CN120539402A - A micro biosensor and its preparation method - Google Patents
A micro biosensor and its preparation methodInfo
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- CN120539402A CN120539402A CN202511040718.8A CN202511040718A CN120539402A CN 120539402 A CN120539402 A CN 120539402A CN 202511040718 A CN202511040718 A CN 202511040718A CN 120539402 A CN120539402 A CN 120539402A
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54366—Apparatus specially adapted for solid-phase testing
- G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
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Abstract
本发明涉及生物传感器技术领域，具体涉及一种微型生物传感器及其制备方法。本发明提供一种微型生物传感器，将功能性生物活性物质负载到传感器的指定位置，采用特定粘度的载药膜液在传感器表面形成载药层，即载药聚合物涂层，载药层的加入在不影响生物传感器正常功能的同时，能够在特定部位长期有效释放，可以减少因生物传感器植入体内引起的异物反应，减少蛋白堆积及纤维包封导致生物传感器后期灵敏度下降的问题，有效延长传感器使用寿命。
The present invention relates to the field of biosensor technology, and more specifically, to a micro-biosensor and a method for preparing the same. The present invention provides a micro-biosensor that loads a functional bioactive substance onto a designated location on the sensor. A drug-loaded film liquid of a specific viscosity is used to form a drug-loaded layer, i.e., a drug-loaded polymer coating, on the sensor surface. The drug-loaded layer, while not affecting the normal function of the biosensor, enables long-term, effective release of the drug at a specific location. This reduces foreign body reactions caused by implantation of the biosensor in the body, mitigates the problem of decreased sensitivity of the biosensor due to protein accumulation and fiber encapsulation, and effectively extends the sensor's service life.
Description
Technical Field
The invention relates to the technical field of biosensors, in particular to a micro-biosensor and a preparation method thereof.
Background
The biosensor can rapidly and sensitively detect corresponding indexes of the body by directly contacting with tissue fluid such as blood or body fluid. However, implantation of the sensor in the body typically causes a host foreign body response. Foreign body reaction is a phenomenon that the function of a sensor is impaired by leukocyte reaction, biological stasis, fiber encapsulation, etc. after the biosensor is implanted in the body. Which ultimately results in reduced sensor sensitivity or equipment failure, thereby reducing sensor life. Foreign body reaction affects the use effect of the sensor, limits further development, and is a critical problem to be solved in clinical application of implantable (micro-invasive) medical instruments.
Therefore, the bioactive substances capable of avoiding foreign body reaction are loaded on the corresponding parts of the biosensor, so that the functional coating can release the bioactive substances at the specific tissue parts for a long time, and the purpose of prolonging the service life of the biosensor is achieved. However, the addition of the drug-loaded coating may affect the original detection function of the sensor, and the sensor of the dynamic blood sugar detection system based on the electrochemical principle is taken as an example, most of the drugs for reducing foreign body reaction belong to hydrophobic drugs, and the polymers with good compatibility with the hydrophobic drugs and optimal drug slow release effect are generally hydrophobic materials. However, glucose can only reach the working electrode through the hydrophilic membrane layer, and the chemical signal is converted into an electrical signal through a series of reactions. These two materials, which are of contradictory nature, present a major technical challenge and risk when applied in combination to the same tiny (micron diameter) biosensor surface. Therefore, the original electrochemical performance of the sensor is not changed while the surface of the sensor is coated with the drug layer, which is a difficult problem to be solved in the prior art.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the related art to some extent. Therefore, an object of the present invention is to provide a micro-biosensor, in which a drug-carrying layer (drug-carrying polymer coating) is formed on the surface of the sensor by using a drug-carrying film liquid with a specific viscosity, and the addition of the drug-carrying layer can effectively release the drug in a specific portion for a long time without affecting the normal function of the biosensor, so that the problems of poor sensitivity of the biosensor due to foreign body reaction caused by implantation of the biosensor in vivo, protein accumulation and fiber encapsulation are reduced, and the service life of the sensor is effectively prolonged.
To this end, a first aspect of the invention provides a micro-biosensor for continuous monitoring of subcutaneous analyte concentration. According to an embodiment of the present invention, the micro-biosensor includes:
An insulating substrate including a first side and a second side disposed opposite to each other;
A conductive layer arranged on the first side surface and/or the second side surface of the insulating substrate;
An electrode disposed on a side of the conductive layer remote from the insulating substrate, the electrode coating a reactant;
The medicine carrying layer is arranged on the conductive layer and is spaced from the electrode,
Wherein the medicine carrying layer is made of medicine carrying film liquid with the viscosity of 50 cP-100 cP.
In order to prolong the service life of the biosensor, the surface of the biosensor is loaded with a bioactive substance capable of avoiding foreign body reaction, so that the functional coating can release the bioactive substance at a specific tissue site for a long time, however, the film liquid of the medicine carrying layer usually contains a volatile organic solvent, and when the organic solvent volatilizes too fast or the viscosity of the medicine carrying layer is too high, the outermost layer of the medicine carrying layer is easy to be rapidly skinned and wrinkled, so that the surface of the medicine carrying layer is not smooth, even the local thickness of the biosensor is too large to be used normally, and the original detection function of the sensor is affected. The invention provides a miniature biological sensor, which adopts medicine carrying film liquid with specific viscosity to form a medicine carrying layer (medicine carrying polymer coating) on the surface of the sensor, and loads functional bioactive substances to the designated position of the sensor, so that the biological sensor can achieve long-acting slow release in the service period of the sensor while the normal function of the biological sensor is not influenced, and the purpose of prolonging the service life of the sensor is met. The viscosity of the drug-loaded film liquid directly influences the thickness of dip coating and the uniformity of dip coating, and if the viscosity of the drug-loaded film liquid is too low, more coating passes are required to reach the target film thickness value. If the viscosity of the drug-carrying film liquid is too high, it is difficult to control the uniformity of the film thickness of the drug-carrying layer.
