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    • 专利摘要:
    Ion sensor based on differential measurement, manufacturing method and measurement method. An ion sensor and its manufacturing method comprising a first and a second ion-selective field effect transistor, an electrode, a substrate on whose surface the two transistors are integrated, a connection tracks and the electrode and a structure adhered on the first transistor that creates a micro deposit, filled with a reference solution, with a microchannel that connects with the outside, as well as a measurement method, which allows to extend the useful life of said sensor, and that while it is not being used, it is immersed in a container filled with the reference solution, which allows to extend the useful life of said sensor. The most common application of this sensor is the measurement of ions. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2542927A2
    申请号:ES201430180
    申请日:2014-02-11
    公开日:2015-08-12
    发明作者:Antoni BALDI COLL；Carlos Domínguez Horna；Cecilia JIMÉNEZ JORQUERA；Cesar FERNÁNDEZ SÁNCHEZ；Andreu Llobera Adan；Angel Merlos Domingo；Alfredo CADARSO BUSTO；Isabel BURDALLO BAUTISTA；Ferran VERA GRAS
    申请人:Consejo Superior de Investigaciones Cientificas CSIC；
    IPC主号:
    专利说明:

    OBJECT OF THE INVENTION
    The present invention relates to an ion sensor based on differential measurement and the manufacturing method thereof. Said sensor measures the concentration of 10 certain ions of a solution by means of ISFET transistors (transistor with a selective field effect to ions) and compares said measurement with that of a reference solution stored in a microdeposit, said measurement being carried out by means of a transistor. ISFET whose door remains in contact with said reference solution, also called a REFET transistor (field effect transistor that does not respond to ion concentration),
    15 and therefore presents a null response to the ions to be measured.
    The technical field in which the present invention is framed is that of the physical technology sector and its most common application is for the measurement of ions, for example of pH (concentration of hydrogen ions in a solution), in various sectors such as
    20 food and biomedicine.
    BACKGROUND OF THE INVENTION
    In the current state of the art, the measurement of concentrations of various ions of a
    25 medium has been carried out in many different ways. One of the most widely used techniques is through the use of test strips. These test strips are strips of paper with different zones that are colored in contact with aqueous solutions, taking different colors depending on the concentration of specific ions of the measurement solution. To identify the concentration of the ions in the solution, after wetting the strip with
    30 the same, the user must compare the colors obtained with those of a table provided by the manufacturer. The result of this measurement technique depends very much on the correct manipulation by the user and on factors such as: the presence of proteins in the sample, the reaction time of the strip with the sample, or the homogeneity of the sample. An incorrect manipulation generates many false results (positive and
    35 negatives). In addition, the resolution of this technique is generally considered to be 0.5 units, for the specific case of the pH measurement, which lacks sufficient value
    diagnosis to make clinical decisions in some biomedical applications such as in Urolithiasis (Kwong T. et al. "Accuracy of urine pH testing in a regional metabolic renal clinic: is the dipstick enough Urolithiasis 2013).
    The standard measurement technique for ion concentration is Atomic Absorption. However, this technique requires a complex installation and its miniaturization is not feasible.
    Ion Selective Electrodes (ISEs) are used for simpler measurements in terms of equipment and are less expensive. These electrodes consist of a selective membrane so that through the exchange or interaction of the ions of the solution with the membrane, the activity of the Ion is converted into an electrical potential. The selective membrane can be of various types, glass, crystalline or based on ion exchange compounds. The latter consist of a pOlimer (for example, polyvinyl chloride, PVC) that immobilizes the ion selective compound. The measurement of the electrical potential of the ISEs requires the use of a reference electrode, which is often integrated into the same body of the ISE (combined electrodes). The reference electrode is generally a metallic electrode immersed in a reference solution which in turn is connected to the solution to be measured through a liquid joint. The main characteristic of the reference electrode is that its potential, that is, the potential between the inside of the metal and the sine of the solution in which it is submerged, does not depend on the composition of said solution. Reference electrodes usually have losses of reference solution through the liquid junction, so they need periodic refilling.
    To obtain precise measurements, these electrodes require a previous calibration consisting of the measurement of the potential generated when the electrode is immersed in a solution of known ionic concentration. These electrodes are part of an instrument, which in the case of pH is known as a pH meter, which is not cheap to manufacture, nor portable, nor autonomous, and requires specific maintenance and cleaning conditions for its proper maintenance. The result of this measurement technique also depends on the correct manipulation by the user (which must be properly trained for this purpose). Incorrect handling or preservation of the electrodes can generate false results.
