JP5074193B2 - Disposable self-contained assay device for quantitative and qualitative measurements - Google Patents

Description

  The present invention relates to a disposable self-contained assay device for quantitative and qualitative measurement of a sample. The measurement result is stored in the device and collected for further analysis at a remote location. It relates to the field of assay devices that can.

  While recent achievements in microelectronic and biochemical sensor technology have created a considerable range of electronic devices for self-diagnosis in health care based on quantitative and / or qualitative measurements, patients When different body fluids can be used to perform a typical disease test, low-cost diagnostic tools are used to make primarily quantitative measurements. Considering the costs associated with testing a large number of potentially serious individuals in a population is generally not practical or cost effective to perform. As a very obvious example, mainly in the western world, the increase in type II diabetes places a very heavy burden on the health care system and, in addition, has a serious impact on the quality of life for affected individuals. Several different studies suggest that a few percent of the population in the average Western country is at risk with a high risk of progressing to diabetes at a later stage. If diabetes is detected early, it can prevent, or at least delay, the outbreak of the disease when appropriate measures are taken. However, because this is a “silence illness”, diabetes is often at a stage where the diagnosis is too late and no simple action can be taken to stop the progression of diabetes. At this stage, oral or subcutaneous administration of insulin is the only treatment, and the treatment is generally for life expectancy. Furthermore, since the disease has progressed for many years, it is common for another disease to occur.

  For patients diagnosed with type II diabetes on whom insulin treatment is given, continuous glucose level monitoring is essential to ensure that the insulin dose is adequate. In a hospital environment, glucose levels can be quantified very accurately by laboratory tests. However, this is not practical for daily dosing at home, because glucose levels need to be closely monitored. Currently, several devices are known in the market for performing quantitative measurements of glucose levels, which generally consist of electronic elements and disposable sensor strips that are discarded after use. Is. In order to obtain an accurate reading, it is necessary to provide calibration data for the sensor used and to perform an appropriate temperature calibration. In other words, this requires additional training and causes errors.

  However, in order to efficiently test a large number of individuals in a group, there are some practical concerns with the above method. In order to send a blood sample to a central laboratory, a special delivery service is required because the blood sample is considered a biohazard and is therefore generally not sent by mail. I will. Furthermore, very rigorous procedures must be followed to ensure that the samples are not lost or mistaken. Another option to retrieve large numbers of individuals to a central location would be quite expensive for a testing scenario. Timing is also an important factor, and some tests require a short time from when the sample is taken to when the analysis is performed.

  Commercially available electronic devices such as those described above are theoretically selectable, but with the necessary training, the associated logistics and capital costs make this option almost impractical to implement.

  Furthermore, it is generally known that the so-called “fasting glucose test” is most accurate because this test is performed as the first task in the morning. However, in real hospital facilities this is not practical at all to do.

  Similar practical problems have been shown in the diagnosis and monitoring of other diseases and / or medical imbalances such as blood cholesterol, blood hemoglobin and infections. Other than blood sampling tests, all other biological sampling tests such as saliva, urine, feces, semen and sweat share obvious logistics and practical problems from a diagnostic point of view.

  Adjacent problem ranges cover field laboratory inspections in a wide range of applications such as chemical analysis, soil analysis, and drinking water analysis in industrial plants. Common to all is that the sample is analyzed for at least one required characteristic and that the test is typically performed in a central laboratory.

  Given the specific use of such tests, field monitoring and diagnostics, there is an easy-to-use disposable self-contained assay device that can be mailed to a large number of individuals and the results returned for analysis. Would be desirable.

  European Patent No. 0972196 describes test means and recording means, which can be separated from the test means. The device is made from a durable material such as reinforced plastic. The recorded portion can be separated by perforation means or by releasing a nail, a latch, a lock or the like. The calibration section has a sample application recess in fluid communication with the conduit, which includes the material for collecting the sample and a ready-to-inspect indicator. This allows the user to determine when the sample has been properly assayed. The separable portion includes a recording device that is in data communication with the assay portion and is configured to store information related to the sample.

  Another disposable electronic assay device is described in EP 0722563. The disposable electronic assay device includes a card-like housing for a sample receiver, sample processing means for generating a signal that correlates with the amount of analyte being processed, and converting the electrical signal into a digital test result output value. And means for displaying the inspection result output value.

  The problems with the prior art are related to the design of the device that can be easily manufactured and can be easily delivered to the user, and the recorded data is collected for further analysis by the central unit. is there. The ability to inspect data that is cost effective and reliable provides significant advantages for the field of application and the diversity of geographic areas in which the inspection can be performed.

