Analyte sensors and methods for fabricating analyte sensors

Analyte sensor and method for manufacturing analyte sensor

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the following rights: U.S. Provisional Patent Application Serial No. 62/504,670 filed on May 11, 2017, the entire contents of which are incorporated herein by reference; U.S. Patent Application filed on February 20, 2018 Serial No. 15/900, 630, the entire content of which is incorporated herein by reference; US Patent Application Serial No. 15/900, 639 filed on February 20, 2018, the entire content of which is incorporated herein by reference.

Technical field

[0003] Embodiments of the subject matter described herein generally relate to sensors for monitoring analyte levels in patients and methods for manufacturing such sensors. More specifically, embodiments of the subject matter relate to glucose sensors, such as for continuous or substantially continuous monitoring of blood glucose levels.

Background technique

[0004] The pancreas of a normal healthy person produces and releases insulin into the bloodstream in response to elevated plasma glucose levels. The beta cells (beta-cells) that reside in the pancreas produce and secrete insulin into the bloodstream when needed. If the beta cells become incapacitated or die, the condition is called type 1 diabetes (or in some cases, if the amount of insulin produced by the beta cells is insufficient, the condition is called type 2 diabetes), which can be provided to the body Insulin to maintain life or health.

[0005] Traditionally, since insulin cannot be taken orally, insulin has been injected with a syringe. Recently, the use of infusion pump therapy has been increasing in a variety of medical situations, including for the delivery of insulin to diabetic patients. For example, external infusion pumps can be worn on belts, pockets, etc., and they can deliver insulin into the body via an infusion tube with a percutaneous needle or a cannula placed in the subcutaneous tissue.

[0006] As of 1995, less than 5% of type 1 diabetes patients in the United States use infusion pump therapy. At present, more than 7% of more than 900,000 type 1 diabetes patients in the United States are using infusion pump therapy. The percentage of patients with type 1 diabetes who use infusion pumps is increasing at a rate of more than 2% per year. In addition, the number of type 2 diabetes patients is increasing at a rate of 3% or more per year, and more and more type 2 diabetes patients who use insulin are also using infusion pumps. In addition, physicians have realized that continuous infusion can better control the condition of diabetic patients, and therefore more and more such prescriptions are prescribed for patients.

[0007] The infusion pump system may include an infusion pump that is automatically and/or semi-automatically controlled to inject insulin into the patient. The infusion of insulin can be controlled to occur at a time and amount based on, for example, blood glucose measurements obtained in real time from an embedded analyte sensor injected into the glucose sensor.

[0008] There are two main types of blood glucose monitoring systems used by patients: single point or discontinuous and continuous. The non-continuous system consists of a measuring instrument and a test strip, and requires blood samples to be drawn from the fingertips or alternative parts (such as the forearms and legs). These systems rely on pricking and manipulation of fingers or alternative blood draw sites, which can be extremely painful and inconvenient, especially for children.

[0009] Continuous monitoring sensors are usually implanted subcutaneously, and measure the glucose level in the interstitial fluid at different times throughout the day, thereby providing data showing the trend of glucose measurement in a short period of time. These sensors are painful during insertion and often require the assistance of a healthcare professional. In addition, these sensors are designed to enable

Use (for example, monitor for several days to determine blood glucose patterns). Sensors implanted subcutaneously can cause infection and immune response complications. [0010] Another major disadvantage of currently available continuous monitoring devices is that they require frequent, usually daily calibrations using blood glucose results, while blood glucose results must be obtained through painful finger piercing using traditional measuring instruments and test strips. . This calibration and recalibration is necessary to maintain the accuracy and sensitivity of the sensor, but it can be cumbersome and painful.

[0011] A typical glucose sensor works according to the following chemical reaction: Formula 1 chrysanthemum and grape bran + o₂ --------------►

[0012] Lycolic acid-h_zo₃

[0013] H3O2 - Ο2Η++2Formula 2

[0014] In Formula 1, glucose oxidase is used to catalyze the reaction between glucose and oxygen to produce gluconic acid and hydrogen peroxide (H2O2). Hydrogen peroxide reacts electrochemically, as shown in Equation 2, and the resulting current can be measured by a potentiostat. These reactions that occur in various oxidoreductases known in the art are used in many sensor designs.

[0015] In the case of a three-electrode design (working electrode, counter electrode, and reference electrode), the reference electrode is not consumed, and the generated 02 (formula 2) is reduced at the counter electrode according to the reaction (3).

[0016] 0₂+2H₂0+4e^40H⁺ （3）

[0017] In the case of a two-electrode design (working electrode and reference electrode only), the following reactions occur at the reference electrode

[0018] AgCl+e"-Ag+C"

[0019] It is necessary to discuss the relative advantages of the 2-electrode and 3-electrode designs. In the case of a 3-electrode design, oxygen is consumed at the counter electrode, which is also required by glucose oxidase (Equation 1). However, the Ag/AgCl reference remained stable; although the sensor's dependence on oxygen increased. In the case of the 2-electrode design, the dependence of the sensor on oxygen is reduced; although AgCl is consumed over time (according to Equation 4), it is necessary to provide a sufficient amount of AgCL to maintain the life of the sensor. [0020] With the analyte The maturity of sensor technology and the development of new applications of sensor technology require improved analyte sensors, such as continuous monitoring sensors used for longer durations. In addition, there is a need to develop advanced methods for sensor manufacturing that can produce factory-calibrated analyte sensors without further external calibration.