    Another type of sensors used for this class of measurements is the ISFET (ion selective field effect transistor) sensors. These are devices manufactured using microelectronic technology. The solution potential (which is the gate potential of the transistor) is controlled by a reference electrode such as those used for measurement with ISE type electrodes. The ISFET is a field effect transistor whose threshold voltage varies with the ion concentration of the solution that is in contact with its gate dielectric. For many types of dielectrics (Si02, Si3N4, A1203, Ta205, Zr02), the ISFET threshold voltage variation depends mainly on the W ion, and is therefore used as a pH sensor. To make sensors of other ions based on the ISFET an additional layer called selective membrane is deposited on the door dielectric layer as described in US5250168. Depending on the deposited membrane, the ISFET will function as a sensor for some specific ions or others. The measurement with these sensors consists in recording the threshold voltage changes of the field effect transistor, which are proportional to the changes in the ion concentration that are to be measured. One way to measure the ISFET threshold voltage changes is by means of a circuit that polarizes the device with a constant drain current and a constant source drain voltage. In this way, the changes in the door voltage applied by the circuit to maintain said polarization are equal to the changes in threshold voltage suffered by the ISFET. Therefore, the gate voltage applied by the circuit is taken as the output signal.
    Both ISE electrode-based and ISFET-based measurement systems require a reference electrode to be able to measure ions. This makes them expensive and requires periodic maintenance. In 1978 a solution for pH measurement was described with ISFET-type devices without reference electrode (PA Comte and J. Janata, "A field effect transistor as a solid-state reference electrode", Analytica Chimica Acta) consisting of the differential measurement of an ISFET and a REFET. In this case the REFET is constituted by an ISFET whose door is kept exposed to a constant pH. The differential measurement consists in measuring the changes in threshold voltage of both devices using a single electrode immersed in the solution as a gate terminal and obtaining the response as a subtraction of the two values obtained. The REFET door is kept exposed at a constant pH by incorporating a microdeposit filled with reference solution (internal solution). Said microdeposit is connected to the outside by means of a microchannel that acts as a liquid junction, so that the potential difference between the external and the reference solution is small and is little influenced by the pH or the concentration of other ions in the solution Exterior. In this way, the potential changes that occur between the electrode and the solution are transferred to both threshold voltage values, and therefore have no impact on the differential value (they are canceled in the subtraction operation). For this reason, this differential measurement system can be implemented with any conductive electrode, without the need for reference. Since the REFET is exposed to a constant pH solution, the variation in the differential value will be equivalent to the ISFET response to the pH change. However, the way to manufacture the REFET described by Compte and Janata is difficult to automate, and therefore would not allow the sensors to be manufactured at a much lower cost than the ISFETs with reference electrode, which would not allow their price to be affordable to the general public. In addition to the design of the ISFET-REFET sensor described by Compte and Janata, the REFET microdeposit is constructed with an epoxy resin. This microdeposit, once the resin has cured, is filled with an agarose gel prepared in buffer solution. Subsequently, a vitreous capillary, which acts as a microchannel, is introduced into the agarose gel and the microdeposit is sealed with a layer of epoxy resin. Thus, if the sensor is stored dry, the microdeposition buffer solution evaporates slowly through the microchannel, being replaced by air. The presence of air inside the microdeposit prevents it from functioning properly when it is used again after a prolonged time of immersion in aqueous solution. This is due to the fact that the filling with water, as well as the necessary diffusion of the air trapped outside, is done only through the microchannel, which is not filled with hydrogel. In addition, the life time of this type of sensor depends on the volume of the microdeposit and the dimensions of the microchannel that connects it with the outside, since the reference solution in the microdeposit will be diluted and contaminating through the microchannel, so that the measurement error can be progressively increased as the pH of said solution varies with respect to its original value. For this reason it is considered a sensor with a short lifetime.
    EP0155725A 1 describes a sensor in which two ISFET sensors are used, one of which is inside a conduit through which the reference solution is flowed. In this way, the aforementioned ISFET is always in contact with uncontaminated solution. However, it is necessary to incorporate into the sensor an injection system of the reference solution as well as feeding means of the injection system that make the described solution more complex and expensive.
    Thus, the state of the art presents the following associated problems: the test strips are not very precise; glass electrodes are expensive, fragile, require maintenance and are little miniaturizable; the current ISFET and ISE type sensors are miniaturizable but are expensive and require maintenance because they have to be used with a reference electrode; The ISFET-REFET sensor proposed by Compte and Janata is expensive to manufacture and has a short life time; and the sensor described in EP 85200263, in addition to being two ISFET transistors, has a higher cost and complexity due to the need to have a reference solution injection system.
    DESCRIPTION OF THE INVENTION
    The present invention describes a novel ion sensor based on differential measurement comprising at least one ISFET transistor and a REFET transistor. The REFET is defined by a structure composed of an ISFET covered by a micro tank where an internal reference solution is contained. A second object of the present invention is the method of manufacturing the previously described sensor that allows its mass production at low cost. A third object of the present invention is an ion measurement method by means of the previously described sensor, which while it is not being used, is immersed in a conditioning vessel filled with the reference solution, which allows to extend the useful life of said sensor.
