Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
  • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
  • G01N27/27—Association of two or more measuring systems or cells, each measuring a different parameter, where the measurement results may be either used independently, the systems or cells being physically associated, or combined to produce a value for a further parameter

Definitions

• the present invention relates to a system, device and method for measuring the concentration of chemical components present within a fluid and, more particularly, to systems, devices and methods for measuring analyte concentration electrochemically.
• Chemical concentration of an analyte in a fluid can be measured by transducing presence of the analyte into measurable physical parameters.
• concentration of an analyte solution can be determined via such techniques as spectroscopy, chromatography, calorimetry, or optical fluorescence.
• Further concentration measurement techniques involve probing the electrical characteristics of the analyte solution. Some such techniques involve coulometry. Others involve amperometric, voltametric, and/or potentiametric titration. Many such techniques are capable of a high degree of accuracy, speed (e.g., throughput), and efficiency. Unfortunately, the equipment required to implement such techniques can tend to be both large and bulky. As a result, the use of such equipment is typically limited to a laboratory setting, and technicians in the field who seek to make concentration determinations via measurement of electrical characteristics are often left with few attractive options.
• an apparatus in an exemplary embodiment of the present disclosure, includes a chamber having a depth dimension for accommodating a volume of a fluid under test, a first electrode disposed within the chamber and extending therewithin along the depth dimension, a second electrode disposed within the chamber and extending therewithin along the depth dimension in laterally spaced relation with the first electrode, and a soluble solid disposed within the chamber between the first and second electrodes so as to substantially completely occupy a lateral gap therebetween to an extent of at least a portion of the depth dimension.
• a rate of dissolution of the soluble solid within the fluid is at least partially dependent on a chemical concentration of a corresponding analyte present in solution in the fluid.
• a method for electrochemical analysis of fluids includes exposing a soluble solid to a fluid, measuring a rate of dissolution of the soluble solid in the fluid, and determining a chemical concentration of a corresponding analyte present in solution in the fluid based on the measured rate of dissolution.
• FIG. 1 is a schematic representation of an embodiment of an analyte concentration measurement tool in accordance with the present disclosure
• Fig. 2 is a downward perspective view of a CMOS die useable to fabricate the Fig 1 measurement tool in accordance with the present disclosure
• Fig 3 is a top plan view of the Fig. 2 CMOS die after modification via formation on an upper margin thereof of a metallic contact pattern in accordance with the present disclosure
• Fig. 4 is a section view of the Fig. 3 modified CMOS die taken along section line 4—4 shown in Fig. 3;
• Fig. 5 is a downward perspective view of the Fig. 3 modified CMOS die
• Fig. 6 is a top plan view of the Fig. 3 modified CMOS die after further modification via formation atop the metallic contact pattern thereof of an array of paired electrodes in accordance with the present disclosure
• Fig. 7 is a section view of the Fig. 6 modified CMOS die taken along section line 7—7 shown in Fig. 6;
• Fig. 8 is a downward perspective view of the Fig. 6 modified CMOS die;
• Fig. 9 is a top plan view of the Fig. 6 modified CMOS die after further modification via formation atop the array of paired electrodes thereof of a dielectric material layer in accordance with the present disclosure;
• Fig. 10 is a section view of the Fig. 9 modified CMOS die taken along section line 10—10 shown in Fig. 9;
• Fig. 11 is a downward perspective view of the Fig. 9 modified CMOS die
• Fig. 12 is a top plan view of the Fig. 9 modified CMOS die after filling of the cylindrical chambers thereof with polymeric materials and associated annealing to form an embodiment of the analyte concentration measurement tool of Fig. 1 in accordance with the present disclosure
• Fig. 13 is a section view of the Fig. 12 analyte concentration measurement tool
• Fig.14 is a section view of a fluid-polymer filled cylinder of the Fig. 12 analyte concentration measurement tool in accordance with the present disclosure
• Fig. 15 is a section view of a fluid filled cylinder of the Fig. 12 analyte concentration measurement tool in accordance with the present disclosure
• Fig. 18 is a schematic diagram of an exemplary electrical circuit.
• An apparatus for electrochemical analysis of fluids is provided that can be adapted to be compact in size, economic to manufacture, and convenient to deploy.