According to an embodiment of the invention, the reactant comprises any one of an enzyme, an antigen, an antibody or an aptamer.
According to an embodiment of the present invention, the thickness of the drug-carrying layer is 5 μm to 100 μm.
If the thickness of the medicine carrying layer is too small, the release amount of the bioactive substances is insufficient, the release time is insufficient, and the effect of prolonging the service life cannot be achieved, and if the thickness of the medicine carrying layer is larger, the medicine carrying amount is more, but the thickness of the medicine carrying layer is not more than 100 mu m due to the limitation of the inner diameter of the half-wall needle.
According to a preferred embodiment of the invention, the thickness of the drug-carrying layer is 20 μm-60 μm.
According to an embodiment of the invention, the drug-loaded membrane fluid comprises a biologically active substance, a carrier material and a solvent,
The mass ratio of the bioactive substances to the carrier material is 1 (1-9), or
The mass fraction of the sum of the mass of the bioactive substances and the mass of the carrier material in the medicine carrying membrane liquid is 1% -20%.
When the mass ratio of the bioactive substances to the carrier material is 1 (1-9), the release amount and the release time of the bioactive substances can be ensured to meet the requirements, the service life of the miniature biosensor can be prolonged, if the content of the bioactive substances is too small, the loading amount is too small, the release amount of the bioactive substances is insufficient, the release time is insufficient, the service life can not be prolonged, and if the content of the bioactive substances is too large, the carrier material is too small, on one hand, the quality (uniformity and smoothness) of a formed medicine carrying layer can be influenced, and on the other hand, the waste of the bioactive substances can be caused. According to a preferred embodiment of the invention, the sum of the mass of the biologically active substance and the mass of the carrier material is in the drug-loaded membrane liquid in a mass fraction of 5% -10%.
According to an embodiment of the invention, the carrier material comprises at least one of a natural polysaccharide material (e.g. chitosan), a natural polypeptide material, bioglass, bioceramics, aliphatic polyesters, aliphatic polycarbonates, polyanhydrides, polyorthoesters, polyurethanes, hydroxypropyl methylcellulose;
The bioactive substances comprise at least one of glucocorticoid medicine, aspirin medicine, growth factor, cytokine and nitric oxide;
the solvent comprises at least one of ethanol, tetrahydrofuran and water.
According to an embodiment of the invention, the glucocorticoid drug comprises dexamethasone drug;
The solvent is a mixed solution of absolute ethyl alcohol and tetrahydrofuran.
According to an embodiment of the invention, the dexamethasone-based drug comprises at least one of dexamethasone acetate, dexamethasone phosphate, and dexamethasone sodium phosphate;
in the solvent mixed solution, the volume ratio of the absolute ethyl alcohol to the tetrahydrofuran is 1:9-9:1.
The second aspect of the present invention provides a method for preparing a micro-biosensor for continuous monitoring of subcutaneous analyte concentration according to the first aspect. According to an embodiment of the invention, it comprises:
And coating the drug-loaded film liquid on the surface of the conductive layer of the micro-biosensor by adopting at least one of dip coating, brush coating, spot coating or spray coating.
The invention provides a preparation method of a miniature biosensor, which adopts bioactive substances to be loaded on a high polymer, forms a uniform medicine carrying layer on the biosensor, can effectively release the medicine carrying layer for a long time at a specific position while not affecting the normal function of the biosensor, can avoid foreign body reaction caused by implantation of the biosensor into the body, reduces the problem of reduced sensitivity of the biosensor in the later period caused by protein accumulation and fiber encapsulation, and effectively prolongs the service life of the sensor. The medicine in the medicine carrying layer can realize the safe and effective sustained release of the medicine in the body for 21 days, reduce foreign body reaction and realize the long-term stable detection of the micro-biosensor relative to the non-medicine carrying sensor.
According to an embodiment of the invention, the electrode comprises a working electrode,
When the medicine carrying layer is far away from the tail end of the implantation section of the miniature biosensor compared with the working electrode, the medicine carrying film liquid is coated in a spraying, spot coating or brush coating mode;
when the medicine carrying layer is closer to the tail end of the implantation section of the miniature biosensor than the working electrode, coating medicine carrying film liquid in a dip-coating mode;
When the medicine carrying layer is positioned on two sides of the working electrode, the medicine carrying film liquid is coated in a dip-coating and spray-coating combined mode.
According to the invention, the polymer coating loaded with the functional substance is coated on the biosensor, and the loading position and the loading mode are regulated and controlled, so that the addition of the polymer coating can be effectively released for a long time at a specific position while the normal function of the biosensor is not affected, the foreign body reaction caused by implantation of the biosensor into a body can be avoided, the problem of the decrease of the sensitivity of the biosensor in the later stage caused by protein accumulation and fiber encapsulation can be reduced, and the service life of the sensor can be effectively prolonged. The invention provides a method for prolonging the service life of a sensor by spatially separating and dividing the functional area of the sensor by regulating and controlling the coating process of a medicine carrying layer of the sensor, and the service life of the sensor is prolonged to 21 days or even longer.
