剖视图； 6 is a cross-sectional view along the line A-A and B-B of the single microneedle micro body fluid sampler in the embodiment of the present application;

图 7是本申请实施例中多微针微型体液采样器的拆分和组装结构示意图； 7 is a schematic view showing the disassembly and assembly structure of the multi-microneedle micro body fluid sampler in the embodiment of the present application;

图 8是本申请实施例中多微针微型体液采样器的拆分和组装结构示意图沿 C-C线的剖视图； Figure 8 is a cross-sectional view along the line C-C of the disassembling and assembling structure of the multi-microneedle micro body fluid sampler in the embodiment of the present application;

图 9是本申请实施例中单个检测室的流通型微流体芯片示意图； 9 is a schematic view of a flow-through microfluidic chip of a single detection chamber in the embodiment of the present application;

图 10是本申请实施例中多个检测室的流通型微流体芯片示意图； 10 is a schematic view of a flow-through microfluidic chip of a plurality of detection chambers in an embodiment of the present application;

图 11是本申请实施例中单个传感器的电极组及其展开示意图； 11 is a schematic diagram of an electrode group of a single sensor and an expanded view thereof in the embodiment of the present application;

图 12是本申请实施例中多个传感器的电极组及其展开示意图； 12 is a schematic diagram of an electrode group of a plurality of sensors and an expanded view thereof in the embodiment of the present application;

图 13是本申请实施例中单检测室及单传感器的生物芯片组装及展开示意图；图 14是本申请实施例中多检测室及多传感器的生物芯片组装及展开示意图。具体实施方式 13 is a schematic diagram showing the assembly and deployment of a biochip of a single detection chamber and a single sensor in the embodiment of the present application; 14 is a schematic diagram showing the assembly and deployment of a biochip of a multi-detection chamber and a multi-sensor in the embodiment of the present application. detailed description

为了使本领域技术领域人员更好地理解本申请中的技术方案，下面将结合本申请实施例中的附图，对本申请实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例，都应当属于本申请保护的范围。实施例一动态连续测定体液中分析物的便携式监测*** In order to make those skilled in the art better understand the technical solutions in the present application, the technical solutions in the embodiments of the present application will be clearly and completely described in the following with reference to the accompanying drawings in the embodiments of the present application. The embodiments are only a part of the embodiments of the present application, and not all of the embodiments. All other embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present application without departing from the inventive scope should fall within the scope of the application. Example 1 Portable Monitoring System for Dynamic and Continuous Determination of Analytes in Body Fluids

1.便携式监测*** 1. Portable monitoring system

参见图 1-3，动态连续测定体液中分析物的便携式监测***用于连续监测体液中的各种分析物，例如血糖、乳酸、钠离子、钙离子、镁离子、氯离子、碳酸氢根离子以及体液中各种蛋白质等等。它由贴身亚*** 31、紧凑型佩带式电子仪 32 以及数据处理和传输终端设备 33组成，数据处理和传输终端设备 33可以是手机、电脑、或其它电子设食 Referring to Figures 1-3, a portable monitoring system for the dynamic and continuous determination of analytes in body fluids is used to continuously monitor various analytes in body fluids such as blood glucose, lactic acid, sodium ions, calcium ions, magnesium ions, chloride ions, bicarbonate ions. And various proteins in body fluids and so on. It consists of a personal sub-system 31, a compact wearable electronic device 32, and a data processing and transmission terminal device 33. The data processing and transmission terminal device 33 can be a mobile phone, a computer, or other electronic device.

当贴身亚*** 31的微针置于皮肤 15内，启动贴身式电子仪 11来控制微流体泵 8和薄膜生物传感器 4后，该监测***开始工作收集数据。收集到待分析物的实时数据后，实时将收集的数据无线传输到紧凑型佩带式电子仪 32进行数据的存储、分析处理、显示分析物的生理结果，分析物的生理结果例如可以是血糖的浓度及变化趋势，并对超过设定阈值范围的结果向病人报警。然后可将结果无线或通过连线 16有线传输给数据处理和传输终端设备 33，进行数据的长期存储，结果的分析处理及显示。数据处理和传输终端设备 33还可将有关数据和结果通过互联网上传到网上的个人 "云" 中，与病人的授权人分享例如如医生、家属、挚友，提供便捷、多方面、长期的个人健康信息，便于诊断、治疗、疾病追踪和管理。 When the microneedles of the sub-system 31 are placed in the skin 15, the intimate electronic instrument 11 is activated to control the microfluidic pump 8 and the thin film biosensor 4, and the monitoring system begins to work to collect data. After the real-time data of the analyte is collected, the collected data is wirelessly transmitted to the compact wearable electronic device 32 for data storage, analysis processing, and physiological results of the analyte, and the physiological result of the analyte may be, for example, blood sugar. Concentration and trend, and alert the patient to results that exceed the set threshold range. The results can then be transmitted wirelessly or via wire 16 to the data processing and transmission terminal device 33 for long term storage of the data, analysis and processing of the results. The data processing and transmission terminal device 33 can also upload relevant data and results to the personal "cloud" on the Internet via the Internet, and share with the patient's authorized person, for example, doctors, family members, and friends, to provide convenient, multi-faceted, long-term personal health. Information for easy diagnosis, treatment, disease tracking and management.

2.贴身亚*** 2. Personal body system

参见图 2-3，贴身亚*** 31包括：体液采样器微针固定器 1及固定的微针 101和微针固定贴士 2，流通型微流体芯片 3和薄膜生物传感器 4，微导管 7，微流体泵 8，分叉式微导管 9，废液收集器 10，贴身式电子仪 11及分叉式微导管 9的开关 12 Referring to FIG. 2-3, the body sub-system 31 includes: a body fluid sampler microneedle holder 1 and a fixed micro-needle 101 and micro-needle fixing tips 2, a flow-through microfluidic chip 3 and a thin film biosensor 4, and a microcatheter 7, Microfluidic pump 8, bifurcated microcatheter 9, waste collector 10, close-fitting electronic instrument 11 and switch 12 of bifurcated microcatheter 9

