Implantable polymer surfaces exhibiting reduced in vivo inflammatory response

Abstract

Embodiments of the present invention provide optimized polymer surfaces suitable for use with implantable medical devices, and methods of making and using such polymer surfaces. These polymer surfaces have feature groups that are used to inhibit or avoid inflammatory immune responses generated by implantable medical devices. Typical embodiments of the present invention include implantable glucose sensors for managing diabetes, which have polymer surfaces with the disclosed feature groups.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under Section 120 to U.S. Application Serial No. 15 / 878,313, filed on January 23, 2018, the contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to methods and materials for use in implantable medical devices, such as glucose sensors for the treatment of diabetes. Background Art

[0004] Patient responses to implanted foreign bodies present challenges in medical device design. The responses of these patients are often characterized by infiltration of inflammatory cells (such as macrophages) and their chronic activation, which can lead to the formation of a fibrous capsule at the implant site. This capsule is often used to isolate the foreign body from the host immune system and can impair the function of many medical devices, including, for example, implanted biosensors and cardiovascular and orthopedic implants. The dense, collagen-rich tissue of the capsule can prevent small molecules such as glucose from diffusing into and out of the implanted device. Although efforts to reduce the immune response to implanted biomaterials have achieved some success, traditional approaches are not sufficient to address the impact of foreign body responses on the function of implanted devices.

[0005] Quantitative determination of analytes in humans and mammals is very important for the diagnosis and maintenance of many pathological conditions. For this reason, implantable analyte sensors are used to monitor a variety of compounds including analytes in the body. Determination of glucose concentration in body fluids is particularly important for diabetic individuals, who must frequently check the glucose levels in their body fluids to regulate the glucose intake in their diet. The results of such tests are crucial for determining which (if any) insulin and / or other drugs need to be administered. Disadvantageously, the response of the mammalian host to the implanted glucose sensor can inhibit the diffusion of glucose to and from the implanted glucose sensor, a phenomenon that can impair the accuracy of the sensor readings over time.

[0006] Therefore, there is a need in the art for implantable devices, such as glucose sensors, that can avoid or minimize host immune responses. Embodiments of the invention disclosed herein satisfy this need as well as other needs. Summary of the invention

[0007] The invention disclosed herein provides a medical device having a polymer surface designed to contact the in vivo environment so as to provide the device with enhanced functionality and / or material properties, such as the ability to avoid or inhibit tissue inflammatory response when implanted in the body. The present disclosure also provides methods for making and using such sensors. As discussed in detail below, typical embodiments of the present invention relate to the use of a sensor device that measures an aqueous analyte of interest or a substance that indicates the concentration or presence of an analyte in the body. In an illustrative embodiment, the sensor is used for continuous glucose monitoring of a diabetic patient.

[0008] The invention disclosed herein has multiple embodiments. One embodiment is a medical device comprising a surface formed of a polymer and suitable for contacting an in vivo environment. Typically, this surface comprises a polymer composition having a characteristic group including a carbon-oxygen ratio greater than 5 and a surface hydrophobicity between 75° and 90°. In addition, the surface also exhibits a morphology characterized by at least one of the following: grooves with an average peak-to-valley height between 0.3 μm and 5 μm; or holes with an average peak-to-valley height between 1 μm and 2 μm; or a grid with an average peak-to-valley height between 2 μm and 4 μm. The selected group of surface elements acts so that when exposed to a surface comprising a polymer composition, RAW264.7 macrophages are affected in a manner that inhibits their differentiation into an inflammatory (M1) phenotype, and / or in a manner that facilitates their differentiation into an anti-inflammatory (M2) phenotype.

[0009] In some embodiments of the present invention, RAW264.7 macrophages exhibit at least 10% reduction in MIP-1α polypeptide expression and / or reduction in surface adhesion when exposed to a surface comprising a polymer composition of the invention disclosed herein, compared to an equivalent polymer surface that does not have a surface morphology characterized by grooves with an average peak-to-valley height between 0.3 μm and 5 μm; and / or an equivalent polymer surface that does not have a surface morphology characterized by pores with an average peak-to-valley height between 1 μm and 2 μm; and / or an equivalent polymer surface that does not have a surface morphology characterized by a grid with an average peak-to-valley height between 2 μm and 4 μm; an equivalent polymer surface that does not have a surface characterized by a carbon-to-oxygen ratio greater than 5; and / or an equivalent polymer surface that does not have a surface hydrophobicity between 75° and 90°.

[0010] A related embodiment of the invention is a method of avoiding and inflammatory response to an implanted medical device, the method comprising implanting a device having a surface suitable for contact with an in vivo environment, the surface comprising a polymer composition having a property group including a carbon-oxygen ratio greater than 5 and a surface hydrophobicity between 75° and 90°. The polymer surface of the invention also exhibits a morphology characterized by at least one of: grooves with an average peak-to-valley height between 0.3 μm and 5 μm; or pores with an average peak-to-valley height between 1 μm and 2 μm; or a grid with an average peak-to-valley height between 2 μm and 4 μm. In such embodiments, the surface avoids an inflammatory response by having a surface feature that causes RAW264.7 macrophages to be affected to differentiate into an anti-inflammatory (M2) phenotype (and / or avoid differentiation into an inflammatory (M1) phenotype) when exposed to a surface comprising a polymer composition. Typically, when exposed to a surface comprising a polymer composition, RAW264.7 macrophages exhibit a 10% reduction in MIP-1 alpha polypeptide expression and also exhibit at least a 10% reduction in surface adhesion compared to an equivalent polymer surface not having the surface properties of the polymer disclosed herein.

[0011] Yet another embodiment of the present invention is a method of modifying the surface of a polymer composition using a laser to form a laser-ablated polymer composition having a defined set of properties, the properties including a carbon-oxygen ratio greater than 5, and a surface hydrophobicity between 75° and 90°. In addition, with this laser ablation method, the surface also exhibits a morphology characterized by at least one of the following: grooves with an average peak-to-valley height between 0.3 μm and 5 μm; or pores with an average peak-to-valley height between 1 μm and 2 μm; or a grid with an average peak-to-valley height between 2 μm and 4 μm. As described above, this set of surface properties at the polymer surface reduces macrophage inflammatory response by having the following properties: the properties cause RAW264.7 macrophages to be affected in a manner that inhibits their differentiation into a (M1) phenotype when exposed to a surface comprising the polymer composition, and / or to be affected in a manner that facilitates their differentiation into an anti-inflammatory (M2) phenotype.

[0012] Other objects, features and advantages of the present invention will be apparent to those skilled in the art from the following detailed description. However, it should be understood that although some embodiments of the present invention are indicated, the detailed description and specific examples are given by way of example and not limitation. Many changes and modifications within the scope of the present invention may be made without departing from its spirit, and the present invention includes all such modifications. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1A shows a general timeline of tissue response to implanted biomaterials (prior art).

[0014] Figure 1Bare photographs showing RAW264.7 macrophages cultured on a glucose sensor surface, demonstrating minimal cell adhesion on the GLM surface.

[0015] Figure 1C is a photograph showing RAW264.7 macrophages cultured on a glucose sensor surface, demonstrating excessive macrophage adhesion on the polyimide surface.

[0016] Figure 1D Four examples of surface topography embodiments created by different laser ablation settings are shown. From left to right, the first figure / example shows grooves (formed by the following laser wavelengths: 193nm, 900mJ / cm'2, 0.5mm / s, 200Hz), the second figure shows dense holes (formed by the following laser wavelengths: 355nm, 8mW, 10mm / s, 100Hz), the third figure shows scattered holes (formed by the following laser wavelengths: 355nm, 8mW, 10mm / s, 100Hz), and the last figure shows a grid (formed by the following laser wavelengths: 355nm, 8mW, 10mm / s, 100Hz).

[0017] Figure 1E Interferometry data on surface topography for different embodiments are shown, including data from grooves (upper left), dense holes (upper right), scattered holes (lower left), and grids (lower right).

[0018] Figure 1F Examples of macrophage adhesion and morphology from different embodiments of the present invention are shown: (a) Control: macrophages adhere to the surface of a microplate with a natural round morphology; (b) Positively activated macrophages (M1) adhere to a microplate with a characteristic elongated morphology; (c) macrophages adhere to an unmodified polyimide surface with a natural round morphology; (d) (e) (f) (g) Macrophage adhesion and morphology on modified surfaces on grooves, dense wells, dispersed wells, and grids. Compared to the control RAW264.7 macrophages from (c), less morphological changes and elongation of RAW264.7 macrophages were observed on these four groups.