According to the embodiment of the invention, when the coating of the drug-carrying film liquid is carried out by adopting a dip-coating mode, the following parameters are set:
the dip-coating time is 0.5 s-3 s;
the speed of the micro-biosensor without the medicine carrying layer being coated is 500 mm/s-1500 mm/s, and the speed of the micro-biosensor being separated from the medicine carrying film liquid is 50 mm/s-200 mm/s;
dip coating for 2-10 times;
The dip coating thickness is 5 μm-100 μm;
the depth of the micro-biosensor without the drug-carrying layer immersed in the drug-carrying film liquid is 1 mm-2 mm.
According to the embodiment of the invention, when the coating of the drug-carrying film liquid is carried out by adopting a spraying mode, the following parameters are set:
the molding air pressure valve pressure is 0.01 psi-0.5 psi;
the moving speed of the spray head relative to the micro-biological sensor is 1 mm/s-10 mm/s,
The speed of spraying the medicine carrying film liquid by the spray head is 0.05 mL/min-1 mL/min;
The spraying times are 2-50 times;
The spraying thickness is 5 μm-100 μm.
In the specific coating mode parameter range, the uniformity of the medicine carrying layer on the surface of the sensor can be further improved, and the service life of the sensor is prolonged.
A third aspect of the invention provides the use of a micro-biosensor according to the first aspect. According to an embodiment of the present invention, the micro-biosensor is used for implantation subcutaneously in order to continuously monitor physiological indicators in blood or interstitial fluid of a user.
According to an embodiment of the invention, the physiological index comprises blood glucose, blood oxygen, ketone, cholesterol, lactic acid, temperature.
Compared with the prior art, the invention has the following advantages:
(1) The method has the advantages that the bioactive substances are uniformly mixed with the polymer through a blending method, different processes are adopted to coat the bioactive substances at specific positions of the biosensor, the operation is simple and efficient, the coating is smooth and uniform, and the coating thickness is controllable;
(2) The bioactive substances used in the invention can achieve sustained and slow release in the wearing period of the biosensor, and achieve ideal controlled release effect;
(3) The invention can effectively avoid biofouling and fiber encapsulation caused by host foreign body reaction after the biosensor is implanted into the body, and improve the problems of reduced sensitivity and the like of the biosensor in the later period of use, thereby prolonging the service life of the sensor to 21 days or even longer days.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
The foregoing and/or additional aspects and advantages of the invention will become apparent and may be better understood from the following description of embodiments taken in conjunction with the accompanying drawings in which:
FIG. 1 shows a part of the structure of a drug-loaded sensor 1# prepared by a dip coating process in example 1;
FIG. 2 shows a part of the structure of drug-loaded sensor 2# prepared by the spray process in example 2;
In fig. 3, (a) shows the drug loading capacity of the drug-loaded sensor 2# prepared by a spraying process, and (b) shows the drug loading capacity of the drug-loaded sensor 1# prepared by a dip-coating process, wherein 5 sensor samples are pumped in each batch for detection;
In fig. 4, (a) shows the in vitro drug release rate of drug-loaded sensor 2# prepared by a spray coating process, and (b) shows the in vitro drug release rate of drug-loaded sensor 1# prepared by a dip coating process, wherein each line represents a sensor drug release result, which is a parallel drug-loaded sensor sample;
Fig. 5 (a) shows the in vitro drug cumulative release amount of drug-loaded sensor 2# prepared by the spray coating process;
FIG. 6 shows a survival curve of a conventional sensor and a drug loaded sensor 2# during wear, where CT5-DL is shown for a drug loaded sensor and conventional CT5 is shown for an unloaded sensor;
FIG. 7 shows the working electrode surface of a conventional non-drug loaded sensor (a) and the working electrode surface of a drug loaded sensor of the present invention (b) after a subject has been clinically worn for 21 days;
FIG. 8 shows a scanning electron microscope image of the working electrode surface of a conventional non-drug-loaded sensor (a) after a subject has been clinically worn for 21 days, and a scanning electron microscope image of the working electrode surface of a drug-loaded sensor according to the present invention (b);
FIG. 9 shows a current diagram of a conventional sensor and a drug-loaded sensor after a subject wears the sensor clinically for 21 days, wherein the current data of the two sensors in the diagram are derived from the same subject, CT4-DL is the drug-loaded sensor of the invention, and conventional CT4 is an unloaded sensor;
a cross-sectional view of the surface corrugated drug-loaded sensor prepared in comparative example 1 is shown in fig. 10.
Detailed Description
Embodiments of the present invention are described in detail below. The following examples are illustrative only and are not to be construed as limiting the invention.
It should be noted that the terms "first," "second," and "second" are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implying a number of technical features being indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. Further, in the description of the present invention, unless otherwise indicated, the meaning of "a plurality" is two or more.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
In order that the invention may be more readily understood, certain technical and scientific terms are defined below. Unless clearly defined otherwise herein in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In this document, the terms "comprise" or "include" are used in an open-ended fashion, i.e., to include what is indicated by the present invention, but not to exclude other aspects.
In this document, the terms "optionally," "optional," or "optionally" generally refer to the subsequently described event or condition may, but need not, occur, and the description includes instances in which the event or condition occurs, as well as instances in which the event or condition does not.