[0021] In addition, there is a need for low-cost mass production of analyte sensors, such as glucose sensors. Conventional batch processing is not suitable for mass production or greatly reducing costs.

[0022] Therefore, it is desirable to have an improved analyte sensor and related manufacturing method that can solve the shortcomings of traditional sensor systems. In addition, other desired features and characteristics will become apparent from the following detailed description and appended claims in conjunction with the accompanying drawings and the foregoing technical field and background technology.

Summary of the invention

[0023] The present invention provides analyte sensors and methods for manufacturing analyte sensors. In an exemplary embodiment, a planar flexible analyte sensor includes a flexible base layer and a first electrode formed by a sputtering clamp layer on the base layer. In addition, the analyte sensor includes an insulating dielectric layer above the base layer, wherein the insulating dielectric layer exposes a portion of the first electrode. In addition, the analyte sensor includes an electrochemical sensing stack above the exposed portion of the first electrode, which includes a glucose oxidase layer above the sputter clamp layer and a glucose confinement membrane above the glucose oxidase layer.

[0024] In another embodiment, the analyte sensor includes a polyester substrate, a clamp layer on the polyester substrate, a clamp layer

The protective layer above, and the electrochemical sensing stack above the platinum layer.

[0025] Another embodiment provides a planar flexible analyte sensor that includes a polyester base layer and a working electrode, and a reference electrode formed from a sputtered platinum layer on the base layer. In addition, the planar flexible analyte sensor includes an insulating dielectric layer over a polyester base layer and a sputtered platinum layer. The insulating dielectric layer exposes part of the first electrode and part of the second electrode. In addition, the flat flexible analyte sensor includes silver/silver chloride ink on the exposed portion of the reference electrode. The planar flexible analyte sensor also includes a glucose oxidase layer above the exposed portion of the working electrode and a glucose confinement membrane above the glucose oxidase layer.

[0026] In another exemplary embodiment, a method for manufacturing a flat flexible analyte sensor includes sputtering platinum onto a polyester base layer to form a platinum layer. The method includes patterning the platinum layer to form a working electrode and additional electrodes. In addition, the method includes forming an insulating dielectric layer over the base layer, wherein the insulating dielectric layer is formed with an opening exposing a portion of the working electrode and a portion of the additional electrode. In addition, the method includes partially separating the individual sensors from the base layer, where each individual sensor is connected to the base layer by an interposer. The method also includes depositing an enzyme layer over the exposed portion of the working electrode, and coating the working electrode with a glucose confinement membrane.

[0027] Another exemplary embodiment provides a method for manufacturing a flat flexible analyte sensor. The method includes providing a polyester base layer having a first side sputtered with a platinum layer and a second side opposite the first side. The method includes patterning the platinum layer to form a working electrode. In addition, the method includes forming an insulating dielectric layer over the first side surface of the base layer, wherein the insulating dielectric layer is formed with an opening exposing a portion of the working electrode. The method also includes printing a silver/silver chloride ink on the second side of the base layer. The method also includes partially separating the individual sensors from the base layer, where each individual sensor is connected to the base layer by an interposer. The method includes depositing an enzyme layer over the exposed portion of the working electrode, and coating the working electrode with a glucose confinement membrane.

[0028] In another embodiment, a method for manufacturing an analyte sensor in a roll-to-roll process includes providing a polyester substrate roll having a first side coated with a platinum layer. This method feeds the polyester substrate from the roll to the electrode patterning stage. Additionally, the method includes patterning the platinum layer to form a working electrode and a reference electrode. This method feeds the polyester substrate to the insulation stage. The method includes forming an insulating dielectric layer over a polyester substrate. This method feeds the polyester substrate to the insulation curing stage. The method includes curing the insulating dielectric layer. This method feeds the polyester substrate to the ink printing stage. The method includes depositing a silver/silver chloride ink over the reference electrode. This method feeds the polyester substrate to the drying stage. The method includes drying the silver/silver chloride ink. This method feeds the polyester substrate to the stamping stage. The method includes stamping the polyester substrate to form a strip, wherein each strip is connected to the remaining polyester substrate web by a tab, and wherein each sensor includes a working electrode and a reference electrode. This method feeds the remaining polyester substrate to the enzyme deposition stage. The method includes depositing an enzyme layer over the working electrode. This method feeds the remaining polyester substrate to the enzyme curing stage. The method includes curing the enzyme layer. This method feeds the remaining polyester substrate to the film formation stage. The method includes coating the working electrode with a glucose confinement membrane.

