WO2022051891A1 - Biocapteur de glucose - Google Patents

Biocapteur de glucose Download PDF

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Publication number
WO2022051891A1
WO2022051891A1 PCT/CN2020/113938 CN2020113938W WO2022051891A1 WO 2022051891 A1 WO2022051891 A1 WO 2022051891A1 CN 2020113938 W CN2020113938 W CN 2020113938W WO 2022051891 A1 WO2022051891 A1 WO 2022051891A1
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Prior art keywords
glucose
cross
glucose dehydrogenase
biosensor
linking agent
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PCT/CN2020/113938
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English (en)
Chinese (zh)
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高志强
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三诺生物传感股份有限公司
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Priority to PCT/CN2020/113938 priority Critical patent/WO2022051891A1/fr
Publication of WO2022051891A1 publication Critical patent/WO2022051891A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements

Definitions

  • the invention relates to the technical field of medical diagnosis, in particular to a glucose biosensor.
  • Diabetes has become a common disease in the world. According to the statistics of the International Diabetes Federation, there are more than 400 million diabetic patients in the world. , the number of diabetic patients in China exceeds 100 million. Diabetes is a chronic disease. Due to the decline of pancreatic function in diabetic patients, enough insulin cannot be produced or insulin can no longer be produced to effectively regulate blood sugar, resulting in excessive blood sugar in diabetic patients. Chronic high blood sugar can cause irreparable damage to human organs, causing complications such as skin ulcers, blindness, kidney failure and cardiovascular disease.
  • the traditional self-monitoring of blood glucose is realized by finger stick blood collection.
  • blood glucose monitoring by finger stick blood collection has great limitations except for the pain caused by acupuncture blood collection to diabetic patients.
  • Blood sugar monitoring by acupuncture blood collection can only provide the blood sugar value at a certain time point in the day.
  • diabetic patients need to perform very frequent finger blood blood sugar testing every day, which gives them Work and life have brought great inconvenience. Therefore, the implantable continuous glucose monitoring system came into being, which has brought good news to thousands of diabetic patients.
  • the implantable glucose continuous monitoring system can make the diabetic patients more convenient and effective to control blood sugar. It can continuously detect blood sugar in real time, and has gradually become a powerful tool for blood sugar control.
  • Dexcom's Dexcom G5 and G6 and Medtronic's Guardian and iPro2. work by electrochemically detecting the hydrogen peroxide generated when the oxygen is reduced during the catalytic oxidation of glucose by glucose oxidase. Monitoring, they rely on oxygen in body fluids such as tissue fluid or blood, the natural mediator of glucose oxidase-catalyzed oxidation of glucose, to monitor glucose, and the oxygen content in body fluids (0.2-0.3 mmol/L) is much lower than Glucose (4-11 mmol/L), therefore, the oxygen content in body fluids becomes the main factor limiting the performance of such implantable continuous glucose monitoring systems, which are less efficient than other implantable continuous glucose monitoring systems. Sensitivity is generally low.
  • glucose biosensors must be able to inhibit the passage of glucose to the greatest extent possible while allowing the passage of oxygen to the greatest extent possible on a highly biocompatible basis. It is well known that oxygen is hydrophobic compared to glucose, so their biocompatible membranes must also be highly hydrophobic. However, the requirement of high hydrophobicity has brought great challenges to the design of biocompatible membranes. Although after more than 20 years of research and exploration, its performance is still far from meeting the needs of continuous glucose monitoring. For example, Medtronic's Guardian and iPro2 also need to be calibrated twice a day, and their working life is only one week.
  • the artificial redox mediator technology developed at the end of the last century has been widely used in biosensors, especially glucose biosensors, including various disposable blood glucose detection tests.
  • Glucose biosensors for implantable continuous glucose monitoring systems such as Abbott Diabetes Care's FreeStyleLibre. Since this type of glucose monitoring system performs direct electrochemical detection of glucose through artificial redox mediators, its sensitivity is significantly improved.
  • oxygen as the natural mediator of glucose oxidase catalyzed oxidation of glucose, inevitably participates in the catalytic oxidation of glucose and becomes an important interference factor in glucose monitoring.
  • people have to eliminate the interference of oxygen to the maximum extent through various algorithms and the introduction of various biocompatible membranes that can effectively simulate oxygen.
