Abstract:
The ability to switch at will between amperometric measurements and potentiometric measurements provides great flexibility in performing analyses of unknowns. Apparatus and methods can provide such switching to collect data from an electrochemical cell. The cell may contain a reagent disposed to measure glucose in human blood.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims priority from U.S. application Ser. No. 60/521,592 filed May 30, 2004, and from U.S. application Ser. No. 60/594,285 filed Mar. 25, 2005, each of which is incorporated herein by reference for all purposes. 
     
    
     BACKGROUND 
       [0002]    Electrochemical reactions may be used to measure quantities and concentrations in solutions. 
         [0003]      FIG. 1  is a schematic diagram of an electrochemical interface apparatus, also known as a potentiostat, for a standard three-electrode configuration. Electrochemical cell  39  has a reference electrode  37 , a counter electrode  36 , and a working electrode  38 . The cell  39  contains a substance being analyzed as well as a reagent selected for its utility. The reagent forms part of an electrochemical reaction. It will be appreciated that there are other circuits that can accomplish the functions described here, and that this is only one embodiment thereof. 
         [0004]    A voltage is applied to the cell at  36 , based upon a voltage input provided at input  34 . This voltage at  34  is defined relative to a ground potential  40 . In some embodiments this is a known voltage. More generally, in a three-electrode system, the voltage at  36  assumes whatever value is needed to make sure that the potential difference between  37  and  38  is substantially equal to the potential difference between  34  and  40 . 
         [0005]    Amplifier  35 , preferably an operational amplifier, is used to provide gain as needed and to provide isolation between the input  34  and the electrodes  36  and  37 . In the arrangement of  FIG. 1  the gain is a unity voltage gain and the chief function of the amplifier  35  is to provide a high-impedance input at  34  and to provide sufficient drive to work with whatever impedance is encountered at electrode  36 . 
         [0006]    As the electrochemical reaction goes forward, current flows. Working electrode  38  carries such current. A selector  31  selects a resistor from a resistor bank  30 , to select a current range for measurement of this current. Amplifier  32 , preferably an operational amplifier, forms part of a circuit by which an output voltage at  33  is indicative of the current through the electrode  38 . The output voltage at  33  is proportional to the product of the current at  38  and the selected resistor. 
         [0007]    In one example, blood such as human blood is introduced into the cell. A reagent in the cell contributes to a chemical reaction involving blood glucose. A constant and known voltage at  34  is maintained. The output voltage at  33  is logged and the logged data are analyzed to arrive at a measurement of the total current that flowed during a defined measurement interval. (Typically this interval is such that the reaction is carried out to completion, although in some embodiments the desired measurements may be made without a need for the reaction to be carried out to completion.) In this way the glucose level in the blood may be measured. 
         [0008]    As will be discussed below, the input at  34  may preferably be other than constant. For example it may be preferable that the input at  34  be a waveform selected to optimize certain measurements. The analog output of a digital to analog converter may be desirably connected at input  34 , for example. 
         [0009]    The measurement just described may be termed an “amperometric” measurement, a term chosen to connote that current through the reaction cell is what is being measured. 
         [0010]    In some measurement situations it is possible to combine the counter electrode and the reference electrode as shown in  FIG. 2 , into a single electrode  41 . 
         [0011]    One example of a prior art circuit is that shown in German patent application DE 41 00 727 A1 published Jul. 16, 1992 and entitled “Analytisches Verfahren fur Enzymelektrodensensoren.” That circuit, however, does not, apparently, perform an amperometric measurement upon the reaction cell. That circuit appears to perform voltage readings, and an integrated function of voltage, with respect to a reference electrode of a cell (relative to a working electrode of the cell) and not with respect to a counter electrode (relative to the working electrode of the cell). 
         [0012]    In this circuit the measured potential is a function of (among other things) the concentration of an analyte. Stating the same point in different terms, this circuit does not and cannot yield a signal that is independent of concentration of the analyte. 
       SUMMARY OF THE INVENTION 
       [0013]      FIG. 3  shows an improvement upon the previously described apparatus. In  FIG. 3 , an ideal voltmeter  42  is provided which can measure the potential across the electrodes  41 ,  38 . Switch  44  is provided which is opened when the potential is to be measured. In this way the cell  39  is “floating” as to at least one of its electrodes, permitting a voltage measurement that is unaffected by signals at the amplifier  35 . 
         [0014]    The switch  44  may be a mechanical switch (e.g. a relay) or an FET (field-effect transistor) switch, or a solid-state switch. In a simple case the switch opens to an open circuit; more generally it could open to a very high resistance. 
         [0015]    The ability to switch at will between amperometric measurements and potentiometric measurements provides great flexibility in performing analyses of unknowns. The various potential benefits of this approach are discussed in some detail in co-pending U.S. application Ser. No. 10/924,510, filed Aug. 23, 2004 and incorporated herein by reference for all purposes. 
         [0016]    Measurement approaches are discussed in some detail in U.S. application Ser. No. (docket 15), filed (when), and in U.S. application Ser. No. (docket 16), filed (when), each of which is incorporated herein by reference for all purposes. 
     