[0029] The summary of the present invention is provided to introduce in a simplified form some concepts that will be further described in the following detailed description. This summary is not intended to determine the main features or basic features of the claimed subject matter, nor is it intended to be used to help determine the scope of the claimed subject matter.

Description of the drawings

[0030] A more complete understanding of the subject matter can be obtained by referring to the detailed description and claims in conjunction with the following drawings, in which the same reference numerals indicate similar elements throughout the drawings.

[0031] FIG. 1 is a side cross-sectional view of a partially manufactured analyte sensor according to an embodiment.

[0032] FIG. 2 is a side cross-sectional view of an analyte sensor according to an embodiment.

[0033] FIG. 3 is a side cross-sectional view of an analyte sensor according to another embodiment.

[0034] FIG. 4 is a schematic diagram of a system and method for manufacturing an analyte sensor according to an embodiment.

[0035] FIG. 5 is a top view of a partially separated substrate manufactured according to the method of FIG. 4.

[0036] FIG. 6 is a schematic diagram of a system and method for manufacturing a platinum sputtering substrate used in the method of FIG. 4 according to one embodiment.

Detailed ways

[0037] The following specific embodiments are merely illustrative in nature and are not intended to limit the embodiments of the subject matter or the application and use of these embodiments. As used herein, the word "exemplary" means "serving as an example, instance, or illustration." Any implementation described herein as an example is not necessarily construed as more preferred or advantageous than other implementations. In addition, it is not intended to be bound by any expressed or implied theory presented in the foregoing technical field, background art, summary of the invention or the following specific embodiments. In addition, although the foregoing background discusses glucose sensing and an exemplary analyte sensor is described herein as a glucose sensor, this description is for convenience and is not limiting. The claimed subject matter may include any type of analyte sensor that utilizes the embodiments of sensor electrodes described herein.

[0038] Blood glucose measurement can be used in infusion systems for regulating the rate of fluid injected into the body. In certain circumstances, the control system may be adapted to regulate the injection of insulin, glucagon, and/or glucose into the patient based at least in part on glucose concentration measurements obtained from the body (eg, from an analyte sensor such as a glucose sensor). rate.

[0039] According to certain embodiments, examples of analyte sensors described herein may be implemented in a hospital environment to monitor glucose levels in a patient. Alternatively, according to certain embodiments, examples of analyte sensors as described herein may be implemented in a non-hospital environment to monitor glucose levels in patients. Here, the patient or other non-medical professional may be responsible for interacting with the analyte sensor.

[0040] In order to maintain healthy glucose levels, people with type 1 diabetes can manage their blood glucose by monitoring their blood glucose levels, controlling their diet, exercising, and self-administering appropriate amounts of insulin at appropriate times. Such deviations in blood glucose management, such as skipping insulin boluses during meals or underestimating the carbohydrate content of meals, may lead to prolonged hyperglycemia. Likewise, for a given blood sugar level and/or meal, receiving too much insulin (for example, through excessive boluses) can lead to severe hypoglycemia. Other external factors such as exercise or stress can also cause blood glucose deviations.

[0041] Errors in reading glucose levels may result in too much or too little insulin being provided. Therefore, the accuracy of the sensor is of the most concern. In addition, the accuracy of the sensor must be maintained during the life of the continuous glucose monitoring device. Long-lived continuous glucose monitoring devices are desired, that is, continuous glucose monitoring devices that are implanted for a longer duration, for example, seven to fourteen days or more. Therefore, in the future, the accuracy of the sensor must be maintained in the body for seven to fourteen days or more. Continuous glucose monitoring sensors provide the ability to continuously track glucose levels in patients and correlate them with their physical activity and diet, thereby providing treatment decisions and adjustments if necessary.

[0042] By more accurately monitoring the patient's glucose level and maintaining an appropriate infusion rate, extreme blood glucose changes can be reduced or completely avoided. This can provide patients with improved blood glucose control in situations where they would otherwise be exposed to undesirable blood glucose extremes.

[0043] Compared with currently commercialized sensors, the embodiments herein provide improved accuracy and will reduce sensor costs through new manufacturing processes. For example, the sensor in this paper can use a platinum sputtering layer formed on a polyester film substrate.

The resulting excimer patterned electrodes.

[0044] FIG. 1 is a cross-sectional view of an example analyte sensor 10 for use with a glucose control system according to one embodiment. A specific embodiment of the analyte sensor 10 includes a planar flexible polymer substrate layer 12, such as a polyester film or substrate. As shown in the figure, the base layer 12 includes a first side 14 and an opposite second side 16 and an end 18. The thickness of an exemplary base layer 12 is about 25 microns (um) (about 1 mil) to about 381 um (about 15 mils), such as about 178 um (about 7 mils) or about 254 um (about 10 mils).

[0045] In some embodiments, the base layer 12 has a surface roughness of about 1 nm to about 240 nm, for example, 5 nm to about 80 nm, for example, about 5 nm to 10 nm, or about 10 nm to 20 nm, or about 20 nm to 30 nm, or Surface roughness of about 30nm to 50nm, or about 50nm to 70nm.

