技术领域technical field
本发明涉及医学测量领域，具体涉及一种无创连续血糖测量系统。The invention relates to the field of medical measurement, in particular to a non-invasive continuous blood sugar measurement system.
背景技术Background technique
糖尿病日益成为危害人类健康的严重疾病，根据世界卫生组织的统计，2015年全球糖尿病患者有超过4亿人，到2040年将超过6亿人。中国糖尿病患者数量居全球第一，有超过1亿人患病。随着人民生活水平的日益提高和运动缺乏等原因，越来越多的人体重超标、肥胖，进而诱发糖尿病。糖尿病的发病年龄也逐渐降低，越来越多的青年人早早就患有了糖尿病。据统计，全球大约每10人中就有1人患有糖尿病，每10人中有5人具有较高的潜在糖尿病患病风险。糖尿病患者的血糖水平如果不能得到很好的控制，会引起眼部、口腔、心血管、肾脏、足部等多器官的并发症，严重者会导致死亡，因此控制血糖水平在稳定的范围内对糖尿病患者延长寿命和维持生活质量至关重要。糖尿病无法被完全治愈，通过控制饮食、增强体育锻炼和终生配合药物和胰岛素注射的方式控制血糖水平。为了控制血糖浓度，需要通过医疗器械测量的方式获得实时的血糖水平。目前最常见的血糖测量方法是通过刺破手指吸取一定量的指尖毛细血管血，并通过血糖仪检测。一般糖尿病患者一天之内需要测量3～4次，病情严重者需要测量更多次。这种测量方法是属于有创测量手段，并且每次测量时会引起患者的疼痛，长期测量会导致手指生茧、手指创口细菌感染，并且因其长期的疼痛和不适，会使患者产生抵触心理，导致血糖测量的依从性差。Diabetes has increasingly become a serious disease that endangers human health. According to the statistics of the World Health Organization, there were more than 400 million people with diabetes in the world in 2015, and it will exceed 600 million people by 2040. The number of diabetic patients in China ranks first in the world, with more than 100 million people suffering from the disease. With the improvement of people's living standards and lack of exercise and other reasons, more and more people are overweight and obese, and then induce diabetes. The age of onset of diabetes is also gradually decreasing, and more and more young people suffer from diabetes at an early age. According to statistics, about 1 in 10 people in the world suffers from diabetes, and 5 in 10 people have a high potential risk of diabetes. If the blood sugar level of diabetic patients cannot be well controlled, it will cause complications in the eyes, mouth, cardiovascular, kidneys, feet and other organs. In severe cases, it will lead to death. Therefore, controlling the blood sugar level within a stable range is important Prolonging longevity and maintaining quality of life in people with diabetes is critical. Diabetes cannot be completely cured, and blood sugar levels can be controlled by controlling diet, increasing physical exercise, and lifelong cooperation with drugs and insulin injections. In order to control the blood sugar concentration, it is necessary to obtain real-time blood sugar level by means of medical device measurement. The most common blood sugar measurement method at present is to draw a certain amount of fingertip capillary blood by pricking a finger, and detect it by a blood glucose meter. Generally, patients with diabetes need to measure 3 to 4 times a day, and those with severe conditions need to measure more times. This measurement method is an invasive measurement method, and each measurement will cause pain to the patient. Long-term measurement will lead to finger calluses, bacterial infection of the finger wound, and because of the long-term pain and discomfort, the patient will have resistance. , resulting in poor compliance with blood glucose measurements.