  • the purpose of the present invention is to provide a glucose biosensor, so that the biosensor does not require oxygen to participate in the reaction (relative to glucose oxidase) through glucose dehydrogenase, and naturally has the ability to avoid oxygen. It has better anti-interference ability to monitor the interference and restriction of glucose, and at the same time, it further modifies and cross-links glucose dehydrogenase, so that it has better electrochemical performance and can better respond to glucose concentration, Promote biosensors to improve the accuracy, reproducibility, stability and specificity of glucose detection, and extend the life of glucose sensors.
  • the present invention provides the following technical solutions:
  • a glucose biosensor comprising a substrate and an electrode on the substrate; wherein, the working electrode is coated with a glucose sensing membrane; the glucose sensing membrane is prepared according to the following preparation method:
  • Glucose dehydrogenase is incubated in a buffer containing urea or guanidine hydrochloride, and the glucose dehydrogenase is fully expanded to expose free carboxyl and amino groups on the surface and inside of its molecule, and then add ruthenium or osmium with free carboxyl or amino groups
  • the complex and the first cross-linking agent are reacted to obtain chemically modified glucose dehydrogenase, so that the glucose dehydrogenase can perform rapid and direct electron exchange with the electrode, and then further cross-link through the second cross-linking agent, An electrochemically active glucose sensing membrane was obtained.
  • the present invention proposes an electrochemical activation technology of glucose dehydrogenase, so that glucose dehydrogenase can directly exchange electrons with electrodes.
  • the glucose dehydrogenase is denatured in high concentration of urea-to open the glucose dehydrogenase, and then by chemically modifying the free carboxyl and amino groups on the surface and inside of the glucose dehydrogenase molecule-the electrochemical performance is excellent with free
  • the ruthenium or osmium complexes of carboxyl or amino groups are covalently bonded to glucose dehydrogenase, and an electron channel is established from the inside to the outside, and the catalytic active center of glucose dehydrogenase can directly conduct very fast electrons with the electrode. exchange.
  • the denatured glucose dehydrogenase can be modified again with ruthenium or osmium complexes with free carboxyl or amino groups before cross-linking.
  • the specific method is to incubate the first chemically modified glucose dehydrogenase in a buffer containing urea or guanidine hydrochloride, and fully expand the glucose dehydrogenase to expose the free carboxyl and amino groups on its molecular surface and inside, and then Adding a ruthenium or osmium complex with a free amino group or a carboxyl group and a first cross-linking agent to react to obtain a second chemically modified glucose dehydrogenase, which can be compared with the first chemically modified glucose dehydrogenase.
  • the electrode performs faster electron exchange; if the first chemical modification uses a ruthenium or osmium complex with a free amino group, the second modification uses a ruthenium or osmium complex with a free carboxyl group; if The first chemical modification uses a ruthenium or osmium complex with a free carboxyl group, and the second modification uses a ruthenium or osmium complex with a free amino group.
  • the cross-linking is to cross-link the modified glucose dehydrogenase with a second cross-linking agent in a buffer solution.
  • the first cross-linking agent can be selected from carbodiimide and N-hydroxysuccinimide
  • the second cross-linking agent is a bifunctional chemical cross-linking agent such as glutaraldehyde, 1,4-butane Glycol diglycidyl ether, poly(dimethylsiloxane)-diglycidyl ether, tetraglycidyl-4,4-diaminodiphenylmethane, polyethylene glycol diglycidyl ether and 4-( 2,3-glycidoxy)-N,N-bis(2,3-glycidoxy)aniline and the like one or more.
  • the concentration of the bifunctional cross-linking agent is 0.1-5%, more preferably 1%, and the cross-linking reaction time is 30-180 min, more preferably 60 min; in the cross-linking process, a buffer solution such as PBS can be used as a crosslinking reaction medium.
  • the cross-linking process of the glucose sensing membrane is to fully mix 2-20 mg/ml of modified glucose dehydrogenase in PBS buffer solution and 0.1-5% glutaraldehyde solution, After 30-180 minutes, a stable cross-linked glucose sensing membrane was obtained.