[0046] In addition, the platinum layer 20 is formed on the first side surface 14 of the base layer 12. In an exemplary embodiment, the platinum layer 20 is formed by sputtering platinum onto the first side surface 14 of the base layer 12. An exemplary platinum layer 20 may have a thickness of about 5 to about 120 nm, for example, a thickness of about 10 nm to about 50 nm.

[0047] During in vivo use, platinum is challenged by the body's immune response when the sensor is implanted. For example, the constant mechanical force applied by body tissues around the implant can impair the adhesion of platinum to the polyester substrate. Therefore, the first side surface 14 of the base layer 12 may undergo surface modification to adjust the adhesion between the platinum layer 20 and the base layer 12. Such surface modification may allow controlled and reproducible tuning of the electrode surface area to improve in vivo sensor performance. In addition, surface modification can provide for grafting functional parts to the first side 14 of the base layer 12 to increase adhesion. The surface modification can be performed by plasma pretreatment of the base layer 12. Other processes may be performed to roughen the surface of the base layer 12.

[0048] In addition, the platinum layer 20 may be formed with an outer surface 26 having a selected surface roughness. The sputtering of platinum on a polyester substrate is a well-known method that produces high uniformity and reproducibility in the surface roughness of the outer surface 26. The surface roughness of the outer surface 26 of the platinum layer 20 is a controlling factor of the electrode surface area. By adjusting the process parameters of the platinum sputtering process, the surface roughness of the platinum layer 20 and the outer surface 26 of the electrode can be controlled.

[0049] As shown, the analyte sensor 10 is formed with electrodes required for sensor operation. For example, the analyte sensor 10 may be formed with a working electrode, a reference electrode, and a counter electrode. In FIG. 1, two electrodes 22 and 24 are shown for simplicity; however, the analyte sensor 10 may include one or more working electrodes, reference electrodes, and counter electrodes. In certain embodiments, the analyte sensor 10 may include a working electrode and a counter electrode in pairs.

[0050] The electrodes 22 and 24 may be formed by patterning the platinum layer 20. For example, a laser ablation process may be performed to pattern the platinum layer 20. In an exemplary embodiment, an excimer laser such as a 248 nm excimer laser is used to pattern the platinum layer 20 with ultraviolet light to form the electrodes 22 and 24. Laser ablation provides high throughput and is highly reproducible during sensor manufacturing processing. For example, in some embodiments, eighteen electrodes of the analyte sensor 10 may be patterned per second by a laser ablation process.

[0051] As shown, the analyte sensor 10 further includes an insulating dielectric layer 30 above the first side surface 14 of the base layer 12. The exemplary insulating dielectric layer 30 may be a polymer crosslinked by ultraviolet radiation or by heat treatment, so that after crosslinking, the insulating dielectric is impermeable to solvents and water and other electrochemically active components in the fluid-containing analyte . The insulating dielectric layer 30 is provided to prevent the electrochemically active components from diffusing to the electrochemically active surface of the electrode, so as to accurately control the electrode signal level.

[0052] The electrode signal is proportional to the surface area exposed to the fluid-containing analyte. An insulating dielectric layer 30 that is impermeable to electrochemically active components in the fluid-containing analyte may be applied and patterned to define the electrochemically active surface area of the electrode. Methods of applying and patterning the dielectric layer include screen printing, drop-on-demand inkjet, transfer pad printing, gravure coating or power

Other photolithographic patterning coating methods known to those skilled in the art.

[0053] The exemplary insulating dielectric layer 30 may be a thermally crosslinked acrylic polymer. The thickness of the exemplary insulating dielectric layer 30 is about 1 um to about 20 um, for example, about 7 um.

[0054] In an exemplary embodiment, the insulating dielectric layer 30 is formed by screen printing or rotary printing of an insulating dielectric material. In certain embodiments, the insulating dielectric layer 30 is patterned or otherwise formed with openings 31 that expose the portion 32 of the electrode 22 and expose the portion 34 of the electrode 24. In other words, after the insulating dielectric layer 30 is formed, the portion 32 of the electrode 22 and the portion 34 of the electrode 24 are not covered by the insulating dielectric layer 30. The opening 31 defines the geometric surface area of the electrodes 22 and 24. In other words, the exposed portions 32 and 34 of the electrodes 22 and 24 are the geometric surface areas of the electrodes 22 and 24.

[0055] In an exemplary embodiment, the electrode 22 is a working electrode, the electrode 24 is a counter electrode, and the width of the insulating dielectric layer 30 is adjusted so that the platinum working electrode 22 and the platinum counter electrode 24 are end-to-end between the opening 31 The distance 28 is changed to improve the overall sensor sensitivity and reduce the sensor's dependence on oxygen concentration. The end-to-end distance between the openings may be about 5 microns to about 200 microns, such as about 15 microns to about 100 microns, for example about 50 microns.

