CN113317785B - Selective-permeation biocompatible membrane and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a selectively permeable biocompatible membrane and a preparation method and application thereof. The biocompatible membrane consists of three functional parts, namely a hydrophobic membrane skeleton, a hydrophilic group, a biocompatible group and the like. The glucose biosensor developed based on the third-generation biosensing technology is covered with the biocompatible film, so that oxygen and glucose can be effectively and accurately regulated and controlled simultaneously, more importantly, the existence of the biocompatible film obviously expands the monitoring range of the glucose, greatly improves the stability and biocompatibility of the glucose biosensor in a human body, fully meets the requirement of a correction-free (factory correction) dynamic glucometer, and lays a solid foundation for the batch production of the correction-free dynamic glucometer. In addition, the biocompatible membrane can also be applied to other implanted continuous monitoring systems, such as monitoring of lactic acid and blood ketones.
Description
Technical Field
The invention relates to the technical field of biological membranes, in particular to a selectively permeable biocompatible membrane and a preparation method and application thereof.
Background
An implanted human body continuous monitoring system, such as a dynamic blood glucose meter, brings good news to millions of diabetics. For diabetics, daily self-blood glucose monitoring is part of life. However, the traditional digital blood glucose detection has great limitation, only provides blood glucose value at a certain time point in a day, and for reliable blood glucose monitoring, diabetics need to frequently detect the digital blood glucose every day, which brings great inconvenience to their work and life. On the other hand, the dynamic blood glucose meter can enable a diabetic patient to regulate and control blood glucose more conveniently and more effectively. The blood glucose detection instrument can continuously detect blood glucose in real time and gradually becomes a powerful tool for regulating and controlling blood glucose. As the main components of the biosensor of the dynamic blood glucose meter and the only interface which is in direct contact with a living body, the performance of the biocompatible membrane directly determines the biocompatibility, sensitivity, stability and anti-interference capability of the dynamic blood glucose meter and the working life of the dynamic blood glucose meter during living body monitoring. The existing dynamic blood glucose meters are developed based on the first or second generation biosensing technology. The working principle of continuous monitoring of glucose by using the first-generation biosensing technology is to indirectly monitor glucose by detecting hydrogen peroxide generated when oxygen is reduced in the catalytic oxidation process of glucose oxidase by an electrochemical method. Since the continuous glucose monitoring system developed based on the first generation of biosensing technology relies on the natural mediator of oxygen-glucose oxidase in body fluid such as interstitial fluid or blood to catalyze and oxidize glucose, so as to realize glucose monitoring, and the oxygen content (0.2-0.3 mmol/L) in the body fluid is far lower than that (5-10 mmol/L) of glucose, the biocompatible membrane of the continuous glucose monitoring system must be capable of maximally allowing the passage of oxygen and effectively simulating the passage of glucose on the basis of high biocompatibility. It is well known that oxygen is hydrophobic compared to glucose, so its biocompatible membrane must also be highly hydrophobic. However, the requirement of being highly hydrophobic presents a significant challenge to the design of biocompatible membranes, since the main component of human interstitial fluid is water. Although they have been explored for more than 20 years, their performance is far from meeting the need for continuous glucose monitoring.