    Thus, the first object of the present invention is an ion sensor based on differential measurement. Said sensor is characterized in that it at least comprises:
    • a first ion selective field effect transistor and at least a second ion selective field effect transistor, electrically connected by means of connection tracks to a measurement circuit;
    • an electrode of a conductive material;
    • at least one chip on whose surface the two field effect transistors are integrated. The chips will preferably be of a semiconductor material;
    • a structure coupled on the first transistor configured to create a microdeposit on the door of said first transistor and at least one microchannel that connects the microdeposit with the outside and the microdeposit and the microchannel being filled with a reference solution. This structure adhered to the first field effect transistor is what the REFET creates; Y,
    • a substrate on which the chips, the connection tracks and the electrode are integrated;
    • an encapsulating material that electrically insulates the connection tracks and partially the first and second transistor of the solution to be measured. This encapsulating material prevents an electric current flow between the solution (which together with the electrode form the gate terminal) and some other terminal of the transistor (drain, source or substrate).
    It is provided, in a particular embodiment of the invention, that the sensor described herein integrates a single REFET and a plurality of selective ISFETs each to a different ion. This is achieved by having a series of selective membranes arranged in each ISFET so that each of them detects a different ion. Both ellSFET and REFET can be on the same chip or on different chips, but all ISFETs perform the differential measurement with respect to the same REFET. This is done with a single sensor, a plurality of measurements of concentrations of different ions at the same time.
    In a particular embodiment of the invention, the reference solution is contained in a hydrogel that occupies the volume of the microdeposit and the microchannel.
    The REFET is preferably constructed from a selective ISFET to the H + ion, the reference solution being a buffer that sets the pH to a certain value, but it is also proposed that the REFET be constructed from a selective ISFET to another ion, that is, to include a selective membrane to said ion on its door dielectric, in which case the reference solution must contain a certain concentration of that ion.
    In another particular embodiment of the invention, the first ion selective field effect transistor is integrated into a first chip and at least a second ion selective field effect transistor is integrated into a second chip. If there are a plurality of second transistors, each of them can be integrated into a separate chip or they can all be integrated together into a single chip.
    In another particular embodiment of the invention, it is also provided that the first ion selective field effect transistor and the at least a second ion selective field effect transistor are integrated into the same chip. This reduces the time and manufacturing costs of the sensor. In another particular embodiment of the invention, the field effect transistors, the connection tracks, the electrode and a part of the measurement circuit are integrated in the same chip. This reduces the manufacturing costs of the sensor further and reduces its size considerably, which may be important for certain applications.
    In another particular embodiment of the invention, the connection of the chips, more specifically of the "connection pads" of the chips, with the connection tracks is carried out by wire welding.
    In another particular embodiment of the invention, the chips are encapsulated by a polymer, the wires and the connecting tracks being covered by said polymer and the doors of the first and second ion-selective field effect transistor being discovered, the output of the microchannel and the electrode.
    In another particular embodiment, it is envisioned that the external walls of the microdeposit of the first transistor (REFET) are, at least partially, of a material permeable to water molecules in the gas and air phase but not to the solution with the pH of reference. Thus the diffusion of the air molecules to the outside and the water molecules to the interior is carried out throughout the surface of said permeable material accelerating the process of tuning the sensor when it will be used after a period in which it has not been used. This allows dry storage of the sensor and rapid rehydration of the microdeposit before use by immersion in a conditioning solution. This obviously greatly extends the useful life of this type of sensors.
    In another particular embodiment of the invention an ion selective membrane is placed on the door of the at least one second transistor (ISFET). Thus, depending on what type of ion the membrane positioned is selective, the ion sensor based on differential measurement object of the present invention can measure concentrations of different ions. In this way, sensors can be obtained to measure concentrations of different ions such as Ca2 +, K +, Na +, CI-, NH4 + or C032-.
    In another particular embodiment of the sensor object of the present invention, the microdepository has a volume between 0.001 mm3 and 1 mm3 and the microchannel has a section between 1 square micrometer and 10,000 square micrometers and a length between 10 microns and 1 mm. The concentration of chemical species inside the microdeposit follows an exponential evolution as these species diffuse through the microchannel outwards. The time constant of this concentration variation is proportional to the section of the microchannel and inversely proportional to the volume of the microdeposit and the length of the microchannel. Therefore, the time it takes to lose a certain amount of the chemical compounds in the buffer that maintain the concentration of ions in the solution inside the microdeposit and the degree of contamination of said solution with compounds from outside is proportional to the microchannel section and inversely proportional to the volume of the microdeposit and the length of the microchannel. That is, a longer and / or thinner microchannel provides a stable sensor signal for a longer time. However, a longer and thinner channel also implies an electrical resistance of the microchannel filled with greater solution. Since the microchannel must electrically connect the solution inside the tank with the solution outside to transmit the electrode potential to the REFET transistor door, the greater the resistance of the microchannel, the greater the susceptibility of the sensor to electrical interference. This limits the dimensions of the microchannel and therefore the stable measurement time that can be obtained with given dimensions of the microdeposit.