[0019] Figure 1G The data presented show that laser beam patterned surfaces exhibit lower RAW264.7 macrophage inflammatory responses based on cytokine quantification. Graphical data from cytokine studies of embodiments with dispersed pore morphology show lower levels of MIP-1α, a pro-inflammatory cytokine, compared to unmodified polyimide control samples.

[0020] Figure 1HData on surface chemistry determined by X-ray photoelectron spectroscopy (XPS) analysis are shown. This XPS analysis shows changes in the carbon chemistry of polyimide before and after laser ablation based on high-resolution C1s spectral envelopes. The laser ablated area shows a shift to amorphous carbon (CC) centered at about 284.8 eV.

[0021] Fig. 1I The data presented show that XPS analysis shows that laser ablation changes the surface chemistry. The laser ablated samples show a higher carbon to oxygen ratio compared to the control samples.

[0022] Figure 2 A sensor design is shown that includes an amperometric analyte sensor formed from multiple planar layered elements.

[0023] Figure 3 Perspective views are provided illustrating a subcutaneous sensor insertion kit, a telemetric characteristics monitor transmitter device, and a data receiving device embodying features of the present invention. DETAILED DESCRIPTION

[0024] Unless otherwise defined, all technical terms, symbols and other scientific terms or special words used herein are intended to have the meanings commonly understood by those skilled in the art to which the present invention belongs. In some cases, for the sake of clarity and / or convenient reference, terms with commonly understood meanings are defined herein, and including such definitions herein should not necessarily be interpreted as representing substantial differences from those generally understood in the art. Many techniques and procedures described or referenced herein are well understood and commonly used by those skilled in the art using conventional methods. As required, unless otherwise noted, procedures involving the use of commercially available kits and reagents are generally performed according to the protocols and / or parameters defined by the manufacturer. Many terms are defined below.

[0025] All the numbers of the values ​​(e.g., the diameter of a disk) listed in the specification and the related claims that refer to the values ​​that can be numerically characterized by values ​​other than integers should be understood to be modified by the term "about". In the case of providing a range of values, it should be understood that each intermediate value between the upper and lower limits of the range (to one tenth of the unit of the lower limit, unless otherwise explicitly stated) and any other stated or intermediate values ​​in the range are included in the present invention. The upper and lower limits of these smaller ranges can be independently included in the smaller range and are also included in the present invention, subject to any specific exclusive restrictions within the range. When the stated range includes one or two limits, the range excluding any one or both of those included limits is also included in the present invention. In addition, all the publications mentioned herein are incorporated herein by reference, thereby disclosing and describing methods and / or materials related to the listed publications. The publications cited herein are cited for their disclosures before the filing date of the present application. Any content herein shall not be interpreted as admitting that the inventor has no right to advance the date of the publication by virtue of an earlier invention priority date or a prior invention date. Further, actual publication dates may vary from those shown and need to be independently verified.

[0026] As used herein, the term "analyte" is a broad term and is used in its general sense, including but not limited to a substance or chemical composition in a fluid such as a biological fluid (e.g., blood, tissue fluid, cerebrospinal fluid, lymph or urine) that can be analyzed. The analyte may include naturally occurring substances, artificial substances, metabolites and / or reaction products. In a common embodiment, the analyte is glucose. However, embodiments of the present invention can be used with sensors designed to detect a variety of other analytes. Illustrative analytes include but are not limited to lactate and naturally occurring salts, sugars, proteins, fats, vitamins and hormones in the body (e.g., in blood or tissue fluid). The analyte may be naturally present in a biological fluid or be endogenous, for example, a metabolite, a hormone, an antigen, an antibody, etc. Alternatively, the analyte may be introduced into the human body or introduced into the body, for example, a contrast agent for imaging, a radioisotope, a chemical reagent, a synthetic blood based on a fluorocarbon, or a drug or pharmaceutical composition, including but not limited to insulin. Metabolites of drugs and pharmaceutical compositions are also covered analytes.

[0027] The term "sensor" is used in its general sense, such as in "analyte sensor", and includes, but is not limited to, devices for detecting compounds such as analytes. A "sensor system" includes, for example, elements, structures, and architectures (e.g., a specific 3-dimensional group of elements) designed to facilitate sensor use and function. A sensor system can include, for example, compositions such as those having selected material properties, and electronic components such as elements and devices used in signal detection and analysis (e.g., current detectors, monitors, processors, etc.).

[0028] As discussed in detail below, embodiments of the present invention relate to laser-ablated polymer surfaces having surface properties that can be used for implantable medical devices. Although the polymers of the present invention may be suitable for use with a variety of such devices, the illustrative embodiments focused on in the present disclosure are analyte sensors, typically electrochemical sensors, that measure the concentration of an analyte of interest, or a substance that indicates the concentration or presence of an analyte (e.g., glucose) in a fluid. However, the laser-ablated polymer surfaces disclosed herein can be used in a variety of other medical devices, including long-term implanted devices (e.g., devices implanted for more than one month), such as orthopedic devices, dental implants, stents, pacemakers, catheters, etc., as well as short-term implanted devices (e.g., devices implanted for less than one month), such as catheters, CGM sensors, infusion tubes of infusion sets, etc.

[0029] Embodiments of the invention disclosed herein provide sensors of the type used, for example, in subcutaneous or transcutaneous monitoring of blood glucose levels in diabetic patients. A variety of implantable electrochemical biosensors have been developed to treat diabetes and other life-threatening diseases. Many existing sensor designs use some form of immobilized enzyme to achieve their biospecificity. Embodiments of the invention described herein can be adapted and implemented using various known electrochemical sensors, including, for example, U.S. Patent Application No. 20050115832, U.S. Patent Nos. 6,001,067, 6,702,857, 6,212,416, 6,119,028, 6,400,974, 6,595,919, 6,141,573, 6,122,536, 6,512,939 , 5,605,152, 4,431,004, 4,703,756, 6,514,718, 5,985,129, 5,390,691, 5,391,250, 5,482,473, 5,299,571, 5,568,806, 5,494,562, 6,120,676, 6,542,765, 7,033,336 and PCT International Publication No. WO 01 / 58348, WO 04 / 021877, WO 03 / 034902, WO 03 / 035117, WO 03 / 035891, WO 03 / 023388, WO 03 / 022128, WO 03 / 022352, WO 03 / 023708, WO 03 / 036255, WO 03 / 036310, WO 08 / 042,625 and WO 03 / 074107, and European Patent Application No. EP 1153571, the contents of each of which are incorporated herein by reference.

[0030] Illustrative embodiments of the invention and related features

[0031] Embodiments of the invention disclosed herein provide medical devices designed to include polymer surfaces that provide enhanced functionality and / or material properties for the device, such as the ability to avoid or inhibit tissue inflammatory responses when implanted in the body. The disclosure also provides methods for making and using such devices. In some embodiments, the implantable device is a subcutaneous, intramuscular, intraperitoneal, intravascular, or transcutaneous device. As discussed in detail below, some embodiments of the present invention relate to the use of a sensor device that is implanted to measure the concentration of an aqueous analyte of interest, or to indicate an analyte concentration or presence in the body. Typically, sensors can be used for continuous glucose monitoring.

[0032] The invention disclosed herein has multiple embodiments. One embodiment is a medical device comprising a surface formed by a laser-ablated polymer surface that has been adapted / modified to contact an in vivo environment containing macrophages. Typically, this laser-ablated polymer surface comprises a polymer composition having a group of properties, the properties including a carbon-oxygen ratio greater than 5 and a surface hydrophobicity between 75° and 90°. In addition, the surface also exhibits a morphology characterized by at least one of the following: grooves with an average peak-to-valley height between 0.3 μm and 5 μm; or holes with an average peak-to-valley height between 1 μm and 2 μm; or a grid with an average peak-to-valley height between 2 μm and 4 μm. In an illustrative embodiment of the present invention, the polymer comprises polyimide, polyamide, polyethylene terephthalate, ethylene tetrafluoroethylene, polyether block amide, polycarbonate, polypropylene, polyethylene, polystyrene, polyvinyl chloride, polymethyl methacrylate, acrylonitrile butadiene, polyetheretherketone, polyurethane, or epoxy resin.