• Exemplary embodiments of apparatus for electrochemical analysis of fluids include a chamber having a depth dimension for accommodating a volume of a fluid under test, and a pair of electrodes disposed within the chamber and extending along the depth dimension thereof in laterally spaced relation to each other.
• a soluble solid is disposed within the chamber between the electrodes, occupying a lateral gap therebetween to an extent of at least a portion of the depth dimension of the chamber.
• a rate of dissolution of the soluble solid within the fluid is at least partially dependent on a chemical concentration of a corresponding analyte present in solution in the fluid
• the fluid fills the void generated by the dissolving solid. Because the soluble solid is a poorer conductor compared to the fluid, dissolution of the soluble solid leads to an increase of conductance between the electrodes.
• the rate of conductance change further depends on the properties of the dissolving solid and the actual analyte concentration in solution in the fluid.
• Materials suitable for use with respect to the soluble solid according to the present disclosure include commercially available materials that exhibit respective solubilities dependent on the concentration in solution of a chemical component or active species of interest, e.g., H+ concentration (i.e., pH), proteins, amino acids, glucose, enzymes and other analytes of interest.
• exemplary materials for use with respect to the soluble solid according to the present disclosure include polymers that exhibit a pH-dependent dissolution rate, such as EUDRAGIT acrylic polymers manufactured by Degussa GmbH, and polymers that exhibit dissolution rates that are dependent on the presence of colon enzyme, such as azo polymers used by Alizyme pic (Cambridge, United Kingdom).
• Apparatus and methods for electrochemical analysis of fluids in accordance with the present disclosure may be used to measure the concentration for a large number of chemical components present within a fluid under test.
• such apparatus and methods rely on polymers with specific solubility depending on concentration of compounds mixed within the fluid, and include an electronic device that allows an accurate measurement of the solubility based upon complex conductance measurements.
• the lifetime of the electronic device may be limited in accordance with embodiments of the present disclosure, and controlled by processing parameters of the device.
• a small, simple, energy efficient 'lab-on-a-chip' solution having a response time in the field at least comparable to, if not superior to, many larger, more bulky systems commonly limited to use within a laboratory.
• Such an apparatus can be implemented through the use of an integrated circuit (IC) electronic device combined with an array of confined micro- cylinders fabricated via MEMS processes at the surface of a die associated with the IC electronic device, and filled with polymers having known etching rate versus chemical concentration of active species in solution in the fluid under test.
• IC integrated circuit
• the disclosed apparatus and methods are described in greater detail herein with reference to a tool for measuring analyte concentration in solution in a fluid under test.
• the disclosed systems and methods have wide ranging applicability, as will be readily apparent to persons skilled in the art, including implementations directed to a variety of analytes.
• the apparatus includes a soluble solid in the form of a polymer that does not dissolve until the pH is above a threshold value and, as a result, the conductance between the electrodes does not increase unless the fluid under test has a pH above this threshold. If the pH of the fluid under test is above the applicable threshold, the conductance between electrodes will advantageously increase proportionally to the difference between the actual pH value of the fluid under test and the lower threshold pH of the soluble polymer.
• the apparatus includes a soluble solid in the form of a polymer that does not dissolve unless the pH of the fluid under test is below a threshold value and, as a result, the conductance between the electrodes does not increase unless the fluid under test has a pH below this threshold. If the pH of the fluid under test is below the applicable threshold, the conductance between electrodes will advantageously increase proportionally to the difference between the actual pH value of the fluid under test and the higher threshold pH of the soluble polymer.
• conductance between each pair of electrodes may be measured as a function of time, and the rate of conductance change may be used to derive the concentration value of the analyte present in solution in the fluid under test.
• One unique advantage of such an apparatus for electrochemically analyzing a fluid is that the apparatus can be operated without absolute calibration. Variation in manufacturing process and environmental conditions, such as overall conductivity of the fluids under test, can cause variation in absolute conductance between electrodes. These variations, however, do not interfere with derivation of the concentration value of an analyte present in solution in a fluid under test because the concentration value is determined by the change rate of conductance, not by the absolute value of conductance.
• such an apparatus can be used in conjunction with a reference electrode to account for environmental changes in the rate of conductance.
• the apparatus 100 may include a silicon-based integrated circuit (IC) 102.