At the end of the last century, heller et al discovered that by introducing a redox species, an artificial redox mediator (a redox small molecule such as ferricyanide, ferrocene and its derivatives or a redox polymer) into a biosensing membrane, glucose oxidase can exchange electrons with an electrode through the artificial mediator. Second generation biosensing technologies developed based on this principle are now widely used in biosensors, particularly glucose biosensors, including dynamic blood glucose meters. Because the second generation of biosensing technology realizes direct electrochemical detection of glucose by introducing an artificially synthesized redox mediator into the biosensor, the detection of glucose can be realized at a very low potential by molecular design and optimization of the redox mediator, thereby greatly improving the anti-interference capability of the dynamic blood glucose meter. Because the glucose monitoring system directly and electrochemically detects glucose through the artificial redox mediator, the sensitivity of the glucose monitoring system is also remarkably improved. On the other hand, although direct electrochemical detection of glucose is realized by introducing an artificially synthesized redox mediator, oxygen, which is a natural mediator for catalyzing and oxidizing glucose by glucose oxidase, inevitably participates in the catalytic oxidation of glucose and becomes an important interference factor for glucose monitoring. In order to further improve the performance of such dynamic glucometers, various biocompatible membranes are introduced, so that on one hand, the interference of oxygen is eliminated to the maximum extent, and on the other hand, the monitoring range of glucose is expanded. Given the significant difference in hydrophilicity between glucose and oxygen, a high degree of hydrophilicity is an essential characteristic of such biocompatible membranes. Although they are very effective in eliminating oxygen interference, it is difficult to achieve effective and accurate simultaneous control of oxygen and glucose. To effectively regulate glucose, the thickness of the biocompatible membrane must be significantly increased. The excessively thick biocompatible film directly causes the response time of the dynamic blood glucose meter to glucose to be too long, so that a serious hysteresis phenomenon occurs, and the accuracy of the dynamic blood glucose meter is greatly reduced. In addition, the existing biocompatible membrane has a chemical crosslinking reaction in the formula, so that the service life of the biocompatible membrane solution is greatly shortened, and the production cost of the dynamic glucometer is invisibly increased. More seriously, as the using time is increased, the chemical crosslinking reaction is more and more, and the viscosity of the biocompatible film solution is more and more, thereby seriously influencing the consistency of the product.
The third generation biosensing technology is developed by direct electrochemistry using oxidoreductases. The biosensor technology can be used for manufacturing a high-performance glucose biosensor urgently needed by an implantable continuous glucose monitoring system, and can also be used for manufacturing other various biosensors containing oxidoreductase. Compared with the second generation of biosensing technology, the direct electrochemistry of the glucose oxidase greatly simplifies the design and manufacture of the glucose biosensor, and also obviously improves the sensitivity, accuracy, stability, specificity and anti-interference capability of the glucose biosensor. On the other hand, similar to the second generation biosensing technology, oxygen, which is a natural mediator for the catalytic oxidation of glucose by glucose oxidase, inevitably participates in the catalytic oxidation of glucose, and becomes an important interference factor for glucose monitoring. Although the efficiency of the catalytic oxidation of glucose by direct electrochemistry is much higher than the efficiency of the catalytic oxidation of glucose oxidase by its natural mediator oxygen, to eliminate the interference of oxygen fundamentally, a selective permeation membrane for eliminating oxygen must be coated on the glucose biosensor. In addition, this permselective membrane must also be able to effectively regulate glucose due to the high sensitivity of direct electrochemical detection of glucose. That is, this permselective membrane must be bifunctional: oxygen and glucose can be regulated simultaneously. Although the simultaneous regulation of oxygen and glucose can be achieved to some extent by adjusting the components of the permselective membrane and the ratios between the components, such as the types and ratios of hydrophobic and hydrophilic components, it is very difficult to achieve the simultaneous and accurate regulation of oxygen and glucose.
Disclosure of Invention
In order to solve the technical problems, the invention discovers through detailed research and experiments that a biocompatible membrane consisting of three functional parts, namely a hydrophobic membrane skeleton, a hydrophilic group, a biocompatible group and the like, is covered on a biosensor which is developed based on a third-generation biosensing technology and contains electrochemically activated glucose oxidase, so that the high biocompatibility of the glucose biosensor can be satisfactorily realized, and the accurate regulation and control of oxygen and glucose can be simultaneously realized.
A first object of the present invention is to provide a method for preparing a selectively permeable biocompatible membrane, comprising the steps of:
s1, copolymerizing a monomer containing a hydrophilic group with a hydrophobic monomer to form a hydrophobic skeleton with the hydrophilic group;
s2, dissolving a hydrophobic skeleton with hydrophilic groups, adding a biocompatible polymer or a biocompatible monomer into the hydrophobic skeleton, performing crosslinking reaction, and adding ethanolamine or amino acid after the reaction to prepare a biocompatible membrane solution;
and S3, carrying out 2-6 times of cyclic operation of uniform coating and drying to form a film on the biocompatible film solution obtained in the step S2 to obtain the selectively permeable biocompatible film.