The present invention addresses the deficiencies of the prior art by providing a method for maintaining sensitivity of an implantable (minimally invasive) biosensor at a later stage of use and for extending the useful life of the sensor. The bioactive substance/material mixture is prepared by adopting a blending mode and is used as a matrix material for preparing the drug-loaded coating of the sensor. By changing the processing technology, the drug-loaded coating is successfully coated on the non-working electrode area of the biosensor. The release rate of the bioactive substances is regulated and controlled by further optimizing the types of the polymers, the concentration of the polymers and the proportion of the bioactive substances, so that the bioactive substances can be continuously and slowly released in the service cycle of the sensor, and the in-vivo service life of the biosensor is prolonged.
According to a specific embodiment of the present invention, there is provided a micro-biosensor for continuous monitoring of subcutaneous analyte concentration, comprising:
An insulating substrate including a first side and a second side disposed opposite to each other;
A conductive layer arranged on the first side surface and/or the second side surface of the insulating substrate;
An electrode disposed on a side of the conductive layer remote from the insulating substrate, the electrode coating a reactant;
The medicine carrying layer is arranged on the conductive layer and is spaced from the electrode,
Wherein the medicine carrying layer is made of medicine carrying film liquid with the viscosity of 50 cP-100 cP.
According to a specific embodiment of the present invention, the drug-loaded layer is made of a drug-loaded film liquid having a viscosity in the range of any of the viscosity values 50 cP-100 cP. For example, the drug-carrying layer is made of drug-carrying film liquid with viscosity of 50 cP, 55 cP, 60 cP, 65 cP, 70 cP, 75 cP, 80 cP, 85 cP, 90 cP, 95 cP or 100 cP.
According to a specific embodiment of the present invention, the conductive layer of the micro-biosensor provided by the present invention includes three electrodes, namely, a working electrode, a counter electrode and a reference electrode, so as to ensure detection accuracy and stability. The working electrode comprises an electrode substrate material and a modification layer, and the surface of the working electrode of the miniature biosensor provided by the invention is coated with a substance (namely the modification layer) for reacting with an analyte, and chemical signals are converted into electric signals based on the contact reaction of the analyte and the substance for reacting with the analyte, so that the continuous monitoring of physiological indexes in blood or tissue fluid is realized.
According to a specific embodiment of the invention, the reactant comprises any one of an enzyme, an antigen, an antibody or an aptamer.
According to a specific embodiment of the invention, when the analyte is blood glucose, glucose oxidase or glucose dehydrogenase is coated on the electrode surface of the micro-biosensor, and when the micro-biosensor is implanted under the skin of a subject, the glucose oxidase can convert glucose in interstitial fluid into hydrogen peroxide, so that the electrode surface is oxidized, a current signal proportional to the concentration of the blood glucose is generated, and real-time continuous monitoring is realized.
According to a specific embodiment of the invention, when the analyte is some protein or polypeptide, the electrode surface of the micro-biosensor is coated with a detection antibody against the protein or polypeptide, but no electroactive product or electron transfer detectable by the electrode is generated due to the antibody-antigen binding itself. The pure antibody coating can not realize conversion from chemical signal to electric signal, and a 'transduction' link is required to be introduced, so that the electric signal is required to be indirectly generated by matching with a marker enzyme (such as horseradish peroxidase (HRP)) or a nano material.
According to a specific embodiment of the invention, when the analyte is a small molecule or an ion, an aptamer combined with the small molecule or the ion can be coated on the electrode surface of the micro-biosensor, and electrochemical signal change is induced by conformational change before and after the aptamer is combined with the target, so that the detection of the target is realized.
According to a specific embodiment of the present invention, the thickness of the drug-loaded layer is 5 μm to 100 μm.
The thickness of the drug-carrying layer may be any value within the range of 5 to 100 μm, for example 5 μm、10 μm、15 μm、20 μm、25 μm、30 μm、35 μm、40 μm、45 μm、50 μm、55 μm、60 μm、65 μm、70 μm、75 μm、80 μm、85 μm、90 μm、95 μm、100 μm.
According to a preferred embodiment of the present invention, the thickness of the drug-loaded layer is 20 μm to 60 μm.
According to a specific embodiment of the present invention, the drug-loaded membrane fluid comprises a biologically active substance, a carrier material and a solvent.
According to a specific embodiment of the invention, the mass ratio of the biologically active substance to the carrier material is 1 (1-9).
For example, the mass ratio of the bioactive substance to the carrier material is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, etc.
The micro-biosensor of the invention has a small volume, a limited area capable of loading the drug layer, and a thickness limited by the diameter of the half-wall needle. Therefore, to maximize the loading of the drug onto the sensor within a limited volume, it is necessary to control the ratio between the drug and the polymer in the drug layer within a proper range. On the other hand, the polymer should be >50% by mass as a major contributor to the mechanical strength of the drug carrier and drug-carrying layer. In combination with the two factors, the invention explores that the mass ratio of the bioactive substances to the carrier material is 1 (1-9). Under these conditions, the drug is fully miscible with the polymer. In the subsequent clinical test and in-vitro drug release test, the mechanical property of the drug carrying layer is good. In addition, the drug-loaded sensor worn continuously for 21 days still can detect drug residues in the sensor after the wearing is finished, which indicates that the loaded drug amount is sufficient.
According to a more preferred embodiment of the invention, the mass ratio of the biologically active substance to the carrier material is 1:1.
According to a specific embodiment of the invention, the sum of the mass of the biologically active substance and the mass of the carrier material is 1% -20% by mass of the drug-loaded membrane liquid.
For example, the mass fraction of the sum of the mass of the bioactive substance and the carrier material in the drug-loaded membrane fluid is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, etc.