  From a quality assurance perspective, it is also important to register the time and temperature conditions of the event during the handling of the device.

  The present invention comprises a data input / sample collection part including a sensor for measuring physical or chemical properties of a foreign substance, and a data acquisition part including an electronic processing / storage means. These parts are an integral part of a package formed from a sheet-like printable and foldable material, which is designed to seal and protect the parts contained therein A disposable self-contained verification / diagnosis device is described. This package may contain various devices that need to be tested.

  For convenience, it is preferable to pack the sample as a kit to hold all the necessary parts together in a built-in package, where the package serves multiple purposes.

  The device can be mounted in a flat shape and can be folded into a self-contained package. This greatly simplifies the manufacturing process.

  This package can be further designed so that it can be discarded when a substantial portion of the package is not needed to hold the collected data after the measurements made. Furthermore, since the sensor is contaminated with chemical and / or biological substances, it is also preferable to remove this part and discard it. By designing the package to have one part that holds the data processing and storage means, the remainder of the package can be torn off and discarded after the measurement is complete. Thereafter, the portion for holding the data can be saved for further analysis. Information can be automatically exchanged with the host computer system when a communication interface is provided that can be remotely controlled.

  A common biosensor is an electrochemical (redox-type) thermodynamic system that relies on either potentiometric or amperometric response relationships or a combination thereof. The sensor response is usually highly temperature dependent. Therefore, one aspect of the present invention is to provide a temperature sensing means that can compensate the recorded response for temperature deviation. In addition, a temperature sensor can be used to alert the user that the temperature is too high or too low to perform an accurate measurement.

  In addition, the presence of a temperature sensor compensates that the assay device was not exposed to temperature extremes during storage and transport, as solidification and / or melting can invalidate the results from the biosensor. It can also be used.

  Depending on the chemistry of the sensor, in order to monitor humidity, it may be necessary to obtain additional measurements because moisture can affect the reliability of the reading. Thus, either a desiccant or a humidity sensor can be added to compensate for humidity fluctuations or to notify the disabled state when the influence of moisture is too great.

  Although the described embodiment represents a diagnostic device for quantitative measurement of blood glucose in a diabetes test, the same basic configuration can be used for other diagnostic applications. For health care applications, samples are often taken from blood, saliva, urine, sweat, mucus, pus, wound fluid, semen or feces, which are uncomfortable and potentially harmful. Also, there is a commonality that it is difficult to process from the viewpoint of logistics. This problem is solved by making a separable design so that the contaminated part is irreversibly separated from the data storage part.

  From an audit perspective, when all recorded events and data points are time stamped and there is an audit trail that is paired with a unique identity, the reliability of the collected data is increased and the final The result is more certain. Data integrity adds a digital signature to the result using data processing means that can be verified to ensure their authenticity when the data is transmitted from the verification device to a remote database This can be further enhanced.

  In some applications, additional information may need to be collected prior to storing the test results. By integrating electronic questionnaires, subjectivity, or other information from the device, such as disclosed in, for example, US Pat. No. 6,628,199, the user collects along with the converted objective data. And can be stored in electronic form.

  In addition, for some applications, there may be a legal and / or non-refusal view of the sample where only a person who has obtained detailed information or has been trained can perform the test, or There is concern that the inspection may be performed by someone other than the intended person. Such tests may include the monitoring or detection of illegal substances that may be doping or narcotic substances found in blood and / or urine tests. The design of a self-contained package with an integrated microprocessor and storage means allows for the integration of the keypad in the package, allowing inspection by a different route than is used to deliver the device itself. Prior to execution, the intended person can obtain detailed information with a secret code or identification code to implement a user identification and authorization plan. By taking into account an input such as a PIN input, a signature by the person performing the test can be used in place.

  However, generally speaking, the assay device may be designed with minimal user interaction to minimize costs, and in some applications, with the exception of the sensor itself, It can be assumed that no input means are provided. On the other hand, additional means, audio elements and additional visual indicators can be added to interact with the user and to synchronize the expected sequence of actions. When the test is for a non-clinical environment, there may be several on-chip diagnostics that inform the result of the test, such as “positive” or “negative”. A typical audible indicator may be a piezoelectric speaker, and a typical visual indicator may be either a light emitting diode (LED) or printed electronic chrome ink.

  However, it is fairly clear that the application area is not limited to a health care environment. Biochemical analyzes of drinking water, industrial samples, soil samples, foods, beverages, etc. can be performed by untrained personnel with a simple arrangement of “sample kits” that can be sent to the desired sampling location. it can. When the inspection is complete, the data carrier is torn off and returned to the inspection center for subsequent analysis with a printed and paid return envelope.