[0056] Therefore, FIG. 1 can be viewed as showing a pair of working electrodes 22 and a counter electrode 24 having a selected intra-pair distance 28. It is conceivable that the sensor 10 includes a plurality of working electrodes (WE) and counter electrodes (CE), wherein each WE/CE pair has a specific, independently selected end-to-end distance 28 between the working electrode and the opening 31 of the counter electrode. . In other words, the sensor 10 may be provided with multiple WE/CE pairs, each pair having an independently selected intra-pair distance. Although WE/CE pairs can have different intra-pair distances from each other, some WE/CE pairs can have the same intra-pair distance.

[0057] The differential response from these multiple WE/CE pairs can provide an understanding of the sensor's dependence on oxygen, which can be used to calibrate sensor performance for sensitivity drift. For example, sensitivity may drift due to sensor degradation caused by exposure to various electrical analytes, such as oxygen radicals. In addition, post-implantation effects, such as biological contamination and foreign body reactions, can also passivate the electrocatalytic activity of the electrode.

[0058] In FIG. 2, further processing may be performed on the analyte sensor 10. In FIG. 2, electrode 22 is processed to form a working electrode, and electrode 24 is processed to form a reference electrode (as described above, multiple electrodes are not shown for clarity). For the reference electrode 24, a silver/silver chloride (Ag/AgCl) ink layer 40 is formed on the electrode 24. The silver/silver chloride layer 40 can be selectively deposited by screen printing or spin printing. Unlike conventional electrodeposition or electrooxidation treatment, when screen printing or rotary printing silver/silver chloride ink, the loading of silver chloride is not limited by the surface area of the electrode. In an exemplary embodiment, the silver/silver chloride layer 40 is overloaded so that the amount of AgCl is always excessive compared to the amount required for 14 days of sensor operation. In some cases, the ratio of AgCl to Ag is greater than 1, and may be about 1 to about 10, such as about 5. It should be noted that the silver/silver chloride (Ag/AgCl) ink layer 40 may be formed before or after the insulating dielectric layer 30 is formed, but a preferred embodiment includes depositing the silver/silver chloride ink before the dielectric material.

[0059] In an exemplary embodiment, the silver/silver chloride ink has a formulation of silver and silver chloride micro- and nano-particles in a polymer binder to enhance silver/chlorine during screen printing or rotary printing. Overload of silver ink. In an exemplary embodiment, the silver/silver chloride layer has a thickness (or height) of about 5 um to about 50 um, such as about 10 um. In an exemplary embodiment, the reference electrode is composed of metal oxide particles and nanoparticles supported in a polymer binder. An exemplary metal oxide is iridium oxide.

[0060] As described above, during in vivo use, platinum is challenged by the body's immune response when the sensor is implanted. For example, the degradation of platinum can be induced by biological pollution and the body's immune response. Unless otherwise specified, platinum may not tolerate biological contamination and degradation caused by the body's immune response. Therefore, the analyte sensor 10 may be provided with a protective layer 45 above the first side 14 of the base layer 12 to protect platinum from biological contamination and other immune response degradation. Exemplary guarantee

The protective layer 45 may be a hydrophilic hydrogel layer, and may be made of various materials known to be suitable for such purposes, such as polyvinyl alcohol, poly(N-isopropylacrylamide), poly(N- Vinyl pyrrolidone), polyethylene glycol, polyurethane, polyacrylic acid, cellulose acetate, Nafion, polyester sulfonic acid hydrogel or any other suitable hydrophilic membrane known to those skilled in the art.

[0061] The thickness of the exemplary protective layer 45 is about 5 nm to about 200 nm, for example, about 50 nm. As shown in FIG. 2, the protective layer 45 covers the entire top side 14 of the base layer 12 and completely encapsulates the platinum layer of the electrodes 22 and 24.

[0062] In an exemplary embodiment, the protective layer 45 is formed by screen printing, spin printing, spray coating, dip coating, spin coating, or brush coating. In some embodiments, the diffusion characteristics of the protective layer 45 are carefully controlled so that the size of the sensor signal is not compromised due to the small diffusion coefficient, which does not allow hydrogen peroxide to pass through, resulting in Equation 2 has the least or no signal. In such embodiments, hydrophobic moieties such as acrylate polymers or surfactants or oxygen-carrying substances (such as fluorocarbons) or oxygenases such as myoglobin or hemoglobin or oxygenases such as catalase are incorporated Into the hydrogel layer to improve the adhesion to hydrogen peroxide and oxygen and to tune permeability.

[0063] FIG. 2 shows that the silver/silver chloride layer 40 is formed before the protective layer 45, so that the silver/silver chloride layer 40 is disposed under the protective layer 45. However, it should be noted that the formation sequence can be reversed so that the protective layer 45 is located under the silver/silver chloride layer 40.