    
     
       DESCRIPTION OF THE DRAWING 
         [0017]    The invention will be described with respect to a drawing in several figures. 
           [0018]      FIG. 1  is a schematic diagram of an electrochemical interface apparatus, also known as a potentiostat, for a standard three-electrode configuration. 
           [0019]      FIG. 2  shows an arrangement in which the counter electrode and the reference electrode are combined into a single electrode  41 . 
           [0020]      FIG. 3  shows an improvement upon the previously described apparatus according to the invention 
           [0021]      FIGS. 4   a  and  4   b  show embodiments in which two switches are used rather than the single switch of  FIG. 3 . 
           [0022]      FIGS. 4   c  and  4   d  show embodiments in which one switch is used to effect the isolation. 
           [0023]      FIGS. 5   a ,  5   b , and  5   c  show a three-electrode cell system in which it is possible to introduce voltage measurements by providing three switches. 
           [0024]      FIGS. 6   a ,  6   b  and  6   c  show a three-electrode cell system in which two switches are employed. 
           [0025]      FIGS. 7   a ,  7   b , and  7   c  show a three-electrode cell system in which it is possible to introduce voltage measurements by providing one switch. 
           [0026]      FIGS. 8   a ,  8   b , and  8   c  show a three-electrode cell system in which another way is shown to introduce voltage measurements by providing one switch. 
           [0027]      FIG. 9  is a test instrument  70  in side view. 
           [0028]      FIG. 10  shows an exemplary schematic diagram of a measurement system according to the invention, in greater detail than in the previous figures. 
           [0029]      FIG. 11  is a perspective view of a test instrument  70 . 
           [0030]      FIG. 12  shows a strip having the ability to serve as an optical waveguide. 
           [0031]      FIG. 13  shows a functional block  62  which can be the analysis circuit of any of the previously discussed figures. 
           [0032]      FIG. 14  shows how, with proper use of analog switches, the number of operational amplifiers may be reduced to as few as two. 
       
    
    