  FIG. 1 shows a verification device before shipment. The device and its package are designed to be self-contained and all parts protected by the package. The notch (101), coupled with the information character (103), can place the device in a typical store display. The package has a recess (102) that is broken prior to use.

  FIG. 2 shows the assay device prior to use. The device and its package were deployed by breaking the recessed area (102 in FIG. 1). The user is presented with a set of questionnaire panels (201) with embossed buttons (202) and a sample area (203). Additional items such as lancets and wipes 204 necessary to collect or prepare the sample are included, but these are preferably attached to the inside of the package by a pressure sensitive adhesive.

  FIG. 3 shows the assay device after sampling has been completed. The data acquisition part (301) is separated from the data input and sampling part (303), which can be discarded with additional supplies (204) as ordinary household waste. Since the sample area will be contaminated with blood, for example, when the test is complete, additional means such as an adhesive line that seals the data entry and sampling area are included prior to disposal. Also good. The recorded data is then returned to the central location for data collection. The part (301) can be sent by plain mail and can be provided with a printed address area (302) so that it can be posted to a post box.

  FIG. 4 shows the test device represented in a simplified exploded plan view. This apparatus includes a laminate composed of a lower sheet (401) and an upper sheet (409). The device is provided with two parts (301, 303), which are separated by a hinged recess area (414) and a notch area (413) and are easily separated by tearing. be able to. The data acquisition part (301) comprises an electronic module (403) having an electronic chip (404), a power source in the form of a battery (411), and connector means (412), said connector means comprising: There is a corresponding print connection point on the print sheet (401). This electronic means is connected to the lower sheet (401) with the printed antenna patch (402) using a conductive adhesive. The recording part (409) is provided with an embossed button (406) and a sensor (418), all connected to the electronic module (403) using conductive printed traces (405, 417). Yes. The button (406) is formed by a print switch point on the lower sheet and a print area on the upper pad (407), where the mechanical force applied to the button (406) causes the pads (407) to An electrical connection between them is created. The sensor (418) is printed with an enzyme material, where the connecting trace (417) acts as an electrode. The sensor (418) is exposed to the user through a notch (not shown) in the upper layer (409).

The electronic chip may be an ASIC having the following functions.
• Microprocessors that execute application programs • Non-volatile data memory for storing information • Real-time clocks for objectively stamping stored events and data • Linking specific devices to records in a database Factory-programmed unique identifier to enable: • On-chip temperature sensor for temperature compensation during data acquisition and for storage and transport of temperature monitoring • Signal for extracting data from said sensor Processing means and analog to digital converter means • A wireless telecommunications interface capable of reading this device through the packaging material, preferably meeting existing radio frequency identification (RFID) standards such as ISO15693. Or Cost savings for alternatives such as the capacitive system described in US Pat. No. 6,615,023 ・ Information to be encrypted and / or signed Cryptographic subsystem that can be sent from device to device

  For ease of manufacture, the device is manufactured in two parts. These two parts are then assembled into a final product.

  The first part with the electronic module (403) with ASIC (404), battery (411) and supporting components is assembled on a thin polymer film, for example a polyester film with etched copper. Yes. The film includes fine pitch conductors that extend to large pads (412) but can be attached to a substrate with conductors at a coarser pitch. The ASIC is attached with stud ridges or by conventional bonding to metal on the film.

  The second part is the actual package. This package is made using methods and equipment well known in the industry. Conductive ink traces (417, 405) are printed on a piece of polymer-coated cardboard, these traces forming a “disposable circuit board”, where the polymer coating is Used to minimize the effects of moisture in sensitive measurements. Although it depends on the requirements, it has been found that good results can be obtained with a conductive ink made of either carbon graphite or silver. The trace connects the sensor (418) and the pressure sensitive print key (406) to the substrate of the conductive pad (412) for connection to the electronic module (403). State-of-the-art methods are then used for additional printed graphics (103), cutting, embossing and creasing applications. A pressure sensitive thin film key (406), as described in US Pat. No. 6,628,199, is formed by applying a conductive ink area on opposite sides of a polymer coated cardboard, Then, it is made into a thin film by lamination. Preferably, the antennas (402, 410) used for communications that can be remotely controlled are also printed on the polymer coating. As a final step, the sensor (418) is applied using a thick film printing method of the sensor compound, where the conductive ink (417) also forms the sensor electrode. Alternatively, the sensor can be applied as a completed component of a third party. Such sensors are generally supplied as strips with connecting electrodes. In such a configuration, a conductive adhesive is printed over the conductive lines in the package.

