JP4531983B2 - Attribute compensation for analyte detection and / or continuous monitoring - Google Patents

Description

[0001]
This application is filed on US Provisional Application No. 60 / 099,733, filed September 10, 1998, US Provisional Application No. 60 / 140,283, filed June 18, 1999, and June 18, 1999. Claim priority to filed US Provisional Application No. 60 / 140,285.
[0002]
BACKGROUND OF THE INVENTION The present invention relates to a system and method for compensating the value of an analyte evaluation value from a small amount of biological fluid collected from a subject's tissue using conditions during collection and verification or measurement. .
[0003]
Current specimen evaluation devices have the disadvantage of inaccuracies that are the result of various confusing conditions at the collection site. For example, a blood glucose meter adjusts calibration measurements for ambient temperature conditions associated with a test strip of glucose when the glucose test strip is inserted into the glucose meter.
[0004]
When trying to reduce the amount of biofluid collected or the time required for the calibration, the conditions further hinder accurate calibration measurements. These conditions include but are not limited to humidity, temperature, ambient light, pressure, and the like. This is especially true for systems that measure glucose concentration from blood or interstitial fluid collected with a collection device located at or near the tissue surface, for example. Attribute compensation is even more important in systems that continuously monitor analytes from collection devices that remain in contact with tissue for hours, days or weeks. By using appropriate sensors, these conditions can be monitored and compensated for these conditions in the desired assay measurement.
[0005]
SUMMARY OF THE INVENTION In accordance with the present invention, at least one sensor is provided for measuring an attribute associated with a biofluidic assay for a biofluid collection operation of the device or one or more analytes by the device. Various attributes or conditions within the biofluid collection site or the biofluid processing portion within the device can affect the accuracy of the assay or other operating parameters of the device. The type of sensor used is based on the conditions being measured. The operating parameters of the sampling device are compensated (ie adjusted) based on the sensed attributes. Examples of attributes include conditions that affect tissue temperature, pH, and biofluid productivity.
[0006]
The present invention provides a system for once measuring an analyte in a biological fluid of a subject obtained from a collection device placed in contact with a tissue, and continuously monitoring a specimen of a subject obtained from such a collection device. Useful in the system. Thus, analytes in a subject's biological fluid are considered to be periodically and frequently repeatedly assayed by the system and method of the present invention.
[0007]
The above and other objects and advantages of the present invention will become more readily apparent by reference to the following description taken in conjunction with the accompanying drawings.
[0008]
Definitions As used herein, “a” or “an” means one or more than one. For example, “an analyte” means one analyte or more than one analyte.
As used in this document, the term “biological membrane” refers to a structure that separates one area of an organism, such as a capillary wall, from another area of the organism, or the skin, buccal mucosa or other mucosa. It means the outer layer of this organism that separates it from its external environment. As used in this document, the term “epithelial tissue” shall mean the inner layers of the skin, mucous membranes and body cavities of an organism.
[0009]
As used in this document, the term “tissue” means a particular type of cell that forms a structural material, as well as a collection of its intercellular material. In order for one embodiment of the present invention to be implemented, it is desirable, but not necessarily, that at least one surface of the tissue be capable of receiving electromagnetic radiation. The preferred tissue is skin. Other tissues suitable for use in the present invention include mucosal tissue and soft organs.
As used in this document, the terms “suction” or “pressure” refer to the relative pressure when compared to the internal pressure of the organism to which the system is bounded. “Vacuum” is used synonymously with “suction”.
[0010]
As used in this document, the term “biological fluid” refers to serum, whole blood, interstitial fluid, lymph fluid, spinal fluid, plasma, cerebrospinal fluid, urine, prostate fluid, bile, pancreatic secretions. Or a combination of these biofluids. Other body fluids that can be collected from the surface of various tissues include biological fluids selected from the group consisting of mucus, saliva, breast milk, tears, stomach secretions and sweat. “Interstitial fluid” means a transparent fluid that occupies the space between cells in the body. It is considered that the biological fluid can be collected from the tissue surface of other organs, particularly during the surgical procedure.
[0011]
As used in this document, “poration”, “microporation” or similar terms are used within a biofilm for a selected purpose or for a particular medical or surgical procedure. In order to reduce the barrier properties of the biofilm against the passage of biological fluids such as analytes from the body or the penetration of permeates or drugs from outside the biofilm into the body, the biofilm, such as the skin or mucous membranes or the outer layer of the organism, to the desired depth or Means that a small hole, opening or hole is artificially formed. The size of the holes or “micropores” formed as described above is about 1-1000 μm in diameter. Although the term “micropore” is used in the singular for simplicity, it should be understood that multiple openings or holes can be formed by an integrated device according to the present invention.