Further, the monomer containing the hydrophilic group is one or more of ethylene glycol ether, acrylate with ethylene glycol group, olefin with ethylene glycol group, vinyl pyrrolidone, functionalized polyethylene oxide and functionalized polypropylene oxide, wherein the functionalization in the functionalized polyethylene oxide or the functionalized polypropylene oxide is ethylene functionalization, amino functionalization, carboxyl functionalization or aldehyde group functionalization.
Further, the hydrophobic monomer is one or more of styrene, vinylpyridine, acrylamide or derivatives thereof, and acrylate or derivatives thereof.
Further, the biocompatible polymer is one or more of aminated polyethylene glycol, polyethylene oxide, copolymer containing polyethylene oxide, polypropylene oxide, copolymer containing polypropylene oxide, polyvinylpyrrolidone, polyvinyl alcohol, polylactic acid, hyaluronic acid or derivatives thereof, chitosan or derivatives thereof, cellulose or derivatives thereof, alginic acid or derivatives thereof; the biocompatible monomer is one or more of ethylene glycol or derivatives thereof, functionalized choline, functionalized betaine, functionalized amino acid, functionalized ethylene oxide, functionalized propylene oxide and vinylpyrrolidone, wherein the functionalization is ethylene functionalization, amino functionalization, carboxyl functionalization or aldehyde group functionalization.
Further, in the step S2, during the crosslinking reaction, one or more of triglycidyl p-aminophenol, glycidyl ether or a derivative thereof, polypropylene glycol glycidyl ether or a derivative thereof, polyethylene glycol diglycidyl ether or a derivative thereof, and glutaraldehyde are used as the crosslinking agent.
Furthermore, the volume ratio of the monomer containing the hydrophilic group to the hydrophobic monomer is 1-3:1.
Further, in the step S2, the concentration of the dissolved hydrophobic skeleton with the hydrophilic group is 100-300mg/mL, the addition amount of the biocompatible polymer or the biocompatible monomer is 10-30mg/mL, and the addition amount of the cross-linking agent is 0.2-5 mg/mL.
Furthermore, the addition amount of the ethanolamine or the amino acid is 0.2-1mg/mL.
Furthermore, the coating is carried out by adopting a dripping coating method, a spin coating method, a spraying method or a dip-coating method.
Further, the preparation method specifically comprises the following steps:
(1) Containing hydrophobic groupsSynthesis of polymers of the Membrane skeleton and hydrophilic groups (such as ethylene glycol based ether and acrylate copolymer): 10-100mL of monomer containing hydrophilic group (ethylene glycol ether), 5-50mL of hydrophobic monomer (acrylate), 20-200mL of absolute ethanol and 2-15mL of water are mixed, and argon is used for deoxygenation for 20-60 minutes. Then adding 20-300mg of Na 2 S 2 O 8 Placing the mixture into a closed container, and reacting for 12-48 hours at 50-75 ℃. Then 500-5000mL of acetone is added to precipitate the polymer (such as ethylene glycol ether and acrylate copolymer) and the mixture is centrifuged. Dissolving in ethanol, adding 500-5000mL acetone for precipitation, and centrifuging. Repeating for several times, and vacuum drying the precipitate at 60-120 deg.C for at least 12 hr.
(2) Introduction of a biocompatible function and preparation of a biocompatible film solution: firstly, dissolving a polymer (such as ethylene glycol ether and acrylate copolymer) in 95% ethanol to prepare a solution of 100-300mg/mL, then adding 10-30mg/mL of a biocompatible polymer or a biocompatible monomer (such as aminated polyethylene glycol) and 0.2-5mg/mL of a cross-linking agent (such as triglycidyl-p-aminophenol cross-linking agent), and mixing thoroughly. Then reacting in a water bath at 60 ℃ for 20-60 minutes.