  • the concentration of the glucose dehydrogenase is 1-10 mg/mL, more preferably 5 mg/mL;
  • the buffer is PBS buffer;
  • the urea concentration is 1-6mol/L, more preferably 3mol/L;
  • the incubation is at 4°C for 8-24h, more preferably at 4°C for 12h;
  • the complex of ruthenium or osmium with free carboxyl or amino groups The concentration of the compound is 1-10mg/mL, more preferably 5mg/mL;
  • the first cross-linking agent can be selected as carbodiimide and N-hydroxysuccinimide, and the concentrations of the two are 0.2-10mmol/L in turn and 0.1-1mmol/L, more preferably 1mmol/L and 0.5mmol/L;
  • the reaction is 8-24h at 4°C, more preferably 12h at 4°C;
  • the chemical modification process also includes using ultrafiltration bag dialysis to separate and purify the modified glucose dehydrogenase after the reaction; the ultrafiltration bag dialysis cut molecular weight is 1000-30000, more preferably 10000 molecular weight;
  • glucose biosensor based on electrochemically activated glucose dehydrogenase not only maintains its catalytic oxidation performance for glucose, but also monitors glucose at a very low potential (20-200 mV). .
  • the direct electrochemistry of glucose dehydrogenase greatly simplifies the design and manufacture of glucose biosensors, while also significantly improving the sensitivity, accuracy, stability, specificity, and anti-interference ability of glucose biosensors.
  • the process of oxidizing glucose catalyzed by glucose dehydrogenase does not require the participation of oxygen, which fundamentally solves the problem of oxygen in the implantable continuous glucose monitoring system.
  • the present invention utilizes cyclic voltammetry to characterize the glucose sensing membrane containing the modified glucose dehydrogenase, and the results show that the ruthenium or osmium complexes with free carboxyl or amino groups with excellent electrochemical performance have been successfully bonded to glucose dehydrogenase.
  • the cyclic voltammogram of the glucose sensing membrane clearly demonstrated a typical electrochemical catalytic process when 5 mmol/L glucose was added to the PBS buffer solution.
  • the glucose dehydrogenase treated as above did not have any electrochemical activity.
  • the present invention also covers the glucose sensing membrane with a biocompatible membrane.
  • the biocompatible film is a copolymer prepared by one or a combination of acrylate and acrylate derivatives.
  • acrylate and acrylate derivatives For example, hydroxyethyl methacrylate is used to polymerize polyhydroxyethyl methacrylate.
  • Ethyl methacrylate the specific method is: under anaerobic conditions, hydroxyethyl methacrylate, ethanol solution and Na 2 S 2 O 8 react in a closed environment to generate polyhydroxyethyl methacrylate, and then add acetone to precipitate polymethyl methacrylate Hydroxyethyl acrylate is then repeatedly processed by means of ethanol dissolution and acetone precipitation, and finally the obtained polyhydroxyethyl methacrylate is dried and separated.
  • the biocompatible membrane is uniformly coated on the surface of the glucose sensing membrane by dipping and pulling.
  • the biocompatible membrane solution was immersed in an environment containing saturated alcohol vapor by immersion pulling method (decline speed: 100-5000 ⁇ m/s, optimal value: 2000, pulling speed 20-500 ⁇ m/s , optimal value: 200) uniformly coated on the glucose biosensors containing electrochemically activated glucose dehydrogenase, and then these glucose biosensors were dried to form films. After the solvent has completely evaporated, the surface of these glucose biosensors has been completely covered by a thin biocompatible film. In order to increase the thickness of the biocompatible film, the above process can be repeated many times, usually 2-8 times (optimal value: 4) can reach the required thickness. Since this biocompatible membrane is formed through multiple film-forming processes, its final glucose-regulating properties can be easily and effectively determined by the thickness of the membrane (number of dips and pulls) and the biocompatible membrane solution. The formula is optimized to achieve the desired effect.
  • the glucose monitoring range is 0-35 mmol/L, and after a week of continuous testing, its current signal has less than 2% attenuation, and oxygen does not interfere with glucose detection. At the same time, the anti-interference ability of acetaminophen is also improved.
  • the biosensor of the present invention can bring extremely high stability and anti-interference ability, which fully meets the needs of an implantable glucose continuous monitoring system.
  • the attached biocompatible membrane can not only regulate the rate of glucose in the blood entering the sensor, avoid entering too fast and shorten the service life of the biosensor, and play the role of osmotic regulation, and at the same time, it can achieve a high degree of biocompatibility.
  • the electrode is coated with a glucose sensing film by a drop coating method or a dip-pulling method and is coated on the electrode.
  • a glucose sensing film by a drop coating method or a dip-pulling method and is coated on the electrode.
  • the layout of each electrode (including the conductive layer) and the substrate is described in detail, such as Abbott, DEXCOM's CGM sensor, various commercially available products will set up different types of electrodes according to needs, which is in the It is within the capabilities of those skilled in the art.