[0064] In FIG. 2, the analyte sensor 10 also includes an electrochemical sensing stack 50 above the exposed portion 32 of the working electrode 22. The electrochemical sensing stack 50 may include multiple layers not separately shown in FIG. 2. In an exemplary embodiment, the electrochemical sensing stack 50 includes an analyte sensing layer, such as an enzyme layer, such as a glucose oxidase layer. An exemplary glucose oxidase layer has an activity of about 1 KU/mL to about 45 KU/mL, for example, about 5 KU/mL to about 20 KU/mL, for example, about 15 KU/mL. In addition, an exemplary glucose oxidase layer has a thickness of about 3 microns to about 10 microns (um), for example, about 4 um to about 5 um, for example, about 4.2 um to about 4.4 um, such as a thickness of about 4.3 um. In an exemplary embodiment, the enzyme layer is deposited over the working electrode 32 by rotary screen printing. In another embodiment, the enzyme layer is deposited over the working electrode 32 by an aerosol-based drop-on-demand inkjet technology. In another embodiment, the enzyme layer is deposited on the working electrode 32 by spin coating or spraying. In another embodiment, the enzyme layer is deposited over the working electrode 32 by one of the aforementioned techniques, and is further cross-linked by ultraviolet radiation or exposure to the vapor of a cross-linking agent such as glutaraldehyde.

[0065] In certain embodiments, the electrochemical sensing stack 50 may include additional layers, such as protein layers. Generally, the protein layer includes proteins, such as human serum albumin, bovine serum albumin, and the like.

[0066] In certain embodiments, the electrochemical sensing stack 50 may include an adhesion promoter layer disposed above the analyte sensing or enzyme layer to facilitate the analyte sensing layer and another overlying layer Contact and/or adhesion between. The adhesion promoter layer can be made of any of a variety of materials known in the art to facilitate the adhesion between such layers. Generally, the adhesion promoter layer contains a silane compound. In an alternative embodiment, the protein or similar molecules in the analyte sensing layer can be sufficiently cross-linked or otherwise prepared to allow the analyte modulation film layer to interact with each other in the absence of an adhesion promoter layer. The analyte sensing layer is in direct contact. In certain embodiments, additional layers such as interference suppression layers may be included in the electrochemical sensing stack 50. Such layers can be formed by spinning or screen printing or spin coating or spraying or by chemical vapor deposition. In another embodiment, the adhesion promoter layer is deposited over the working electrode 32 by one of the aforementioned techniques, and is further cross-linked by ultraviolet radiation or exposure to the vapor of a cross-linking agent such as glutaraldehyde.

[0067] Therefore, in certain embodiments, the stack 50 includes a protein layer on the glucose oxidase layer, such as a human serum albumin (HSA) layer, and an adhesion promoting layer on the protein layer. In other embodiments, the electrochemical sensing stack 50 does not include a protein layer or adhesion promoting layer.

[0068] In FIG. 2, the electrochemical sensing stack 50 is shown as further comprising an analyte modulation layer 60 above the enzyme layer.

Such as glucose limiting membrane (GLM) 60. The analyte modulation layer 60 is provided to adjust the contact of the analyte with the analyte sensing layer or the enzyme layer. For example, the analyte modulation membrane layer may be a glucose limiting membrane that regulates the amount of glucose that contacts enzymes such as glucose oxidase present in the analyte sensing layer. Such glucose-restricting membranes can be made of various materials known to be suitable for such applications, for example, silicone compounds such as polydimethylsiloxane, polyurethane, polyurea cellulose acetate, Nafion, polyester sulfonic acid (E.g. Kodak AQ), hydrogel or any other suitable membrane known to those skilled in the art. In an exemplary embodiment, the thickness of the glucose confinement membrane 60 is about 10 micrometers to about 30 micrometers (um), for example, about 18 um to about 25 um, for example, about 20 um to about 22 um, for example, about 21 um.

[0069] As shown, the glucose confinement membrane 60 may be formed around the entire end 18 of the analyte sensor 10, that is, over both the first side 14 and the second side 16 of the base layer 12, including the reference electrode And above the counter electrode. In an exemplary embodiment, the glucose-restricting membrane 60 may be formed by dip coating the end 18 of the analyte sensor 10 such that the glucose-restricting membrane 60 encapsulates the analyte sensor 10 for insertion into the interstitial fluid of the patient.

[0070] In addition to the glucose limiting membrane 60, other membranes may be formed on the end 18 of the analyte sensor 10 to suppress foreign body reactions after implantation. For example, a foreign body response (FBR) film may be formed on the glucose limiting film 60, for example, by dip coating the end 18 of the analyte sensor 10.

[0071] FIG. 3 shows an alternative or additional embodiment of the analyte sensor 10. In FIG. 3, the reference electrode 24 is not formed by the platinum layer 20 on the first side 14 of the base layer 12. In contrast, the reference electrode 24 is formed on the second side 16 of the base layer 12. Specifically, the reference electrode 24 is formed of a silver/silver chloride ink layer 40 deposited on the second side 16 of the base layer 12. The silver/silver chloride ink can be selectively deposited on the second side 16 of the base layer 12 by screen printing or spin printing. In such embodiments, the entire second side 16 can be overprinted or overloaded by the silver/silver chloride ink to allow more silver chloride loading. In addition, this type of implementation eliminates position alignment process capability to reduce overall manufacturing process errors. As shown in FIG. 3, the glucose confinement film 60 completely covers the reference electrode 24 formed by the silver/silver chloride ink layer 40 on the second side 16 of the base layer 12.