[0033] As is known in the art, classically activated macrophages (M1) are pro-inflammatory effectors, while alternatively activated macrophages (M2) exhibit anti-inflammatory properties. The selected population of surface elements of the laser ablated polymer acts so that when exposed to a surface comprising a polymer composition, RAW264.7 macrophages are affected to differentiate into an anti-inflammatory (M2) phenotype and / or are inhibited from differentiating into an inflammatory (M1) phenotype (e.g., as shown by: reduced MIP-1α expression, or undergoing less morphological changes and elongation, compared to RAW264.7 macrophages contacting a control surface without the element population disclosed herein). This is important because macrophages, particularly their activation state, are closely related to the progression of inflammatory responses, which can be detrimental to the function of implanted devices. (See, e.g., Anderson Annu. Rev. Mater. Res. 2001. 31:81-110; Li et al. Hum Exp Toxicol. 2017 Jan 1:960327117714039. doi:10.1177 / 0960327117714039. [Epub ahead of print]; Kianoush et al. J Biomed Mater Res A. 2017 Sep;105(9):2499-2509. doi:10.1002 / jbm.a.36107. Epub 2017 Jun 6; and Chen et al. Diabetes Metab Res. Rev., 2015 Nov;31(8):781-9. doi:10.1002 / dmrr.2761. Epub 2015 Nov 20).

[0034] Certain embodiments of the invention include medical devices having polymer surfaces of the invention that show quantitative effects on macrophages. For example, in some embodiments of the invention, RAW264.7 macrophages exhibit at least 10% reduction in MIP-1α polypeptide expression when exposed to a surface comprising a polymer composition of the invention disclosed herein, compared to an equivalent polymer surface that does not have a surface topography characterized by grooves with an average peak-to-valley height between 0.3 μm and 5 μm; and / or an equivalent polymer surface that does not have a surface topography characterized by holes with an average peak-to-valley height between 1 μm and 2 μm; and / or an equivalent polymer surface that does not have a surface topography characterized by a grid with an average peak-to-valley height between 2 μm and 4 μm; an equivalent polymer surface that does not have a surface characterized by a carbon-to-oxygen ratio greater than 5; and / or an equivalent polymer surface that does not have a surface hydrophobicity between 75° and 90°. Figure 1G Data are provided for working examples of the invention having these properties.

[0035] Other embodiments of the invention include medical devices having polymer surfaces of the invention that show other quantitative effects on macrophages. For example, in some embodiments of the present invention, when exposed to a surface comprising an inventive polymer composition disclosed herein, RAW264.7 macrophages exhibit at least 10% inhibition of surface adhesion (and / or exhibit at least 10% reduction in morphological changes and elongation of RAW264.7 macrophages) compared to control RAW264.7 macrophages contacting an equivalent polymer surface that does not have a surface morphology characterized by pores with an average peak-to-valley height of between 0.3 μm and 5 μm, and / or an equivalent polymer surface that does not have a surface morphology characterized by pores with an average peak-to-valley height of between 1 μm and 2 μm; and / or an equivalent polymer surface that does not have a surface morphology characterized by a grid with an average peak-to-valley height of between 2 μm and 4 μm; an equivalent polymer surface that does not have a surface characterized by a carbon-to-oxygen ratio greater than 5; and / or an equivalent polymer surface that does not have a surface hydrophobicity between 75° and 90°. Figure 1F Data are provided for working examples of the invention having these properties.

[0036] In a typical embodiment of the present invention, the implantable device comprising a polymer in contact with in vivo tissue is a glucose sensor. In certain embodiments, the glucose sensor comprises a substrate, a working electrode, a reference electrode, and a counter electrode disposed on the substrate, an analyte sensing layer disposed above the working electrode, wherein the analyte sensing layer comprises glucose oxidase, and an analyte modulating layer disposed above the analyte sensing layer, wherein the analyte modulating layer modulates the diffusion of glucose therethrough. Optionally, the glucose sensor further comprises at least one of: an interference suppression layer disposed above the working electrode, an adhesion promoting layer disposed between the analyte sensing layer and the analyte modulating layer, a protein layer disposed on the analyte sensing layer; or a covering layer disposed above the analyte modulating layer.

[0037] A related embodiment of the invention is a method of avoiding and inflammatory response to an implanted medical device, the method comprising implanting a device having a surface suitable for contact with an in vivo environment, the surface comprising a polymer composition having a property group including a carbon-oxygen ratio greater than 5 and a surface hydrophobicity between 75° and 90°. In addition, the surface also exhibits a morphology characterized by at least one of the following: grooves with an average peak-to-valley height between 0.3 μm and 5 μm; or pores with an average peak-to-valley height between 1 μm and 2 μm; or a grid with an average peak-to-valley height between 2 μm and 4 μm. The surface avoids inflammatory response by having the following surface properties: the surface properties cause RAW264.7 macrophages to be affected to differentiate into an anti-inflammatory (M2) phenotype (and / or avoid differentiation into an inflammatory (M1) phenotype) when exposed to a surface comprising a polymer composition. This can be observed by many of the phenomena disclosed herein, such as macrophages undergoing at least 10% less morphological changes and elongation compared to RAW264.7 macrophages contacting a surface that does not have the property group disclosed herein. Optionally, the medical device is implanted into the interstitial space. In typical embodiments, the medical device is a glucose sensor. In illustrative embodiments, the polymer is a polyimide. Typically, when exposed to a surface comprising a polymer composition, RAW264.7 macrophages exhibit a 10% decrease in MIP-1α polypeptide expression and also exhibit at least a 10% decrease in surface adhesion compared to an equivalent polymer surface not having the surface properties of the polymer disclosed herein.

[0038] Yet another embodiment of the present invention is a method of modifying the surface of a polymer composition using a laser to form a laser ablated polymer composition having a defined set of properties, the properties including a carbon to oxygen ratio greater than 5, and a surface hydrophobicity between 75° and 90°. In addition, the surface also exhibits a morphology characterized by at least one of the following: grooves with an average peak-to-valley height between 0.3 μm and 5 μm; or pores with an average peak-to-valley height between 1 μm and 2 μm; or a grid with an average peak-to-valley height between 2 μm and 4 μm. This set of surface properties on the polymer surface avoids an inflammatory response by having properties such that RAW264.7 macrophages are affected to differentiate into an anti-inflammatory (M2) phenotype when exposed to a surface comprising the polymer composition. In an illustrative embodiment, the polymer is a polyimide. The method uses an art-recognized method for laser ablation and can include, for example, using a laser processing system coupled to a software-based controller, exposing a polymer surface to a laser ablation modification process; and ablating the surface so that the surface exhibits the carbon-oxygen ratio, surface hydrophobicity, and surface topography characteristics disclosed herein, so that the laser-ablated polymer surface avoids an inflammatory response by having surface properties that affect RAW264.7 macrophages to differentiate into an anti-inflammatory (M2) phenotype when exposed to a surface comprising a polymer composition. In the present invention, a system from Aerotech was used for laser processing and machining (EDU173, software version 2.14).

[0039] Typically, the polymer surface of the present invention comprises polyimide, polyamide, polyethylene terephthalate, ethylene tetrafluoroethylene, polyether block amide, polycarbonate, polypropylene, polyethylene, polystyrene, polyvinyl chloride, polymethyl methacrylate, acrylonitrile butadiene, polyether ether ketone, polyurethane or epoxy resin. In addition, when exposed to a surface comprising a polymer composition, RAW264.7 macrophages exhibit a 10% decrease in MIP-1α polypeptide expression compared to an equivalent polymer surface not exposed to the laser ablation modification process; and / or exhibit at least a 10% decrease in surface adhesion, and / or exhibit less morphological changes and elongation compared to RAW264.7 macrophages exposed to an equivalent polymer surface that has not been manipulated by the laser ablation modification process. Certain embodiments of the present invention also include placing the laser ablated surface on an implantable medical device (e.g., a glucose sensor) in an orientation where the surface contacts the macrophages when the device is implanted in the body.

[0040] Another embodiment of the present invention is a polymer composition for forming a surface, the composition comprising a carbon-oxygen ratio greater than 5, a surface hydrophobicity between 75° and 90°, a surface topography characterized by grooves with an average peak-to-valley height between 0.3 μm and 5 μm; and / or pores with an average peak-to-valley height between 1 μm and 2 μm; and / or a grid with an average peak-to-valley height between 2 μm and 4 μm. When exposed to a surface comprising the polymer composition, RAW264.7 macrophages exhibit a 10% reduction in MIP-1α polypeptide expression and also exhibit at least a 10% reduction in surface adhesion compared to an equivalent polymer surface not having the surface properties of the polymer disclosed herein (i.e., when exposed to the surface, RAW264.7 macrophages are affected to differentiate into an anti-inflammatory (M2) phenotype).

