Abstract: The invention relates to a method for producing a device for the electrochemical detection of molecules by way of redox cycling, to a device therefor, and to the use thereof. A porous dielectric layer is present between two electrode layers, which is able to receive redox-active molecules and may be biofunctionalized. The individual layers are preferably applied by way of an ink jet printing method.

Abstract: A method of detecting at least one analyte in a test sample is provided comprising a) contacting the test sample (i) to an active chemistry matrix changing at least one electrochemical property dependent on an enzymatic activity active in the presence of the analyte, the active chemistry matrix contacting a first electrode; and (ii) to an inactive chemistry matrix, the inactive chemistry matrix contacting a second electrode, b) closing an electrical circuit including the first electrode, the second electrode, and the active chemistry matrix and inactive chemistry matrix, followed by determining a first value of the at least one electrochemical property, c) inverting electrical polarity of the electrical circuit of b), followed by determining a second value of the at least one electrochemical property, and d) detecting the at least one analyte based on the first value and on the second value.

Abstract: Enzyme compositions including lactate responsive enzyme and stabilizing agent, including electrodes, sensors, and systems having the same. The stabilizing agent stabilizes the lactate responsive enzyme in a manner sufficient to increase sensitivity to lactate, such as for use in in vivo detection of lactate. In some compositions the lactate responsive enzyme is lactate oxidase and the sensor includes a heterocycle-containing polymer and a crosslinker.

Abstract: Electrochemical impedance-based label-free and rapid biosensor for select bodily fluid biomolecule levels. Monoclonal antibodies to of biomolecule such as Cortisol were covalently attached to a 16-mercaptohexadecanoic acid functionalized gold working electrode using zero-length crosslinkers N-(3-dimethylaminopropyl)-N-ethylcarbodiimide and 10 mM N-hydroxysulfosuccinimide. Cortisol was detected in phosphate buffered saline (simulated tear fluid) using a simple ferrocyanide reagent with a lower limit of detection of 18.73 pM and less than 10% relative standard deviation.

Abstract: A TFT biosensor includes a gate electrode (silicon substrate), a reference electrode, and enzyme that is fixed to an insulating substrate spatially separated from the gate electrode and the reference electrode. A pH variation in the vicinity of an ion-sensitive insulating film is induced by a reaction between the enzyme and a sensing object material. The TFT biosensor can detect a concentration of the sensing object material with high sensitivity by detecting the pH variation as a threshold voltage shift of characteristics of a gate-source voltage to a source-drain current.

Abstract: Systems and methods of use involving sensors having a signal-to-noise ratio that is substantially unaffected by non-constant noise are provided for continuous analyte measurement in a host. In some embodiments, a continuous analyte measurement system is configured to be wholly, transcutaneously, intravascularly or extracorporeally implanted.

Abstract: Provided is a method for measuring the concentration of a substance in a blood sample, the method comprising the steps of: supplying the blood sample to a biosensor comprising a hematocrit electrode for measuring a hematocrit value on the surface of which electrode an electrically conductive polymer is coated by physical adsorption in the absence of a crosslinking agent; and calculating the concentration of the substance from the measured value of a first current resulting from application of a first voltage; and correcting the concentration of the substance with the value of a second current resulting from application of a second voltage or the hematocrit value calculated from the value of the second current.

Abstract: There is provided a sensor testing method including: applying at least one of a first voltage that obtains a response caused by a substance and a second voltage that either obtains no response or substantially no response caused by the substance across a first electrode and a second electrode of a sensor; measuring current flowing between the first electrode and the second electrode; and determining whether or not there is a defect present in the sensor based on a quantity related to an amount of change per specific period of time of a current measured when the first voltage and/or the second voltage have been applied.

Abstract: Electrochemical test cells are made with precision and accuracy by adhering an electrically resistive sheet having a bound opening to a first electrically conductive sheet. A notching opening is then punched through the electrically resistive sheet and the first electrically conductive sheet. The notching opening intersects the first bound opening in the electrically resistive sheet, and transforms the first bound opening into a notch in the electrically resistive sheet. A second electrically conductive sheet is punched to have a notching opening corresponding to that of first electrically conductive sheet, and this is adhered to the other side of the electrically resistive sheet such that the notching openings are aligned. This structure is cleaved from surrounding material to form an electrochemical cell that has a sample space for receiving a sample defined by the first and second conductive sheets and the notch in the electrically resistive sheet.