另外，人的血糖水平变化是一个连续的变化过程，饮食、运动和身体状态的改变都会引起血糖的波动，目前一天之内有限次数血糖测量的方式具有一定的局限性，无法准确和完整的获知血糖超过正常值和低于正常值的时刻。另外当人在睡眠中血糖会有显著的下降，对于糖尿病患者来说低血糖会引起致命的结果，而目前血糖仪测量方法无法实现睡眠中的血糖测量。对于糖尿病患者来说，实时和连续的血糖测量是最有效和安全的血糖水平监控手段，而又因为连续测量需要测量大量数据，因此要求这种血糖测量方法是无创或者微创的，以减低患者的疼痛。In addition, the change of human blood sugar level is a continuous change process. Changes in diet, exercise and physical condition will cause fluctuations in blood sugar. The current way of measuring blood sugar a limited number of times in a day has certain limitations and cannot be accurately and completely known. Moments when blood sugar exceeds and falls below normal. In addition, when a person sleeps, blood sugar will drop significantly, and hypoglycemia will cause fatal results for diabetic patients. However, the current blood glucose meter measurement method cannot realize blood sugar measurement during sleep. For diabetics, real-time and continuous blood glucose measurement is the most effective and safe means of monitoring blood glucose levels, and because continuous measurement requires a large amount of data, it is required that this blood glucose measurement method be non-invasive or minimally invasive to reduce the risk of pain.
微创血糖连续测量的产品以美敦力、雅培、德康等品牌为代表，其方法为将一根软针插入患者皮下并长期佩戴，测量患者皮下组织液中的葡萄糖浓度得到连续的组织液中葡萄糖浓度值，因为组织液中葡萄糖浓度与血液血糖浓度正相关，因此组织液的测量可以一定程度上代表血糖的浓度变化，但是这种方法仍属于有创测量方法，并且病人佩戴不方便，长期使用会引起疼痛，另外组织液的葡萄糖浓度与血液中葡萄糖浓度的具体相关关系不确定，并且具有一定时间的滞后性。Minimally invasive blood glucose continuous measurement products are represented by brands such as Medtronic, Abbott, and Dekang. The method is to insert a soft needle into the patient's skin and wear it for a long time, measure the glucose concentration in the patient's subcutaneous tissue fluid to obtain continuous glucose concentration values in the tissue fluid , because the glucose concentration in the interstitial fluid is positively correlated with the blood glucose concentration, the measurement of the interstitial fluid can represent the concentration change of blood glucose to a certain extent, but this method is still an invasive measurement method, and it is inconvenient for the patient to wear it, and long-term use will cause pain. In addition, the specific relationship between the glucose concentration in the interstitial fluid and the glucose concentration in the blood is uncertain and has a certain time lag.
无创血糖测量的产品大多以红外光谱、拉曼光谱、皮肤阻抗、热量代谢、电磁测量为主，其测量的原理依赖于葡萄糖对不同外界刺激信号的响应，以上原理对葡萄糖的测量的特异性差，容易在水分子、红细胞等物质的存在下被干扰，测量不准确，因此没有能够成为被医学认可的无创连续血糖测量系统。唯一一种曾经通过FDA认证并销售的无创血糖测量产品glucowatch使用的是反向离子渗透方法，但是这种方法需要对皮肤施加较大的电流用于驱动组织液中葡萄糖外涌到皮肤表面测量，但是长时间使用会引起皮肤红肿和过敏等反应，最终停止生产和销售。目前还没有一种能够真实实现无创和准确测量的连续血糖测量方法。Most of the non-invasive blood glucose measurement products are based on infrared spectroscopy, Raman spectroscopy, skin impedance, heat metabolism, and electromagnetic measurement. The measurement principle depends on the response of glucose to different external stimulus signals. The specificity of the above principles for glucose measurement is poor. It is easy to be interfered by substances such as water molecules and red blood cells, and the measurement is inaccurate. Therefore, there is no non-invasive continuous blood glucose measurement system that can be recognized by medicine. The only non-invasive blood glucose measurement product glucowatch that has been certified and sold by the FDA uses the reverse ion osmosis method, but this method requires a large current to be applied to the skin to drive the glucose in the interstitial fluid to the skin surface for measurement. But prolonged use can cause reactions such as skin redness and allergies, and eventually stop production and sales. At present, there is no continuous blood glucose measurement method that can truly achieve non-invasive and accurate measurement.
发明内容Contents of the invention
针对以上现有技术中存在的问题，本发明提出了一种无创连续血糖测量系统。Aiming at the above problems in the prior art, the present invention proposes a non-invasive continuous blood glucose measurement system.