[0041] In a typical glucose sensor embodiment of the present invention, the electrochemical glucose sensor is operably connected to a sensor input capable of receiving a signal from the electrochemical sensor; and a processor connected to the sensor input, wherein the processor is capable of characterizing one or more signals received from the electrochemical sensor. In certain embodiments of the present invention, the electrode's electrical conduit is connected to a potentiostat. Optionally, a pulse voltage is used to obtain a signal from the electrode. In certain embodiments of the present invention, the processor is capable of comparing a first signal received from the working electrode in response to a first working potential with a second signal received from the working electrode in response to a second working potential. Optionally, the electrode is connected to a processor suitable for converting data obtained by observing fluctuations in the current from a first format to a second format. Such embodiments include, for example, a processor designed to convert a sensor current input signal (e.g., ISIG in nA) into a blood glucose concentration.

[0042] In an embodiment of the present invention, the sensor includes another biocompatible polymer region suitable for in vivo implantation and direct contact with the in vivo environment. In an embodiment of the present invention, the biocompatible region may include any polymer surface that contacts in vivo tissue. In this way, the sensor used in the system of the present invention can be used to sense a variety of analytes in different aqueous environments. In certain embodiments, the sensor includes a discrete probe that pierces the in vivo environment. In some embodiments of the present invention, the electrode is connected to a piercing member (such as a needle) suitable for implantation in the body. Although the sensor embodiment of the present invention may include one or two piercing members, optionally, this type of sensor device may include 3 or 4 or 5 or more piercing members, which are connected to the base element and extend therefrom and are operably connected to 3 or 4 or 5 or more electrochemical sensors (such as microneedle arrays, embodiments of which are disclosed in, for example, U.S. Patent Nos. 7,291,497 and 7,027,478, and U.S. Patent Application No. 20080015494, the contents of which are incorporated herein by reference).

[0043] Embodiments of the present invention include analyte sensor devices designed to utilize polymer surfaces disclosed herein. Such devices typically include a base on which conductive members are disposed and constructed to form working electrodes. In some embodiments of the present invention, an array of conductive members is connected to a common electrical conduit (e.g., such that the conductive members of the array are not wired separately, but are electrically linked as a group). Optionally, the electrical conduit is connected to a power source suitable for sensing fluctuations in the current of the working electrode array. Typically, the device includes a reference electrode; and an opposing electrode. Optionally, one or more of these electrodes also include a plurality of conductive members disposed in an array on a substrate. In some embodiments, each of the conductive members of the electrode (e.g., the opposing electrode) includes an electroactive surface suitable for sensing current fluctuations at the electroactive surface; and the conductive member group is connected to a power source (e.g., a potentiostat, etc.).

[0044] In some embodiments of the invention, the device includes a plurality of working electrodes, counter electrodes, and reference electrodes that are grouped together in a unit consisting essentially of one working electrode, one counter electrode, and one reference electrode; and the grouped units are longitudinally distributed on a substrate in a repeating unit pattern. In some sensor embodiments, the distributed electrodes are organized / arranged within a flexible circuit assembly (i.e., a circuit assembly utilizing flexible rather than rigid materials). Such flexible circuit assembly embodiments provide an interconnected assembly of elements (e.g., electrodes, electrical conduits, contact pads, etc.) that is configured to contribute to the comfort of the wearer (e.g., by reducing the stiffness of the pad and the discomfort of the wearer).

[0045] In some embodiments of the present invention, the analyte sensing layer is disposed above the conductive member and includes a reagent selected for its ability to detectably change the current at the working electrode in the presence of an analyte. In a working embodiment of the invention disclosed herein, the reagent is glucose oxidase, which is a protein that undergoes a chemical reaction in the presence of glucose, which causes a change in the current at the working electrode. These working embodiments also include an analyte regulating layer disposed above the analyte sensing layer, wherein the analyte regulating layer regulates the diffusion of glucose when glucose migrates from the in vivo environment to the analyte sensing layer. In certain embodiments of the present invention, the analyte regulating layer comprises a hydrophilic comb-type copolymer having a central chain and a plurality of side chains connected to the central chain, wherein at least one side chain comprises a siloxane portion. In certain embodiments of the present invention, the analyte regulating layer comprises the following blended mixture: a linear polyurethane / polyurea polymer and a branched acrylate polymer; and the linear polyurethane / polyurea polymer and the branched acrylate polymer are blended in a ratio between 1:1 and 1:20 (e.g., 1:2) by weight percentage. In working embodiments of the present invention, the signal strength and O2 response of microarray sensor electrodes can be improved by using a 2-fold selectively permeable GLM (glucose limiting membrane). Typically, this analyte modulating layer composition comprises a first polymer formed from a mixture comprising: a diisocyanate; at least one hydrophilic diol or hydrophilic diamine; and a siloxane; the first polymer is blended with a second polymer formed from a mixture comprising: 2-(dimethylamino)ethyl methacrylate; methyl methacrylate; polydimethylsiloxane monomethacryloxypropyl; poly(ethylene oxide) methyl ether methacrylate; and 2-hydroxyethyl methacrylate. Additional material layers may be included in such devices. For example, in some embodiments of the present invention, the device includes an adhesion promoting layer disposed between the analyte sensing layer and the analyte modulating layer.

[0046] Figure 2 One sensor embodiment shown in the figure is an amperometric sensor 100 having multiple layered elements, which includes a substrate 102 (e.g., a substrate formed from a polymer disclosed herein), a conductive layer 104 (e.g., a conductive layer including multiple conductive members) disposed on and / or coupled to the substrate 102. Typically, the conductive layer 104 includes one or more electrodes. An analyte sensing layer 110 (typically including an enzyme, such as glucose oxidase) can be disposed on one or more exposed electrodes of the conductive layer 104. A protein layer 116 can be disposed on the analyte sensing layer 110. An analyte modulating layer 112 can be disposed above the analyte sensing layer 110 to modulate the proximity of an analyte (e.g., glucose) to the analyte sensing layer 110. As shown in FIG. Figure 2As shown, an adhesion promoter layer 114 is disposed between the layers, such as between the analyte modulating layer 112 and the analyte sensing layer 110, to facilitate their contact and / or adhesion. This embodiment also includes a cover layer 106 that can be disposed on a portion of the sensor 100, such as a polymer surface coating disclosed herein. Holes 108 can be formed in one or more layers of such sensors. Amperometric glucose sensors having this type of design are disclosed, for example, in U.S. Patent Application Publication Nos. 20070227907, 20100025238, 20110319734, and 20110152654, the contents of each of which are incorporated herein by reference.

[0047] Yet another embodiment of the present invention is a method of sensing an analyte in a mammal. Generally, the method comprises implanting an analyte sensor comprising one or more anti-inflammatory polymer surfaces into a mammal (e.g., in the interstitial space of a diabetic individual), sensing a change in current at a working electrode in the presence of an analyte; and then correlating the change in current with the presence of an analyte, such that the analyte is sensed.

[0048] Embodiments of the present invention also provide articles and kits for observing analyte concentrations. In illustrative embodiments, the kit includes a sensor including a polymer surface discussed herein. In a typical embodiment, the sensor is disposed in a kit in a sealed sterile dry package. Optionally, the kit includes an insertion device that facilitates sensor insertion. The kit and / or sensor kit typically include a container, a label, and an analyte sensor as described above. Suitable containers include, for example, easily opened packages made of materials such as metal foil, bottles, vials, syringes, and test tubes. The container can be formed of a variety of materials, such as metal (e.g., foil) paper products, glass, or plastics. The label on or associated with the container indicates that the sensor is used to analyze the selected analyte. The kit and / or sensor kit may include other materials desired from a commercial and user perspective, including buffers, diluents, filters, needles, syringes, and packaging inserts with instructions for use.

[0049] Certain aspects of embodiments of the invention are discussed in detail in the following sections.

[0050] Typical components, configurations, and analyte sensor embodiments of the present invention

[0051] A. Typical Elements Found in Embodiments of the Invention

[0052] Figure 2 and Figure 3 Schematic diagrams of various sensor and sensor system embodiments of the present invention are provided.

[0053] Figure 2A cross section of a typical sensor embodiment 100 of the present invention is illustrated. This sensor embodiment is formed of multiple components, which are generally in the form of layers of various conductive and non-conductive components disposed on each other according to art-recognized methods disclosed herein and / or specific methods of the present invention. The components of the sensor are generally characterized herein as layers because, for example, it allows for easy characterization of Figure 2 However, the skilled person will appreciate that in certain embodiments of the present invention, the sensor components are combined such that multiple components form one or more heterogeneous layers. In this case, the skilled person will appreciate that in various embodiments of the present invention, the order of the layered components may be changed.