Abstract: A biosensor system determines an analyte concentration of a biological sample using an electrochemical process without Cottrell decay. The biosensor system generates an output signal having a transient decay, where the output signal is not inversely proportional to the square root of the time. The transient decay is greater or less than the ?0.5 decay constant of a Cottrell decay. The transient decay may result from a relatively short incubation period, relatively small sample reservoir volumes, relatively small distances between electrode surfaces and the lid of the sensor strip, and/or relatively short excitations in relation to the average initial thickness of the reagent layer. The biosensor system determines the analyte concentration from the output signal having a transient decay.

Abstract: The present disclosure relates to a micro-fluidic probe card that deposits a fluidic chemical onto a substrate with a minimal amount of fluidic chemical waste, and an associated method of operation. In some embodiments, the micro-fluidic probe card has a probe card body with a first side and a second side. A sealant element, which contacts a substrate, is connected to the second side of the probe card body in a manner that forms a cavity within an interior of the sealant element. A fluid inlet, which provides a fluid from a processing tool to the cavity, is a first conduit extending between the first side and the second side of the probe card body. A fluid outlet, which removes the fluid from the cavity, is a second conduit extending between the first side and the second side of the probe card body.

Abstract: An ultra violet (UV) light dose monitoring system may include an implantable microchip for injection below the surface of a person's skin. The microchip may include a solar cell, a data telemetry transmitter, and a first sensor cell that absorbs UV light that passes through the skin. The system may also include a remote reader. The remote reader may include a data telemetry receiver that receives the data from the microchip and a processor for controlling operation of the remote reader. The data telemetry transmitter may transmit data indicative of a UV light intensity for the UV light absorbed by the first sensor cell to the data telemetry receiver, and the processor may calculate a UV dose based on the data.

Abstract: A disposable electrochemical test sensor designed to facilitate sampling of fluid samples. It has a fluid chamber having a novel extra wide sampling entrance, but no additional air escape vent. The chamber provides a reservoir from which a sample fluid can be drawn into the chamber through capillary action. The extra wide sampling entrance provided by the present invention can draw blood into the chamber through any part of the opening, thus it allows easy targeting the samples with small volume, picking up smeared samples and it is more tolerant to users who jam the tip of the sensor into users' finger.

Abstract: The disclosure is directed to techniques to evenly distribute current in interdigited leadframes by decoupling current between interdigited pads. The leadframe may use a perpendicular structure between the leadframe conductive pads and the lead traces. The perpendicular structure provides a short path for the current to travel from electrode pad openings on a device to the lead traces carrying current to other portions of a circuit. The conductive pad may be parallel to the electrode pad opening to lower spreading resistance. In an example of a transistor, the transistor may have two or more electrode pads for every current carrying node. Therefore, several electrode pads may have the same node, such as the source or drain of the device. For example, two or more source pads may be connected though the leadframe to evenly distribute the current and decouple the current from a single transistor.

Abstract: The present invention relates to a method for removing turbidity-inducing agents from a lipid phase.

Abstract: Certain embodiments of the present application describe a process to perform activation of carbon based electrodes in a controlled manner, where the degree of activation is monitored and calculated simultaneously with the ongoing activation process. Such an approach is intended to improve the reproducibility of electrodes that may include, but are not limited to, the following parameters: electrochemical capacitance, electrochemical transfer coefficient, amperiometric response to enzymatic reactions.

Abstract: Generally, embodiments of the invention relate to self-powered analyte determining devices (e.g., electrochemical analyte monitoring systems) that include a working electrode, a counter electrode, and an optional resistance value, where the working electrode includes analyte sensing components and the self-powered analyte determining device spontaneously passes a current directly proportional to analyte concentration in the absence of an external power source. Also provided are systems and methods of using the, for example electrochemical, analyte sensors in analyte monitoring.

Abstract: Provided are sensors for determining the concentration of an analyte in a sample fluid. In certain embodiments, the sensors include conductive particles and exhibit improved uniformity of distribution of one or more sensing chemistry components, increased effective working electrode surface area, and/or reduced entry of interfering components into a sample chamber of the sensor. Methods of using and manufacturing the sensors are also provided.