    In another particular embodiment of the invention, it is envisioned that there are 2 or more microchannels that connect the microdeposit with the outside. Increasing the number of microchannels can reduce their section without increasing the electrical resistance between the solution of the microdeposit and the solution to be measured. A sufficiently reduced section of the microchannels prevents the entry of certain microorganisms into the microdeposit that could alter the characteristics of the reference solution or the surface of the REFET door dielectric.
    In another particular embodiment of the invention, it is provided that external and removable sealing means, such as adhesive tape or the like, be provided at the outlet of the microchannel to seal the contents of the reservoir and the microchannel. The adhesive tape has the proper shape to be able to be removed manually. This allows to extend the life of the sensor since the solution inside the REFET is isolated, preventing evaporation, until the first use of the sensor. Additionally, the material from which the structure that creates the microdeposit and microchannel has been manufactured will be non-permeable to the reference solution.
    In another particular embodiment of the invention, the structure that creates the microdeposit is at least partially of a gas permeable polymer, such as polydimethylsiloxane, which allows the sensor to be stored dry and can be used after a few hours of soaking. This advantage is important to facilitate the storage and commercialization of the sensor or to facilitate its transport in case it is used in portable measuring equipment.
    A second object of the present invention is the method of manufacturing the ion measurement sensor based on differential measurement described above. Said method at least comprises the following phases:
    - equally disposing a plurality of first ion selective field effect transistors on a first wafer;
    - coupling, preferably by welding, a structure of weldable material on the first wafer, creating a plurality of microdeposits and microchannels equispaced in correspondence with the first ion-selective field effect transistors, so that each microdeposit is placed in correspondence and
    10 aligned with each first ion selective field effect transistor; -cut the first chip wafer, where each chip comprises a first field effect transistor and a structure with a microdeposit and at least one microchannel; - solder on a substrate the first ion-selective field effect transistor with the microdeposition and the microchannel, a second ion-selective field effect transistor, the electrode and the connection tracks; -connect the connection tracks to the first and second transistors and encapsulate said first and second transistors and the connection tracks.
    For the case where the first and second ion selective field effect transistor is
    20 integrated into the same chip, the second weld material wafer has at least one hole in proximity to each microdeposit, so that each hole during the welding phase is placed in correspondence with the door of a second field effect transistor leaving said second transistor door exposed to the outside so that it is in contact with the solution to be measured.
    In a particular embodiment of the method object of the present invention, the coupling phase of the structure on the first wafer comprises adding a plurality of layers of weldable material previously subjected to a photolithography process on the first wafer, to generate the structure with the microdeposit and the microchannels.
    In another particular embodiment of the method object of the present invention, the coupling phase of the structure on the first wafer comprises previously subjecting the weldable material structure to a recessing process for the creation of microdeposits and microchannels. This recessing process can be by emptying, molding, extrusion or the like
    35 of a second wafer.
    In another particular embodiment, it is provided that the microchannel is integrated into the chip by means of a longitudinal recess in the surface of the first wafer, that is, of the chip. In this way, the REFET structure is completed by welding a second wafer that already contains only the deposits, or by adding layers of
    5 weldable and photolithographic material on the ISFETs, to form the walls of the microdeposit and the covers of said microdeposits.
    It is planned to deposit a layer of insulating material on the surface of the first and second field effect transistors to isolate the drain and the source of the first and second field effect transistors and the solution substrate. Thus, only the door of the first and second field effect transistors remains in contact with the solutions, both the reference and the one that wants to know the ion concentration. In another embodiment of the invention, additionally encapsulating material is deposited on all edges of the first and second ion selective field effect transistor for
    15 electrically isolate the substrate of the first and second ion-selective field effect transistor of the solution to be measured.
    Alternatively, some wafer structure can be used that provides insulation so that said transistors are electrically isolated from the substrate without the need for encapsulating material at their edges. For example, SO1 wafers (thin semiconductor layer on an insulating layer) can be used to form the two field effect transistors on them. To obtain the insulation, once the transistors are formed, a trench must be made in the surrounding semiconductor layer. totally each of the transistors, then deposit
    25 the insulating layer, and finally remove the insulating layer from the transistor door and wire welding areas (connection pads). Another way to obtain isolation is to form the transistors within a semiconductor region isolated from the rest of the substrate through a p-n junction. In this case it is necessary to ensure that the p-n junction is in reverse, that is, that the potential of the p region is more negative than that of the n region.
    30 The method of manufacturing the ion sensor based on differential measurement described herein, has the advantages, compared to the state of the art, that it is more easily automatable and achievable on a large scale, and therefore allows a significant cost reduction of manufacturing it.
    A third object of the present invention is an ion measurement method by said previously described sensor. Where, while the sensor is not being used, it is introduced into a conditioning vessel that is filled with the reference solution, which allows the solution contained in said microdeposit to be renewed by diffusion through the microchannel, to preserve the sensor previously described between measures that allows to extend the life of the sensor indefinitely.