[0054] Figure 2 The illustrated embodiment includes a substrate 102 that supports the sensor 100. The substrate 102 can be made of a material such as a polymer surface having an element group disclosed herein, a metal and / or a ceramic, which can be self-supporting or can be additionally supported by another material known in the art. Embodiments of the present invention include a conductive layer 104 disposed on and / or combined with the substrate 102. Typically, the conductive layer 104 includes one or more conductive elements that function as electrodes. The operating sensor 100 typically includes a plurality of electrodes, such as a working electrode, a counter electrode, and a reference electrode. Other embodiments may also include a plurality of working electrodes and / or counter electrodes and / or reference electrodes and / or one or more electrodes that perform multiple functions, such as an electrode that functions as both a reference electrode and a counter electrode.

[0055] As discussed in detail below, many known techniques and materials may be used to produce the base layer 102 and / or the conductive layer 104. In certain embodiments of the present invention, the circuit of the sensor is defined by etching the conductive layer 104 into a desired conductive path pattern. A typical circuit for the sensor 100 includes two or more adjacent conductive paths having an area at the proximal end to form a contact pad and an area at the distal end to form a sensor electrode. An electrically insulating cover layer 106 such as a polymer coating may be provided on a portion of the sensor 100. Acceptable polymer coatings for use as the insulating protective cover layer 106 may include, but are not limited to, polymers having a feature group disclosed herein, non-toxic biocompatible polymers such as silicone compounds, polyimides, biocompatible solder masks, epoxy acrylate copolymers, and the like. In the sensor of the present invention, one or more exposed areas or holes 108 may be formed through the cover layer 106 to open the conductive layer 104 to the external environment and, for example, allow an analyte such as glucose to penetrate the sensor layer and be sensed by the sensing element. The holes 108 may be formed by a variety of techniques, including laser ablation, tape masking, chemical milling or etching, or photolithographic development, etc. In certain embodiments of the present invention, during manufacturing, a second photoresist may also be applied to the protective layer 106 to define areas of the protective layer to be removed to form one or more holes 108. The exposed electrodes and / or contact pads may also undergo secondary processing (e.g., through the holes 108), such as additional plating processes, to prepare the surface and / or enhance the conductive area.

[0056] exist Figure 2 In the sensor configuration shown, the analyte sensing layer 110 is disposed on one or more exposed electrodes of the conductive layer 104. Typically, the analyte sensing layer 110 is an enzyme layer. Most typically, the analyte sensing layer 110 includes an enzyme capable of producing and / or utilizing oxygen and / or hydrogen peroxide, such as the enzyme glucose oxidase. Optionally, the enzyme in the analyte sensing layer is combined with a second carrier protein such as human serum albumin, bovine serum albumin, etc. In an illustrative embodiment, an oxidoreductase such as glucose oxidase in the analyte sensing layer 110 reacts with glucose to produce hydrogen peroxide, which is a compound that then regulates the current on the electrode. Since this regulation of the current depends on the concentration of hydrogen peroxide, and the concentration of hydrogen peroxide is related to the concentration of glucose, the concentration of glucose can be determined by monitoring this regulation of the current. In a specific embodiment of the present invention, hydrogen peroxide is oxidized on a working electrode (also referred to herein as an anode working electrode) as an anode, and the resulting current is proportional to the concentration of hydrogen peroxide. This modulation of the current caused by changes in hydrogen peroxide concentration can be monitored by any of a variety of sensor detector devices, such as the Universal Sensor amperometric biosensor detector or one of a variety of other similar devices known in the art, such as the glucose monitoring device produced by Medtronic Diabetes.

[0057] In embodiments of the present invention, the analyte sensing layer 110 can be applied over a portion of the conductive layer or over the entire area of ​​the conductive layer. Typically, the analyte sensing layer 110 is disposed on a working electrode, which can be a positive electrode or a negative electrode. Optionally, the analyte sensing layer 110 is also disposed on an opposing electrode and / or a reference electrode. Methods for producing a thin analyte sensing layer 110 include brushing the layer onto a substrate (e.g., a reactive surface of a platinum black electrode), as well as spin coating processes, dip coating and drying processes, low shear spray processes, inkjet printing processes, screen printing processes, and the like. In certain embodiments of the present invention, brushing is used to: (1) allow precise positioning of the layer; (2) push the layer deep into the architecture of the reactive surface of the electrode (e.g., platinum black produced by an electrodeposition process).

[0058] Typically, the analyte sensing layer 110 is coated and / or arranged to be close to one or more additional layers. Optionally, one or more additional layers include a protein layer 116 arranged on the analyte sensing layer 110. Typically, the protein layer 116 includes proteins, such as human serum albumin, bovine serum albumin, etc. Typically, the protein layer 116 includes human serum albumin. In some embodiments of the present invention, the additional layer includes an analyte regulating layer 112, which is arranged above the analyte sensing layer 110 to regulate the contact of the analyte with the analyte sensing layer 110. For example, the analyte regulating membrane layer 112 may include a glucose limiting membrane, which regulates the amount of glucose contacted with an enzyme such as glucose oxidase present in the analyte sensing layer. Such glucose limiting membranes can be made of a variety of materials known to be suitable for such purposes, such as silicone compounds, such as polydimethylsiloxane, polyurethane, polyurea cellulose acetate, Nafion, polyester sulfonic acid (e.g., Kodak AQ), hydrogels, or any other suitable hydrophilic membranes known to those skilled in the art.

[0059] In a typical embodiment of the present invention, Figure 2 As shown, the adhesion promoter layer 114 is disposed between the analyte modulating layer 112 and the analyte sensing layer 110 to facilitate their contact and / or adhesion. Figure 2 As shown, an adhesion promoter layer 114 is disposed between the analyte modulating layer 112 and the protein layer 116 to facilitate their contact and / or adhesion. The adhesion promoter layer 114 can be made of any of a variety of materials known in the art to facilitate adhesion between these layers. Typically, the adhesion promoter layer 114 includes a silane compound. In alternative embodiments, the protein or similar molecules in the analyte sensing layer 110 can be sufficiently cross-linked or otherwise prepared to allow the analyte modulating membrane layer 112 to be disposed in direct contact with the analyte sensing layer 110 in the absence of the adhesion promoter layer 114.

[0060] B. Typical Analyte Sensor Components Used in Embodiments of the Invention

[0061] The following disclosure provides examples of typical elements / ingredients used in sensor embodiments of the present invention. Although these elements can be described as discrete units (e.g., layers), it will be appreciated by those skilled in the art that sensors can be designed to include some or all combinations of material properties and / or functions of the elements / ingredients discussed below (e.g., elements that serve as both support base components and / or conductive components, and / or matrices for analyte sensing components and further used as electrodes in sensors). It will be appreciated by those skilled in the art that these thin film analyte sensors can be suitable for many sensor systems, such as those described below.

[0062] Base components

[0063] The sensors of the present invention generally include a basic component (e.g., Figure 2 102 in the device). The term "base component" is used herein according to a term recognized in the art and refers to a component in the device that generally provides a support matrix for multiple components stacked on each other and includes a functional sensor. In one form, the base component includes a thin film sheet of insulating (e.g., electrically insulating and / or water-impermeable) material (such as a polymer including a surface having a feature group disclosed herein, which is used to modulate an immune response). This base component can be made of a variety of materials having desired qualities (such as the feature groups disclosed herein as well as dielectric properties, water impermeability, and airtightness). Some materials include metals and / or ceramics and / or polymer substrates, etc.

[0064] Conductive components

[0065] The electrochemical sensor of the present invention generally comprises a conductive component disposed on a base component, the conductive component comprising at least one electrode for contacting an analyte to be assayed or its byproducts (e.g., oxygen and / or hydrogen peroxide) (see, e.g., Figure 2104 in the element 104). The term "conductive component" is used herein according to a specialized term recognized in the art and refers to a conductive sensor element disposed in an array on a substrate, such as a plurality of conductive members (e.g., to form a microarray electrode) and the conductive component is capable of measuring a detectable signal and conducting it to a detection device. Such an illustrative example is a conductive component forming a working electrode that can measure an increase or decrease in current in response to exposure to a stimulus (such as a change in the concentration of an analyte or its byproducts) compared to a reference electrode that does not experience a change in the concentration of an analyte (a co-reactant (e.g., oxygen) or a reaction product (e.g., hydrogen peroxide) used when the analyte interacts with a composition (e.g., the enzyme glucose oxidase) present in the analyte sensing component 110). Illustrative examples of such elements include electrodes that are capable of producing a variable detectable signal in the presence of a variable concentration of a molecule such as hydrogen peroxide or oxygen.