[0012]
As used in this document, “artificial opening” means a physical rupture of a biofilm of a size suitable for sending or extracting fluid through it, including micropores.
As used in this document, a “harvesting device” is placed in contact with tissue to collect a sample of biological fluid from the tissue and analyze it to determine the characteristics of the biological fluid. Means a device suitable for Sampling devices are designed for single use, i.e. for discrete use, or in contact with tissue for longer periods of time, e.g. hours, days or weeks, periodic, continuous or continuous specimen monitoring. Can be designed to be deployed. The harvesting device can optionally be fitted with a piercing element (defined below).
[0013]
The term “porating element” forms the micropores, holes or openings described above, including by thermal ablation, mechanical rupture of tissue with a lancet or needle and other known techniques Including any means for An example of a mechanical perforation element is disclosed in published PCT application WO9800193 "Several microperforations of skin or mucosa". Another drilling technique suitable for use in connection with this system is PCT Application No. PCT / US99 / 15967, filed July 14, 1999, “Controlling Biofilms by Spark Charge for Transmembrane Transport. Removed ".
[0014]
When used in connection with an analyte monitoring system, the term “continuously” or “continuously” continues with a frequency or rate that varies depending on the particular application of the system. Means to work. For example, the sensor output can be read periodically, such as every minute, every few minutes, every hour, every few hours, and so on. Further, for each reading, the sensor output is optionally sampled multiple times to obtain multiple readings relatively densely in time to determine the final reading to be displayed or recorded. The readings are averaged or otherwise adjusted.
[0015]
As used in this document, an “analyte” is a chemical or biological substance or compound suitable for passing through a biofilm by the techniques described in the present invention or by techniques known in the art Means a substance or compound that is the subject for which you want to know the concentration or activity in an individual's body. Glucose is a good example of a specimen because glucose is a sugar that is suitable for passage through the skin, for example, those who suffer from diabetes may want to know their blood glucose levels. Other examples of analytes include, but are not limited to, compounds such as sodium, potassium, bilirubin, urea, ammonia, calcium, lead, iron, lithium, salicylate.
[0016]
An “attribute” is a physical condition at a collection site, an assay site, or other physical condition related to the operation of the collection device. An example of an attribute is temperature. Other attributes or conditions that are useful to measure are humidity, ambient light, pressure, vacuum, tissue stiffness, tissue thickness, tissue moisture, oxygen, pH, and the like.
[0017]
FIG. 1 shows one embodiment of a system that includes a collection device 10 and a calibration meter 70. The collection device 10 collects a biological fluid sample from a tissue such as skin. The biological fluid is collected through the opening 20 in the skin contact surface 12. The harvesting device 10 can incorporate tissue penetration or perforation means such as thermal ablation (optical or electrical heating) as disclosed in Lancet, US Pat. No. 5,885,211. For variations of the harvesting device that include any on-board tissue penetrating or perforating elements, see PCT Application No. PCT / US99 / 16378 filed July 20, 1999, PCT filed March 5, 1999. / US99 / 04990 and PCT / US99 / 04983 filed March 5, 1999.
[0018]
The collected biofluid is moved, for example, by a vacuum applied to the opening 20 and / or by capillary action, such that the biofluid flows in, across or over the analyte detection strip or sensor 50. Analyte sensor 50 is coupled to calibration meter 70 by optical or electrical link 60. One or more sensors 40 are placed on the collection device 10 to measure the condition of the collection site when the biological fluid is collected. Sensor 40 is coupled to the calibration meter by an electrical or optical link 30.
[0019]
The type of sensor depends on the type of attribute or condition being measured. As described above, attributes can be temperature, humidity, ambient light, pressure, vacuum, tissue conditions that indicate biofluid productivity (tissue firmness, tissue thickness, and / or tissue moisture), etc., or combinations thereof. is there. Measurement points also depend on the type of attribute or condition being measured. Proximity to the assay is important to measure all environmental dependencies of the assay, except for those common to the measurement environment such as humidity, pressure, and vacuum. For example, in one embodiment, a hose is provided for applying a suction force or vacuum to the collection device to aspirate biological fluid from the tissue into the collection device and onto the analytical sensor. This hose provides a mechanism for measuring environmental parameters along the hose that match the calibration environment, such as humidity, pressure and vacuum level. Environmental dependencies to be measured near the assay include ambient light, pH and temperature. In order to correct the assay temperature dependence, the temperature measurement point must be as close as possible to the assay within the same housing material but usually without touching the specimen. Since the pH of the measured body fluid can be used to compensate for the effect of pH on the assay and can vary with the assay process, the pH should be measured in the sample immediately before the assay in the flow path .