当设计和选择贴身亚*** 31的部件时，确保微针固定器 1的流体出口微导管 103与微流体生物芯片的流体入口 301无缝匹配；流通型微流体芯片 3的流体出口 307与薄膜生物传感器 4的流体出口 410对齐，组装成生物芯片 6; 微导管 7的流体入口 701与薄膜生物传感器 4的流体出口 410无缝匹配，同时微导管 7的流体出口 702与微流体泵 8 的流体入口 801无缝匹配；分叉式微导管 9的流体入口 901与微流体泵 8 的流体出口 802无缝匹配，同时分叉式微导管 9的流体出口 903与废液收集器 10的流体入口无缝匹配。当组装贴身亚*** 31时，将微导管流体出口 103与流体入口 301，流体出口 410与流体入口 701，流体出口 702与流体入口 801，流体出口 802与流体入口 901，流体出口 903与废液收集器 10的流体入口；用胶分别将每对匹配的出口与入口固定在一起，保证所有联接处联接死体积最小。亚*** 31的各个部分依次相互连接贯通，组成一个完整流体通路。 When designing and selecting the components of the body sub-system 31, the fluid outlet microcatheter 103 of the microneedle holder 1 is ensured The fluid inlets 301 of the microfluidic biochip are seamlessly matched; the fluid outlets 307 of the flow-through microfluidic chip 3 are aligned with the fluid outlets 410 of the membrane biosensor 4, assembled into a biochip 6; the fluid inlets 701 and membrane biosensors of the microcatheters 7 The fluid outlets 410 of 4 are seamlessly matched while the fluid outlets 702 of the microcatheters 7 are seamlessly matched with the fluid inlets 801 of the microfluidic pump 8; the fluid inlets 901 of the bifurcated microcatheters 9 are seamless with the fluid outlets 802 of the microfluidic pump 8 Matching, while the fluid outlet 903 of the bifurcated microcatheter 9 seamlessly matches the fluid inlet of the waste collector 10. When assembling the body sub-system 31, the microcavity fluid outlet 103 and fluid inlet 301, fluid outlet 410 and fluid inlet 701, fluid outlet 702 and fluid inlet 801, fluid outlet 802 and fluid inlet 901, fluid outlet 903 and waste collection The fluid inlet of the device 10; each pair of matched outlets and the inlet are respectively fixed by glue, ensuring that the dead volume of all joints is minimized. The various portions of sub-system 31 are connected to each other in turn to form a complete fluid path.

当使用该监测***时，先将微针固定贴士 2贴在皮肤取样部位 15，将凸起插头 102 放入凹入插座 202中，并且保证伸出微针 101在固定贴士 2的孔处对准，然后用手指力按压固定器 1，推动固定的微针 101 穿剌进入皮肤中，并且保留在皮肤中，由贴在皮肤上的微针固定贴士 2固定住。将生物芯片 6的仪器插口的凸出块 409***贴身式电子仪 11的传感器接口 1101，微流体泵 8的仪器插口的凸出块 803***贴身式电子仪 11的微流体泵接口 1102，贴身式电子仪 11就可控制微流体泵 8和薄膜生物传感器 4。 When the monitoring system is used, the microneedle fixing tip 2 is first attached to the skin sampling portion 15, the protruding plug 102 is placed in the concave socket 202, and the protruding microneedle 101 is secured at the hole of the fixing tip 2. Align, then press the holder 1 with a finger force, push the fixed micro-needle 101 into the skin, and keep it in the skin, and fix it by the micro-needle fixing Tip 2 attached to the skin. The protruding block 409 of the instrument socket of the biochip 6 is inserted into the sensor interface 1101 of the personal electronic device 11, and the protruding block 803 of the instrument socket of the microfluidic pump 8 is inserted into the microfluidic pump interface 1102 of the electronic device 11 for close-fitting The electronic instrument 11 can control the microfluidic pump 8 and the thin film biosensor 4.

启动贴身式电子仪 11，驱动微流体泵 8和薄膜生物传感器 4，体液就会连续或间断地从剌入的微针 101中抽取，通过流体出口 103，流体入口 301，流过生物芯片 6并与嵌入的薄膜生物传感器 4中的电极组接触，产生待测分析物的检测信号，然后通过流体出口 307、 410，流经微导管 7，微流体泵 8，分叉式微导管 9，进入废液收集器 10。在绝大多数时间内，即非传感器信号校准时段，开关 12关闭了体液进入滴管状的流体出口 902的通道，体液最终都会进入含有超高吸水性材料的废液收集器 10，以极大地减少废液收集器 10的体积。 The on-body electronic instrument 11 is activated to drive the microfluidic pump 8 and the thin film biosensor 4, and the body fluid is continuously or intermittently extracted from the infiltrated microneedle 101, through the fluid outlet 103, the fluid inlet 301, flowing through the biochip 6 and Contact with the electrode group in the embedded membrane biosensor 4 to generate a detection signal of the analyte to be tested, then flow through the fluid outlets 307, 410, through the microcatheter 7, the microfluidic pump 8, the bifurcated microcatheter 9, into the waste liquid Collector 10. In the vast majority of the time, i.e., the non-sensor signal calibration period, the switch 12 closes the passage of bodily fluids into the drip tubular fluid outlet 902, and the body fluid eventually enters the waste collector 10 containing the superabsorbent material to greatly reduce The volume of the waste collector 10.

该贴身亚*** 31可用于连续监测体液中的待测分析物，收集待测分析物的实时数据后，实时将收集的数据无线传输到紧凑型佩带式电子仪 32进行数据的存储、分析处理、显示。 The personal sub-system 31 can be used for continuously monitoring the analyte to be tested in the body fluid, collecting the real-time data of the analyte to be tested, and transmitting the collected data to the compact wearable electronic device 32 in real time for data storage, analysis and processing, display.

3.便携式监测***校准 3. Portable monitoring system calibration

参见图 4，测试校准室与废液收集器 10平行，含有一次性使用的须校准分析物的测试条 13和测试分析物的便携式仪表 14。当进行传感器信号校准时，先将一次性使用的须校准分析物的测试条 13如血糖试纸条的仪表插口端 1302， ***该测试分析物的便携式仪表 14如自我测试血糖仪的插口 1401 ; 将测试条 13的样品采样窗口 1301正好置于滴管状的流体出口 902 的下方，以便流出流体出口 902 的体液正好滴在样品采样窗口 1301；开启便携式仪表 14，开关 12关闭体液进入流体通道 903，不能进入废液收集器 10，让体液流经滴管状的流体出口 902滴在样品采样窗口 1301，进行采样，检测读数。读取便携式仪表 14 的该分析物实时读数，将该读数立即输入紧凑型佩带式电子仪 32 中，进行传感器的实时信号校准。校准完成后，立即打开废液收集器的通道 903，同时关闭体液进入滴管状的流体出口 902开关，让采集的体液进入废液收集器 10; 这样的校准方法无需剌穿皮肤另外取样，做到无痛校准。实施例二微针微型体液采样器 Referring to Figure 4, the test calibration chamber is in parallel with the waste collector 10 and contains a disposable test strip 13 for the analyte to be calibrated and a portable meter 14 for testing the analyte. When performing sensor signal calibration, first use the one-time use The test strip 13 of the analyte to be calibrated, such as the meter socket end 1302 of the blood glucose test strip, the portable meter 14 inserted into the test analyte, such as the socket 1401 of the self-test blood glucose meter; the sample sampling window 1301 of the test strip 13 is placed just in the drop Below the tubular fluid outlet 902, so that the body fluid flowing out of the fluid outlet 902 just drops in the sample sampling window 1301; the portable meter 14 is turned on, the switch 12 closes the body fluid into the fluid channel 903, and cannot enter the waste collector 10, allowing the body fluid to flow through the droplet A tubular fluid outlet 902 is dropped into the sample sampling window 1301 for sampling and detecting readings. The analyte real-time reading of the portable meter 14 is read and immediately entered into the compact wearable electronic instrument 32 for real-time signal calibration of the sensor. After the calibration is completed, the channel 903 of the waste collector is immediately opened, and the body fluid is turned into the fluid outlet 902 of the drop tube to allow the collected body fluid to enter the waste collector 10; such a calibration method does not need to pierce the skin and sample separately. Painless calibration. Example 2 microneedle micro body fluid sampler