According to a preferred embodiment of the invention, the sum of the mass of the biologically active substance and the mass of the carrier material is in the drug-loaded membrane liquid in a mass fraction of 5% -10%.
According to a specific embodiment of the invention, the carrier material may be a hydrophobic or non-hydrophobic material, or a polar or non-polar material.
According to a specific embodiment of the present invention, the carrier material comprises at least one selected from the group consisting of natural polysaccharide materials, natural polypeptide materials, bioglass, bioceramics, aliphatic Polyesters (APs), aliphatic Polycarbonates (APCs), polyanhydrides (PAs), polyorthoesters (POEs), polyurethanes (PUs), hydroxypropyl methylcellulose.
It should be noted that the modified polysaccharide materials, polypeptide materials, bioglass, bioceramics and the like can be used as carrier materials of the invention for preparing drug-carrying membrane liquid by mixing with bioactive substances, and are also covered in the protection scope of the invention.
According to a specific embodiment of the present invention, the natural polysaccharide material includes Hyaluronic Acid (HA), alginic acid (Alg), chitosan (CS), etc., and the natural polypeptide material includes fibrin, collagen or silk fibroin, etc. Aliphatic polyesters include, for example, polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymers (PLGA), and Polycaprolactone (PCL), and the like. Aliphatic polycarbonates include polyethylene carbonate (PEC), polypropylene carbonate (PPC), and polytrimethylene carbonate (PTMC), and the like. The materials mentioned above can be used as drug-loaded polymeric materials either alone or by blending/copolymerizing.
According to a specific embodiment of the invention, the bioactive substance comprises at least one of a glucocorticoid, an aspirin, a growth factor, a cytokine, and nitric oxide.
According to a specific embodiment of the present invention, the microbial biosensor provided by the present invention comprises a drug-loaded membrane solution, wherein the bioactive substance contained in the drug-loaded membrane solution is a steroidal anti-inflammatory drug or a non-steroidal anti-inflammatory drug.
According to a specific embodiment of the present invention, the bioactive substances contained in the drug-loaded membrane solution include, but are not limited to, glucocorticoids, non-steroidal anti-inflammatory drugs (aspirin, etc.), growth factors (such as Vascular Endothelial Growth Factor (VEGF)), cytokines, nitric oxide, etc., and these bioactive substances may be mixed with a carrier material alone in a solvent to prepare the drug-loaded membrane solution, or may be mixed with a plurality of bioactive substances in the drug-loaded membrane solution, which is covered in the protection scope of the present invention.
According to a specific embodiment of the present invention, the solvent comprises at least one of ethanol, tetrahydrofuran, water.
In the micro-biosensor provided by the invention, the solvent contained in the drug-carrying membrane liquid comprises at least one of ethanol, tetrahydrofuran and water, but is not limited to the solvents.
According to a preferred embodiment of the present invention, the solvent is a mixture of absolute ethanol and tetrahydrofuran.
According to a preferred embodiment of the invention, the glucocorticoid drug comprises a dexamethasone drug.
It should be noted that, in the micro-biosensor provided by the invention, the bioactive substances contained in the drug-carrying membrane liquid are glucocorticoid drugs, the glucocorticoid drugs include but are not limited to dexamethasone drugs, the dexamethasone drugs include at least one of dexamethasone acetate, dexamethasone phosphate and dexamethasone sodium phosphate, and other non-enumerated dexamethasone drugs or pharmaceutically acceptable salts thereof are all included in the protection scope of the invention.
According to a preferred embodiment of the present invention, the carrier material is a hydrophobic polymer (e.g., polyurethane (PUs)), the bioactive substance is a hydrophobic drug (e.g., dexamethasone drug), and the drug-carrying layer is formed on the biosensor by carrying the hydrophobic drug on the hydrophobic polymer, so as to obtain the implantable micro-biosensor with longer service life.
According to a preferred embodiment of the present invention, when the solvent is a mixed solution of absolute ethanol and tetrahydrofuran, the volume ratio of absolute ethanol to tetrahydrofuran in the solvent mixed solution is 1:9 to 9:1.
For example, when the solvent is a mixed solution of absolute ethanol and tetrahydrofuran, the volume ratio of absolute ethanol to tetrahydrofuran in the solvent mixed solution is 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or the like.
According to a specific embodiment of the present invention, there is also provided a method of manufacturing the aforementioned micro-biosensor for continuous monitoring of subcutaneous analyte concentration, comprising:
And coating the drug-loaded film liquid on the surface of the conductive layer of the micro-biosensor by adopting at least one of dip coating, brush coating, spot coating or spray coating.
According to the preparation method provided by the invention, the specific bioactive substances and the carrier material are dissolved in the solvent to form the medicine carrying film liquid, and the medicine carrying film liquid is coated on the surface of the conductive layer of the micro-biosensor in at least one of dip coating, brush coating, spot coating or spray coating modes, so that the prepared micro-biosensor can realize safe and effective sustained release of medicines in 21 days in vivo, reduce foreign body reaction and realize longer-term stable detection.
The mixing method used when the bioactive substance and the carrier material are dissolved in the solvent is not particularly limited, and for example, the bioactive substance and the carrier material may be stirred, sonicated, or vortexed until the mixture solution becomes transparent.
According to a specific embodiment of the invention, the electrode comprises a working electrode,
When the medicine carrying layer is far away from the tail end of the implantation section of the miniature biosensor compared with the working electrode, the medicine carrying film liquid is coated in a spraying, spot coating or brush coating mode;
when the medicine carrying layer is closer to the tail end of the implantation section of the miniature biosensor than the working electrode, coating medicine carrying film liquid in a dip-coating mode;
When the medicine carrying layer is positioned on two sides of the working electrode, the medicine carrying film liquid is coated in a dip-coating and spray-coating combined mode.