[0020]
Tissue characteristics such as firmness, thickness and moisture must be measured near the same tissue sampling site. For example, if the specimen collection site is on the forearm central palm side, tissue characteristics must be measured on the forearm central palm side close to this site. Variations in characteristics were measured between the lower forearm central palm side and the upper forearm palm side.
[0021]
Temperature is particularly important when the collection device 10 is part of a discrete or continuous glucose monitoring system. For example, the temperature sensitive attribute sensor 40 is preferably located as close as possible to the analyte sensor (even if not above) so that the effects of temperature variations on the analyte sensor can be minimized. . Many types of temperature sensors suitable for use in connection with the present invention are known in the art. Commonly used sensors include forward biased semiconductor diodes, thermistors, thermocouples, resistance temperature and temperature detectors (RTDs), radiation thermometers, fiber optic sensors, bead thermocouples and solid state sensors. As an example, a thermistor is used because its temperature characteristics are known, readily available, and low cost. The response time of the temperature sensor should be less than 10 seconds per degree Celsius so that the measured temperature can track changes in the assay with minimal noise.
[0022]
With reference to FIGS. 2 and 3, an embodiment of a sensor head 500 of the harvesting device 10 is shown in which one or more attribute sensors are arranged. The analyte sensor 50 is, for example, a “primary” sensor of glucose in this application, and in this configuration, the pH or oxygen content can also be measured through the working electrode, reference electrode, etc. 51. The attribute sensor 40 (1) is a thermistor disposed near the analyte sensor 50 in order to measure temperature. The attribute sensor 40 (2) is a photosensor source pair for indicating the outline of the boundary in the tissue to which the device 10 is attached, such as skin. The attribute sensor 40 (3) mainly measures ambient light in the ultraviolet (UV) range where harm to the assay sensor 50 is commonly seen. The attribute sensor 40 (4) is a microdurometer for measuring skin conditions or properties including firmness / stiffness related to tissue moisture.
[0023]
The condition of tissue such as skin is beneficial because it indicates the degree of biofluid productivity of the tissue. Dry and hard skin produces less fluid than softer skin. If the output of the micro-durometer indicates that the tissue thickness, hardness and / or dryness is above normal, the harvesting device 10 is used to ensure that a sufficient amount of biological fluid is extracted. The amount of suction force applied to the is increased. Conversely, if the microdurometer output indicates that the skin is relatively soft, the vacuum level can be maintained or lowered. This is particularly beneficial in a continuous monitoring system where biofluid is continuously collected from a collection device located at or around the same collection site of tissue.
[0024]
As shown in FIG. 3, the sensor head 500 is attached to the calibration meter 70 (FIG. 1) by a conduit cord 510 that carries vacuum and electrical signals. The attribute sensor 40 (5) is attached to a meter body that measures the pressure and / or vacuum and humidity of the hose inside the conduit cord 510 that sends a vacuum to the sensor head 500.
[0025]
Referring to FIG. 4, in the calibration meter 70 or as a separate component, the attribute signal of the attribute sensor 40 is connected to a compensation element 110 that determines the appropriate compensation based on the attribute signal from the attribute sensor 40. Compensation element 110 generates appropriate compensation that is output to processor 80, such as a microprocessor or other computational element. The sample sensor 50 generates a measurement signal based on the type of sample to be measured. The measurement signal is connected to a calibration element 90 inside the calibration meter 70. The assay element 90 performs a traditional assay of the specimen, generates a signal that matches this value, and outputs this signal to the processor 80. The processor 80 generates a corrected test value based on the compensation signal from the compensation element 110 and the test signal from the test element 90, and sends a signal matching this value to the output means 100 such as a display, a monitoring device or a signal processing device. Output.
[0026]
The type of compensation for the measurements made by the calibration element 90 depends on the conditions sensed at the collection site. The applied compensation can be linear or non-linear with respect to the confounding condition, or it can utilize neural network or fuzzy logic. Instead, the correction can be done using a look-up table or equation based algorithm. For example, pH affects the efficiency of an assay sensor based on glucose oxidase for glucose measurement. As the pH changes, a correction value obtained from a lookup table is applied to the test results to compensate for this variation. The humidity measurement is used in a discrete sampling system where after the sample is calibrated, it is disposed of by the system before the next sample is collected. The humidity measurement is also useful in this case for determining whether a sample has been collected, and the humidity difference is used to quantify the concentration change of the analyte to be measured.