Abstract: Provided is a method for measuring the concentration of a substance in a blood sample, comprising: supplying the blood sample to a biosensor comprising a hematocrit electrode for measuring a hematocrit value on the surface of which electrode an electrically conductive polymer is covalently immobilized; and calculating the concentration of the substance from the measured value of a first current resulting from application of a first voltage; and correcting the concentration of the substance with the value of a second current resulting from application of a second voltage or the hematocrit value calculated from the value of the second current.

Abstract: Embodiments of the present disclosure relate to stabilized lactate oxidase compositions, and electrodes, sensors and systems that include the same. Also provided are methods for making the compositions and for detecting and/or measuring lactate in vivo with stable lactate enzyme compositions.

Abstract: A machine for processing continuous glucose monitoring data and issuing an alert if hypoglycemia is imminent has three modules: (a) a pre-processing module that receives and modulates continuous glucose monitoring data by reducing noise and adjusting for missed data points and shifts due to calibration; (b) a core algorithm module that receives data from the pre-processing module and calculates a rate of change to make a hypoglycemia prediction, and determine if hypoglycemia is imminent; and (c) an alarm mode module that receives data from the core algorithm and issues an audio or visual alert or warning message or a negative feedback signal to an insulin delivery device if hypoglycemia is imminent.

Abstract: The present invention provides a method for determining radioactivity in an ion-sensitive field effect transistor array, the method comprising the steps of incubating the array with electron-sensitive silver-halide material and then incubating the array with a developer solution reducing the silver halides that have been exposed to radioactivity to elemental silver and simultaneously measuring pH at each separate reaction chambers, wherein decrease of the pH indicates the presence of radioactivity in a reaction chamber.

Abstract: A method of depositing reagent on an electrochemical test sensor adapted to determine information relating to an analyte includes providing a base and forming an electrode pattern on the base. The method further includes depositing the reagent on at least the electrode pattern using a reagent-dispensing system. The reagent-dispensing system applies mechanical force to the reagent in the reagent-dispensing system to assist in providing a wet reagent droplet on at least the electrode pattern.

Abstract: The present invention provides a sensor head for use in an implantable device that measures the concentration of an analyte in a biological fluid which includes: a non-conductive body; a working electrode, a reference electrode and a counter electrode, wherein the electrodes pass through the non-conductive body forming an electrochemically reactive surface at one location on the body and forming an electronic connection at another location on the body, further wherein the electrochemically reactive surface of the counter electrode is greater than the surface area of the working electrode; and a multi-region membrane affixed to the nonconductive body and covering the working electrode, reference electrode and counter electrode. In addition, the present invention provides an implantable device including at least one of the sensor heads of the invention and methods of monitoring glucose levels in a host utilizing the implantable device of the invention.

Abstract: A method of measuring a quantity of a substrate contained in sample liquid is provided. This method can reduce measurement errors caused by a biosensor. The biosensor includes at least a pair of electrodes on an insulating board and is inserted into a measuring device which includes a supporting section for supporting detachably the biosensor, plural connecting terminals to be coupled to the respective electrodes, and a driving power supply which applies a voltages to the respective electrodes via the connecting terminals. One of the electrodes of the biosensor is connected to the first and second connecting terminals of the measuring device only when the biosensor is inserted into the measuring device in a given direction and has a structure such that the electrode becomes conductive between the first and second connecting terminals due to a voltage application by the driving power supply.

Abstract: Generally, embodiments of the invention relate to self-powered analyte determining devices (e.g., electrochemical analyte monitoring systems) that include a working electrode, a counter electrode, and an optional resistance value, where the working electrode includes analyte sensing components and the self-powered analyte determining device spontaneously passes a current directly proportional to analyte concentration in the absence of an external power source. Also provided are systems and methods of using the, for example electrochemical, analyte sensors in analyte monitoring.

Abstract: A biosensor including light emitting elements and a light receiving element disposed on a principal surface of a wiring board; a light shielding portion disposed between a light-emitting-element sealing portion and a light-receiving-element sealing portion; a base medium having light transmitting properties, disposed in parallel with the wiring board with the light shielding portion therebetween; an adhesion layer having light transmitting properties that bonds the base medium with the light-emitting-element sealing portion, the light-receiving-element sealing portion, and the light shielding portion; and a first electrocardiograph electrode attached to a principal surface of the base medium. Both end portions of the adhesion layer and both end portions of the base medium are disposed such that they overlap neither of the light-receiving-element sealing portion nor the light-emitting-element sealing portion when viewed from a direction normal to the principal surface of the wiring board.