本发明的无创连续血糖测量系统包括：调控物质、正电极、负电极、电源以及皮肤表面的葡萄糖测量仪；其中，正电极与负电极分别放置在皮肤表面，并分别连接至电源；在正电极与皮肤之间放置设定体积和浓度的调控物质；调控物质为能够改变组织液的渗透压的物质，调控物质的形态为膏状、凝胶状、凝露状或胶贴状；调控物质的放置方式为涂抹在正电极表面、涂抹在正电极对应的皮肤表面或者粘贴在正电极表面；调控物质带有正电；电源通过正电极在皮肤表面形成方向垂直于皮肤的电场，方向指向皮肤内，通过离子导入的方式驱动带有正电的调控物质进入皮下；调控物质进入组织液后，提高了组织液的渗透压，渗透压的增加导致血液向组织液的滤过压增加，因为滤过压与滤过量成正比，所以血液中的葡萄糖向组织液中的过滤作用增强，最终导致血液中的葡萄糖滤过血管主动外流到组织液的摩尔质量增加，增加的葡萄糖的质量与滤过压的增加量成正比；电源通过负电极在皮肤表面形成方向垂直于皮肤的电场，方向指向皮肤外，通过反向离子渗透的方式将组织液中的葡萄糖驱动至皮肤表面，形成皮肤表面葡萄糖；通过皮肤表面的葡萄糖测量仪测量皮肤表面葡萄糖的浓度I，并根据事先标定的比例系数K，从而得到人体的血液中的葡萄糖浓度C＝KI。The non-invasive continuous blood sugar measurement system of the present invention comprises: a regulating substance, a positive electrode, a negative electrode, a power supply, and a glucose measuring instrument on the skin surface; wherein, the positive electrode and the negative electrode are respectively placed on the skin surface and connected to the power supply; A regulating substance with a set volume and concentration is placed between the skin; the regulating substance is a substance that can change the osmotic pressure of the interstitial fluid, and the form of the regulating substance is paste, gel, gel or paste; the placement of the regulating substance The method is to smear on the surface of the positive electrode, smear on the surface of the skin corresponding to the positive electrode, or paste on the surface of the positive electrode; the regulating substance is positively charged; the power supply forms an electric field on the surface of the skin through the positive electrode, and the direction points to the skin. Drive the positively charged regulating substance into the subcutaneous through iontophoresis; after the regulating substance enters the interstitial fluid, the osmotic pressure of the interstitial fluid is increased, and the increase of the osmotic pressure leads to an increase in the filtration pressure of the blood to the interstitial fluid, because the filtration pressure and the filtration volume It is directly proportional to the glucose in the blood, so the filtering effect of the glucose in the blood to the interstitial fluid is enhanced, which eventually leads to an increase in the molar mass of the glucose in the blood that actively flows out of the blood vessels to the interstitial fluid, and the mass of the increased glucose is proportional to the increase in the filtration pressure; the power supply The negative electrode forms an electric field perpendicular to the skin on the skin surface, and the direction points out of the skin. The glucose in the interstitial fluid is driven to the skin surface by reverse ion osmosis to form skin surface glucose; the skin is measured by a glucose meter on the skin surface The surface glucose concentration I, and according to the proportional coefficient K calibrated in advance, thus obtain the glucose concentration C=KI in the blood of the human body.
在测量血糖浓度前，需要先标定比例系数：设定体积和浓度的调控物质放置在皮肤表面与正电极之间，通过正电极施加方向垂直于皮肤向内的电场，驱动带正电的调控物质进入组织液，从而增加血液中的葡萄糖渗透到组织液中，通过负电极施加方向垂直于皮肤向外的电场，驱动组织液中的葡萄糖至皮肤表面，通过皮肤表面的葡萄糖测量仪测量皮肤表面葡萄糖的浓度I0，利用测量指尖毛细血管血或静脉血血测量得到此时血液的葡萄糖浓度C0，得到在设定体积和浓度的调控物质下，皮肤表面葡萄糖的浓度I0与血液的葡萄糖浓度C0之间的比例系数K：K＝C0/I0。Before measuring the blood sugar concentration, the proportional coefficient needs to be calibrated first: the regulating substance with a set volume and concentration is placed between the skin surface and the positive electrode, and the positive electrode is applied with an electric field perpendicular to the skin inward to drive the positively charged regulating substance Enter the interstitial fluid, so as to increase the penetration of glucose in the blood into the interstitial fluid, apply an electric field perpendicular to the skin outward through the negative electrode, drive the glucose in the interstitial fluid to the skin surface, and measure the concentration I of glucose on the skin surface by a glucose meter on the skin surface0 , measure the blood glucose concentration C0 by measuring fingertip capillary blood or venous blood at this time, and obtain the glucose concentration I0 on the skin surface and the glucose concentration C0 in the blood under the control substance with a set volume and concentration The coefficient of proportionality K between: K=C0 /I0 .