The assembly of the device is accomplished by applying the first part with the electronic module using a conductive adhesive onto the second part of the paper substrate at the printed conductor pad substrate (412). Done. The product is then folded together and heat sealed using a printed or sprayed heat activated adhesive .

  Prior to placement, the electronic module needs to be initialized with the correct time source and optional calibration data for the sensor. Furthermore, depending on the type and chemistry of the sensor, a reference voltage calibration step may be required. In order to conserve battery power, the power consumption of the ASIC is very low when it is not initialized. Once the clock and calibration data are initialized, the product is ready for use. The required battery capacity should be calculated for the expected time zone from placement to use. On the other hand, this time is generally limited by the shelf life of the sensor compound. Some sensors may be sensitive to low and / or high environmental temperatures during storage. By utilizing a temperature sensor in the ASIC, the environmental temperature can be continuously monitored. If the temperature limit for the sensor is exceeded, the user will be warned that the device will not produce the expected results. Alternatively, appropriate adjustment and recalibration can be performed during conversion when the sensor has a known temperature profile and / or aging profile.

The usage scenario can be explained as follows.
1. The assay / diagnostic device kit is assembled at the central manufacturing site, containing all the necessary equipment and information needed to perform the desired test.
2. This device is supplied to the patient by ordinary mail service. The package is designed to withstand normal misuse and humidity fluctuations expected during transport and storage. In order to minimize waste and material consumption, the package is made as an integral part of this diagnostic device.
3. The user physically opens the encapsulating package by breaking the recessed area (102) in the package sealing design. When opened, the integrated electronic component detects the opening and switches the working mode to “active”. A time stamp is stored in the memory of the electronic module to maintain a record when the package seal is broken. When the kit is opened, the device performs a self-test and verifies that the device is not damaged and has not been subjected to temperature extremes during shipping and storage.
4). To clearly synchronize the desired measurement operation, the user presses a start button embossed into the package material. When this start button is pressed, the time stamp is stored in the memory of the electronic module. From the point of view of usefulness, instructions on how to perform the test are printed inside the kit. For this reason, the “Start” button is affixed with the label “Press this key when you have read and understood the instructions on how to perform the inspection.”
5. A reminder signal and / or visual indicator prompts the user to respond to a limited number of questions (201) related to the measurement being performed. The input is performed at the embossed button (202) and the response is recorded and stored in the electronic module's memory along with a time stamp.
6). Different alert signals and / or visual indicators prompt the user to expose the blood sample to the sensor (203, 418). An electronic module continuously monitors the sensor, and significant changes in physical properties indicate the presence of the sample at the sensor. Depending on the chemistry of the sample and sensor, the actual sampling by the electronic module is carried out for a predetermined time. For user convenience, the package includes a sterile lancet and a bactericidal cleaning swab.
7). When the sampling is complete, the user is alerted that the measurement is complete.
8). When the user of the device has additional comments or information that needs to be carried to the analysis location of the data carrier, that information is written to a writing pad in the data carrier portion. To avoid manual reading of all data carriers or additional optical scanning, and to obtain an objective time stamp for when that information was written, the writing pad is pressure sensitive. It is made to be. When the writing pad is affected by the pen pressure, this is recorded and time stamped by the data processing and storage means.
9. The user then selects a recessed area (41
3) tearing or cutting the package along with it, so that the data acquisition part (301) with its stored data and its enclosing and other part (303) that no longer need to collect and convert the sample Isolate.
10. A part that contains a contaminated sensor and is now useless (303
) Is disposed of as ordinary waste by the user of this device. The disposable parts are designed to hold used lancets and swabs so that they can be folded together and sealed prior to disposal.
11. The “data carrier” has a fee-paid stamp on one side (302) and a printed return address, so the user posts it to regular mail for return to the central data scanning facility.
12 At the central data scanning facility, the “data carrier” portion (301) is read by the RFID scanner and the result is transferred to the central database. By using the long-distance RFID method with a collision prevention function, a large number of data carriers can be scanned at high speed even when stored in a mail bag.
13. When the data reaches the central database, a server-based application decrypts the data and verifies the digital signature. The data may then require additional processing to convert it into useful results.
14 When additional information is entered as described in step 6 above, an automated scan detects that the information is present on the writing pad. Data carriers that have this information will then need manual reading and data entry.