According to a specific embodiment of the invention, when the coating of the drug-carrying film liquid is carried out by dip coating, the parameters are set as follows:
the dip-coating time is 0.5 s-3 s;
the speed of the micro-biosensor without the medicine carrying layer being coated is 500 mm/s-1500 mm/s, and the speed of the micro-biosensor being separated from the medicine carrying film liquid is 50 mm/s-200 mm/s;
dip coating for 2-10 times;
The dip coating thickness is 5 μm-100 μm;
the depth of the micro-biosensor without the drug-carrying layer immersed in the drug-carrying film liquid is 1 mm-2 mm.
According to a specific embodiment of the invention, when the coating of the drug-carrying film liquid is carried out by spraying, the following parameters are set:
the molding air pressure valve pressure is 0.01 psi-0.5 psi;
the moving speed of the spray head relative to the micro-biological sensor is 1 mm/s-10 mm/s,
The speed of spraying the medicine carrying film liquid by the spray head is 0.05 mL/min-1 mL/min;
The spraying times are 2-50 times;
The spraying thickness is 5 μm-100 μm.
The invention also provides the use of a micro-biosensor as described above, which can be used for implantation subcutaneously in a user to continuously monitor physiological indicators in the blood or interstitial fluid of the user.
It should be noted that the physiological index covers all physiological indexes in blood or tissue fluid of a user to be detected in the medical field. Depending on the purpose of the detection, it is correspondingly necessary to apply different reactants to the electrodes.
According to a specific embodiment of the invention, the physiological index comprises blood glucose, blood oxygen, ketone, cholesterol, lactic acid, temperature.
According to a specific embodiment of the present invention, the micro-biosensor comprises an implantable biosensor by direct contact with blood or interstitial fluid, such as a dynamic blood glucose detection system (CGM), a continuous blood ketone detection system (CKM), etc.
The aspects of the present disclosure will be explained below with reference to examples. Those skilled in the art will appreciate that the following examples are illustrative of the present disclosure and should not be construed as limiting the scope of the present disclosure. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1 polyurethane drug-loaded sensor 1# prepared using a dip coating process
The drug-loaded layer is coated by dip-coating when the drug-loaded layer is closer to the end of the implanted segment of the micro-biosensor than the working electrode. And adding dexamethasone acetate with the mass fraction of 55% into the polyurethane solution, and obtaining a first solution after uniform mixing. Before dip-coating, the first solution is diluted, and the diluted solution is a mixed solvent of tetrahydrofuran and absolute ethyl alcohol (the volume ratio of the tetrahydrofuran to the absolute ethyl alcohol is 1:9) so as to obtain a second solution. Wherein the mass ratio of dexamethasone acetate to polyurethane in the second solution is 1:1, and the mass fraction of the sum of the mass of dexamethasone acetate and polyurethane in the second solution is 5%. The second solution had a viscosity of 50 cp. The second solution was placed in a polytetrafluoroethylene mold and sensor dip-coating was performed.
The dip-coating depth and the drug-loaded coating thickness of the drug-loaded coating are controlled by adjusting the second solution, the sensor drop height, the drop speed and the residence time. Specifically, under the condition of room temperature, dip coating time of each time is 1s, sensor rising speed is 100 mm/s, sensor falling speed is 900 mm/s, coating times are 6 times, coating depth is 2mm, and a drug-loaded coating with thickness of 30 μm is obtained. Fig. 1 shows a sensor tip prepared by dip coating, and it can be observed that the dip coating tip has a distinct drug-loaded layer demarcation line.
Example 2 polyurethane drug-loaded sensor 2# prepared using spray coating Process
And when the medicine carrying layer is far away from the tail end of the implantation section of the miniature biosensor compared with the working electrode, the medicine carrying layer is loaded in a spraying/dispensing mode, and the medicine carrying layer is coated on the upper part or the back surface of the sensor. And adding dexamethasone acetate with the mass fraction of 55% into the polyurethane solution, and obtaining a first solution after uniform mixing. Before spraying, the first solution is diluted, and the diluted solution is a mixed solvent of tetrahydrofuran and absolute ethyl alcohol (the volume ratio of the tetrahydrofuran to the absolute ethyl alcohol is 9:1) to obtain a second solution. Wherein the mass ratio of dexamethasone acetate to polyurethane in the second solution is 9:11, and the mass fraction of the sum of the mass of dexamethasone acetate and polyurethane in the second solution is 10%. The second solution had a viscosity of 60 cp.
The spraying speed, the spraying times and the spraying track are controlled, and the spraying area of the drug-carrying coating and the thickness of the drug-carrying coating are controlled. The parameters are set as follows, the pressure of a forming air pressure valve is 0.01 psi, the moving speed of a spray head relative to a biological sensor is 2 mm/s, the speed of spraying the medicine carrying film liquid by the spray head is 0.1 mL/min, and the spraying is carried out for 20 times, so that the medicine carrying coating with the thickness of 20 mu m is obtained. Fig. 2 shows the sensor surface prepared by spraying, and a distinct drug-loaded layer boundary can be observed.
Example 3 polyurethane drug-loaded sensor 3# prepared using spray/dip coating Process
When the medicine carrying layer is positioned on two sides of the working electrode, a medicine coating is coated by adopting a method combining dip coating and spray coating. The application of the sensor drug coating is realized through single drug/multi-drug combination. For such sensors, a functional role may be played by a single/multi-zone drug-loaded layer.