  • the biosensor of the present invention is provided with a working electrode, a reference electrode, a counter electrode and a conductive layer on the substrate; preferably, the working electrode is a carbon working electrode, the counter electrode is a carbon counter electrode, and the reference electrode It is a silver/silver chloride reference electrode, the conductive layer is a carbon conductive layer, and the matrix is a polyethylene terephthalate matrix.
  • the working electrode of the glucose biosensor is coated with a glucose sensing membrane, which is located on the same electrode layer as the counter electrode, and is located on both sides of the base layer with the conductive layer, and the reference electrode layer is located on the first side of the conductive layer. Then the whole is wrapped by a biocompatible film.
  • a glucose sensing membrane which is located on the same electrode layer as the counter electrode, and is located on both sides of the base layer with the conductive layer, and the reference electrode layer is located on the first side of the conductive layer. Then the whole is wrapped by a biocompatible film.
  • the present invention chemically modifies glucose dehydrogenase so that it can directly exchange electrons with electrodes, and the glucose sensing membrane prepared based on it is used in glucose biosensors, which can fundamentally eliminate the
  • the restriction of oxygen on glucose detection improves the sensitivity, accuracy, reproducibility, stability, specificity and anti-interference ability of glucose dynamic detection, and prolongs the service life of the implantable continuous glucose monitoring system, while greatly reducing glucose Cost of biosensors.
  • FIG. 1 shows a schematic structural diagram of the glucose biosensor of the present invention
  • Figure 2 shows the electrochemical characterization of the glucose sensing membrane containing modified glucose dehydrogenase; among them, a is the cyclic voltammogram without adding glucose, and b is the cyclic voltammogram after adding 5 mmol/L glucose ;
  • Figure 3 shows the glucose concentration-current curve of the glucose biosensor; wherein, a is the glucose concentration-current curve of the glucose biosensor not covered with poly(hydroxyethyl methacrylate), and b is the glucose concentration-current curve of the glucose biosensor covered with poly(hydroxyethyl methacrylate) Glucose concentration-current curves of ester-based glucose biosensors;
  • Figure 4 shows the stability test results of the glucose biosensor; wherein, a is a glucose biosensor covered with a polyhydroxyethyl methacrylate film, and b is a glucose biosensor without a polyhydroxyethyl methacrylate film;
  • FIG. 5 shows the detection result of the anti-interference performance of the glucose biosensor of the present invention.
  • the embodiment of the present invention discloses a glucose biosensor, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters to achieve. It should be particularly pointed out that all similar substitutions and modifications apparent to those skilled in the art are deemed to be included in the present invention.
  • the glucose biosensor of the present invention has been described through the preferred embodiments, and it is obvious that relevant persons can make changes or appropriate changes and combinations of the glucose biosensor described herein without departing from the content, spirit and scope of the present invention. and application of the technology of the present invention.
  • the biocompatible film of the present invention adopts polyhydroxyethyl methacrylate, which can be prepared with reference to existing methods or purchased directly.
  • the present invention also provides a method for preparing polyhydroxyethyl methacrylate. Hydroxyethyl acrylate, anhydrous ethanol, and water react with Na 2 S 2 O 8 in an oxygen-free state to generate poly(hydroxyethyl methacrylate); One or more purifications are carried out, and finally it is precipitated with acetone and dried to obtain polyhydroxyethyl methacrylate.
  • the alcohol solution of poly(hydroxyethyl methacrylate) is uniformly coated on the glucose containing the chemically modified glucose dehydrogenase of the present invention by dipping and pulling method.
  • the biosensor is then dried to form a film. After the solvent has completely evaporated, the surface of these glucose biosensors has been completely covered by a thin biocompatible film (see Figure 1).
  • the above process can be repeated many times, usually 2-8 times to achieve the required thickness. Since this biocompatible membrane is formed through multiple film-forming processes, its final glucose-regulating properties can be easily and effectively determined by the thickness of the membrane (number of dips and pulls) and the biocompatible membrane solution. The formulation is optimized to achieve the desired desired effect.
  • glucose dehydrogenase Incubate 1-10 mg/mL glucose dehydrogenase (optimal value: 5) in PBS buffer solution containing 1-6 mol/L urea (optimal value: 3) at 4 degrees for 8-24 hours (optimal value: 3). value: 12), the glucose dehydrogenase was fully developed.