1.单微针微型体液采样器 1. Single micro needle micro body fluid sampler

参见图 5和图 6，体液采样器包括三个主要组件：微针 101，微针固定器 1，和微针固定贴士 2。微针 101在微针体中具有通道，该通道具有能够将出口 103与体液连通的孔。 Referring to Figures 5 and 6, the body fluid sampler consists of three main components: Microneedle 101, Microneedle Holder 1, and Microneedle Fixing Tip 2. The microneedle 101 has a channel in the microneedle body that has a hole that can connect the outlet 103 to the body fluid.

微针固定器 1包括以下四个部分：在底部具有孔的凸起插头 102，在侧面的流体出口 103，微针固定器 1内的流体通道 104，和微针固定器主体 105。凸起插头 102位于微针固定器 1的底部和在凸起插头 102的底部孔用于容纳单微针 101。微针 101密封地固定在凸起插头 102 的底部孔中，并且以特定长度伸出凸起插头 102，伸出凸起插头 102 的长度通常小于 10 mm, 优选地小于 5 mm, 和更优选地小于 3 mm。流体通道 104连接微针 101和出口 103。 The microneedle holder 1 comprises the following four parts: a raised plug 102 having a hole at the bottom, a fluid outlet 103 at the side, a fluid passage 104 in the microneedle holder 1, and a microneedle holder body 105. The raised plug 102 is located at the bottom of the microneedle holder 1 and at the bottom hole of the raised plug 102 for receiving the single microneedle 101. The microneedle 101 is sealingly secured in the bottom aperture of the male plug 102 and projects the raised plug 102 by a particular length, typically extending less than 10 mm, preferably less than 5 mm, and more preferably Less than 3 mm. The fluid passage 104 connects the microneedle 101 and the outlet 103.

微针固定贴士 2包括以下四个部分：在凹入插座 202中的孔 201，在微针固定贴士主体 204中间的凹入插座 202，在凹入插座 202周围的凸缘 203，和贴在凸缘 203的底部上具有衬垫的医用粘合剂 205。孔 201和凹入插座 202两者分别与微针 101和凸起插头 102在位置、尺寸和几何形状上精确地匹配。 The microneedle fixing tip 2 comprises the following four parts: a hole 201 in the recessed socket 202, a recessed socket 202 in the middle of the microneedle fixing tip body 204, a flange 203 around the recessed socket 202, and a sticker A medical adhesive 205 having a liner on the bottom of the flange 203. Both the aperture 201 and the recessed receptacle 202 are precisely matched in position, size and geometry to the microneedle 101 and the raised plug 102, respectively.

当体液取样时，用酒精清洁皮肤取样部位，剥去医用粘合剂 205 的衬垫，将凸缘 203贴在皮肤取样部位；将凸起插头 102放入凹入插座 202中，并且保证伸出微针 101 在孔 201处对准，然后用手指力按压固定器主体 105，推动固定的微针 101通过孔 201 穿剌进入皮肤中，并且保留在皮肤中，由贴在皮肤上的微针固定贴士 2固定住。剌入皮肤的深度由伸出微针 101 的长度控制，和凸起插头 102限制穿入深度以保证安全，不管使用者的技能如何。可以通过穿入皮肤中不同的深度来取样不同体液，例如可以取样组织液、血液、或者组织液和血液的混合物。 When the body fluid is sampled, the skin sampling site is cleaned with alcohol, the liner of the medical adhesive 205 is peeled off, the flange 203 is attached to the skin sampling site; the raised plug 102 is placed in the recessed socket 202, and the protrusion is secured. The microneedle 101 is aligned at the hole 201, and then the holder body 105 is pressed with a finger force, and the fixed microneedle 101 is pushed through the hole 201 into the skin, and remains in the skin, and is fixed by the microneedle attached to the skin. Tip 2 is fixed. The depth of the skin is controlled by the length of the protruding microneedle 101, and the protruding plug 102 limits the penetration depth to ensure safety, regardless of What is the user's skill. Different body fluids can be sampled by penetrating into different depths in the skin, for example, tissue fluid, blood, or a mixture of tissue fluid and blood can be sampled.

根据特定应用需要，流体出口 103可以直接连接至微流体泵，或者先通过其它装置，例如生物芯片，然后连接至微流体泵。当运行连接的微流体泵时，体液连续或间断地从剌入的微针 101 中抽取，流动通过流体通道 104和流体出口 103，进入到检测装置中用于连续监测体液中的分析物，例如体液中的血糖、乳酸等等。 Depending on the needs of the particular application, the fluid outlet 103 can be directly connected to the microfluidic pump or first through other means, such as a biochip, and then to the microfluidic pump. When the connected microfluidic pump is operated, body fluid is continuously or intermittently drawn from the infiltrated microneedles 101, flows through the fluid channel 104 and the fluid outlet 103, into the detection device for continuous monitoring of analytes in the body fluid, such as Blood sugar, lactic acid, etc. in body fluids.

当需要去除时，用手指将整个微针固定器 1和微针固定贴士 2从皮肤拿开，然后将其安全地丢弃。 2.多微针微型体液采样器 When removal is required, use the fingers to remove the entire microneedle holder 1 and microneedle fixing tips 2 from the skin and then safely discard them. 2. Multi-micro needle micro body fluid sampler

参见图 7和图 8，单微针微型体液采样器和多微针微型体液采样器之间的主要区别是：在微针固定器 1 中凸起插头 102的底部的多个孔和多个微针 101密封地固定插头 102的底部。同时，在固定贴士 2内凹入插座 202和多个孔 201分别与凸起插头 102和多个微针 101在位置、尺寸和几何形状上精确地匹配。在微针固定器 1中另外通道 106用于聚集来自多个微针的多个流体流动路径进入到一个路径中，连接到流体通道 104和出 Π 103。 Referring to Figures 7 and 8, the main difference between the single microneedle micro-body sampler and the multi-microneedle micro-body sampler is: a plurality of holes and a plurality of micros at the bottom of the raised plug 102 in the microneedle holder 1. The needle 101 sealingly secures the bottom of the plug 102. At the same time, the recessed receptacle 202 and the plurality of apertures 201 in the securing tip 2 are precisely matched in position, size and geometry to the raised plug 102 and the plurality of microneedles 101, respectively. In the microneedle holder 1 an additional channel 106 is used to collect a plurality of fluid flow paths from the plurality of microneedles into one path, connecting to the fluid channel 104 and the exit pupil 103.