(3) Coating of biocompatible film: the biocompatible membrane solution is uniformly coated on the biosensor by a dripping coating method, a spin coating method, a spraying method or a dip-coating method, and then dried to form a membrane at room temperature, and the steps are repeated for 2 to 6 times.
The second purpose of the invention is to provide a selective permeable biocompatible membrane prepared by the method.
A third object of the present invention is to provide the use of said permselective biocompatible membrane in an implantable monitoring system.
By the scheme, the invention at least has the following advantages:
the glucose biosensor developed based on the third-generation biosensing technology is covered with the biocompatible film, so that oxygen and glucose can be effectively and accurately regulated and controlled simultaneously, more importantly, the existence of the biocompatible film obviously expands the monitoring range of the glucose, greatly improves the stability and biocompatibility of the glucose biosensor in a human body, fully meets the requirement of a correction-free (factory correction) dynamic glucometer, and lays a solid foundation for the batch production of the correction-free dynamic glucometer. In addition, the biocompatible membrane can also be applied to other implanted continuous monitoring systems, such as monitoring of lactic acid and blood ketones.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following description is made with reference to the preferred embodiments of the present invention and the accompanying detailed drawings.
Drawings
FIG. 1 is a schematic diagram of the structure of a biocompatible membrane;
FIG. 2 is a graph showing the relationship between the current of a glucose biosensor in a PBS buffer solution containing 10mmol/L glucose and the number of dipping and pulling times, and the test temperature is 23-25 ℃;
fig. 3 is stability and anti-interference performance of PBS buffer solutions of glucose at (1) 10mmol/L and (2) 20mmol/L for a glucose biosensor covered with a three-layer biocompatible film (interferents at 1mmol/L, test temperature 23-25 ° C);
FIG. 4 is a glucose concentration-current curve of a glucose biosensor covered with three layers of biocompatible membranes, the glucose concentration varying: 5mmol/L, test temperature 23-25 ° C;
FIG. 5 shows the results of a test of a human body with a glucose biosensor covered with three layers of biocompatible films in a dynamic blood glucose meter (the squares refer to the tip blood test results).
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1:
as shown in fig. 1, the biocompatible membrane of this embodiment is composed of three functional portions, i.e., a hydrophobic membrane skeleton, a hydrophilic group, and a biocompatible group, and is specifically prepared as follows:
(1) Synthesis of Polymer-ethylene glycol Ether and acrylate copolymer containing hydrophobic Membrane backbone and hydrophilic groups: 50mL of ethylene glycol ether, 25mL of acrylate, 100mL of absolute ethanol and 10mL of water were mixed and deoxygenated with argon for 40min. Then 150mg of Na was added 2 S 2 O 8 And placing the mixture in a closed container to react for 24 hours at 60 ℃. Then 2500mL of acetone was added to precipitate the ethylene glycol ether and acrylate copolymer, and the mixture was centrifuged. Dissolving with ethanol, adding 2500mL of acetone for precipitation, and centrifuging. Repeating for several times, and finally vacuum drying the precipitate at 100 deg.C for at least 12h.
(2) Introduction of a biocompatible function and preparation of a biocompatible film solution: first, ethylene glycol ether and acrylate copolymer were dissolved in 95% ethanol to prepare a 200mg/mL solution, and then 20mg/mL aminated polyethylene glycol and 2mg/mL triglycidyl-p-aminophenol crosslinker were added and mixed well. Then the reaction was carried out in a water bath at 60 ℃ for 40min.