Abstract: Disclosed herein are systems and methods for a continuous analyte sensor, such as a continuous glucose sensor. One such system utilizes first and second working electrodes to measure additional analyte or non-analyte related signal. Such measurements may provide a background and/or sensitivity measurement(s) for use in processing sensor data and may be used to trigger events such as digital filtering of data or suspending display of data.

Abstract: A reader for communicating with both an eye-mountable device and a display device is provided. The reader can transmit radio frequency power to a tag that is part of the eye-mountable device. The reader can communicates with the tag using a first protocol. Communicating with the tag can include having the reader request data from the tag and receive the requested data from the tag. The reader can process the received data. The reader can store the processed data. The reader can communicates with the display device using a second protocol, where the first and second protocols can differ. Communicating with the display device can include having the reader transmit the stored data to the display device. The display device can receive the transmitted data, process the transmitted data, and generate one or more displays including the transmitted and/or processed data.

Abstract: A disposable electrochemical test sensor designed to facilitate sampling of fluid samples. It has a fluid chamber having a novel extra wide sampling entrance, but no additional air escape vent. The chamber provides a reservoir from which a sample fluid can be drawn into the chamber through capillary action. The sampling entrance provided can draw fluid into the chamber through any part of the opening, allowing easy targeting the samples with small volume, picking up smeared samples, and added tolerance to users who jam the tip of the sensor into users' finger. The sampling entrance also serves as air escape vent. Such one opening sensor alleviates over-flow issue often encountered in convenient sensors.

Abstract: A sensor utilizing a non-leachable or diffusible redox mediator is described. The sensor includes a sample chamber to hold a sample in electrolytic contact with a working electrode, and in at least some instances, the sensor also contains a non-leachable or a diffusible second electron transfer agent. The sensor and/or the methods used produce a sensor signal in response to the analyte that can be distinguished from a background signal caused by the mediator. The invention can be used to determine the concentration of a biomolecule, such as glucose or lactate, in a biological fluid, such as blood or serum, using techniques such as coulometry, amperometry, and potentiometry. An enzyme capable of catalyzing the electrooxidation or electroreduction of the biomolecule is typically provided as a second electron transfer agent.

Abstract: Electrochemical test cells are made with precision and accuracy by adhering an electrically resistive sheet having a bound opening to a first electrically conductive sheet. A notching opening is then punched through the electrically resistive sheet and the first electrically conductive sheet. The notching opening intersects the first bound opening in the electrically resistive sheet, and transforms the first bound opening into a notch in the electrically resistive sheet. A second electrically conductive sheet is punched to have a notching opening corresponding to that of first electrically conductive sheet, and this is adhered to the other side of the electrically resistive sheet such that the notching openings are aligned. This structure is cleaved from surrounding material to form an electrochemical cell that has a sample space for receiving a sample defined by the first and second conductive sheets and the notch in the electrically resistive sheet.

Abstract: A biosensor system for determining the concentration of an analyte in a sample includes a plurality of test sensors, and includes a container including a desiccant and the plurality of test sensors, sealed in the container. When the container is stored for two weeks at a temperature of 50° C., and each test sensor is subsequently removed from the container, connected through the at least two conductors to a measurement device and then contacted with one of a plurality of samples including an analyte, where the plurality of samples has analyte concentrations that span the range of 50 mg/dL-600 mg/dL, and the analyte concentration in each sample is determined by the test sensor and the measuring device, the bias of each determined analyte concentration may be within ±10 mg/dL or ±10%, and the coefficient of variation of the determined analyte concentrations may be at most 2.5%.

Abstract: A sensor utilizing a non-leachable or diffusible redox mediator is described. The sensor includes a sample chamber to hold a sample in electrolytic contact with a working electrode, and in at least some instances, the sensor also contains a non-leachable or a diffusible second electron transfer agent. The sensor and/or the methods used produce a sensor signal in response to the analyte that can be distinguished from a background signal caused by the mediator. The invention can be used to determine the concentration of a biomolecule, such as glucose or lactate, in a biological fluid, such as blood or serum, using techniques such as coulometry, amperometry, and potentiometry. An enzyme capable of catalyzing the electrooxidation or electroreduction of the biomolecule is typically provided as a second electron transfer agent.