当将凸起插头 102放入到凹入插座 202中时，确保在推动凸起插头 102进入到凹入插座 202中时，伸出的多个微针 101精确地对准它们相应孔 201。 When the raised plug 102 is placed into the recessed receptacle 202, it is ensured that the plurality of extended microneedles 101 are accurately aligned with their respective apertures 201 as the pusher plug 102 is pushed into the recessed receptacle 202.

多微针微型体液采样器的其它结构、运行和操作方式与单微针微型体液采样器基本相同，这里不重复地说明。实施例三微型生物芯片 The other structure, operation, and operation of the multi-microneedle micro-body sampler are substantially the same as for a single micro-needle micro-body sampler and will not be repeated here. Example 3 micro biochip

1.具有单检测室和单传感器的微型生物芯片 1. Micro biochip with single detection chamber and single sensor

参见图 9、 11和 14，具有单检测室和单传感器的生物芯片 6用于连续监测体液中的各种分析物，例如血糖、乳酸、钠离子、钙离子、镁离子、氯离子、碳酸氢根离子以及体液中各种蛋白质等等等。它由流通型微流体芯片 3和薄膜生物传感器 4组装而成。它可以用于连续检测体液中的单个待分析物。 Referring to Figures 9, 11, and 14, a biochip 6 with a single detection chamber and a single sensor is used to continuously monitor various analytes in body fluids, such as blood glucose, lactic acid, sodium ions, calcium ions, magnesium ions, chloride ions, hydrogen carbonate. Root ions and various proteins in body fluids, etc. It is assembled from a flow-through microfluidic chip 3 and a thin film biosensor 4. It can be used to continuously detect a single analyte in a body fluid.

1.1流通型微流体芯片 1.1 flow-through microfluidic chip

参见图 9，流通型微流体芯片 3 的微流体线路通常是由以下几个部分组成：流体入口 301，微孔 302，蛇形通道 303，检测室 310，微通道 306，和流体出口 307。流通型微流体芯片 3 的各个部分依次相互连接贯通，组成一个完整流体通路。上述各个部分都嵌入微流体生物芯片主体 3。 Referring to Figure 9, the microfluidic circuit of the flow-through microfluidic chip 3 is generally composed of the following components: a fluid inlet 301, a micropore 302, a serpentine channel 303, a detection chamber 310, a microchannel 306, and a fluid outlet 307. Circulation type micro The various portions of the fluid chip 3 are sequentially connected to each other to form a complete fluid passage. Each of the above sections is embedded in the microfluidic biochip body 3.

上述各个部分根据不同需要可以具有不同的尺寸和形状，微孔 302 的不同大小的尺寸用于调节微流体的流动阻力和体外***中的背压或阻力；蛇形通道 303 的不同的长度和曲率用于调节微流体的流动阻力和体外***中的背压或阻力；检测室 310不同的尺寸和几何形状、位置及布局，与放置嵌入检测室 310的各种尺寸和几何形状的薄膜生物传感器相匹配。 The various sections described above may have different sizes and shapes according to different needs, and the different sizes of the microholes 302 are used to adjust the flow resistance of the microfluids and the back pressure or resistance in the extracorporeal system; the different lengths and curvatures of the serpentine channels 303 Used to adjust the flow resistance of the microfluidics and the back pressure or resistance in the in vitro system; the different dimensions and geometry, position and layout of the detection chamber 310, and the thin film biosensors of various sizes and geometries embedded in the detection chamber 310 match.

1.2薄膜生物传感器 1.2 Thin film biosensor

参见图 11，薄膜生物传感器通常由以下几个部分组成：圆形的工作电极 401，环绕工作电极 401的环带型对电极 405，参比电极 406，多个电极与仪器连接的接触垫 408，多条连接多个电极与多个接触垫的连线 407，用于***仪器插口的凸出块 409，连接体液的穿透孔 410，电极的绝缘层 420，及与多个电极匹配的绝缘层图案开孔 421。所述组分都负载于薄膜生物传感器的主体 4上。 Referring to FIG. 11, the thin film biosensor generally comprises the following parts: a circular working electrode 401, a ring-type counter electrode 405 surrounding the working electrode 401, a reference electrode 406, and a plurality of contact pads 408 connected to the instrument. a plurality of wires 407 connecting the plurality of electrodes and the plurality of contact pads, a protruding block 409 for inserting the instrument socket, a through hole 410 connecting the body fluid, an insulating layer 420 of the electrode, and an insulating layer matched with the plurality of electrodes Pattern opening 421. The components are all loaded on the body 4 of the thin film biosensor.

检测室 310与嵌入的薄膜生物传感器的工作电极 401、对电极 405、参比电极 406匹配，并确保嵌入的工作电极 401、对电极 405、参比电极 406匹配的表面总是与流经的体液接触，确保连续监测体液中的各种物质。微流体生物芯片 3 的微流体线路的各个部分的各种几何形状和表面，还必须允许体液在微流体生物芯片 3 中流通顺利并且死体积最小，无气泡。微流体线路的各种尺寸和几何形状，结合微流体泵，使***以不同的速率采集不同量的体液；调整到适当的速率，可以避免了采取大量的体液，因此不需要将采取的体液送回体内，避免了这种不利和非常危险的情况。 The detection chamber 310 is matched with the working electrode 401, the counter electrode 405, and the reference electrode 406 of the embedded thin film biosensor, and ensures that the surface of the embedded working electrode 401, the counter electrode 405, and the reference electrode 406 is always matched with the body fluid flowing through. Contact to ensure continuous monitoring of various substances in body fluids. The various geometries and surfaces of the various portions of the microfluidic circuit of the microfluidic biochip 3 must also allow for the smooth flow of body fluids in the microfluidic biochip 3 with minimal dead volume and no bubbles. The various sizes and geometries of microfluidic circuits, combined with microfluidic pumps, allow the system to collect different amounts of body fluids at different rates; adjusting to an appropriate rate avoids the need to take large amounts of body fluids, so there is no need to take bodily fluids Back to the body, this unfavorable and very dangerous situation is avoided.

薄膜生物传感器的性能决定于传感器工作电极上的膜。固定多种不同的生物敏感膜和其它不同功能膜在工作电极上，制成多种不同的生物传感器。例如，在 R 电极上固定葡萄糖氧化酶，可制成检测血糖的生物传感器；在电极上固定各种离子选择性膜，可以制成检测体液中离子浓度的离子电极；在电极上固定各种抗体，可以制成检测体液中各种蛋白质浓度的电极。通过控制固定膜的厚度，制成薄膜生物传感器 4，然后可与流通型微流体芯片 3组装成生物芯片 6，用于连续监测体液中的分析物。 The performance of a thin film biosensor is determined by the membrane on the working electrode of the sensor. A variety of different biosensors and other different functional membranes are immobilized on the working electrode to make a variety of different biosensors. For example, a glucose oxidase can be immobilized on the R electrode to prepare a biosensor for detecting blood sugar; various ion selective membranes can be immobilized on the electrode to prepare an ion electrode for detecting the ion concentration in the body fluid; and various antibodies are immobilized on the electrode. It can be used as an electrode for detecting various protein concentrations in body fluids. The thin film biosensor 4 is fabricated by controlling the thickness of the fixed film, and then assembled into the biochip 6 with the flow-through microfluidic chip 3 for continuous monitoring of the analyte in the body fluid.