• the IC 102 may incorporate an input/output (10) data block 104, a data processor and control unit (DPCU) 106, an amplitude and frequency control unit (AFCU) 108, a complex admittance measurement unit (CAMU) 110, and an electrode selector (ES) 112.
• the apparatus 100 may further include an electrode array (EA) 114.
• the IO 104 may be an interface of the circuit with respect to external devices.
• the EA 114 is a matrix of electrodes present at an upper margin or surface of the IC 102. Each of the electrodes of the EA 114 can be connected through the ES 112 block to corresponding measurement ports of the CAMU 110. All other electrodes of the EA 114 may be grounded.
• the ES 112 may be an array of analog switches which allows the selection of a single electrode out of the EA 114.
• the CAMU 110 can measure the complex admittance of the circuit connected at the selected electrode from the EA 114. The frequency and amplitude of the test signal can be controlled and/or imposed by the AFCU 108.
• the DPCU 106 may receive analog signals provided by the CAMU 110 and convert the same to digital values.
• the DPCU 106 may further store and/or process such digital values, take decisions regarding the frequencies and amplitudes of operations from the AFCU 108 and operate the ES 112 accordingly.
• the DPCU 106 may further be employed to transfer to the IO 104 measurement results with respect to concentration(s) of one or more analytes present in solution in the fluid under test.
• the CMOS die 200 shown in Fig. 2 can embody the Fig. 1 IC 102.
• the CMOS die 200 may include an upper margin 202 featuring an array of peripherally-disposed contacts 204 associated with an input/output interface of the circuit (e.g., associated with the Fig. 1 IO 104).
• a MEMS process may be utilized to modify and/or convert the CMOS die 200 of Fig. 2 to form an embodiment of the Fig. 1 apparatus 100 in accordance with the present disclosure.
• An example of such a process is shown and described below with reference to Figs. 3-13.
• a modified CMOS die 300 can be formed by modifying the Fig. 2 CMOS die 102 via conventional metal deposition process and associated appropriate patterning to form a contact pattern 302 on an upper margin 304 of the die 300 operative to permit electrical interconnection between an IC (e.g., Fig. 1 IC 102) and an electrode array (e.g., Fig. 1 EA 114) in accordance with the present invention.
• an IC e.g., Fig. 1 IC 102
• an electrode array e.g., Fig. 1 EA 11
• a modified CMOS die 600 can be formed by further modifying the Fig. 3 modified CMOS die 300 via an appropriate aluminum-silicon deposition and etch processes (e.g., with a highly selective RIE) to form a mask 602.
• the mask 602 may include an array of chambers 604 for accommodating small volumes of a liquid under test, each of which may include a cylindrically shaped microbarrel 606 connected to ground and a column shaped central electrode 608.
• the central electrodes 608 may be disposed within the microbarrels 606, and, further may be coaxial with, and/or coextensive (e.g., depthwise) therewith.
• a modified CMOS die 900 can be formed by further modifying the Fig. 6 modified CMOS die 600 via an appropriate material layer deposition and etch process, e.g., to form a dielectric material layer 902 atop the Fig. 6 mask 602.
• the dielectric material layer 902 may be a SiO 2 -Si 3 N 4 layer.
• One or more of the Fig. 6 chambers 604 may be masked during this step so as to prevent the dielectric material layer 902 from extending thereto.
• an analyte concentration measurement tool may be positioned on respective corners 904, 906, 908, 910 of the die 900, and/or may be used to measure air admittance (e.g., as part of a measurement control function).
• air admittance e.g., as part of a measurement control function.
• the tool 1200 may be implemented to embody the analyte concentration measurement tool 100 of Fig. 1.
• the tool 1200 can be formed by further modifying the Fig. 9 modified CMOS die 900 via filling one or more of the Fig. 6 chambers 604 with similar and/or different polymers and executing an appropriate annealing process to form fluid-polymer filled cylinders or chambers 1202 (described further hereinbelow), wherein the dissolution rate of each such polymer may be specific to one or more of the same or different chemical compounds in solution in a fluid under test.
• the Fig. 9 corner-disposed chambers 904, 906, 908, 910 may be left unfilled with polymer for purposes of measuring air admittance as part of a measurement control function.