  • glucose dehydrogenase To further improve the faster electron exchange between the glucose dehydrogenase and the electrode, we can add the purified glucose dehydrogenase to the PBS buffer solution containing 1-6 mol/L urea (optimal value: 3) again Incubate at 4 degrees for 8-24 hours (optimal value: 12), and once again fully develop the glucose dehydrogenase. Then, 1-10 mg/ml (optimum value: 5) of ruthenium or osmium complexes with free carboxyl groups and 0.2-10 mmol/l carbodiimide (optimal value: 5) were added to the solution sequentially.
  • the glucose sensing membrane containing modified glucose dehydrogenase was characterized by cyclic voltammetry, and the results are shown in Figure 2.
  • Curve a in Figure 2 clearly shows that after the above treatments, redox small molecules with superior electrochemical performance have been successfully bonded to glucose dehydrogenase.
  • the cyclic voltammogram of the glucose-sensing membrane clearly demonstrated a typical electrochemical catalytic process when 5 mmol/L glucose was added to the PBS buffer solution (Fig. 2, curve b).
  • the above-treated glucose dehydrogenase did not have any electrochemical activity.
  • the surface of these glucose biosensors has been completely covered by a thin biocompatible film.
  • the above process can be repeated many times, usually 2-8 times (optimal value: 4) can reach the required thickness. Since this biocompatible membrane is formed through multiple film-forming processes, its final glucose-regulating properties can be easily and effectively determined by the thickness of the membrane (number of dips and pulls) and the biocompatible membrane solution.
  • the formulation is optimized to achieve the desired desired effect.
  • the carbon counter electrode is coated with the glucose sensing film of the present invention, the silver/silver chloride reference electrode and the carbon conductive layer, and then prepared according to the layout shown in Figure 1, and then polyhydroxyethyl methacrylate is coated on the the entire outer surface.
  • glucose biosensors covered with the poly(hydroxyethyl methacrylate) film and the glucose biosensor not covered with the poly(hydroxyethyl methacrylate) film were tested by cyclic voltammetry in PBS buffer solution containing 5 mmol/L glucose. stability, the results are shown in Figure 4.
  • Figure 4 shows that, after one week of continuous testing, the current signal of the glucose biosensor covered with poly(hydroxyethyl methacrylate) film showed less than 2% attenuation (Fig. 4, curve a), compared to that without The current signal of the glucose biosensor of the hydroxyethyl methacrylate thin film decayed by more than 60% during continuous testing over one week (Fig. 4, curve b).
  • the existing glucose biosensors are all prepared on the basis of glucose oxidase.
  • oxygen becomes a major factor restricting the performance of the implanted glucose continuous monitoring system.
  • the glucose dehydrogenase in the glucose biosensor of the present invention does not require the participation of oxygen when oxidizing glucose. This is tested by cyclic voltammetry to see if this is the desired effect.
  • the current of the glucose biosensor covered with a biocompatible membrane did not have any decay when oxygen was bubbled through a PBS buffer solution containing 10 mmol/L glucose and when the oxygen in the solution was completely removed by argon. .
  • the detection of glucose was performed at a very low potential (20-200 mV)
  • the anti-interference ability of acetaminophen was very significantly improved (Fig. 5).

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Abstract

Un biocapteur de glucose se rapportant au domaine technique du diagnostic médical. Le biocapteur comprend une matrice (4) et une électrode (5) qui est positionnée sur la matrice (4). L'électrode (5) est revêtue d'une membrane de détection de glucose (7). La membrane de détection de glucose (7) est formée grâce à la réticulation de groupements carboxyliques libres sur la surface et à l'intérieur de molécules de glucose déshydrogénase et de glucose déshydrogénase avec des groupements aminés couplés à un complexe de ruthénium ou d'osmium ayant des groupements carboxyliques libres ou des groupements aminés. La glucose déshydrogénase est chimiquement modifiée pour échanger directement des électrons avec l'électrode (5). Lorsque la membrane de détection de glucose (7) ainsi obtenue est appliquée à un biocapteur de glucose, la contrainte d'oxygène sur la détection de glucose est fondamentalement éliminée, la sensibilité, la précision, la reproductibilité, la cohérence, la spécificité et la résistance à l'interférence de la détection de glucose dynamique sont améliorées, et la durée de vie d'un système de surveillance de glucose continu implanté est prolongée.
PCT/CN2020/113938 2020-09-08 2020-09-08 Biocapteur de glucose WO2022051891A1 (fr)

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CN114778628B (zh) * 2022-04-25 2024-05-24 北京怡成生物电子技术股份有限公司 柔性工作电极及酶传感器

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