[0027]
Humidity measurements are also useful for quantifying transepidermal water loss (TEWL). The effect of temperature on the efficiency of an assay based on glucose oxidase is measured and used to generate a look-up table or formula to compensate the assay results for temperature variations. As explained above, tissue firmness and thickness measurements are useful for estimating the vacuum level required to maintain sufficient sample flow for proper assay function. As the tissue at the test site is hydrated, the tissue becomes thicker and softened, reducing the amount of vacuum required to obtain the same amount of sample flux.
[0028]
As an example, FIG. 5 shows a graph representing a measurement compensation process that uses the temperature measured with a thermistor to compensate for glucose measurements. The upper graph in FIG. 5 shows the conversion from the output of the temperature sensor to the temperature value. The lower graph of FIG. 5 shows the compensation factor for a given temperature value derived from the data of the upper graph of FIG. The compensation factor is applied (added or subtracted) to the glucose measurement to improve the accuracy of the glucose measurement. In actual implementation, the transformation process can be implemented in a variety of ways, including a data lookup table representing the graph shown in FIG. It should be noted that each attribute has a compensation process similar to the process represented by the graph of FIG. 5, but the data is different. Similarly, a multi-dimensional lookup table can be used to efficiently map the output of a multi-attribute sensor to a single calibration compensation factor.
[0029]
FIG. 6 shows the steps involved in the process according to the invention. In the first step 200, a biological fluid is collected for the assay. Step 240 requires obtaining conditional measurements (ie, attributes) related to the calibration, such as temperature and humidity. This step may be before, during or after step 200. Step 280 determines a test compensation value from the measured conditions. Step 220 performs a traditional assay for analyte concentration from the biological fluid collected in step 200. Step 260 calculates a corrected test value by modifying the test value determined in step 220 using the compensation factor or adjustment factor determined in step 280. Finally, step 300 outputs the corrected assay value for subsequent use, such as a display or processing device.
[0030]
A specific example of the process of FIG. 6 relates to a glucose assay. Blood and interstitial fluid are collected through the micropores at the collection site in step 200. In step 240, the temperature of the analyte sensor 50 is measured. Step 220 calibrates the collected interstitial fluid for glucose levels using traditional assay techniques. A compensation factor for a test based on attributes such as temperature is determined in step 280. A compensated test value is calculated from the traditional test value obtained from step 220 and the compensation value obtained from step 260. The compensated glucose concentration value is output at step 300.
[0031]
In a continuous sample monitoring system as disclosed in PCT Application No. PCT / US99 / 16378 filed on July 20, 1999, also compensate for variations in attributes in the collection site, collection device or particularly the sample sensor. Is desirable. The process shown in FIG. 6 is continuously repeated. For example, attributes are measured continuously, and for each calibration or measurement from the analyte sensor, the attribute signal from one or more attribute sensors is used to compensate the measurement signal obtained from the analyte sensor.
[0032]
Turning to FIG. 7, another embodiment of the present invention is shown. In this embodiment, the processor 400 performs all the calculations necessary to derive a value from the analyte sensor 50 that is compensated for one or more attributes obtained from the one or more attribute sensors 40. . For example, the processor 400 may be a microprocessor or other programmable processing device that executes the calibration program 410 to derive a calibration value that is compensated for one or more attributes by using the compensation program or data 420. It is. The processor 400 reads the measurement signal from the analyte sensor 50 and one or more attribute signals from the attribute sensor and executes the calibration program 410 along with the compensation program 420 to obtain a measurement value. The compensation program 420 can be a mathematical algorithm or one or more lookup tables (for each attribute) described above in connection with FIG. This can be discrete or continuous depending on the type of environment in which the system is used. The value generated by processor 400 can be coupled to display 430. User interaction with the processor can occur through the keypad 440. The system shown in FIG. 7 may further include a memory for storing the value of the attribute signal, particularly in a continuous monitoring system. It is desirable to keep an archive of information here.
[0033]
In summary, the present invention relates to a system for detecting and measuring an analyte in an animal biofluid, which is placed on the surface of an animal tissue and collects the biofluid therefrom. A sampling device comprising an analyte sensor that is arranged in contact with the collected biological fluid and generates a measurement signal representing the sample, and measures an attribute associated with the operation of the sampling device and generates an attribute signal representing the attribute 1 One or more attribute sensors, a processor coupled to the attribute sensor and the analyte sensor to receive the attribute signal and the measurement signal, wherein the processor adjusts an operating parameter of the collection device based on the attribute signal.
[0034]
Furthermore, the present invention relates to a method for detecting and measuring a specimen in a biological fluid of a subject, the method collecting a biological fluid from an animal tissue surface using a collection device, and a specimen sensor. Contacting a biological fluid on a tissue surface; detecting an analyte in the biological fluid using an analyte sensor; sensing an attribute associated with the operation of the collection device; and adjusting an operating parameter of the collection device based on the attribute Including steps.