  In the above usage scenario, only the recording and conversion of a single sample is shown, but the device can be placed prominently at multiple sensor locations to allow long-term testing. It will be clear. Furthermore, depending on the inspection requirements, it may be useful to monitor two or more foreign objects simultaneously. In such a setting, several sensors can be placed in a plane close to each other's proximity so that the sample is evenly distributed across all the individual sensors.

FIG. 1 shows the assembled assay device. FIG. 2 shows the deployed test device. FIG. 3 shows the separated data carrier part and sensor part of the assay device. FIG. 4 shows an exploded view of the package portion .

Claims (21)

A data input / sample collection part (303) including a sensor (418) for measuring the physical property or chemical property of a foreign substance, and a data acquisition part (301) including an electronic processing / storage means The data input / sample portion (303) and the data acquisition portion (301) are an integral part of a package formed from a sheet-like printable and foldable material, A disposable self-contained measuring device, characterized in that it is designed to seal and protect the components housed therein. The foldable material comprises a laminate comprising a lower sheet (401) and an upper sheet (409), and the electronic module (403) is applied and fixed on the flexible film (605), and is electrically conductive. trace is printed on the lower sheet (401), said lower sheet and the upper sheet, by a conductive adhesive layer (506) are joined together in the top of each other, characterized in that The apparatus of claim 1. Sensor (418) may, according to claim 2 together with are printed on the lower sheet (401) is connected to the electronic module is connected to the (403) conductive traces (417), characterized in that The device described in 1. Device according to claim 2 , characterized in that the sensor (418) is attached to the lower sheet (401) by means of a conductive adhesive layer.   The device is characterized by having multiple sensors that can perform several acquisitions in two or more single events, or can perform several measurements in a single acquisition The apparatus according to claim 3 or 4.   6. A device according to claim 2, 3, 4 or 5, characterized in that the lower sheet and the upper sheet (401, 409) are coated with a moisture barrier (502, 505).   Device according to claim 1, 2, 3, 4 or 6, characterized in that the data acquisition part (301) is removable from the data entry and sampling part (303).   8. The device of claim 7, wherein each removable portion is provided with a unique indicia so that it can be identified from a different device after it has been removed. The apparatus of claim 1, wherein the package is capable of containing additional items (204) that are necessary to perform measurements. Data acquisition portion (301) includes an electronic chip (404), a power supply (411) consists of an electronic module (403) that includes a data communication means for exchanging data (402, 410), said chip , A data acquisition means, a data processing means, a nonvolatile data storage means, and a time measurement means, and the time measurement means is used for attaching a time stamp to the generated data stored in the data storage means. 10. The device according to any one of claims 1 to 9, characterized in that   The electronic module (403) was connected to a corresponding print connector means for connecting the electronic module to a conductive print trace (417) connected to a sensor (418) in the data entry and sampling section (401). Device according to claim 10, characterized in that it comprises a connection point (412).   12. Device according to claim 10 or 11, characterized in that the electronic chip (404) has temperature measuring means for quantifying the temperature in the vicinity of the sensor (418). The temperature measuring means provides a quantified value of the environmental temperature value at the time the acquisition is taking place, and the temperature value is used as an operator in converting the temperature dependence of the measurement result. The apparatus according to claim 12, wherein: The temperature measuring means is used to monitor whether the allowable temperature limit of the device has exceeded the lifetime of the device from the time of manufacture until the end of the acquisition. Item 14. The device according to Item 12 or 13. Said time measuring means is initialized from the time source at the central facility and the time measuring means, the acquisition is maintained by the power supply (411) to the time of completion, then the power in order to conserve power ( 411) The apparatus of claim 10, wherein the apparatus is switched off. Electronic Module (403) A device according to claim 10 for interaction with the user of the device, audible means walk you include a variable vision means, it is characterized. Before asked viewing means is a printed form on the surface of the lower sheet using electronic chrome ink, according to claim 16. 11. The device according to claim 10, characterized in that it comprises a compartment for desiccant to remove moisture that may affect the reliability of the measurement by the sensor (418) . Data communication means (402, 410) for exchanging data is used for exchanging data between said data processing means and an external host computer for receiving data. The apparatus as described in any one of 10-18. 20. Package according to any one of the preceding claims, characterized in that the package comprises an additional part with a questionnaire panel (201) to which the user of this device can give an additional view. The device described. The data acquisition part (301) is a printed address area (302) that can be mailed or retrieved after the data entry and removal from the sampling part without any additional work by the user of the device. 21. The device according to claim 1, wherein the device is in the form of a card provided.