Abstract: A biosensor includes a working electrode 101, a counter electrode 102 opposing the working electrode 101, a working electrode terminal 103 and a working electrode reference terminal 10 connected to the working electrode 101 by wires, and a counter electrode terminal 104 connected to the counter electrode 102 by a wire. By employing a structure with at least three electrodes, it is possible to assay a target substance without being influenced by the line resistance on the working electrode side.

Abstract: A biosensor includes a working electrode 101, a counter electrode 102 opposing the working electrode 101, a working electrode terminal 103 and a working electrode reference terminal 10 connected to the working electrode 101 by wires, and a counter electrode terminal 104 connected to the counter electrode 102 by a wire. By employing a structure with at least three electrodes, it is possible to assay a target substance without being influenced by the line resistance on the working electrode side.

Abstract: A biosensor includes a working electrode 101, a counter electrode 102 opposing the working electrode 101, a working electrode terminal 103 and a working electrode reference terminal 10 connected to the working electrode 101 by wires, and a counter electrode terminal 104 connected to the counter electrode 102 by a wire. By employing a structure with at least three electrodes, it is possible to assay a target substance without being influenced by the line resistance on the working electrode side.

Abstract: A biosensor includes a working electrode 101, a counter electrode 102 opposing the working electrode 101, a working electrode terminal 103 and a working electrode reference terminal 10 connected to the working electrode 101 by wires, and a counter electrode terminal 104 connected to the counter electrode 102 by a wire. By employing a structure with at least three electrodes, it is possible to assay a target substance without being influenced by the line resistance on the working electrode side.

Abstract: The present disclosure relates to an electrode strip, a sensor strip, a system thereof and a manufacturing method thereof. The sensor strip includes a first reactive film, a second reactive film and a vent hole. The first reactive film includes a substrate, a first electrode layer and a first insulation layer. The first end of the first insulation layer is concaved to a first depth to form a first reactive area. The second reactive film includes a second electrode layer and a second insulation layer. The first end of the second insulation layer is concaved to a second depth to form a second reactive area. The vent hole penetrates the second insulation layer, the second electrode layer and the first insulation layer so as to connect the first reactive area and the second reactive area.

Abstract: The present disclosure relates to an electrode strip, a sensor strip, a system thereof and a manufacturing method thereof. The sensor strip includes a first reactive film, a second reactive film and a vent hole. The first reactive film includes a substrate, a first electrode layer and a first insulation layer. The first end of the first insulation layer is concaved to a first depth to form a first reactive area. The second reactive film includes a second electrode layer and a second insulation layer. The first end of the second insulation layer is concaved to a second depth to form a second reactive area. The vent hole penetrates the second insulation layer, the second electrode layer and the first insulation layer so as to connect the first reactive area and the second reactive area.

Abstract: An auto-calibration system for diagnostic test strips is described for presenting data individually carried on each test strip readable by a diagnostic meter. The test strip meter may provide a predetermined varying resistance on one strip or a plurality of varying resistances from strip lot to strip lot.

Abstract: An eye-mountable device includes an electrochemical sensor embedded in a polymeric material configured for mounting to a surface of an eye. The electrochemical sensor includes a working electrode, a reference electrode, and a reagent that selectively reacts with an analyte to generate a sensor measurement related to a concentration of the analyte in a fluid to which the eye-mountable device is exposed. The working electrode can have at least one dimension less than 25 micrometers. The reference electrode can have an area at least five times greater than an area of the working electrode. A portion of the polymeric material can surround the working electrode and the reference electrode such that an electrical current conveyed between the working electrode and the reference electrode is passed through the at least partially surrounding portion of the transparent polymeric material.

Abstract: An analyte sensor for the continuous or semi-continuous monitoring of physiological parameters and a method for making the analyte sensor are disclosed. The analyte sensor includes a crosslinked, hydrophilic copolymer sensing layer in contact with a surface of an electrode, where the sensing layer includes methacrylate-derived backbone chains having covalent bonds to an analyte sensing component. The method includes combining the precursor components of the sensing layer, depositing the combined mixture on a surface of an electrode, and curing the deposited mixture.