• an entire row 1204 of chambers 1206, also referred to herein as fluid filled cylinders or chambers 1206, may be left unfilled with polymer for purposes of measuring an admittance of the fluid under test as described more fully below.
• the tool 1200 includes an IC 1208 which can embody, for example, the Fig. 1 IC 102, and a MEMS region 1210 which can embody the Fig. 1 EA 114.
• the MEMS region 1210 can be configured to be exposed to the fluid under test, while the IC 1208 can be configured such that its internally-disposed electrical circuitry and/or functions are secured from damage from the fluid under test.
• Fig. 14 when exposed to fluid 1400 from the fluid under test, the soluble solid 1402 (e.g., polymer) within the chamber 1202 is dissolved by the analyte present in solution in the fluid under test.
• Fig. 14 gives a vertical plane cross-section through a fluid-polymer filled cylinder (FPC) 1202 after the soluble solid 1402 contained therein was etched to an etch value equal to hfl ul d.
• Fig. 15 gives a vertical plane cross-section through a fluid filled cylinder (FC) 1206.
• the fluid- filled cylinders 1206, containing no soluble solid e.g., containing no polymer
• the 12 tool 1200 measures the complex admittances for all of the FPCs 1202 and FCs 1206 of the MEMS region 1210 at specific time intervals and estimates the electrical properties of polymers within the FPCs 1202 and the fluid within the FCs 1206 and the etch rate for every type of polymer from every FPC 1202. Based on the etching rate, one may determine the concentrations of active chemical species within the fluid under test. The capacity to make such determinations may last as long as the polymers within the FPCs 1202 are not completely dissolved within the fluid under test.
• Exemplary electric equivalent circuits 1600, 1700 for FPCs 1202 and FCs 1206 are given, respectively, in Figs. 16 and 17.
• the below-described algorithm is executable by a processor (e.g., by the Fig. 1
• DPCU 106 in accordance with the present disclosure to allow the determination at a time t, of the concentration of species present in solution in the fluid under test, given the FPC 1202 are filled with different polymers with etching rates specific to every chemical concentration of the species.
• the complex impedance of the circuit from Figure 8 (seen by the voltage source voltage source P ) is:
• the resistors are not frequency dependent (the voltage source frequency is smaller than the minimum ionic rotation frequency within the fluid or polymer).
• Step 1 Device in air
• Step2 Measure the fluid and polymer admittance at any time after the device has been immersed in a fluid.
• the etching of the polymer within a FPC h fllud is calculated based on the initial values of the impedance of the FPC (FPC in air) and the adjacent FPC measurement. This does not solve the variations of the polymer electrical parameters vs. time.
• the poles and zeros for f x / , ⁇ . can be estimated from the Bode plot of fc ⁇ I , therefore one can extract P 701 ⁇ n , and ⁇ pa i )**r at 3 W ⁇ during the measurement of the fluid.
• ⁇ 4 cylinders of the AMA are not covered with Si 3 N 4 ZSiO 2 dielectrics and are used to measure (in air) the specifics of the dielectric covering the Al electrodes ( E 1 ⁇ 114 . f ⁇ , /Mft ⁇ : ⁇ .
• NrccytmAr cylinders (different from the 4 above) are not filled with any polymers.
• N p nfymtr A ⁇ KII ⁇ X ⁇ /M *,, - ⁇ >r.c ⁇ _»iAr -4 cylinders arc filled with ⁇ ,,. different types of polymers.
• ⁇ bvery polymer is chemically sensitive to a specific chemical species within the fluid under test.
• the fluid under test confines ⁇ ' ⁇ ta , active species with concentrations C ⁇ n ,.
• the polymer in cylinder k e ⁇ fl,.., N polr ⁇ m ⁇ . I c N reacts with the active species within the fluid. As a resuh of the reactions, the polymer will become soluble within the solution.
• the rate of solubility is related to the etching rate of the polymer with a function isomorphic with: where:
• the total etch rate for polymer k while reacting to all species N spcctc within the fluid is the sum of the etch rate of the polymer per specie:
• the AMA structure is measured in air and the specifics of all N p01 ⁇ , are stored as
• the admittance measurement circuit measures for every cylinder (Fluid Polymer filled Cylinders (FPF) and Fluid-filled Cylinders (FC)) at a sample rate S all complex admittances and calculates:

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