[0066] In addition to the working electrode, the analyte sensor of the present invention generally also includes a reference electrode or a combined reference and counter electrode (also referred to as a quasi-reference electrode or counter / reference electrode). If the sensor does not have a counter / reference electrode, it may include a separate counter electrode, which may be made of the same or different material as the working electrode. A typical sensor of the present invention has one or more working electrodes and one or more counter, reference and / or counter / reference electrodes. An embodiment of the sensor of the present invention has two, three or four or more working electrodes. These working electrodes in the sensor may be connected as a whole or may remain separate. Optionally, the electrode may be arranged on a single surface or side of the sensor structure. Optionally, the electrode may be arranged on multiple surfaces or sides of the sensor structure (and, for example, may be connected to the surface on which the electrode is arranged by passing through a through hole of one or more sensor materials). In certain embodiments of the present invention, the reactive surface of the electrode has different relative areas / sizes, such as a 1X reference electrode, a 2.6X working electrode, and a 3.6X counter electrode.

[0067] Interference suppression components

[0068] The electrochemical sensor of the present invention optionally includes an interference suppression component disposed between the electrode surface and the environment to be detected. Specifically, certain sensor embodiments rely on the oxidation and / or reduction of hydrogen peroxide produced by an enzymatic reaction on the surface of the working electrode at a constant applied potential. Because amperometric detection based on direct oxidation of hydrogen peroxide requires a relatively high oxidation potential, sensors using this detection scheme may experience interference from oxidizable substances present in biological fluids, such as ascorbic acid, uric acid, and acetaminophen. In this context, the term "interference suppression component" is used herein according to the art-recognized special terms and refers to a coating or membrane in the sensor that acts to suppress false signals generated by such oxidizable substances, which interfere with the detection of the signal generated by the analyte to be sensed. Certain interference suppression components act by size exclusion (e.g., by excluding interfering species of a specific size). Examples of interference suppression components include one or more layers or coatings of compounds, such as hydrophilic polyurethanes, cellulose acetate (including cellulose acetate bound to reagents such as polyethylene glycol, polyethersulfone, polytetrafluoroethylene, perfluoroionomer Nafion TM , polyphenylene diamine, epoxy resin, etc.).

[0069] Analyte sensing components

[0070] The electrochemical sensors of the present invention include analyte sensing components disposed on electrodes of the sensor (see, e.g., Figure 2 110 in). The term "analyte sensing component" is used herein according to the specialized words recognized in the art, and refers to a component that contains an analyte that can identify or react with an analyte to be detected by an analyte sensor device. Typically, this material in the analyte sensing component usually produces a detectable signal via the electrode of the conductive component after interacting with the analyte to be sensed. In this regard, the electrodes of the analyte sensing component and the conductive component work in a combined manner to produce an electrical signal read by a device associated with the analyte sensor. Typically, the analyte sensing component includes an oxidoreductase that can react with a molecule and / or produce a molecule (e.g., oxygen and / or hydrogen peroxide) whose concentration change can be measured by measuring the current change at the electrode of the conductive component, such as glucose oxidase. An enzyme that can produce a molecule such as hydrogen peroxide can be arranged on an electrode according to many methods known in the art. The analyte sensing component can coat all or part of the various electrodes of the sensor. In this context, the analyte sensing component can cover the electrode to an equal degree. Alternatively, the analyte sensing component may coat different electrodes to different extents, such as the working electrode having a coated surface that is greater than the coated surface of the counter electrode and / or reference electrode.

[0071] Typical sensor embodiments of this element of the invention utilize an enzyme (e.g., glucose oxidase) that has been bound to a second protein (e.g., albumin) at a fixed ratio (e.g., an enzyme typically optimized for glucose oxidase stability properties) and then applied to the surface of an electrode to form a thin enzyme component. In typical embodiments, the analyte sensing component includes a GOx and HSA mixture. In typical embodiments of the analyte sensing component with GOx, GOx reacts with glucose present in the sensing environment (e.g., the body of a mammal) and produces hydrogen peroxide.

[0072] As described above, the enzyme and the second protein (e.g., albumin) are typically treated to form a cross-linked matrix (e.g., by adding a cross-linking agent to the protein mixture). As known in the art, the cross-linking conditions can be controlled to adjust factors such as the retention of biological activity of the enzyme, its mechanical and / or operational stability. Illustrative cross-linking procedures are described in U.S. Patent Application Serial No. 10 / 335,506 and PCT Publication WO 03 / 035891, which are incorporated herein by reference. For example, an amine cross-linking agent, such as but not limited to glutaraldehyde, can be added to the protein mixture. Adding a cross-linking agent to the protein mixture will produce a protein paste. The concentration of the cross-linking agent to be added can vary depending on the concentration of the protein mixture. Although glutaraldehyde is an exemplary cross-linking agent, other cross-linking agents may also be used or used in place of glutaraldehyde. As will be apparent to those skilled in the art, other suitable cross-linking agents may also be used.

[0073] As described above, in some embodiments of the present invention, the analyte sensing component includes a reagent (e.g., glucose oxidase) that can generate a signal (e.g., a change in oxygen and / or hydrogen peroxide concentration) that can be sensed by a conductive element (e.g., an electrode that senses changes in oxygen and / or hydrogen peroxide concentration). However, other useful analyte sensing components can be formed by any composition that can generate a detectable signal that can be sensed by a conductive element after interacting with a target analyte to be detected for its presence. In some embodiments, the composition includes an enzyme that regulates the concentration of hydrogen peroxide when reacting with the analyte to be sensed. Alternatively, the composition includes an enzyme that regulates the concentration of oxygen when reacting with the analyte to be sensed. In this context, a variety of enzymes that use or generate hydrogen peroxide and / or oxygen in reactions with physiological analytes are known in the art, and these enzymes can be easily incorporated into the analyte sensing component composition. A variety of other enzymes known in the art can generate and / or utilize compounds, and the regulation of the compound can be detected by a conductive element such as an electrode incorporated into the sensor design described herein. Such enzymes include, for example, those described specifically in Table 1, pages 15-29 and / or Table 18, pages 111-112 of Protein Immobilization: Fundamentals and Applications (Bioprocess Technology, Vol 14), Richard F. Taylor (ed.), Publisher: Marcel Dekker (January 7, 1991), the entire contents of which are incorporated herein by reference.

[0074] Protein composition

[0075] The electrochemical sensors of the present invention optionally include a protein component disposed between the analyte sensing component and the analyte modulating component (see, e.g., Figure 2 116 in). The term "protein component" is used herein according to art-recognized terminology and refers to a component containing a carrier protein, etc., which is selected to be compatible with the analyte sensing component and / or the analyte modulating component. In a typical embodiment, the protein component comprises albumin, such as human serum albumin. The HSA concentration can vary between about 0.5%-30% (w / v). Typically, the HSA concentration is about 1-10% w / v, most typically about 5% w / v. In alternative embodiments of the present invention, collagen or BSA or other structural proteins used in these cases can be used instead of or in addition to HSA. According to protocols recognized in the art, this component is typically cross-linked to the analyte sensing component.

[0076] Adhesion promoting ingredients

[0077] The electrochemical sensors of the present invention may include one or more adhesion promoting (AP) components (see, e.g., Figure 2 114 in the sensor). The term "adhesion promoting component" is used herein according to a specialized term recognized in the art, and refers to a component that includes a material selected because it can promote adhesion between adjacent components in the sensor. Typically, the adhesion promoting component is disposed between the analyte sensing component and the analyte regulating component. Typically, the adhesion promoting component is disposed between the optional protein component and the analyte regulating component. The adhesion promoter component can be made of any of a variety of materials known in the art to facilitate bonding between such components, and can be applied by any of a variety of methods known in the art. Typically, the adhesion promoter component includes a silane compound, such as γ-aminopropyltrimethoxysilane.

[0078] Analyte Modulating Components

[0079] The electrochemical sensors of the present invention include an analyte modulating component disposed on the sensor (see, e.g., Figure 2 112 in the sensor). The term "analyte modulating component" is used herein according to a term recognized in the art, and refers to a component that typically forms a film on the sensor that is used to modulate the diffusion of one or more analytes, such as glucose, through the component. In certain embodiments of the present invention, the analyte modulating component is an analyte limiting membrane that is used to prevent or restrict the diffusion of one or more analytes, such as glucose, through the component. In other embodiments of the present invention, the analyte modulating component is used to facilitate the diffusion of one or more analytes through the component. Optionally, such analyte modulating components can be formed to prevent or restrict the diffusion of one type of molecule through the component (e.g., glucose), while allowing or even facilitating the diffusion of other types of molecules through the component (e.g., O2).

[0080] About glucose sensor, in known enzyme electrode, glucose and oxygen from blood and some interferences such as ascorbic acid and uric acid diffuse through the primary membrane of sensor.When glucose, oxygen and interferences arrive at analyte detection component, enzyme such as glucose oxidase catalyzes glucose to convert into hydrogen peroxide and gluconolactone.Hydrogen peroxide can diffuse back through analyte regulating component, or can diffuse to electrode, where hydrogen peroxide can react to form oxygen and proton, thereby producing electric current proportional to glucose concentration.Analyte regulating sensor membrane assembly is used for several functions, including selectively allowing glucose to pass therethrough (see, e.g., U.S. Patent Application No. 2011-0152654).