    Since the chips that contain the transistors are encapsulated on a surface that contains metal connection tracks, it is easy to add other components to the sensor (by welding on the tracks). Some examples would be: 1) A transient voltage suppressor to protect the transistors from electrostatic discharges, for example connected between the electrode and the transistor substrate terminal, 2) a thermistor to measure temperature and compensate for the thermal drift of the sensor, 3 ) a memory for storing sensor parameters, for example the ion sensitivity and the coefficients of variation with the temperature of each sensor, 4) a polarization and measurement circuit of the ISFET-REFET pair, 5) an analog-digital converter, 6) a microcontroller, 7) a display to show the measurement data, 8) an interface circuit to communicate the data by means of a serial protocol (for example the USB standard) with an electronic device (for example a computer or a mobile phone smart), 8) a battery, 9) a communications circuit and an antenna to communicate data wirelessly to other electronic equipment. A particular combination of these components would be the one that would give rise to an RFID type ion sensor (Radio Frequency Identification). In this case, the ISFET and REFET would be integrated with a measuring circuit and an analog-digital converter and with the rest of the circuitry and components typical of an RFID tag. This would allow an RFID tag reader to be used to obtain the ion measurement data from the outside of a closed container, the RFID sensor being immersed in the liquid to be measured inside the container.
    BRIEF DESCRIPTION OF THE FIGURES
    Figure 1.- Shows a sectional view of a particular embodiment of the ion sensor based on differential measurement object of the present invention.
    Figure 2.- Shows a sectional view of the particular embodiment of the ion sensor shown in Figure 1 to which a microchannel and microdeposition sealing means has been added.
    Figure 3.- Shows a particular embodiment of the ion sensor manufacturing method
    based on differential measurement, object of the present invention. Figure 3a shows the alignment phase of both wafers. Figure 3b shows the welding phase of both wafers. Figure 3c shows the phase of filling the tanks with solution or hydrogel. The 3d figure shows the cutting phase of the resulting wafer in chips.
    Figure 4.- Shows a particular embodiment of an alternative method of manufacturing the
    ion sensor based on differential measurement, object of the present invention. Figure 4a shows the ISFET. Figures 4b to 4g show the subsequent welding phases of polymer layers alternated with photolithography phases to configure the microdeposition and the microchannel.
    Figure 5.-Figure 5a shows a plan view of an embodiment example of the sensor with all its components. Figure 5b shows the sensor of Figure 5a in which the encapsulating polymer has been added.
    Figure 6.- Shows an example of the use of the ion sensor of Figure 1 in the measurement of a determined ion concentration of any solution
    DESCRIPTION OF AN EXAMPLE OF REALIZATION OF THE INVENTION
    Then, a description of an embodiment of the invention is made, by way of illustration and not limitation, with reference to the numbering adopted in the figures.
    Figure 1 shows an embodiment of the ion sensor based on the differential measurement, object of the present invention, for the specific case in which it has been designed for the measurement of the H + ion, that is, for the case in which want to measure the pH of a
    concrete solution Said sensor is formed by an ISFET (1) and a REFET (2), where the REFET (2) is in turn constituted by another ISFET (3) whose door (4) is kept exposed to a constant pH by incorporating a structure (5) that creates a microdeposit (6) filled with a reference solution (internal solution) with a constant pH. Said microdeposit (6) is connected to the outside by means of a microchannel (7). This microchannel in this specific embodiment comprises being formed by two sections thereof perpendicular to each other, but could be formed by a single longitudinal section or have any other configuration.
    Both the ISFET (1) and REFET (2), both integrated in two chips, are in turn fixed on a substrate (8) that has a defined metal layer in the form of connection tracks (9) and an electrode area (10) The chips are partially encapsulated using "chip-on-board" techniques, that is, wire-bonding connection (solder of the pads (14) of chip connection by wire (12 »and glob-top protection ( encapsulating polymer (11).) The encapsulating polymer (11) covers the connecting wires (12) and the connecting tracks (9) and partially covers the ISFET (1) and the REFET (2). of ISFET (13) and REFET (4) and the output of the microchannel (7) of REFET (2), as well as the electrode area (10).
    The REFET chip (2) is constituted by the ISFET chip (3) with the structure (5) adhered to its surface forming the microdeposit (6) on the door (4) of said ISFET (3) and the microchannel (7), so that the walls and ceiling of both the microdeposit (6) and the microchannel (7) are of the material of said structure (5), while the floor is formed by the surface of the ISFET (3).
    Figure 2 shows a concrete embodiment in which sealing means of the microchannel (7) and the microdeposit (6) have been adhered to the outlet of the microchannel (7) Specifically, an adhesive strip (15) has been adhered which has of a portion without adhesive material so that it can be easily removed by a user. This specific embodiment allows to extend the life of the sensor since the reference solution in the microdeposit (6) and in the microchannel (7) of the REFET (2) is completely isolated preventing leakage or evaporation of the same so far in that the sensor will be used for the first time and the adhesive strip (15) is removed.