And adding 5% of aspirin into the polyurethane solution by adopting a spraying mode for the upper part and the back area of the working electrode, and obtaining a first solution after uniformly mixing. Before spraying, the first solution is diluted, and the diluted solution is a mixed solvent of tetrahydrofuran and absolute ethyl alcohol (the volume ratio of the tetrahydrofuran to the absolute ethyl alcohol is 1:1) to obtain a second solution. Wherein the mass ratio of the aspirin to the polyurethane in the second solution is 2:3, and the mass fraction of the sum of the aspirin and the polyurethane in the second solution is 1%. The second solution had a viscosity of 80 cp.
The spraying speed, the spraying times and the spraying track are controlled, and the spraying area of the drug-carrying coating and the thickness of the drug-carrying coating are controlled. The parameters are set as follows, the pressure of a forming air pressure valve is 0.1 psi, the moving speed of a spray head relative to a biological sensor is 5 mm/s, the speed of spraying the medicine carrying film liquid by the spray head is 0.5 mL/min, and the spraying is carried out for 15 times, so that the medicine carrying coating with the thickness of 15 mu m is obtained.
And adding dexamethasone acetate with the mass fraction of 55% into the polyurethane solution by dip-coating in the area below the working electrode, and obtaining a first solution after uniform mixing. Before dip-coating, the first solution is diluted, and the diluted solution is a mixed solvent of tetrahydrofuran and absolute ethyl alcohol (the volume ratio of the tetrahydrofuran to the absolute ethyl alcohol is 1:5) to obtain a second solution. Wherein the mass ratio of dexamethasone acetate to polyurethane in the second solution is 1:9, and the mass fraction of the sum of the mass of dexamethasone acetate and polyurethane in the second solution is 20%. The second solution was placed in a polytetrafluoroethylene mold and sensor dip-coating was performed. The second solution had a viscosity of 100 cp.
The dip-coating depth and the drug-loaded coating thickness of the drug-loaded coating are controlled by adjusting the second solution, the sensor drop height, the drop speed and the residence time. Under the condition of room temperature, the dip coating time of each time is 1 s, the rising speed of the sensor is 100 mm/s, the falling speed of the sensor is 1000 mm/s, the coating times are 3 times, the coating depth is 2 mm, and the drug-loaded coating with the thickness of 15 μm is obtained.
Example 4 cellulose based drug-loaded sensor 4# prepared using spray/dip coating process
The procedure for the preparation of cellulose-based drug-loaded sensor 4# using the spray/dip coating process was the same as in example 3, except that the drug-loaded polymer polyurethane was changed to hydroxypropyl methylcellulose, the selected dilutions were ethanol and water (volume ratio of 1:9), and the remaining steps were the same as in example 3.
The inventor carries out microscopic observation on the medicine carrying sections of the medicine carrying sensors No.1, no.2, no. 3 and No. 4 prepared in the examples 1-4, and discovers that the medicine carrying layers have no folds, uniform texture and smooth surface.
Experimental example:
The drug-loaded sensors 1# and 2# prepared in examples 1 and 2 were subjected to a sensor drug loading test, an in vitro drug release rate test, and an in vivo clinical wear test, respectively, by the following test methods:
The sensor drug loading amount is shown in figure 3, wherein (a) the drug loading amount of the drug loading sensor 2# prepared by a spraying process is shown, and (b) the drug loading amount of the drug loading sensor 1# prepared by a dip coating process is shown, and the results show that the coating processes of the two drug loading layers meet the preset target of the drug loading amount of more than or equal to 5 mug/sensor.
In vitro drug release rate in vitro drug release experiments were validated by placing drug-loaded sensors prepared using two processes, dip-coating and spray-coating, in a release medium (phosphate buffer). At 8, 24, 48, 72, 120, 168, 216, 264, 312, 360 h, the sensor is placed in a new release medium and the resulting biosensor drug coating is prepared to achieve sustained and effective release over a period of use. The in vitro medicine cumulative release rate is shown in figure 4, wherein (a) shows the in vitro medicine release rate of the medicine carrying sensor 2# prepared by a spray coating process, (b) shows the in vitro medicine release rate of the medicine carrying sensor 1# prepared by a dip coating process, the in vitro medicine cumulative release amount is shown in figure 5, wherein (a) shows the in vitro medicine release amount of the medicine carrying sensor 2# prepared by a spray coating process, and (b) shows the in vitro medicine release amount of the medicine carrying sensor 1# prepared by a dip coating process, which shows that the medicine can be slowly released in a 14-day period by spraying or dip coating the medicine carrying layer, and the medicine release rate is about 80% in the last day of medicine release.
The calculation formula of the accumulated release amount of the drug is as follows:
wherein V is the volume of the test solution, and C is the concentration of the test solution.