[0081] Covering ingredients

[0082] The electrochemical sensors of the present invention include one or more covering components, which are typically electrically insulating protective components (see, e.g. Figure 2 106 in). Typically, such covering components can be in the form of a coating, sheath or tube and are disposed on at least a portion of the analyte modulating component. Typically, such features include a polymer comprising a surface having a feature group disclosed herein, which is used to modulate an immune response. Acceptable polymer coatings used as insulating covering components may include, but are not limited to, non-toxic biocompatible polymers such as silicone compounds, polyimides, biocompatible solder masks, epoxy acrylate copolymers, and the like. In addition, these coatings may be photoimageable to facilitate photolithographic formation of holes through the conductive component. Typical covering components include staple fibers on silicone. As known in the art, this component may be a commercially available RTV (room temperature vulcanized) silicone composition. In this context, a typical chemical is polydimethylsiloxane (based on acetoxy).

[0083] C. Typical Analyte Sensor System Embodiments of the Present Invention

[0084] Embodiments of sensor elements and sensors can be operably connected to a variety of other system elements (e.g., structural elements, such as piercing members, insertion kits, etc., and electronic components such as processors, monitors, drug infusion pumps, etc.) that are commonly used with analyte sensors, such as to adapt them to various environments (e.g., implanted in mammals). One embodiment of the present invention includes a method for monitoring a user's physiological characteristics using an embodiment of the present invention, the embodiment including an input element (which can receive a signal based on a sensed physiological characteristic value of the user from a sensor), and a processor for analyzing the received signal. In a typical embodiment of the present invention, the processor determines the dynamic behavior of the physiological characteristic value and provides an observable indicator based on the dynamic behavior of the physiological characteristic value so determined. In some embodiments, the physiological characteristic value is a measure of the user's blood glucose concentration. In other embodiments, the process of analyzing the received signal and determining the dynamic behavior includes repeatedly measuring the physiological characteristic value to obtain a series of physiological characteristic values, so as to, for example, combine comparative redundancy into the sensor device in a manner designed to provide confirmation information about sensor function, analyte concentration measurement results, the presence of interference, etc.

[0085] FIG. 11 in U.S. Patent Publication 2014 / 0163346 shows a schematic diagram of a potentiostat that can be used to measure current in an embodiment of the present invention. As shown in FIG. 11 in U.S. Patent Publication 2014 / 0163346, a potentiostat 300 may include an operational amplifier 310 connected in a circuit so as to have two inputs: Vset and Vmeasured. As shown, Vmeasured is the measured value of the voltage between the reference electrode and the working electrode. On the other hand, Vset is the optimal desired voltage between the working electrode and the reference electrode. The current between the opposing electrode and the reference electrode is measured, thereby creating a current measurement result (isig) output from the potentiostat.

[0086] Embodiments of the present invention include devices that process display data from measurements of sensed physiological characteristics (e.g., blood glucose concentration) in a customized manner and format to allow a user of the device to easily monitor and (if necessary) adjust the physiological state of the characteristic (e.g., adjust blood glucose concentration via insulin administration). An illustrative embodiment of the present invention is a device that includes: a sensor input that is capable of receiving a signal from a sensor that is based on a sensed physiological characteristic value of a user; a memory for storing multiple measurements of the sensed physiological characteristic value of the user of the received signal from the sensor; and a display for presenting a text and / or graphical representation (e.g., text, line graphs, etc., bar graphs, etc., grid graphs, etc., or a combination thereof) of multiple measurements of the sensed physiological characteristic value. Typically, the graphical representation displays real-time measurements of the sensed physiological characteristic value. Such devices can be used in a variety of situations, such as in combination with other medical devices. In some embodiments of the present invention, the device is used in combination with at least one other medical device (e.g., a glucose sensor).

[0087] An illustrative system embodiment consists of a glucose sensor, a transmitter and a pump receiver and a blood glucose meter. In this system, a radio signal from a transmitter can be sent to a pump receiver every 5 minutes to provide a real-time sensor glucose (SG) value. The value / graph is displayed on the monitor of the pump receiver so that the user can use his insulin pump to self-monitor blood glucose and deliver insulin. Typically, the embodiments of the device disclosed herein communicate with a second medical device via a wired or wireless connection. Wireless communication may include, for example, the reception of an emitted radiation signal that occurs during signal transmission via radio frequency telemetry, infrared transmission, optical transmission, sound waves, and ultrasonic transmission. Optionally, the device is a component of a drug infusion pump (e.g., an insulin pump). Typically, in such devices, physiological characteristic values ​​include multiple measurements of blood glucose.

[0088] Figure 3A perspective view of a general embodiment of a subcutaneous sensor insertion system and a block diagram of a sensor electronics arrangement are provided according to an illustrative embodiment of the present invention. Additional elements commonly used with such sensor system embodiments are disclosed in U.S. Patent Application No. 20070163894, the contents of which are incorporated by reference. Figure 3 A perspective view of a telemetric characteristic monitoring system 1 is provided, which includes a subcutaneous sensor kit 10, which is provided for subcutaneous placement of an active portion of a flexible sensor 12 at a selected site on a user's body, etc. The subcutaneous or percutaneous portion of the sensor kit 10 includes a hollow slotted insertion needle 14 having a sharp tip 44 and a cannula 16. Inside the cannula 16 is a sensing portion 18 of the sensor 12 to expose one or more sensor electrodes 20 to the user's bodily fluids through a window 22 formed in the cannula 16. The sensing portion 18 is joined to a connecting portion 24 that terminates in a conductive contact pad or the like, which is also exposed through one of the insulating layers. The connecting portion 24 and the contact pads are typically adapted for direct wired electrical connection to a suitable monitor 200 coupled to a display 214 to monitor the user's condition in response to signals originating from the sensor electrodes 20. The connecting portion 24 can be conveniently electrically connected to the monitor 200 or characteristic monitor transmitter 100 via a connector block 28 (or the like).

[0089] like Figure 3 As shown in , according to an embodiment of the present invention, the subcutaneous sensor kit 10 can be configured or formed to work with a wired or wireless property monitoring system. The proximal portion of the sensor 12 is mounted in a mounting base 30 suitable for placement on the skin of a user. The mounting base 30 can be a pad having an underside surface coated with a suitable pressure-sensitive adhesive layer 32, and a release paper strip 34 is usually provided to cover and protect the adhesive layer 32 until the sensor kit 10 is ready for use. The mounting base 30 includes an upper layer 36 and a lower layer 38, and the connecting portion 24 of the flexible sensor 12 is sandwiched between the layers 36 and 38. The connecting portion 24 has a front portion that is joined to the active sensing portion 18 of the sensor 12, and the front portion is folded at an angle to extend downward through a bore 40 formed in the lower base layer 38. Optionally, the adhesive layer 32 (or another portion of the device that contacts the tissue in the body) includes an anti-inflammatory agent to reduce the inflammatory response and / or an antibacterial agent to reduce the chance of infection. The insertion needle 14 is adapted to be received by a needle port 42 formed in the upper substrate 36 and through a lower bore 40 in the lower substrate 38 in a sliding fit. After insertion, the insertion needle 14 is withdrawn to leave the cannula 16, and the sensing portion 18 and sensor electrodes 20 in place at the selected insertion site. In this embodiment, the telemetry characteristic monitoring transmitter 100 is coupled to the sensor assembly 10 via a wire 102 through a connector 104, which is electrically coupled to the connector block 28 of the connector portion 24 of the sensor assembly 10.

[0090] exist Figure 3 In the illustrated embodiment, the telemetry characteristic monitor 100 includes a housing 106 that supports a printed circuit board 108, a battery 110, an antenna 112, and a wire 102 having a connector 104. In some embodiments, the housing 106 is formed by an upper housing 114 and a lower housing 116 that are ultrasonically welded and sealed to form a waterproof (or corrosion-resistant) seal to permit cleaning by immersion (or wiping) with water, detergent, alcohol, etc. In some embodiments, the upper housing 114 and the lower housing 116 are made of medical grade plastic. However, in alternative embodiments, the upper housing 114 and the lower housing 116 can be connected together by other methods, such as snap fit, sealing rings, RTV (silicone sealant) and bonded together, etc., or formed of other materials, such as metals, composite materials, ceramics, etc. In other embodiments, a separate housing can be omitted, and the assembly is simply potted with epoxy or other moldable materials that are compatible with electronic devices and are fairly moisture-resistant. As shown, the lower housing 116 may have an underside surface covered with a suitable pressure sensitive adhesive layer 118, with a release paper strip 120 typically provided to cover and protect the adhesive layer 118 until the sensor suite telemetry characteristic monitor transmitter 100 is ready for use.