    Figure 3 shows an exemplary embodiment of the sensor manufacturing method described herein. The method is based on the formation of the microdeposit and the microchannel and its soldier on the ISFET by means of planar technology processes, such as those used for the manufacture of microfluidic systems. Figure 3A shows a first wafer (16) where ISFETs, (20) and connection pads (14) and a second wafer (17) with microdeposits (18) and microchannels have been integrated in an equally balanced manner.
    (19) previously performed on its lower face. This second wafer (17) is made of a material that allows it to be welded to the first wafer (16). Both wafers (16.17) are aligned so that each ISFET (20) corresponds to a microchannel (19) and a microdeposit (18). The phase in which the welding between both wafers (16,17) is performed is shown in the figure
    38.
    In this sense and for the welding phase between both wafers (16,17) the following process is planned. Welding is preferably of the chemical type, that is, by means of surface functionalization with molecules that react forming covalent bonds, but other welding techniques can also be used, as long as they do not distort the geometry of the microchannels (19). Many combinations of materials that can be functionalized and chemically welded are known in the state of the art. In this sense, one possibility is that the first wafer (16) has the surface of silicon oxide or oxynitride and the second wafer (17) is of polydimethylsiloxane (PDMS), both functional hoisted by means of an oxygen plasma.
    The second wafer (17) is easily manufactured with microfabrication technologies used for the implementation of microfluidic systems. It is planned to have the structure already formed by molding or some other technique.
    ISFETs (20) are manufactured with a technology that allows them to be isolated from the substrate (8). This technique is based on the use of SO1 wafers and the definition of isolation trenches around ISFETs. This way the encapsulation is facilitated because it is no longer necessary to protect the chip edges_ This allows encapsulating chips of smaller area, since the distance from the ISFET door to the edges of the chip is no longer critical because there is no danger of The door is accidentally covered when the encapsulating polymer is applied.
    After cutting the wafers (16.17) into individual chips (21), as shown in Figure 3D, these can be encapsulated by automatic techniques similar to those already established in the microelectronic industry such as the so-called "chip on board" . This consists of gluing the chips (21) to a substrate (typically a printed circuit board), connecting them by welding with wires (12) (wire-bonding) and protecting the assembly with an encapsulating polymer (11). The variation in this case with respect to the standard technique is that the encapsulating polymer (glob-top) does not cover the entire chip, but only applies to the area of the connecting wires. The sensor with all its components already assembled on the substrate is shown in figures 1 or 2.
    Figure 4 shows another alternative technique of manufacturing REFETs, where starting from a chip where an ISFET is integrated, a REFET is obtained by adding layers. Figure 4a shows an ISFET on a chip (22) in which said ISFET comprises a source pad
    (23) connected to the source (27) of the transistor, a drain pad (25) connected to the
    drain (28) of the transistor and a substrate pad (24) (all of them form the connection pads (14) of the ISFET) and a door (26). Subsequently a first layer is deposited
    (29) of polymer by welding or a prepolymer is deposited by centrifugation and then thermo-curing, as shown in Figure 4b. This polymer layer (29) is structured (figure 4c) by lithography creating the microchannel (30) and the microdeposit (3 1) and leaving free the connection pads (23,24,25) of polymer. Subsequently, and as shown in Figure 4d, a second layer (32) of polymer is welded by rolling onto the first layer (29) of polymer. Again, this second polymer layer (32) is structured by photolithography increasing the volume of the microdeposit (31) and closing the microchannel (30) (figure 4e) but leaving the exit orifice (33) of the microchannel (30) free. Finally, a third layer (34) of polymer is welded and structured by lithography (Figures 4f and 4g) so that the microdeposit (31) is closed and only the outlet orifice (33) of the microchannel (30) remains open. The three layers of pOlimer (29,32,34), which can be of SUB, define the microdeposit (31) and the microchannel (30) which in turn connects with the outside through its exit orifice (33) . This outlet orifice (33) allows the microchannel (30) and the microdeposition (31) to be filled at the wafer level with hydrogel or with any reference solution.
    The structure of an ISFET is similar to that of a MOS transistor (diffusion of drainage and source in a doped semiconductor substrate) with the difference that it has no gate electrode and the gate dielectric is exposed. For the ISFET and REFET devices to work properly they must have the door dielectric in contact with the solution, the ISFET door dielectric with the solution to be measured and the REFET door dielectric with the reference solution, but they must have the drain, the source and the substrate isolated from the respective solutions. To ensure this, a layer of insulating material is deposited on the surface of the chips during their manufacture (at the wafer level), and the edges of the chip during the encapsulation process are protected with the encapsulating polymer. Alternatively, a manufacturing technology that allows electrically insulating the substrate of the device from the edges of the chip can be used, so that it is not necessary to protect them with polymer, for example using SO1 wafers (Silicon on insulator). In order to use the standard chip-on-board encapsulation technique, the two ways of insulating the substrate can be used, but the first requires a large space (-2mm) between the ISFET door and the edge of the chip in all the directions, forcing large chips, and therefore expensive. The second option, through the use of SO1 wafers, is made more suitable for the manufacture of the ISFET-REFET sensor described here, since it allows the encapsulation of small area chips, requiring only that the separation be large in one direction (for example , on a rectangular chip the door of
    ISFET would be placed at one end of the chip and the connection pads to be protected with glob-top at the other end of the chip).