In vivo clinical wearing test, compared with the conventional sensor without drug carrier prepared by the same process (example 1), aims to evaluate whether the current of the sensor with drug carrier is maintained at a higher level in the later period of wearing, and the specific embodiment is that the attenuation-free condition or the attenuation condition is relieved compared with the control group. We made a survival curve of a conventional sensor and a drug-loaded sensor during wearing of a subject, and quantitatively analyzed the curve. As shown in fig. 6, the optimal Ks for each sensor for 3-7 days was regarded as 1, normalized sensor-by-sensor Ks (IW/BG), and the subjects worn the sensors with less than 80% of the average Ks per day normalized for a single sensor for two consecutive days were regarded as dead, with the result that 97.5% of the drug-loaded sensors survived while the survival rate of the drug-unloaded sensors was only 50% as seen at day 16. In addition, microscopic morphology observation is carried out on the sensor worn by the subject for 21 days to explore the reason of current attenuation, and the results are shown in fig. 7 and 8, and show that the working electrode of the medicine-carrying sensor is smooth, no obvious biofouling is found, and the working electrode of the medicine-carrying conventional sensor is not smooth and has obvious biofouling. Fig. 9 shows a current diagram of a conventional sensor and a drug-loaded sensor worn by a subject for 21 days, and the result shows that the current of the sensor loaded with the drug layer provided by the invention still maintains a higher level for 21 days without attenuation, and the current signal of the conventional sensor is obviously attenuated after 15 days of wearing.
Comparative example 1:
the process for preparing the drug-loaded sensor was the same as in example 1, except that the drug-loaded film liquid with a viscosity of 110 cp (polyurethane viscosity of 110 cp) was used for dip-coating 3 times, and the cross section was as shown in fig. 10, and the obtained drug-loaded layer was found to be uneven in thickness.
In the description of the present specification, the descriptions of the terms "one embodiment," "some embodiments," "examples," "particular examples," "some embodiments," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (11)
1. A micro-biosensor for continuous monitoring of subcutaneous analyte concentration, comprising:
An insulating substrate including a first side and a second side disposed opposite to each other;
A conductive layer arranged on the first side surface and/or the second side surface of the insulating substrate;
An electrode disposed on a side of the conductive layer remote from the insulating substrate, the electrode coating a reactant;
The medicine carrying layer is arranged on the conductive layer and is spaced from the electrode,
Wherein, the medicine carrying layer is made of medicine carrying film liquid with the viscosity of 50 cP-100 cP.
2. The microbial biosensor of claim 1, wherein the reactant comprises any one of an enzyme, an antigen, an antibody, or an aptamer.
3. The micro-biosensor of claim 1, wherein the drug-loaded layer has a thickness of 5 μm to 100 μm.
4. The micro-biosensor of claim 1, wherein the drug-loaded membrane fluid comprises a bioactive substance, a carrier material, and a solvent,
The mass ratio of the bioactive substances to the carrier material is 1 (1-9), or
The mass fraction of the sum of the mass of the bioactive substances and the mass of the carrier material in the medicine carrying membrane liquid is 1% -20%.
5. The microbial biosensor of claim 4, wherein the carrier material comprises at least one of a natural polysaccharide material, a natural polypeptide material, bioglass, bioceramics, aliphatic polyesters, aliphatic polycarbonates, polyanhydrides, polyorthoesters, polyurethanes, hydroxypropyl methylcellulose;
The bioactive substances comprise at least one of glucocorticoid medicine, aspirin medicine, growth factor, cytokine and nitric oxide;
the solvent comprises at least one of ethanol, tetrahydrofuran and water.
6. The micro-biosensor of claim 5, wherein the glucocorticoid drug comprises a dexamethasone drug;
The solvent is a mixed solution of absolute ethyl alcohol and tetrahydrofuran.
7. The micro-biosensor of claim 6, wherein the dexamethasone-based drug comprises at least one of dexamethasone acetate, dexamethasone phosphate, and dexamethasone sodium phosphate;
in the solvent mixed solution, the volume ratio of the absolute ethyl alcohol to the tetrahydrofuran is 1:9-9:1.
8. A method of manufacturing a micro-biosensor for continuous monitoring of subcutaneous analyte concentration as claimed in any of claims 1-7, comprising:
And coating the drug-loaded film liquid on the surface of the conductive layer of the micro-biosensor by adopting at least one of dip coating, brush coating, spot coating or spray coating.
9. The method of manufacturing according to claim 8, wherein the electrode comprises a working electrode,
When the medicine carrying layer is far away from the tail end of the implantation section of the miniature biosensor compared with the working electrode, the medicine carrying film liquid is coated in a spraying, spot coating or brush coating mode;
when the medicine carrying layer is closer to the tail end of the implantation section of the miniature biosensor than the working electrode, coating medicine carrying film liquid in a dip-coating mode;
When the medicine carrying layer is positioned on two sides of the working electrode, the medicine carrying film liquid is coated in a dip-coating and spray-coating combined mode.
10. The method according to claim 9, wherein when the coating of the drug-carrying film liquid is performed by dip coating, the parameters are set as follows:
the dip-coating time is 0.5 s-3 s;
the speed of the micro-biosensor without the medicine carrying layer being coated is 500 mm/s-1500 mm/s, and the speed of the micro-biosensor being separated from the medicine carrying film liquid is 50 mm/s-200 mm/s;
dip coating for 2-10 times;
The dip coating thickness is 5 μm-100 μm;
the depth of the micro-biosensor which is not coated with the drug-carrying layer and immersed in the drug-carrying film liquid is 1mm-2 mm.
11. The method according to claim 9, wherein when the coating of the drug-carrying film liquid is performed by spraying, the parameters are set as follows:
the molding air pressure valve pressure is 0.01 psi-0.5 psi;
the moving speed of the spray head relative to the micro-biological sensor is 1 mm/s-10 mm/s,
The speed of spraying the medicine carrying film liquid by the spray head is 0.05 mL/min-1 mL/min;
The spraying times are 2-50 times;
The spraying thickness is 5 μm-100 μm.
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