Abstract: An analyte sensor for the continuous or semi-continuous monitoring of physiological parameters and a method for making the analyte sensor are disclosed. In one aspect, the analyte sensor includes an electrode, a sensing layer in contact with a surface of the electrode, and a protective membrane. The sensing layer is a crosslinked, hydrophilic copolymer including poly(alkylene oxide) and poly(vinyl pyridine), and an analyte sensing component is immobilized within the crosslinked, hydrophilic copolymer. The protective membrane is a crosslinked, hydrophilic copolymer including alkylene oxide, vinyl pyridine and styrene units. The method involves the formation of a sensing layer on a surface of an electrode, followed by the formation of a protective membrane on a surface of the sensing layer.

Abstract: An analyte sensor for the continuous or semi-continuous monitoring of physiological parameters and a method for making the analyte sensor are disclosed. In one aspect, the analyte sensor includes a crosslinked, hydrophilic copolymer in contact with a surface of an electrode, and an analyte sensing component embedded within the crosslinked, hydrophilic copolymer. The crosslinked, hydrophilic copolymer has methacrylate-derived backbone chains of first methacrylate-derived units, second methacrylate-derived units and third methacrylate-derived units. The first and second methacrylate-derived units have side chains that can be the same or different, and the third methacrylate-derived units in different backbone chains are connected by hydrophilic crosslinks.

Abstract: An eye-mountable device includes an electrochemical sensor embedded in a polymeric material configured for mounting to a surface of an eye. The electrochemical sensor includes a working electrode and a reference electrode that reacts with an analyte to generate a sensor measurement related to a concentration of the analyte in a fluid to which the eye-mountable device is exposed. An example assembly process includes: forming a sacrificial layer on a working substrate; forming a first layer of a bio-compatible material on the sacrificial layer; providing an electronics module on the first layer of the bio-compatible material, forming a second layer of the bio-compatible material to cover the electronics module; and annealing the first and second layers of the bio-compatible material together to form an encapsulated structure having the electronics module fully encapsulated by the bio-compatible material.

Abstract: An eye-mountable device includes an electrochemical sensor embedded in a polymeric material configured for mounting to a surface of an eye. The electrochemical sensor includes a working electrode, a reference electrode, and a reagent that selectively reacts with an analyte to generate a sensor measurement related to a concentration of the analyte in a fluid to which the eye-mountable device is exposed. The working electrode can have a first side edge and a second side edge. The reference electrode can be situated such that at least a portion of the first and second side edges of the working electrode are adjacent respective sections of the reference electrode.

Abstract: An eye-mountable device includes an electrochemical sensor embedded in a polymeric material configured for mounting to a surface of an eye. The electrochemical sensor includes a working electrode and a reference electrode that reacts with an analyte to generate a sensor measurement related to a concentration of the analyte in a fluid to which the eye-mountable device is exposed. An example assembly process includes: forming a sacrificial layer on a working substrate; forming a first layer of a bio-compatible material on the sacrificial layer; providing an electronics module on the first layer of the bio-compatible material, forming a second layer of the bio-compatible material to cover the electronics module; and annealing the first and second layers of the bio-compatible material together to form an encapsulated structure having the electronics module fully encapsulated by the bio-compatible material.

Abstract: The present invention relates to improved electrochemical biosensor strips and methods for determining the concentration of an analyte in a sample. By selectively measuring a measurable species residing in a diffusion barrier layer, to the substantial exclusion of the measurable species residing exterior to the diffusion barrier layer, measurement errors introduced by sample constituents, such as red blood cells, and manufacturing variances may be reduced.

Abstract: Disclosed herein is a device that functions as a glucose sensor. The device has a reference electrode; a counter electrode, a working electrode; an electrically conducting membrane; an enzyme layer; a semi-permeable membrane; a first layer of a first hydrogel in operative communication with the working electrode; the first layer of the first hydrogel being operative to store oxygen; wherein the amount of stored oxygen is proportional to the number of freeze-thaw cycles that the hydrogel is subjected to; and a second layer of the second hydrogel. Disclosed too is a method that comprises using periodically biased amperometry towards interrogation of implantable glucose sensors to improve both sensor's sensitivity and linearity while at the same time enable internal calibration against sensor drifts that originate from changes in either electrode activity or membrane permeability as a result of fouling, calcification and/or fibrosis.