[0091] exist Figure 3 In the illustrative embodiment shown, the subcutaneous sensor kit 10 facilitates the precise placement of a type of flexible thin film electrochemical sensor 12 for monitoring specific blood parameters indicative of a user's condition. The sensor 12 monitors glucose levels in the body and can be used in conjunction with an external or implantable automatic or semi-automatic drug infusion pump such as described in U.S. Pat. Nos. 4,562,751; 4,678,408; 4,685,903 or 4,573,994 to control insulin delivery to a diabetic patient.

[0092] exist Figure 3 In the illustrative embodiment shown in , the sensor electrode 10 can be used for a variety of sensing applications and can be configured in a variety of ways. For example, the sensor electrode 10 can be used for physiological parameter sensing applications where a certain type of biomolecule is used as a catalyst. For example, the sensor electrode 10 can be used for glucose and oxygen sensors, which have glucose oxidase that catalyzes the reaction with the sensor electrode 20. The sensor electrode 10, along with the biomolecule or some other catalyst, can be placed in the human body in a vascular or non-vascular environment. For example, the sensor electrode 20 and the biomolecule can be placed in a vein and subjected to blood flow, or can be placed in the subcutaneous or peritoneal area of ​​the human body.

[0093] exist Figure 3In the embodiment of the present invention shown, the monitor 200 of the sensor signal may also be referred to as the sensor electronics device 200. The monitor 200 may include a power supply, a sensor interface, processing electronics (i.e., a processor), and data formatting electronics. The monitor 200 may be connected to the sensor kit 10 via the wire 102 through a connector electrically connected to the connector block 28 of the connecting portion 24. In an alternative embodiment, the wire may be omitted. In this embodiment of the present invention, the monitor 200 may include a suitable connector for directly connecting to the connecting portion 104 of the sensor kit 10. The sensor kit 10 may be modified to have the connector portion 104 located in a different position (e.g., located at the top of the sensor kit) to facilitate placing the monitor 200 above the sensor kit.

[0094] Although the analyte sensors and sensor systems disclosed herein are generally designed to be implantable in mammals, the invention disclosed herein is not limited to any particular environment, but can be used in a variety of environments, such as for analyzing most in vivo and in vitro fluid samples, including biological fluids such as interstitial fluid, whole blood, lymph, plasma, serum, saliva, urine, feces, sweat, mucus, tears, cerebrospinal fluid, nasal secretions, cervical or vaginal secretions, semen, pleural fluid, amniotic fluid, peritoneal fluid, middle ear fluid, joint fluid, gastric fluid, etc. In addition, solid or dried samples can be dissolved in an appropriate solvent to provide a liquid mixture suitable for analysis.

[0095] It should be understood that the present invention is not limited to the specific embodiments described, as they can certainly vary. It should also be understood that the special terms used herein are only for the purpose of describing specific embodiments, and do not wish to be restrictive, because the scope of the present invention is limited only by the appended claims. In the description of the preferred embodiments, reference is made to the accompanying drawings that form a part of the description, and the accompanying drawings illustrate specific embodiments that can be practiced of the present invention by way of illustration. It should be understood that other embodiments can be utilized and structural changes can be made without departing from the scope of the present invention.

Claims

1. A medical device comprising a surface adapted to contact an in vivo environment, the surface comprising a polymer composition having the following properties: A carbon-oxygen ratio greater than 5; Surface hydrophobicity between 75° and 90°; Characterized by the following surface morphology: Grooves with an average peak-to-valley height between 0.3 μm and 5 μm; Pores with an average peak-to-valley height between 1 μm and 2 μm; or Grids with an average peak-to-valley height between 2 μm and 4 μm; in: When exposed to said surface comprising said polymer composition, RAW264.7 macrophages are affected in a manner that inhibits their differentiation into an inflammatory (M1) phenotype, and / or in a manner that facilitates their differentiation into an anti-inflammatory (M2) phenotype.

2. The medical device according to claim 1, wherein: The device is a glucose sensor.

3. The medical device according to claim 2, wherein: The glucose sensor comprises: Grassroots; A working electrode, a reference electrode and a counter electrode are disposed on the substrate; an analyte sensing layer disposed over the working electrode, wherein the analyte sensing layer comprises glucose oxidase; and An analyte modulating layer is disposed over the analyte sensing layer, wherein the analyte modulating layer modulates diffusion of glucose therethrough.

4. The medical device according to claim 3, wherein: When exposed to said surface comprising said polymer composition, RAW264.7 macrophages exhibit at least a 10% reduction in MIP-1 alpha polypeptide expression compared to an equivalent polymer surface not having a surface topography characterized by: Grooves with an average peak-to-valley height between 0.3 μm and 5 μm; Pores with an average peak-to-valley height between 1 μm and 2 μm; or Grid with average peak-to-valley height between 2 μm and 4 μm.

5. The medical device according to claim 4, wherein: When exposed to said surface comprising said polymer composition, adhesion of RAW264.7 macrophages to said surface is inhibited by at least 10% compared to an equivalent polymer surface not having a surface topography characterized by: Grooves with an average peak-to-valley height between 0.3 μm and 5 μm; Pores with an average peak-to-valley height between 1 μm and 2 μm; or Grid with average peak-to-valley height between 2 μm and 4 μm.

6. The medical device according to claim 5, wherein: The polymer includes polyimide, polyamide, polyethylene terephthalate, ethylene tetrafluoroethylene, polyether block amide, polycarbonate, polypropylene, polyethylene, polystyrene, polyvinyl chloride, polymethyl methacrylate, acrylonitrile butadiene, polyether ether ketone, polyurethane or epoxy resin.

7. The medical device according to claim 1, wherein: The surface topography is characterized by a grid with an average peak-to-valley height between 2 μm and 4 μm.

8. The medical device according to claim 1, wherein: The surface topography is characterized by pores with an average peak-to-valley height between 1 μm and 2 μm.

9. The medical device according to claim 1, wherein: The surface topography is characterized by grooves having an average peak-to-valley height between 0.3 μm and 5 μm.

10. A method of using a laser to modify the surface of a polymer composition to form a laser ablated polymer composition having the following properties: A carbon-oxygen ratio greater than 5; Surface hydrophobicity between 75° and 90°; Characterized by the following surface morphology: Grooves with an average peak-to-valley height between 0.3 μm and 5 μm; Pores with an average peak-to-valley height between 1 μm and 2 μm; or Grids with an average peak-to-valley height between 2 μm and 4 μm; The method comprises: exposing the polymer surface to a laser ablation modification process using a laser processing system coupled to a software-based controller; and ablating the surface so that the surface exhibits the carbon-oxygen ratio, surface hydrophobicity, and surface topography characteristics; in: The laser ablated polymer surface avoids inflammatory responses by having surface properties such that RAW264.7 macrophages are influenced to differentiate into an anti-inflammatory (M2) phenotype when exposed to the surface comprising the polymer composition.

11. The method according to claim 10, wherein: The polymer includes polyimide, polyamide, polyethylene terephthalate, ethylene tetrafluoroethylene, polyether block amide, polycarbonate, polypropylene, polyethylene, polystyrene, polyvinyl chloride, polymethyl methacrylate, acrylonitrile butadiene, polyether ether ketone, polyurethane or epoxy resin.

12. The method according to claim 11, wherein: When exposed to said surface comprising said polymer composition, compared to an equivalent polymer surface not exposed to said laser ablation modification process, RAW264.7 macrophages: exhibit a 10% decrease in MIP-1α polypeptide expression; and Exhibits at least a 10% reduction in adhesion to said surface.

13. The method of claim 12, further comprising positioning the laser-ablated surface on an implantable medical device in an orientation where the surface contacts macrophages when the device is implanted in vivo.

14. The method according to claim 13, wherein: The implantable medical device is a glucose sensor.

15. A surface-forming polymer composition comprising: A carbon-oxygen ratio greater than 5; Surface hydrophobicity between 75° and 90°; Characterized by the following surface morphology: Grooves with an average peak-to-valley height between 0.3 μm and 5 μm; Pores with an average peak-to-valley height between 1 μm and 2 μm; or Grids with an average peak-to-valley height between 2 μm and 4 μm; in When exposed to the surface, RAW264.7 macrophages were influenced to differentiate into an anti-inflammatory (M2) phenotype.

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