设定调控物质的体积浓度为0.05％～0.5％；设定调控物质的体积为0.33～5000μL；调控物质的体积和浓度与标定比例系数时的体积和浓度相同。The volume concentration of the regulating substance is set to be 0.05%-0.5%; the volume of the regulating substance is set to be 0.33-5000 μL; the volume and concentration of the regulating substance are the same as those when the proportional coefficient is calibrated.
组织液的葡萄糖来源自血液中葡萄糖透过血管壁的渗透，因此组织液中葡萄糖浓度和血液的葡萄糖浓度具有确定的比例关系，但是两者的相关度没有完全达到医疗诊断的水平，所以有时其浓度的比例关系不再适用，会引起测量的误差，超过临床诊断的容许误差范围。通过调控物质增强了血液中的葡萄糖向组织液中净流出的质量，这样组织液中的葡萄糖浓度与血液的葡萄糖浓度的相关度就会大大提高，可以在临床诊断容许的误差范围内使用组织液葡萄糖浓度和血液葡萄糖浓度的比例关系，达到测量组织液葡萄糖浓度就可以比较准备反推得到血液葡萄糖浓度的效果。通过本方法进行无创血糖测量的开始阶段，需要利用测量指尖毛细血管血或静脉血血糖对无创血糖测量的结果进行标定和修正，针对使用者确定出符合其个人具体情况的组织液葡萄糖浓度和血液葡萄糖浓度的比例关系，作为测量结果与血糖水平的转换关系。The glucose in interstitial fluid comes from the penetration of glucose in the blood through the blood vessel wall, so the glucose concentration in the interstitial fluid and the glucose concentration in the blood have a definite proportional relationship, but the correlation between the two has not fully reached the level of medical diagnosis, so sometimes the concentration The proportional relationship is no longer applicable, which will cause measurement errors, exceeding the allowable error range of clinical diagnosis. The quality of the net outflow of glucose in the blood to the interstitial fluid is enhanced by regulating the substance, so that the correlation between the glucose concentration in the interstitial fluid and the glucose concentration in the blood will be greatly improved, and the glucose concentration in the interstitial fluid and the concentration of glucose in the blood can be used within the allowable error range of clinical diagnosis. The proportional relationship of blood glucose concentration can be compared to the effect of reverse deduction to obtain blood glucose concentration by measuring the glucose concentration of interstitial fluid. In the initial stage of non-invasive blood glucose measurement by this method, it is necessary to calibrate and correct the results of non-invasive blood glucose measurement by measuring fingertip capillary blood or venous blood glucose, and determine the tissue fluid glucose concentration and blood glucose concentration in line with their individual specific conditions for the user. The proportional relationship of the glucose concentration as a conversion of the measurement result to the blood glucose level.
调控物质采用分子量大于100万的透明质酸、糖蛋白、氨基酸和脂肪酸中的一种。The regulating substance adopts one of hyaluronic acid, glycoprotein, amino acid and fatty acid with a molecular weight greater than 1 million.
驱动时间在10～30分钟之间；正电极和负电极的面积在1～30cm2之间。电源为恒压源或恒流源；恒压源的输出电压在2～5V之间；恒流源的输出电流为0.5～10mA/cm2，正电极与负电极之间的中心距离为1～5cm。The driving time is between 10 and 30 minutes; the area of the positive electrode and the negative electrode is between 1 and 30 cm2 . The power supply is a constant voltage source or a constant current source; the output voltage of the constant voltage source is between 2 and 5V; the output current of the constant current source is 0.5 to 10mA/cm2 , and the center distance between the positive electrode and the negative electrode is 1 ~ 5cm.