1.3.组装生物芯片 1.3. Assembling the biochip

参见图 13，将刻有流体通路的流通型微流体芯片 3和固定了所需膜的薄膜生物传感器 4按设计对齐，并调整薄膜生物传感器 4，使生物传感膜层朝下。在流通型微流体芯片 3和薄膜生物传感器 4之间，放入带匹配的图案开孔的薄层双面胶 5，对齐；确保流体孔 307、 501、 410对齐，同时开孔 502正好位于检测室 310上面。然后加压固定，得到组装的生物芯片 6。 Referring to Figure 13, a flow-through microfluidic chip 3 engraved with a fluid path and a thin film biosensing to which a desired membrane is attached The device 4 is aligned as designed and the membrane biosensor 4 is adjusted such that the biosensor film layer faces downward. Between the flow-through microfluidic chip 3 and the thin film biosensor 4, a thin layer of double-sided tape 5 with matching pattern openings is placed, aligned; ensure that the fluid holes 307, 501, 410 are aligned, and the opening 502 is located just in the detection Above the chamber 310. Then, it is fixed by pressurization to obtain an assembled biochip 6.

选择与流体入口 301和出口 307通道在尺寸和几何形状上匹配的合适微导管，用胶将选好的微导管分别固定在入口 301和出口 307上，然后与连续监测体液中物质的分析 ***中的体液采样器和微流体泵连接，并使连接通道的死体积最小。当生物芯片通过流体入口 301与体液采样器，和通过流体出口 307与微流体泵连接后，启动微流体泵，体液就会从体内经体液采样器通过流体入口 301、微孔 302、蛇形通道 303、检测室 310、微通道 306、和流体出口 307流过微流体生物芯片 3，流经微流体泵，进入废液收集器；在检测室 310中体液与薄膜生物传感器中的工作电极 401、对电极 405、参比电极 406接触。 A suitable microcatheter that is sized and geometrically matched to the fluid inlet 301 and outlet 307 channels is selected, and the selected microcatheters are respectively fixed to the inlet 301 and the outlet 307 by glue, and then in an analysis system for continuously monitoring the substance in the body fluid. The body fluid sampler is connected to the microfluidic pump and minimizes the dead volume of the connecting channel. When the biochip is connected to the body fluid sampler through the fluid inlet 301 and the fluid pump 307, the microfluidic pump is activated, and the body fluid passes from the body through the body fluid sampler through the fluid inlet 301, the micropore 302, and the serpentine channel. 303, the detection chamber 310, the microchannel 306, and the fluid outlet 307 flow through the microfluidic biochip 3, through the microfluidic pump, into the waste collector; in the detection chamber 310, the working electrode 401 in the body fluid and the thin film biosensor, The counter electrode 405 and the reference electrode 406 are in contact.

2.具有多检测室和多传感器的生物芯片 2. Biochip with multiple detection chambers and multiple sensors

参见图 10、 12和 14，具有多检测室以及多传感器的生物芯片 6用于连续监测体液中的各种分析物，例如血糖、乳酸、钠离子、钙离子、镁离子、氯离子、碳酸氢根离子以及体液中各种蛋白质等等等。它由流通型微流体芯片 3和薄膜生物传感器 4组装而成。它可以用于同时连续地检测体液中的多个待分析物。 2.1流通型微流体芯片 Referring to Figures 10, 12 and 14, a biochip 6 with multiple detection chambers and multiple sensors is used to continuously monitor various analytes in body fluids, such as blood glucose, lactic acid, sodium ions, calcium ions, magnesium ions, chloride ions, hydrogencarbonate. Root ions and various proteins in body fluids, etc. It is assembled from a flow-through microfluidic chip 3 and a thin film biosensor 4. It can be used to simultaneously detect multiple analytes in body fluids continuously. 2.1 flow-through microfluidic chip

参见图 10，流通型微流体芯片 3 的微流体线路由以下几个部分组成：流体入口 301 , 微孔 302，蛇形通道 303，检测室 310和 311，微通道 304、 305和 306，以及流体出口 307。各个部分依次连接贯通。组成一个完整流体通路。上述各个部分都嵌入微流体生物芯片主体 3。 Referring to Fig. 10, the microfluidic circuit of the flow-through microfluidic chip 3 is composed of the following parts: a fluid inlet 301, a micropore 302, a serpentine channel 303, detection chambers 310 and 311, microchannels 304, 305 and 306, and a fluid. Exit 307. The various parts are connected in series. Form a complete fluid pathway. Each of the above sections is embedded in the microfluidic biochip body 3.

2.2薄膜生物传感器 2.2 Thin film biosensor

参见图 12，薄膜生物传感器 4通常是由以下几个部分组成： 4个圆形的工作电极 401、 402、 403、 404，对电极 405，参比电极 406，多个电极与仪器连接的接触垫 408，多条连接多个电极与多个接触垫的连线 407，用于***仪器插口的凸出块 409，连接体液的穿透孔 410，电极的绝缘层 420，以及与多个电极匹配的绝缘层图案开孔 421。上述各个部分都负载于主体 4上。具有多检测室和多传感器的生物芯片与具有单检测室和单传感器的微型生物芯片不同之处：有两个检测室 310、 311；与之匹配的薄膜生物工作电极组 401-406包括 4个工作电极 401、 402、 403、和 404，其中工作电极 401、 402对应于检测室 310，工作电极 403、 404对应于检测室 311。 2个微通道 304将体液分流入检测室 310和 311； 2个微通道 305将分流入检测室 310和 311的体液汇合在一起。 Referring to Fig. 12, the thin film biosensor 4 is generally composed of the following parts: 4 circular working electrodes 401, 402, 403, 404, counter electrode 405, reference electrode 406, contact pads of a plurality of electrodes connected to the instrument 408, a plurality of wires 407 connecting the plurality of electrodes and the plurality of contact pads, a protruding block 409 for inserting the instrument socket, a through hole 410 connecting the body fluid, an insulating layer 420 of the electrode, and matching with the plurality of electrodes The insulating layer pattern opening 421. Each of the above parts is loaded on the main body 4. A biochip with multiple detection chambers and multiple sensors differs from a micro biochip with a single detection chamber and a single sensor: there are two detection chambers 310, 311; the matched thin film bio-working electrode groups 401-406 include four The working electrodes 401, 402, 403, and 404, wherein the working electrodes 401, 402 correspond to the detecting chamber 310, and the working electrodes 403, 404 correspond to the detecting chamber 311. The two microchannels 304 divide the body fluid into the detection chambers 310 and 311; the two microchannels 305 merge the body fluids flowing into the detection chambers 310 and 311 together.