[0035]
Furthermore, the present invention relates to a device suitable for placing on a tissue surface of an animal and collecting a biological fluid therefrom, the device being arranged to contact the collected biological fluid and representing a measurement signal. And at least one attribute sensor for measuring an attribute related to the operation of the collection device and generating an attribute signal representing the attribute.
[0036]
The above description is intended for purposes of illustration and is not intended to limit the invention except as defined in the appended claims.
[Brief description of the drawings]
FIG. 1 is a block diagram illustrating a system according to one embodiment of the present invention.
FIG. 2 is a diagram of a sensor head showing the position of an attribute sensor according to the present invention.
FIG. 3 is a diagram illustrating the use of a vacuum / pressure sensor according to the present invention.
FIG. 4 is a block diagram of the components of a calibration meter that forms part of the system of FIG.
FIG. 5 is a diagram illustrating the use of a compensation data graph to compensate a calibration measurement for temperature.
FIG. 6 is a diagram representing the steps carried out by the process according to the invention.
FIG. 7 is a block diagram of a system according to another embodiment of the present invention.

Claims (14)

A system for detecting and measuring an analyte in a biological fluid of an animal,
A collection device comprising a sample sensor that is arranged on the surface of an animal tissue and is suitable for collecting a biological fluid therefrom, and arranged to contact the collected biological fluid to generate a measurement signal representing the sample;
At least one attribute sensor that measures an attribute associated with the operation of the sampling device and generates an attribute signal representative of the attribute;
A processor coupled to the attribute sensor and the analyte sensor to receive the attribute signal and the measurement signal, wherein the processor adjusts an operating parameter of the sampling device based on the attribute signal;
Equipped with,
A system in which the attribute sensor detects a condition of a tissue exhibiting biofluid productivity, and the processor generates a signal that controls the amount of suction force applied to the collection device based on the attribute signal .   The attribute sensor measures an operational parameter of the analyte sensor, and the processor generates an output signal indicating a measured value of the analyte in the biological fluid that is compensated for the attribute measured by the attribute sensor. The described system.   The system of claim 2, wherein the attribute sensor comprises a temperature sensor coupled to the analyte sensor to measure the temperature of the analyte sensor.   The system of claim 2, wherein the attribute sensor continuously measures attributes.   The system of claim 2, wherein the processor continuously reads the attribute signal and the measurement signal and continuously generates an output signal.   The system of claim 2, further comprising a display coupled to the processor for displaying a value of the output signal generated by the processor.   The system of claim 1, wherein the analyte sensor is a glucose sensor. A method for detecting and measuring a specimen in a biological fluid of a subject,
Collecting a biological fluid from an animal tissue surface using a collection device;
Contacting an analyte sensor with a biological fluid on the tissue surface;
Detecting the analyte in the biological fluid using the analyte sensor;
Sensing attributes associated with operation of the harvesting device; and
Adjusting operating parameters of the sampling device based on the attributes;
Equipped with,
The attribute sensing step includes sensing tissue conditions indicative of biofluid productivity, and in the method, the adjusting step is applied to the collection device to draw biofluid from the tissue into contact with the analyte sensor. A method comprising adjusting the suction force produced .   9. The method of claim 8, comprising calculating a measured value of an analyte in the biological fluid based on a signal from the analyte sensor, wherein the adjusting step further includes adjusting a calculated measured value based on the attribute. the method of.   The method of claim 9, wherein the attribute sensing step includes sensing a temperature of the analyte sensor.   The collecting step includes continuous collection of biological fluid from a tissue surface, the step of detecting a specimen in the biological fluid of the subject includes continuous detection of the specimen, and the attribute sensing step is performed on the specimen sensor. 9. The method of claim 8, comprising continuous sensing of adjacent attributes, and wherein the adjusting step comprises continuous adjustment of operating parameters of the sampling device. A device suitable for collecting biological fluid from an animal tissue surface,
An analyte sensor disposed in contact with the collected biological fluid to generate a measurement signal representative of the analyte analyte; and
At least one attribute sensor that measures an attribute associated with the operation of the sampling device and generates an attribute signal representative of the attribute;
Equipped with,
An apparatus wherein the attribute sensor detects a condition of a tissue exhibiting biological fluid productivity .   The apparatus of claim 12, wherein the attribute sensor measures an operating parameter of the analyte sensor.   The apparatus of claim 13, wherein the attribute sensor is a temperature sensor disposed on the analyte sensor to measure the temperature of the analyte sensor.

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