正电极和负电极的形状为圆形、方形或不规则形状；正电极和负电极采用导电物质，金属、导电聚合物或者导电氧化物半导体；金属例为金、银、铜、铝和锌中的一种；导电聚合物为聚噻吩、聚吡咯、聚乙烯二氧噻吩和聚苯胺中的一种，导电氧化物半导体为氧化铟锡。The shape of the positive electrode and the negative electrode is circular, square or irregular; the positive electrode and the negative electrode are made of conductive materials, such as metal, conductive polymer or conductive oxide semiconductor; metal examples are gold, silver, copper, aluminum and zinc The conductive polymer is one of polythiophene, polypyrrole, polyethylenedioxythiophene and polyaniline, and the conductive oxide semiconductor is indium tin oxide.
皮肤表面的葡萄糖测量仪采用葡萄糖氧化酶生物传感器、红外光谱测量仪器、拉曼光谱葡萄糖测量仪器、微流体芯片、基于场效应管的葡萄糖传感器、荧光反应葡萄糖传感器中的一种。The glucose measuring instrument on the skin surface adopts one of glucose oxidase biosensor, infrared spectrum measuring instrument, Raman spectrum glucose measuring instrument, microfluidic chip, glucose sensor based on field effect tube, and fluorescent reaction glucose sensor.
本发明的优点：Advantages of the present invention:
本发明通过离子导入的方式由正电极向皮下组织液中导入带正电的调控物质，人为调控血液和组织液的渗透压平衡，使得血液中的葡萄糖主动外流到组织液中，再将组织液中原有的葡萄糖和血液外流的葡萄糖通过反向离子渗透的方式由负电极将组织液中的葡萄糖驱动至皮肤表面驱动到皮肤表面，实现无创连续测量；本发明完全无创，测量中不会引起皮肤的不良反应，与可穿戴的血糖测量设备相结合可以实现无创连续的血糖监测；本发明通过控制血液中葡萄糖主动外流的方式，增加了能够被测量到的葡萄糖的含量，并提高了测量对象与血液血糖的相关程度，提高了测量的精度，适合与医疗级的血糖监测。The present invention introduces positively charged regulatory substances from the positive electrode into the subcutaneous tissue fluid by way of iontophoresis, artificially regulates the osmotic pressure balance of blood and tissue fluid, so that the glucose in the blood actively flows out into the tissue fluid, and then the original glucose in the tissue fluid The glucose in the interstitial fluid is driven to the skin surface by the negative electrode through reverse ion osmosis to realize non-invasive continuous measurement; the invention is completely non-invasive and will not cause adverse skin reactions during the measurement. The combination of wearable blood glucose measuring equipment can realize non-invasive and continuous blood glucose monitoring; the present invention increases the content of glucose that can be measured by controlling the active outflow of glucose in the blood, and improves the degree of correlation between the measurement object and blood glucose , which improves the accuracy of measurement and is suitable for medical-grade blood glucose monitoring.
附图说明Description of drawings
图1为本发明的无创连续血糖测量系统的一个实施例的结构示意图。Fig. 1 is a schematic structural diagram of an embodiment of the noninvasive continuous blood glucose measurement system of the present invention.
具体实施方式Detailed ways
下面结合附图，通过具体实施例，进一步阐述本发明。The present invention will be further elaborated below through specific embodiments in conjunction with the accompanying drawings.
如图1所示，本实施例的无创连续血糖测量系统包括：调控物质4、正电极2、负电极3、恒压源1以及皮肤表面的葡萄糖测量仪；其中，正电极2与负电极3分别放置在皮肤表面5，并分别连接至恒压源1；在正电极与皮肤之间涂抹设定体积和浓度的调控物质4；调控物质带有正电；恒压源1通过正电极在皮肤表面形成垂直于皮肤的电场，方向指向皮肤内，通过离子导入的方式驱动带有正电的调控物质进入皮下。As shown in Figure 1, the non-invasive continuous blood glucose measurement system of the present embodiment includes: a regulating substance 4, a positive electrode 2, a negative electrode 3, a constant voltage source 1, and a glucose measuring instrument on the skin surface; wherein, the positive electrode 2 and the negative electrode 3 respectively placed on the skin surface 5, and connected to the constant voltage source 1 respectively; between the positive electrode and the skin, apply a regulation substance 4 with a set volume and concentration; the regulation substance is positively charged; the constant voltage source 1 passes through the positive electrode on the skin An electric field perpendicular to the skin is formed on the surface, and the direction points into the skin, and the positively charged regulatory substance is driven into the subcutaneous area through iontophoresis.