在这 4个不同的工作电极上可制备 4个不同的生物工作电极，例如血糖、乳酸、氧气、 pH值生物传感器。工作电极 401、 402顺联地嵌入检测室 310，工作电极 403、 404 顺联地嵌入检测室 311，同时工作电极 401、 402与工作电极 403、 404并联地置于生物芯片 6。因此，可同时接续地监测 4种不同的分析物。并将可能有相互干扰的传感器并联置于不同的检测室中，避免了干扰。 Four different bio-working electrodes, such as blood glucose, lactic acid, oxygen, pH biosensors, can be prepared on these four different working electrodes. The working electrodes 401, 402 are slidably embedded in the detection chamber 310, and the working electrodes 403, 404 are compliantly embedded in the detection chamber 311, while the working electrodes 401, 402 are placed in parallel with the working electrodes 403, 404 on the biochip 6. Therefore, four different analytes can be monitored simultaneously. Sensors that may interfere with each other are placed in parallel in different test chambers to avoid interference.

2.3组装生物芯片 2.3 assembling biochips

参见图 14，将刻好的流通型微流体芯片 3和固定了所需膜的薄膜生物传感器 4按设计对齐，并调整薄膜生物传感器 4，使生物传感膜层朝上。在流通型微流体芯片 3和薄膜生物传感器 4之间，放入带匹配的图案开孔的薄层双面胶 5，对齐；确保流体孔 307、 501、 410很好地对齐，同时开孔 502正好位于检测室 310上面，开孔 503正好位于检测室 311上面。然后加压固定，就得到组装的生物芯片 6。 Referring to Fig. 14, the flow-through microfluidic chip 3 and the thin film biosensor 4 to which the desired film is attached are aligned as designed, and the thin film biosensor 4 is adjusted so that the biosensor film layer faces upward. Between the flow-through microfluidic chip 3 and the thin film biosensor 4, a thin layer of double-sided tape 5 with matching pattern openings is placed, aligned; ensuring that the fluid holes 307, 501, 410 are well aligned while opening 502 Just above the detection chamber 310, the opening 503 is located just above the detection chamber 311. Then, the assembled biochip 6 is obtained by pressurization.

选择与流体入口 301和出口 307通道在尺寸和几何形状上匹配的适合的微导管，用胶将选好的微导管分别固定在入口 301和出口 307上，然后与连接连续监测体液中的分析物***中的体液采样器和微流体泵，并使连接通道的死体积最小。当生物芯片通过流体入口 301与体液采样器，及流体出口 307与微流体泵连接后，启动微流体泵，体液就会从体内经体液采样器通过流体入口 301、微孔 302、蛇形通道 303、分流微通道 304，将体液分别导入检测室 310和 311，在检测室中与薄膜生物工作电极 401-406接触；然后汇集入微通道 305、微通道 306，和经过流体出口 307，流经微流体泵，进入废液收集器。 A suitable microcatheter that is sized and geometrically matched to the fluid inlet 301 and outlet 307 channels is selected, and the selected microcatheters are respectively fixed to the inlet 301 and the outlet 307 with glue, and then the analytes in the body fluid are continuously monitored with the connection. The body fluid sampler and microfluidic pump in the system minimize the dead volume of the connecting channel. When the biochip is connected to the body fluid sampler through the fluid inlet 301 and the fluid outlet 307, and the microfluidic pump is connected, the microfluidic pump is activated, and the body fluid passes from the body through the body fluid sampler through the fluid inlet 301, the microhole 302, and the serpentine channel 303. Dividing the microchannels 304, introducing the body fluids into the detection chambers 310 and 311, respectively, contacting the membrane bio-working electrodes 401-406 in the detection chamber; then collecting into the microchannels 305, the microchannels 306, and passing through the fluid outlets 307, flowing through the microfluids Pump, enter the waste collector.

以上实施例示出了 2个检测室及相应的 4个工作电极的多检测室生物芯片结构；本领域技术人员将意识到到根据需要，本发明的生物芯片可以具有更多个检测室的生物芯片，用于检测体液中更多个物质。 The above embodiment shows a multi-detection chamber biochip structure of two detection chambers and corresponding four working electrodes; those skilled in the art will recognize that the biochip of the present invention can have more biochips of the detection chamber as needed. , used to detect more substances in body fluids.

应该理解到披露的本发明不仅仅限于描述的特定的方法、方案和物质，因为这些均可变化。还应理解这里所用的术语仅仅是为了描述特定的实施方式方案的目的，而不是意欲限制本发明的范围，本发明的范围仅受限于所附的权利要求。 It is to be understood that the invention disclosed is not limited to the specific methods, aspects, and materials described, as these may vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only The scope of the invention is intended to be limited only by the scope of the appended claims.

本领域的技术人员还将认识到，或者能够确认使用不超过常规实验，在本文中所述的本发明的具体的实施方案的许多等价物。这些等价物也应包含在所附的权利要求中。 Those skilled in the art will also recognize, or be able to ascertain, many equivalents of the specific embodiments of the invention described herein. These equivalents are also intended to be included in the appended claims.

Claims

权利要求书 Claim

1.一种动态连续测定体液中分析物的便携式监测***，其特征在于，其包括：贴身亚***，所述贴身亚***包括通过微导管依次相互连接贯通、组成一个完整流体通路的微型体液采样器和微型生物芯片，其中： WHAT IS CLAIMED IS: 1. A portable monitoring system for dynamically and continuously measuring analytes in body fluids, comprising: a body sub-system comprising micro-body fluid sampling sequentially connected to each other through a microcatheter to form a complete fluid pathway And micro biochips, where:

流通型微流体芯片包括：依次相互连通，组成一个完整流体通路的流体入口，微孔和 /或微型通道，检测室，微通道，流体出口； The flow-through microfluidic chip comprises: a fluid inlet, a micropore and/or a microchannel, a detection chamber, a microchannel, a fluid outlet, which are sequentially connected to each other to form a complete fluid passage;

2.根据权利要求 1所述的便携式监测***，其特征在于，所述贴身亚***还包括：微流体泵，微流体泵位于微型体液采样器与微型生物芯片之间，或紧接在微型生物芯片之后；提供可控的动力，将吸取的体液流过微型生物芯片。 2. The portable monitoring system according to claim 1, wherein the body sub-system further comprises: a microfluidic pump, the microfluidic pump being located between the micro body fluid sampler and the micro biochip, or immediately adjacent to the micro organism After the chip; provides controllable power to flow the bodily fluids through the micro biochip.