In order to fully stabilize the viscosity of the solution, ensure the consistency of the product and prolong the service life of the biocompatible membrane solution as far as possible, 0.6mg/mL ethanolamine is added into the reacted biocompatible membrane solution, and after fully mixing, the solution is reacted in a water bath at 60 ℃ for 40min again. The purpose of the ethanolamine addition is to completely consume the free radicals (crosslinking agents) in the solution that have not yet participated in the reaction. After ethanolamine treatment, the stability and service life of the biocompatible membrane solution are greatly improved, and the stability and service life of the biocompatible membrane solution are not obviously changed within two years.
All of the above formulations of biocompatible membranes are based on synthetic and purified polymers, provided that the formulated solutions can be used indefinitely by dissolving them in a suitable solvent such as methanol, ethanol, propanol, isopropanol, water, N-dimethylacrylamide, dimethylsulfoxide, sulfolane, tetrahydrofuran, dioxane etc.
(3) Coating of the biocompatible film: the biocompatible film solution is uniformly coated on the biosensor film by a dripping coating method, a spin coating method, a spraying method or a dipping and pulling method, and then is dried at room temperature to form a film, and the process is repeated for 2 to 6 times. For example, a biocompatible membrane solution is uniformly coated on glucose biosensors by a dip-coating method, and then the glucose biosensors are dried to form a membrane in a strictly controlled environment. After complete evaporation of the solvent, the glucose biosensor surfaces have been completely covered by a thin biocompatible film. To increase the thickness of the biocompatible film, the above process can be repeated several times, usually 3-4 times to achieve the desired thickness. Because the biocompatible membrane is formed through a plurality of membrane forming processes, the final regulation and control performance on oxygen and glucose can be conveniently and effectively optimized through the thickness (the dipping and pulling times) of the membrane and the formula of a biocompatible membrane solution, so that the expected effect is achieved.
As shown in fig. 2, when the glucose biosensor is completely coated with the biocompatible film, the catalytic oxidation current for glucose is exponentially and rapidly decreased as the number of times of dip-coating (thickness of the film) is increased, and the current of the glucose biosensor is decreased to less than 1% of the original current after four cycles of dip-coating and drying. The experimental result shows that the biocompatible membrane can effectively regulate and control glucose (the reaction is on the current of catalytic oxidation of glucose).
Example 2:
for a glucose biosensor developed based on a third-generation biosensing technology, when glucose is directly detected electrochemically, oxygen is a natural mediator for catalyzing and oxidizing glucose by glucose oxidase, so that oxygen in body fluid such as interstitial fluid or blood inevitably participates in the catalytic oxidation of glucose. If the glucose biosensor does not effectively regulate oxygen, the interference of oxygen can pose a great challenge to accurate glucose monitoring. Further experiments confirmed that this layer of biocompatible membrane is also capable of substantially eliminating the interference of oxygen (fig. 3). As shown in FIG. 3, when oxygen gas was introduced into PBS buffer solution containing 10mmol/L glucose, the glucose biosensor coated with the biocompatible membrane showed only less than 1% decay, and the current signal was restored to the original level when the oxygen gas in the solution was completely removed by argon gas (FIG. 3, curve 1). Since the detection of glucose is carried out at very low potentials (-50-100 mV), its interference rejection against common interfering substances such as ascorbic acid, uric acid, salicylic acid, acetaminophen, etc. is very significantly improved (fig. 3, curve 1), while the glucose biosensor coated with a biocompatible membrane shows excellent stability at both high and low glucose concentrations in continuous tests for up to one week (fig. 3, curves 1 and 2).
The glucose biosensor is coated with a biocompatible membrane to successfully realize the precise regulation of oxygen and glucose, and the glucose biosensor which has good accuracy, reproducibility and stability and can be used for a dynamic glucometer is required to be prepared. For example, when the glucose biosensor is subjected to dip-coating and drying cycles of three cycles in a biocompatible membrane solution, the current signal is well controlled by the biocompatible membrane, and the stability of the glucose biosensor is significantly improved, although the response time to glucose is extended from 1 minute to 3 minutes, as compared to a glucose biosensor not covered with any biocompatible membrane. Meanwhile, the monitorable range of the glucose is successfully expanded from 10mmol/L to 30mmol/L, the glucose monitoring requirement of a diabetic patient is completely met (figure 4), and a solid foundation is laid for the application in a dynamic blood glucose meter.