[0072] Refer now to FIG. 4, which describes a system 100 and method for manufacturing the analyte sensor 10. As shown, the system 100 manufactures an analyte sensor in a roll-to-roll process by processing a roll 101 of a flexible substrate (such as a polyester film) including a sputtered platinum layer as described above. In the system 100, the polyester substrate 105 is fed from the roll 101 to the electrode patterning stage 110. At the electrode patterning stage 110, according to the desired analyte sensor, the platinum layer is patterned, for example, by laser ablation to form a working electrode and a counter electrode, and optionally a reference electrode. Then, the polyester substrate 115 is fed from the electrode patterning stage 110 to the insulating stage 120. At the insulation stage 120, an insulating dielectric material is selectively deposited over the polyester substrate 115. For example, the insulating dielectric material can be screen printed or spin printed over the polyester substrate.

[0073] The polyester substrate 125 is then fed from the insulation stage 120 to the insulation curing stage 130. In the insulation curing stage, the insulating dielectric material is cured to form an insulating dielectric layer. For example, an ultraviolet curing process can be performed. Then, the polyester substrate 135 is fed from the insulation curing stage 130 to the ink printing stage 140. At the ink printing stage 140, if such a reference electrode has been formed from sputtered platinum, a silver/silver chloride ink is deposited above the reference electrode. Alternatively, a silver/silver chloride ink is deposited on the second side or back of the polyester substrate to form a reference electrode. The silver/silver chloride ink can be selectively deposited by screen printing or by spin printing.

[0074] As shown in the figure, the polyester substrate 145 is then fed from the ink printing stage 140 to the drying stage 150. In the drying stage 150, the silver/silver chloride ink is dried to form a silver/silver chloride ink layer on the polyester substrate. After drying, the polyester substrate 155 is then fed to the protective layer stage 160, where a protective material is deposited on the polyester substrate 155. Specifically, the protective material is deposited on the entire side of the polyester substrate 155 where the sputtered platinum electrode is located. The protective material can be screen printed

Deposited by brush or spin printing. The polyester substrate 165 is then fed to a curing stage 170 where the protective material is cured to form a protective layer.

[0075] The polyester substrate 175 is then fed to the stamping stage 180. At the stamping stage 180, the polyester substrate is stamped, or in other words cut, to form a partially separated strip for forming a separated analyte sensor. For example, a polyester substrate can be laser cut to form partially separated strips. As shown, the polyester substrate 175 can pass under the visual alignment device 178 to ensure that the polyester substrate 175 is correctly aligned for stamping. After punching, each strip is still connected to the remaining polyester substrate web by an insert. In an exemplary embodiment, each strip or analyte sensor includes a working electrode and a reference electrode. Specifically, each strip or analyte sensor includes a desired number of working electrodes, reference electrodes, and counter electrodes without further forming electrodes.

[0076] The punched portion or waste portion 181 of the polyester substrate 175 can be wound into the roll 184 from the stamping stage 180. The remaining polyester substrate 185 (including the separated analyte sensor in the form of a strip) is fed to the enzyme deposition stage 190. At the enzyme deposition stage 190, an enzyme such as glucose oxidase is deposited above the working electrode. For example, the enzyme can be screen-printed or spin-printed onto a polyester substrate. Alternatively, the enzyme can be deposited by aerosol-based drop-on-demand inkjet technology. In addition to enzymes, other materials used to form the electrochemical sensing stack may also be deposited on the polyester substrate at the enzyme deposition stage 190.

[0077] Then, the polyester substrate 195 is fed to the enzyme curing stage 200. In the enzyme curing stage 200, the enzyme (and other deposition materials) is cured, for example, by a curing method initiated by ultraviolet light. During the curing process, the enzyme is cross-linked and immobilized. The polyester substrate 205 can then be fed to the film formation stage 210. At the film formation stage 210, the end of each strip may be coated with a glucose limiting film and other desired films. For example, the end of each strip can be dip-coated or slot-coated to form the desired film. [0078] In certain embodiments, the system 100 can terminate the roll-to-roll process at this stage and produce a polyester substrate 215 that includes each analyte sensor connected to the polyester substrate web. In the form of strips, in preparation for further integration with the production of the glucose monitoring system. Alternatively, the roll-to-roll process can continue to process the individual analyte sensors on the polyester substrate 215. Specifically, each analyte sensor on the polyester substrate 215 may be processed through the function inspection stage 220. At the functional check phase 220, each analyte sensor is exposed to a buffer solution containing glucose, and the signal time distribution of the sensor is recorded and evaluated.