3.根据权利要求 2所述的便携式监测***，其特征在于，所述贴身亚***还包括：贴身式电子仪，通过传感器接口和微流体泵接口，分别与微型生物芯片和微流体泵连接；当启动所述贴身式电子仪，驱动微流体泵和薄膜生物传感器，体液连续或间断地从剌入皮肤的微针管中抽取，流过流通型微流体芯片并与嵌入的薄膜生物传感器中的电极组接触，产生待测分析物的检测信号。 The portable monitoring system according to claim 2, wherein the personal body system further comprises: a personal electronic device, which is respectively connected to the micro biochip and the microfluidic pump through a sensor interface and a microfluidic pump interface; When the on-body electronic instrument is activated, the microfluidic pump and the thin film biosensor are driven, the body fluid is continuously or intermittently extracted from the microneedle tube that has penetrated the skin, flows through the flow-through microfluidic chip and interacts with the electrode in the embedded thin film biosensor The group contacts, generating a detection signal of the analyte to be tested.

4.根据权利要求 2所述的便携式监测***，其特征在于，所述贴身亚***还包括：测试校准室和废液收集器，其中测试校准室固定设置在贴身亚***内或者在校准时加入到贴身亚***中；在测定体液中分析物时，体液进入废液收集器，校准时，体液进入测试校准室；测试校准室位于微型体液采样器与微型生物芯片之间，或与废液收集器并行地紧接在微流体泵之后。 The portable monitoring system according to claim 2, wherein the personal body system further comprises: a test calibration room and a waste liquid collector, wherein the test calibration room is fixedly disposed in the body sub-system or is added during calibration In the body-contact sub-system; when measuring the analyte in the body fluid, the body fluid enters the waste collector, and when it is calibrated, the body fluid enters the test calibration chamber; the test calibration chamber is located between the micro-body sampler and the micro-biochip, or with the waste liquid collection The device is immediately after the microfluidic pump.

5.根据权利要求 1所述的便携式监测***，其特征在于，所述便携式监测***还包括：紧凑型佩带式电子仪，和 /或，数据处理和传输终端设备； The portable monitoring system according to claim 1, wherein the portable monitoring system further comprises: Compact wearable electronics, and / or, data processing and transmission terminal equipment;

所述紧凑型佩带式电子仪或所述数据处理和传输终端设备直接实时、无线传输地接收贴身亚***产生的待测分析物的检测或校准信号，然后进行数据的存储、分析处理、和显示分析物的生理结果；或者所述数据处理和传输终端设备通过无线或有线传输方式接收所述紧凑型佩带式电子仪的显示分析物的生理结果，并将测试结果传输到互联网上存储，与其他人分享。 The compact wearable electronic device or the data processing and transmission terminal device directly receives the detection or calibration signal of the analyte to be detected generated by the body sub-system in real-time and wireless transmission, and then performs data storage, analysis processing, and display. Physiological results of the analyte; or the data processing and transmission terminal device receives the physiological result of displaying the analyte of the compact wearable electronic device by wireless or wired transmission, and transmits the test result to the Internet for storage, and other People share.

6.根据权利要求 1所述的便携式监测***，其特征在于： 6. The portable monitoring system of claim 1 wherein:

所述微针固定器包括：在底部具有孔的凸起插头，流体出口，微针固定器内的流体通道，和微针固定器主体； The microneedle holder includes: a raised plug having a hole at the bottom, a fluid outlet, a fluid passage in the microneedle holder, and a microneedle holder body;

所述微针固定贴士包括：微针固定贴士主体中的凹入插座，凹入插座中的孔，在凹入插座周围的凸缘； The microneedle fixing tips include: a recessed socket in the microneedle fixing tip body, a hole recessed into the socket, and a flange around the recessed socket;

所述微针固定器的凸起插头位于微针固定器的底部，所述凸起插头的底部孔用于容纳微针，微针密封地固定在凸起插头的底部孔中，并且伸出凸起插头； The protruding plug of the microneedle holder is located at the bottom of the microneedle holder, the bottom hole of the protruding plug is for accommodating the microneedle, and the microneedle is sealingly fixed in the bottom hole of the protruding plug, and protrudes convexly Plug up

所述微针在微针体中具有将所述微针固定器的流体出口与体液连通的孔；所述微针固定贴士的孔和凹入插座分别与所述微针和所述微针固定器的凸起插头在位置、尺寸和几何形状上匹配。 The microneedle has a hole in the microneedle body that communicates a fluid outlet of the microneedle holder with body fluid; the microneedle fixing tip hole and the recessed socket are respectively associated with the microneedle and the microneedle The raised plugs of the holder match in position, size and geometry.

7.根据权利要求 6所述的便携式监测***，其特征在于，所述微针固定器中凸起插头的底部具有多个孔，所述微针固定贴士的凹入插座中具有多个孔，多个所述微针密封地固定在凸起插头的底部多个孔中，所述微针固定贴士内凹入插座和多个孔分别与所述凸起插头和多个微针在位置、尺寸和几何形状上匹配。 The portable monitoring system according to claim 6, wherein the bottom of the protruding plug of the microneedle holder has a plurality of holes, and the microneedle fixing tips have a plurality of holes in the recessed socket a plurality of the microneedles are sealingly fixed in a plurality of holes in the bottom of the protruding plug, the microneedle fixing tips are recessed into the socket and the plurality of holes are respectively in position with the protruding plug and the plurality of microneedles , size and geometry match.

8.根据权利要求 7所述的便携式监测***，其特征在于，所述微针固定器中具有用于聚集来自多个微针的多个流体流动路径进入到一个路径中的通道。 8. The portable monitoring system of claim 7, wherein the microneedle holder has a channel for collecting a plurality of fluid flow paths from the plurality of microneedles into a path.

9.根据权利要求 6所述的便携式监测***，其特征在于，所述微型体液采样器面积小于 5 cw²，高度小于 10 mm The portable monitoring system according to claim 6, wherein the micro body fluid sampler has an area of less than 5 cw ² and a height of less than 10 mm.

10.根据权利要求 6所述的便携式监测***，其特征在于，所述微针伸出凸起插头的长度小于 10 mm。 10. A portable monitoring system according to claim 6 wherein the length of the microneedle projecting projection plug is less than 10 mm.

1 1.根据权利要求 10所述的便携式监测***，其特征在于，所述微针伸出凸起插头的长度小于 5 。 A portable monitoring system according to claim 10, wherein the length of the microneedle projecting the protruding plug is less than five.

12.根据权利要求 6所述的便携式监测***，其特征在于，所述微针穿入体内并留在体内进行采样，对皮肤及皮下组织只有微创或几乎无创。 12. The portable monitoring system according to claim 6, wherein the microneedles penetrate into the body and remain in the body for sampling, and are only minimally invasive or almost non-invasive to the skin and subcutaneous tissue.