    An interesting variant of the REFET is the one with the microdeposit and the microchannel filled with a hydrogel. The advantages in this case are the avoidance of bubble formation problems in the microchannel and the microdeposit (which could cause a malfunction) and the possibility of storing the sensor dry until it is used. The hydrogel would be soaked in reference solution and would do the same function as the internal solution without hydrogel. This material is very hygroscopic, so it would take much longer to dry if the sensor is left out of the solution. If it dries completely, it can be easily rehydrated by re-immersing it in distilled water or in reference solution without danger of bubbles forming.
    Figure 5 shows a plan view of an exemplary embodiment of a pH sensor according to the present invention. Figure 5a shows a substrate peB (35) in which an ISFET and a REFET have been fixed as described in Figure 4, an electrode (36) and connection tracks (37). These tracks are connected to both the ISFET and the REFET via the connection pads (23,24,25) by welding with wires (38). Figure 5b shows the sensor of Figure 5a in which the encapsulating material (39) that partially covers both the ISFET and the REFET has been deposited and totally to the connections thereof with the connection tracks (37).
    Finally, it is also planned to integrate the ISFET and REFET into a single chip and further reduce the cost of the sensor.
    Another object of the invention is also an ion measurement method by means of a described ISFET / REFET sensor. While not being used, the sensor (40) is inserted into a conditioning vessel (41) filled with a reference solution (42) (Figure 6a). This reference solution (42) also serves as a calibration solution as its known ion concentration. Once the sensor (40) has been introduced into the reference solution (42) for the first time and sufficient time has been allowed for the microdeposit (6) to fill or soak up said solution (42), said sensor (40 ) is removed from the conditioning vessel (41), rinsed, and immersed in the solution to be measured (43) located within a measuring vessel (44), keeping the micro-reservoir (6) of the REFET filled with the reference solution (42) (Figure 6b). After use, the sensor (40) is cleaned and reinserted into the conditioning vessel (41) so that the solution of the microdeposit (6) is equilibrated with the solution of the vessel and returns to its original ion concentration. The sensor (40) will function properly as long as the usage time is less than the time the sensor (40) is immersed in the reference solution (42) inside the conditioning vessel. What brings the present invention to the forefront is that the sensor (40) is kept in the conditioning vessel (41) between one measure and the next, which means that the sensor does not have a limited lifetime due to contamination of the reference or diffusion solution of its components abroad. An added advantage is that since the conditioning vessel (41) is filled with the reference solution (42), whose ion concentration is fixed (for example, a buffered solution to maintain the constant pH in the event that the ISFET is selective at pH and the REFET is constructed with a pH selective ISFET), the sensor can be calibrated before being removed from it transparently to the user.
    Among the multiple applications that can be given to the ion sensor object of the present invention is to integrate the sensor into a self-diagnostic medical device by measuring, for example, urine ions, which may be of interest for the control of diseases such as lithiasis and osteoporosis. Another possible application would be the measurement of vaginal pH for birth control, where the measurement made by the sensor was transmitted to a mobile device (for them the sensor object of the present invention must have an interface for communication with the mobile device) . Another possible application for the sensor would be the monitoring of ions in cell cultures. By introducing the sensor into the culture medium, the condition of the cells could be continuously monitored without opening the container lid. In this case, the measurement could be transmitted through a wireless communications system integrated in the sensor itself.
    权利要求:
    Claims (20)
    [1]
    1. Ion sensor based on differential measurement, characterized in that it comprises:
    • a first ion selective field effect transistor and at least a second ion selective field effect transistor, electrically connected by means of connection tracks to a measurement circuit;
    • an electrode;
    • at least one chip on whose surface the ion selective field effect transistors are integrated;
    • a structure adhered to the first ion-selective field effect transistor configured to create a microdeposit on a gate of the first transistor, the microdeposit being full of the reference solution;
    • at least one microchannel that connects the microdeposit with the outside, the at least one microchannel being filled with the reference solution;
    • a substrate on which the at least one chip, the connection tracks and the electrode are integrated; Y,
    • an encapsulating material that completely isolates the connection tracks and partially the first and second ion-selective field effect transistor of the solution to be measured.
    [2]
    2. Ion sensor based on differential measurement, according to claim 1, characterized in that the reference solution is contained in a hydrogel.