Example 3:
we applied a glucose biosensor covered with a biocompatible membrane to a dynamic glucometer on the basis of in vitro work, and in 20 consecutive human tests, the sensitivity (baseline) did not significantly decay (fig. 5), which is the glucose biosensor for human monitoring with the longest working life so far, and more importantly, the monitored glucose concentration was highly consistent with the results of blood glucose detection.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.
Claims (6)
1. A method for preparing a selectively permeable biocompatible membrane for use in a biosensor containing an electrochemically activated glucose oxidase, wherein the membrane can simultaneously control oxygen and glucose, comprising the steps of:
s1, copolymerizing a monomer containing a hydrophilic group with a hydrophobic monomer to form a hydrophobic skeleton with the hydrophilic group;
s2, dissolving a hydrophobic skeleton with hydrophilic groups, adding a biocompatible polymer or a biocompatible monomer into the hydrophobic skeleton, performing crosslinking reaction, and adding ethanolamine or amino acid after the reaction to prepare a biocompatible membrane solution;
s3, performing 2~6 times of uniform coating and drying to form a film on the biocompatible film solution obtained in the step S2 to obtain the selectively permeable biocompatible film;
the monomer containing the hydrophilic group is one or more of ethylene glycol ether, acrylate with an ethylene glycol group, olefin with an ethylene glycol group, vinyl pyrrolidone, functionalized polyethylene oxide and functionalized polypropylene oxide, wherein the functionalization in the functionalized polyethylene oxide or the functionalized polypropylene oxide is ethylene functionalization, amino functionalization, carboxyl functionalization or aldehyde group functionalization;
the hydrophobic monomer is one or more of styrene, vinylpyridine, acrylamide or derivatives thereof, and acrylate or derivatives thereof;
the biocompatible polymer is one or more of aminated polyethylene glycol, polyethylene oxide, copolymer containing polyethylene oxide, polypropylene oxide, copolymer containing polypropylene oxide, polyvinylpyrrolidone, polyvinyl alcohol, polylactic acid, hyaluronic acid or derivatives thereof, chitosan or derivatives thereof, cellulose or derivatives thereof, and alginic acid or derivatives thereof; the biocompatible monomer is one or more of ethylene glycol or derivatives thereof, functionalized choline, functionalized betaine, functionalized amino acid, functionalized ethylene oxide, functionalized propylene oxide and vinylpyrrolidone, wherein the functionalization is ethylene functionalization, amino functionalization, carboxyl functionalization or aldehyde group functionalization;
the volume ratio of the monomer containing the hydrophilic group to the hydrophobic monomer is 1 to 3.
2. The method of claim 1, wherein in the step S2, one or more of triglycidyl p-aminophenol, glycidyl ether or a derivative thereof, polypropylene glycol glycidyl ether or a derivative thereof, polyethylene glycol diglycidyl ether or a derivative thereof, and glutaraldehyde are used as the crosslinking agent in the crosslinking reaction.
3. The preparation method according to claim 1, wherein in the step S2, the concentration of the dissolved hydrophobic skeleton with the hydrophilic group is 100 to 300mg/mL, the addition amount of the biocompatible polymer or the biocompatible monomer is 10 to 30mg/mL, and the addition amount of the cross-linking agent is 0.2 to 5mg/mL.
4. The method according to claim 1, wherein the ethanolamine or the amino acid is added in an amount of 0.2 to 1mg/mL.
5. A selectively permeable biocompatible membrane produced by the method of any one of claims 1~4.
6. An implantable monitoring system comprising the selectively permeable biocompatible membrane of claim 5.
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| CN113717955A (en) * | 2021-09-02 | 2021-11-30 | 苏州中星医疗技术有限公司 | Glucose biosensor, glucose sensing membrane thereof and glucose dehydrogenase |
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