当人摄入糖后，食物分解得到的葡萄糖在胃的消化吸收作用下进入到血液中，在全身血液循环的作用下流遍全身各处，从动脉血管流动到毛细血管的动脉段，并经毛细血管的静脉端流向静脉血管。在毛细血管区域存在着组织液和血液的物质交换，血液中的葡萄糖在毛细血管的动脉端渗透出血管进入组织液，参与细胞的新陈代谢活动，剩余的葡萄糖被毛细血管的静脉端重吸收回毛细血管中。血液和组织液的互相交换决定于两种液体之间的渗透压和液体压强差。在正常状态下，滤过作用比重吸收作用稍强，以此维持组织液中保有一定浓度的葡萄糖。滤过作用和重吸收作用的差为有效滤过压，其决定公式为：When a person ingests sugar, the glucose obtained by decomposing the food enters the blood under the action of digestion and absorption by the stomach, and flows throughout the whole body under the action of the blood circulation of the whole body, from the arterial vessel to the arterial section of the capillary, and then passes through the capillary The venous end of the blood vessel flows into the venous vessel. In the capillary area, there is a material exchange between tissue fluid and blood. The glucose in the blood seeps out of the blood vessel at the arterial end of the capillary and enters the tissue fluid to participate in the metabolic activities of the cells. The remaining glucose is reabsorbed back into the capillary by the venous end of the capillary. . The mutual exchange of blood and interstitial fluid depends on the osmotic pressure and fluid pressure difference between the two fluids. Under normal conditions, filtration is slightly stronger than reabsorption, so as to maintain a certain concentration of glucose in interstitial fluid. The difference between filtration and reabsorption is the effective filtration pressure, and its determination formula is:
NDF＝(Pc+πi)-(Pi+πc)NDF＝(Pc +πi )-(Pi +πc )
其中NDF为有效滤过压大小，Pc为毛细血管血压，πi为组织液渗透压，Pi为组织液静水压，πc为血浆渗透压。正常情况下NDF＞0。Among them, NDF is the effective filtration pressure, Pc is capillary blood pressure, πi is the osmotic pressure of interstitial fluid, Pi is the hydrostatic pressure of interstitial fluid, and πc is the plasma osmotic pressure. Normally NDF>0.
在本发明中，利用离子导入的方式，给待测皮肤表面施加一个垂直的恒定电场，并在正电极正极和人皮肤之间涂抹一定量的调控物质，透明质酸是人体组织液的主要成分，并且带正电，能够在电场的驱动下进入到皮下的组织液中，根据组织液渗透压的公式：In the present invention, a vertical constant electric field is applied to the surface of the skin to be tested by means of iontophoresis, and a certain amount of regulatory substance is applied between the positive electrode of the positive electrode and the human skin. Hyaluronic acid is the main component of human tissue fluid. And it is positively charged, and can enter the subcutaneous interstitial fluid under the drive of the electric field. According to the formula of interstitial fluid osmotic pressure:
πi＝iMRTπi = iMRT
其中，πi为渗透压的大小，i为渗透常数，M为溶质的摩尔浓度，R为理想气体常数，T为开尔文温度。提高了组织液中溶质透明质酸的浓度后，可以提高组织液的渗透压，在不改变其他参数的前提下，这样的操作将引起有效滤过压的提高，滤过压与滤过量成正比，因此此时血液中的葡萄糖向组织液中的滤过作用被增强，重吸收作用被减弱，最终导致血液中的葡萄糖滤过血管进入组织液的量增加。此时组织液中的葡萄糖浓度更高，其与血液中血糖浓度变化的相关度也更高。Among them,πi is the size of the osmotic pressure, i is the permeability constant, M is the molar concentration of the solute, R is the ideal gas constant, and T is the Kelvin temperature. After increasing the concentration of the solute hyaluronic acid in the interstitial fluid, the osmotic pressure of the interstitial fluid can be increased. Under the premise of not changing other parameters, such an operation will lead to an increase in the effective filtration pressure. The filtration pressure is proportional to the filtration volume, so At this time, the filtration of glucose in the blood to the interstitial fluid is enhanced, and the reabsorption is weakened, which eventually leads to an increase in the amount of glucose in the blood that filters into the interstitial fluid through blood vessels. At this time, the glucose concentration in the interstitial fluid is higher, and its correlation with the blood glucose concentration change is also higher.