    [3]
    3. Ion sensor based on differential measurement, according to claim 1 or 2, characterized in that the first ion selective field effect transistor is integrated in a first chip and at least a second ion selective field effect transistor It is integrated into a second chip.
    [4]
    4. Ion sensor based on differential measurement, according to claim 1 or 2, characterized in that the first ion selective field effect transistor and the second ion selective field effect transistor are integrated in the same chip.
    [5]
    5. Ion sensor based on differential measurement, according to claim 1 or 2, characterized in that the first and second ion-selective field effect transistors, the
    connection tracks, the electrode and a part of the measuring circuit are integrated in the same chip.
    [6]
    6. Ion sensor based on differential measurement, according to claim 3 or 4, characterized in that the connection of some points of connection of the chip with the connection tracks is carried out by wire welding.
    [7]
    7. Ion sensor based on differential measurement, according to claim 6, characterized in that the chips are encapsulated by a polymer, the wires and the connection tracks being covered by the polymer and the doors of the first and second transistor being discovered. Field effect and microchannel output.
    [8]
    8. Ion sensor based on differential measurement, according to any one of the preceding claims, characterized in that the structure adhered to the first ion-selective field effect transistor is at least partially of a gas permeable and impermeable material. reference solution.
    [9]
    9. Ion sensor based on differential measurement, according to any one of the preceding claims, characterized in that the microchannel is a groove made in the chip on which the first ion selective field effect transistor is integrated.
    [10]
    10. Ion sensor based on differential measurement, according to any one of claims 1 to 8, characterized in that the microchannel is part of the structure adhered to the first ion selective field effect transistor
    [11]
    11. Ion sensor based on differential measurement, according to any one of the preceding claims, characterized in that the microdeposit has a volume between
    [0]
    0.001 mm3 and 1 mm3, and the microchannel has a section between 1 square micrometer and 10,000 square micrometers and a length between 10 microns and 1 mm.
    [12]
    12. Ion sensor based on differential measurement, according to any one of claims 1 to 7 and 9 to 11, characterized in that the microchannel has external and removable sealing means for sealing the microdeposit and microchannel contents.
    [13]
    13. Ion sensor based on differential measurement, according to any one of the preceding claims, characterized in that the chips are made of silicon on insulation.
    [14]
    14. Ion measurement method by means of the sensor described in claim 1, characterized in that it comprises the following phases: - inserting the sensor into a conditioning vessel filled with a reference solution so that a microdeposit is filled or soaked with said solution, remove the sensor from the conditioning vessel, rinse, and immerse in a
    solution to measure,
    - measure the solution to be measured with the sensor
    - clean the sensor
    - reinsert the sensor into the conditioning vessel so that the microdepository solution is balanced with the container solution and returns to its original ion concentration.
    [15]
    15. Ion measurement method by means of the sensor, according to claim 14, characterized in that the solution to be measured is located within a measuring vessel.
    [16]
    16.-Method of manufacturing the ion sensor based on differential measurement, described in any one of claims 1 to 13, characterized in that it comprises the following phases:
    - integrally integrating a plurality of first ion-selective field effect transistors on a first wafer;
    - coupling a structure of weldable material on the first wafer, creating a plurality of microdeposits and microchannels equispaced in correspondence with the first ion-selective field effect transistors, so that each microdeposit is placed in correspondence and aligned with each first transistor of ion selective field effect;
    - cutting the first wafer transversely creating chips, where each chip comprises a first ion-selective field effect transistor and a structure with a microdeposit and at least one microchannel;
    - fix on a substrate a chip, at least a second field effect transistor, the electrode and the connection tracks;
    - connect the connection tracks to the first and second field effect transistors and encapsulate the first and second field effect transistors and the connection tracks.
    [17]
    17.- Method of manufacturing the ion sensor based on differential measurement, according to the
    Claim 16, characterized in that it comprises adding a plurality of layers of weldable material subjected to a photolithography process on the first wafer, to generate the structure of weldable material with the microdeposits and microchannels.
    [18]
    18.-Method of manufacturing the ion sensor based on differential measurement, according to the
    Claim 16, characterized in that it comprises previously subjecting the weldable material structure to a recessing process for the creation of microdeposits and microchannels.
    [19]
    19.- Method of manufacturing the ion sensor based on differential measurement, according to the
    Claim 16, characterized in that additionally encapsulating material is deposited on edges of the first and second ion selective field effect transistor to electrically isolate the substrate of the first and second ion selective field effect transistor
    20. Method of manufacturing the ion sensor based on differential measurement, according to any one of the preceding claims, characterized in that different ion selective membranes are fixed on the second ion selective field effect transistors.
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    ES201430180A|ES2542927R1|2014-02-11|2014-02-11|Ion sensor based on differential measurement, manufacturing method and measurement method|ES201430180A| ES2542927R1|2014-02-11|2014-02-11|Ion sensor based on differential measurement, manufacturing method and measurement method|
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