[0079] In addition, the polyester substrate 225 may be removed from the functional inspection stage 220 and may be fed to the separation stage 230. At the separation stage 230, each analyte sensor in the form of a strip connected to the polyester base web can be separated by complete separation from the polyester base web. The separation stage 230 may be used as part of the final system assembly and packaging system separate from the roll-to-roll processing system 100 described herein.

[0080] It should be noted that the system 100 of FIG. 4 may include additional elements for manufacturing the analyte sensor, such as idler wheels, driven wheels, vacuum boxes, and additional, optional or repeated processing stages.

[0081] FIG. 5 is a top view of a partially separated substrate 70 manufactured according to the method of FIG. 4. Specifically, the partially separated substrate 70 is shown to be formed after being flushed out, after forming the enzyme layer, and after film formation, for example, after the film formation stage 210 of FIG. 4 or after the function inspection stage 220. In addition, at the separation stage 230 of FIG. 4, the partially separated substrate 70 is shown before the analyte sensor is completely separated from the polyester substrate.

[0082] As shown in FIG. 5, the partially separated substrate 70 includes individual analyte sensors 72 in the form of strips. Each individual analyte sensor 72 is connected to the polyester base web 74 by a tab at the end 76. The complete separation and separation of the individual analyte sensors 72 can be performed by cutting at each tab at the end 76. As shown, each analyte sensor 72 terminates at an end 78. The end 78 may be dip-coated with a film-forming material or coated in other ways at the film-forming stage 210 of FIG. 4. The gap 80 between adjacent analyte sensors 72 is removed by removing portions of the polyester substrate during the stamping process.

(For example, the punched-out part or the waste part 181 in FIG. 4).

[0083] FIG. 6 shows a system 300 and method for manufacturing the platinum sputtered polyester substrate introduced in FIG. 4 on a roll 110. In Figure 6, a polyester substrate 305 is provided. The polyester substrate 305 can be introduced into the polyester surface modification stage 310. At the polyester surface modification stage 310, the surface of one or both sides of the polyester substrate 305 is modified. Specifically, the surface of the polyester may be roughened to improve the adhesion between the polyester and the platinum layer formed thereon. In addition, polyester surface modification can provide grafting of functional moieties to the surface to increase adhesion. The surface modification can be performed by plasma pretreatment of the polyester substrate 305. Other methods of surface modification may include electrical discharge, surface grafting, flame treatment, ultraviolet radiation, or wet chemical etching.

[0084] Other treatments may be performed to roughen the surface of the polyester substrate 305, and include wet chemical etching, hydrolysis in an alkaline solution, pickling, or laser irradiation.

[0085] As shown, the polyester substrate 315 is then fed to the platinum deposition stage 320. In the platinum deposition stage 320, platinum is deposited on one side of the polyester substrate 315. For example, platinum can be sputtered onto a polyester substrate. Sputtering is a physical vapor deposition method. A commercially available sputtering reactor using RF (Radio Frequency) can be used for sputtering. Magnetron sputtering can also be used. Magnetron sputtering uses a magnetic field to concentrate electrons near the target surface to increase the deposition rate. The thickness of an exemplary sputtered platinum layer is about 5 nm to about 100 nm, for example, about 10 nm to about 50 nm. When depositing multiple layers, the total thickness of the layers may have a thickness within the above-mentioned range.

[0086] The characteristics of the platinum film produced by sputtering vary according to process parameters, such as the characteristics of the platinum sputtering target material, including purity and microstructure, sputtering rate, the energy of the sputtered platinum atoms to reach the polyester substrate, and the temperature And/or other parameters.

[0087] Control of the process parameters can produce a platinum sputtered polyester substrate 325 with the desired characteristics. For example, by adjusting the process parameters of the platinum sputtering process, the surface roughness of the outer surface of the platinum layer can be controlled. Alternatively, the platinum sputtered polyester substrate 325 can withstand further processing. For example, a platinum sputtered polyester substrate 325 may be introduced into the platinum surface modification stage 330. At the platinum surface modification stage 330, plasma surface modification treatment or other surface modification treatments can be performed as needed to adjust the surface characteristics of the platinum layer. Thereafter, the platinum sputtered polyester layer 335 may be wound on the roll 340 for use in the manufacturing method 100 of FIG. 4.

[0088] It should be pointed out that although various aspects of the above methods, systems, and sensors have been described in a specific order and specific arrangement, such specific order and arrangement are merely embodiments and are protected by the claims. The subject matter is not limited to the order and arrangement described.

[0089] Although the features currently considered as features of the embodiments have been illustrated and described, those skilled in the art should understand that various other modifications can be made without departing from the subject matter protected by the claims. And can be equivalently replaced. In addition, without departing from the central concept described herein, many modifications can be made to adapt a particular situation to the teachings of the subject matter protected by the claims. Therefore, it is intended that the subject matter protected by the claims is not limited to the specific embodiments disclosed, but such subject matter protected by the claims may also include all those falling within the scope of the appended claims and their equivalents. aspect.