采用离子导入的方式和反向离子渗透的方式，向皮肤施加离子导入电场后调控物质注入皮肤组织液中的体积流量满足：Using iontophoresis and reverse ion osmosis, after applying an iontophoresis electric field to the skin, the volume flow rate of the substance injected into the skin tissue fluid is adjusted to satisfy:
其中，Jv为体积流量，单位为体积×时间-1×面积-1，LVE为电渗流系数，为皮肤中的电场梯度，离子导入组织液的调控物质体积为体积流量×离子导入时间×离子导入电极面积。Among them, Jv is the volume flow rate, the unit is volume × time-1 × area-1 , LVE is the electroosmotic flow coefficient, is the electric field gradient in the skin, and the regulating substance volume of iontophoresis interstitial fluid is volume flow × iontophoresis time × iontophoresis electrode area.
在采用离子导入法驱动调控物质进入皮下组织中，调控物质的体积与体积流量满足上式，典型情况下，体积流量的范围为1～600μL h-1cm-2，或者1～200μL h-1cm-2，200～400μL h-1cm-2，400～600μL h-1cm-2，200～400μL h-1cm-2，100～500μL h-1cm-2，200～500μL h-1cm-2。在驱动时间20分钟，正电极和负电极为正方形，面积2m2的情形下，离子导入的调控物质的体积为0.33-5000μL范围内，体积范围还可以为0.33～100μL，100～1000μL，1000～2500μL，2500～5000μL，100～3000μL，500～2500μL等。When using the iontophoresis method to drive the regulating substance into the subcutaneous tissue, the volume and volume flow of the regulating substance satisfy the above formula. Typically, the volume flow ranges from 1 to 600 μL h-1 cm-2 , or 1 to 200 μL h-1 cm-2 , 200～400μL h-1 cm-2 , 400～600μL h-1 cm-2 , 200～400μL h-1cm-2 , 100～500μL h-1 cm-2 , 200～500μL h-1 cm-2 . When the driving time is 20 minutes, the positive electrode and the negative electrode are square, and the area is2m2 , the volume of the regulating substance for iontophoresis is in the range of 0.33-5000μL, and the volume range can also be 0.33-100μL, 100-1000μL, 1000-2500μL , 2500~5000μL, 100~3000μL, 500~2500μL, etc.
本实施例的无创的连续血糖测量方法，包括以下步骤：The non-invasive continuous blood glucose measurement method of the present embodiment comprises the following steps:
1)测量前标定比例系数：1) Calibration scale factor before measurement:
驱动体积浓度为0.3％，分子量200万，体积为1000μL的透明质酸调控物质进入组织液，从而增加血液中的葡萄糖渗透到组织液中，然后驱动组织液中的葡萄糖至皮肤表面，采用皮肤表面的葡萄糖测量方法，测量皮肤表面葡萄糖的浓度I0，利用测量指尖毛细血管血或静脉血血测量得到此时血液的葡萄糖浓度C0，得到在设定体积和浓度的调控物质下，皮肤表面葡萄糖的浓度I0与血液的葡萄糖浓度C0之间的比例系数K：C0＝KI0。Drive the hyaluronic acid regulating substance with a volume concentration of 0.3%, a molecular weight of 2 million, and a volume of 1000 μL into the interstitial fluid, thereby increasing the penetration of glucose in the blood into the interstitial fluid, and then driving the glucose in the interstitial fluid to the skin surface, using the glucose measurement on the skin surface The method is to measure the concentration I0 of glucose on the skin surface, and obtain the glucose concentration C0 of the blood at this time by measuring fingertip capillary blood or venous blood, and obtain the concentration of glucose on the skin surface under the control substance with a set volume and concentration The coefficient of proportionality K between I0 and the blood glucose concentration C0 : C0 =KI0 .