13.根据权利要求 6所述的便携式监测***，其特征在于，所述微针固定贴士底面有带胶的宽边，用于将整个微型体液采样器固定在采样处皮肤表面，进行采样。 The portable monitoring system according to claim 6, wherein the microneedle fixing tip has a wide side with a glue for fixing the entire micro body fluid sampler to the skin surface of the sampling place for sampling.

14.根据权利要求 6所述的便携式监测***，其特征在于，所述微针固定贴士还包括：贴在凸缘底部上的医用粘合剂。 14. The portable monitoring system of claim 6, wherein the microneedle fixing tips further comprise: a medical adhesive attached to the bottom of the flange.

15.根据权利要求 6所述的便携式监测***，其特征在于，所述微型体液采样器固定在采样处皮肤表面，进行采样。 The portable monitoring system according to claim 6, wherein the micro body fluid sampler is fixed to a surface of the skin at the sampling place for sampling.

16.根据权利要求 1所述的便携式监测***，其特征在于，在流通型微流体芯片和薄膜生物传感器之间，放入具有与薄膜生物传感器匹配的图案开孔的薄层双面胶进行组装；或通过盖印方法转移与薄膜生物传感器图案匹配的液体胶进行组装；或通过超声焊接或激光焊接的方法组装流通型微流体芯片和薄膜生物传感器。 16. The portable monitoring system according to claim 1, wherein a thin layer of double-sided tape having a pattern opening matching the film biosensor is assembled between the flow-through microfluidic chip and the thin film biosensor. Or by means of a stamping method to transfer the liquid glue matched with the film biosensor pattern for assembly; or to assemble a flow-through microfluidic chip and a thin film biosensor by ultrasonic welding or laser welding.

17.根据权利要求 1所述的便携式监测***，其特征在于，微导管分别固定在流体入口和流体出口中，固定在流体入口的微导管将流体入口与连续监测体液中物质的分析系统中的体液采样器连接，固定在流体出口的微导管将流体出口与微流体泵连接。 17. The portable monitoring system according to claim 1, wherein the microcatheters are respectively fixed in the fluid inlet and the fluid outlet, and the microcatheter fixed at the fluid inlet is in the fluid inlet and the analysis system for continuously monitoring the substance in the body fluid. The body fluid sampler is connected, and the microcatheter fixed to the fluid outlet connects the fluid outlet to the microfluidic pump.

18.根据权利要求 1所述的便携式监测***，其特征在于，流通型微流体芯片包括两个以上的检测室，在薄膜生物传感器中具有与检测室数量相匹配的工作电极。 18. The portable monitoring system of claim 1 wherein the flow-through microfluidic chip comprises more than two detection chambers having a working electrode in the membrane biosensor that matches the number of detection chambers.

19.根据权利要求 1所述的便携式监测***，其特征在于，流通型微流体芯片的面积小于 5 cw²，高度小于 2 mm 19. The portable monitoring system according to claim 1, wherein the flow-through microfluidic chip has an area of less than 5 cw ² and a height of less than 2 mm

20.根据权利要求 1所述的便携式监测***，其特征在于，检测体液中物质是血糖、乳酸、氧气、 pH值、血细胞比容、电解质其中之一或任意组合。 The portable monitoring system according to claim 1, wherein the substance in the body fluid is detected as one or any combination of blood sugar, lactic acid, oxygen, pH, hematocrit, and electrolyte.

21.根据权利要求 20所述的便携式监测***，其特征在于，通过注塑或激光蚀刻的方法在塑料上加工制备用于测量血糖的流通型微流体芯片。 21. A portable monitoring system according to claim 20, wherein the flow-through microfluidic chip for measuring blood glucose is processed on plastic by injection molding or laser etching.

22.根据权利要求 1 所述的便携式监测***，其特征在于，工作电极是直径小于 1.5 m 的圆形单电极，或微电极阵列；制备工作电极的材料是 Pt、 Pd、 R 、或 Ru。 22. The portable monitoring system according to claim 1, wherein the working electrode is a circular single electrode having a diameter of less than 1.5 m, or a microelectrode array; and the material for preparing the working electrode is Pt, Pd, R, or Ru.

23.根据权利要求 1 所述的便携式监测***，其特征在于，参比电极是尺寸小于 3 ²的环绕工作电极的环形带；制备参比电极的材料是 Ag或 Ag/AgCl。 23. The portable monitoring system according to claim 1, wherein the reference electrode is an annular band of a working electrode that is smaller than 3 ² in size; and the material for preparing the reference electrode is Ag or Ag/AgCl.

24.根据权利要求 1所述的便携式监测***，其特征在于，对电极是尺寸小于 3 ² 的环绕工作电极的环形带；制备对电极的材料是 Au、 Pt、 Pd、 R 、 Ru、或〔。 24. The portable monitoring system according to claim 1, wherein the counter electrode is an endless belt of a working electrode that is smaller than 3 ² in size; and the material for preparing the counter electrode is Au, Pt, Pd, R, Ru, or [ .

25.根据权利要求 1所述的便携式监测***，其特征在于，流通型微流体芯片的总体积小于 15微升，在小于 15分钟，以连续或间歇的速率，更新所有在微型生物芯片内的流体。 25. The portable monitoring system of claim 1 wherein the flow-through microfluidic chip has a total volume of less than 15 microliters and updates all of the micro-biochips at a continuous or intermittent rate in less than 15 minutes. fluid.

26.根据权利要求 1所述的便携式监测***，其特征在于，薄膜生物传感器的电极使用多层的生物传感器膜，连续监测体液中的物质。 26. The portable monitoring system of claim 1 wherein the electrodes of the thin film biosensor use a plurality of layers of biosensor membranes to continuously monitor substances in the body fluid.

27.根据权利要求 1所述的便携式监测***，其特征在于，薄膜生物传感器还包括：用于***仪器插口的凸出块。 27. The portable monitoring system of claim 1 wherein the thin film biosensor further comprises: a raised block for insertion into the instrument socket.

28.根据权利要求 1所述的便携式监测***，其特征在于，以并联或串联方式，在同一个电极基板上集成排列的不同类型的工作电极，同时连续监测多种分析物； The portable monitoring system according to claim 1, wherein different types of working electrodes are arranged on the same electrode substrate in parallel or in series, and a plurality of analytes are continuously monitored;

或，以并联或串联方式，在同一个电极基板上集成排列多个同类型的工作电极，同时连续监测一种分析物。 Or, in parallel or in series, a plurality of working electrodes of the same type are integrally arranged on the same electrode substrate, and one analyte is continuously monitored.

29.根据权利要求 1所述的便携式监测***，其特征在于，对电极和参比电极是同一个电极。 29. The portable monitoring system of claim 1 wherein the counter electrode and the reference electrode are the same electrode.

30.根据权利要求 1所述的便携式监测***，其特征在于，流通型微流体芯片的微型通道是蛇形通道。 30. The portable monitoring system of claim 1 wherein the microchannel of the flow-through microfluidic chip is a serpentine channel.