2)在人体的皮肤表面涂抹调控物质4，调控物质采用透明质酸。2) Apply regulating substance 4 on the skin surface of the human body, and the regulating substance adopts hyaluronic acid.
3)采用离子导入法驱动透明质酸进入皮下的组织液：3) Use iontophoresis to drive hyaluronic acid into the subcutaneous tissue fluid:
a)将正电极2与恒压源1的正极相连，将负电极3与恒压源1的负极相连；a) Connect the positive electrode 2 to the positive pole of the constant voltage source 1, and connect the negative electrode 3 to the negative pole of the constant voltage source 1;
b)将正电极2和负电极3直接贴附在人体的皮肤表面，并且在皮肤表面的中心距离为2cm；b) directly attaching the positive electrode 2 and the negative electrode 3 on the skin surface of the human body, and the distance between the centers of the skin surface is 2 cm;
c)启动恒压源1的电压输出，电压3V。c) Start the voltage output of the constant voltage source 1, the voltage is 3V.
4)通过控制调控物质的摩尔浓度，改变组织液的渗透压，通过增加渗透压增加血液向组织液的滤过压，滤过压与滤过量成正比，从而增强血液7中的葡萄糖向组织液中的过滤作用，血液和组织液的渗透压平衡，最终导致血液中的葡萄糖滤过血管主动外流到组织液，保持20分钟。4) Change the osmotic pressure of interstitial fluid by controlling the molar concentration of regulatory substances, increase the filtration pressure of blood to interstitial fluid by increasing the osmotic pressure, and the filtration pressure is proportional to the filtration amount, thereby enhancing the filtration of glucose in blood 7 to interstitial fluid Function, the osmotic pressure balance of blood and interstitial fluid, and finally lead to the active outflow of glucose in the blood through the blood vessels to the interstitial fluid, which lasts for 20 minutes.
5)在电场的驱动下，通过反向离子渗透的方式，组织液6中的葡萄糖由皮肤5流到负电极3与皮肤接触的表面，形成皮肤表面葡萄糖8。5) Driven by the electric field, the glucose in the interstitial fluid 6 flows from the skin 5 to the surface of the negative electrode 3 in contact with the skin through reverse ion osmosis to form glucose 8 on the skin surface.
6)采用葡萄糖传感器，测量皮肤表面葡萄糖8的浓度I，通过比例系数K，从而得到人体的血液中的葡萄糖浓度C＝KI。6) A glucose sensor is used to measure the concentration I of glucose 8 on the skin surface, and through the proportional coefficient K, the glucose concentration C=KI in the blood of the human body is obtained.
最后需要注意的是，公布实施例的目的在于帮助进一步理解本发明，但是本领域的技术人员可以理解：在不脱离本发明及所附的权利要求的精神和范围内，各种替换和修改都是可能的。因此，本发明不应局限于实施例所公开的内容，本发明要求保护的范围以权利要求书界定的范围为准。Finally, it should be noted that the purpose of the disclosed embodiments is to help further understand the present invention, but those skilled in the art can understand that various replacements and modifications can be made without departing from the spirit and scope of the present invention and the appended claims. It is possible. Therefore, the present invention should not be limited to the content disclosed in the embodiments, and the protection scope of the present invention is subject to the scope defined in the claims.
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| CN201711381140.8ACN108209942B (en) | 2017-12-20 | 2017-12-20 | A kind of non-invasive continuous blood sugar measuring system |
| PCT/CN2018/102441WO2019119851A1 (en) | 2017-12-20 | 2018-08-27 | Non-invasive continuous blood glucose measurement system |
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| CN201711381140.8ACN108209942B (en) | 2017-12-20 | 2017-12-20 | A kind of non-invasive continuous blood sugar measuring system |
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