     DETAILED DESCRIPTION 
       [0033]    Variations upon the topology will now be described. 
         [0034]      FIGS. 4   a  and  4   b  show embodiments in which two switches are used rather than the single switch of  FIG. 3 . In each embodiment, two switches are opened to isolate the cell for purposes of voltage measurement by means of voltmeter  42 . 
         [0035]    In  FIG. 4   a , switches  45 ,  46  are opened to isolate the two-electrode cell  39  from the output of amplifier  35  and from the feedback path to the inverting input of amplifier  35 . 
         [0036]    In  FIG. 4   b , switches  44 ,  47  are opened to isolate the two-electrode cell  39  at both the electrode  41  and the electrode  38 . 
         [0037]      FIGS. 4   c  and  4   d  show embodiments in which one switch is used to effect the isolation. In each embodiment, a single switch is opened to isolate the cell for purposes of voltage measurement by means of voltmeter  42 . 
         [0038]    In  FIG. 4   c , switch  46  is opened to isolate the two-electrode cell  39  from the output of amplifier  35 . 
         [0039]    In  FIG. 4   d , switch  47  is opened to isolate the two-electrode cell  39  at the electrode  38 . 
         [0040]    In  FIGS. 4   a ,  4   b ,  4   c , and  4   d , and indeed in many examples that follow, a single feedback resistor  43  is shown for simplicity, and is meant to represent the selector  31  and the current-range resistors  30 . 
         [0041]    In a three-electrode cell system (see for example  FIG. 1 ) it is possible to introduce voltage measurements by providing three switches, as shown in  FIGS. 5   a ,  5   b , and  5   c . In each embodiment, switch  46  isolates the electrode  36  from the output of amplifier  35 , switch  45  isolates the electrode  37  from the feedback path of amplifier  35 , and switch  47  isolates the electrode  38  from the amperometric circuitry  32 . In this way all three electrodes of the cell  39  are “floating” relative to other circuitry. 
         [0042]    It is then possible to use a voltmeter to measure voltages. The voltage being measured is between the reference electrode  37  and the working electrode  38  ( FIG. 5   a ), or between the counter electrode  36  and the working electrode  38  ( FIG. 5   b ), or between the reference electrode  37  and the counter electrode  36  ( FIG. 5   c ). 
         [0043]    It will be appreciated that in some analytical applications, it may be desirable to measure more than one potential difference between electrodes of the cell. 
         [0044]    In a three-electrode cell system it is possible to introduce voltage measurements by providing two switches, as shown in  FIGS. 6   a ,  6   b , and  6   c.    
         [0045]    In  FIGS. 6   a  and  6   c , switch  45  isolates the electrode  37  from the feedback path of amplifier  35 . 
         [0046]    In  FIGS. 6   a  and  6   b , switch  47  isolates the electrode  38  from the amperometric circuitry  32 . 
         [0047]    In  FIGS. 6   b  and  6   c , switch  46  isolates the electrode  36  from the output of amplifier  35 . 
         [0048]    In this way two of the three electrodes of the cell  39  are “floating” relative to other circuitry. 
         [0049]    It is then possible to use a voltmeter to measure voltages. The voltage being measured is between the reference electrode  37  and the working electrode  38  ( FIG. 6   a ), or between the counter electrode  36  and the working electrode  38  ( FIG. 6   b ), or between the reference electrode  37  and the counter electrode  36  ( FIG. 6   c ). It should be borne in mind that such potential difference measurements may be made between any two points that are electrically equivalent to the two points of interest. Thus, for example, in  FIG. 7   a  or  7   b , the voltmeter  42 , instead of being connected to electrode  38 , could be connected instead to ground (which is one of the inputs of amplifier  32 ). This is so because the action of the amplifier  32  is such that the potential at  38  is forced to be at or very near the potential at the grounded input to the amplifier. In  FIGS. 7   c ,  8   a , and  8   c , the voltmeter  42 , instead of being connected to electrode  37 , could be connected with the electrically equivalent (so far as potential is concerned) point  34 . 
         [0050]    In a three-electrode cell system it is possible to introduce voltage measurements by providing one switch, as shown in  FIGS. 7   a ,  7   b , and  7   c . In each case, switch  46  isolates the electrode  36  from the output of amplifier  35 . 
         [0051]    It is then possible to use a voltmeter to measure voltages. The voltage being measured is between the reference electrode  37  and the working electrode  38  ( FIG. 7   a ), or between the counter electrode  36  and the working electrode  38  ( FIG. 7   b ), or between the reference electrode  37  and the counter electrode  36  ( FIG. 7   c ). 
         [0052]    In a three-electrode cell system there is another way to introduce voltage measurements by providing one switch, as shown in  FIGS. 8   a ,  8   b , and  8   c . In each case, switch  47  isolates the electrode  38  from the amperometric circuitry of amplifier  32 . 
         [0053]    It is then possible to use a voltmeter to measure voltages. The voltage being measured is between the reference electrode  37  and the working electrode  38  ( FIG. 8   a ), or between the counter electrode  36  and the working electrode  38  ( FIG. 8   b ), or between the reference electrode  37  and the counter electrode  36  ( FIG. 8   c ). 
         [0054]    It should also be appreciated that this approach can be generalized to cells with more than three electrodes. 
         [0055]      FIG. 10  shows an exemplary schematic diagram of a measurement system according to the invention, in greater detail than in the previous figures, and corresponding most closely to the embodiment of  FIG. 3 . 
         [0056]    Resistor bank  30  may be seen, which together with selector  31  permits selecting feedback resistor values for amplifier  32 . In this way the output at  33  is a voltage indicative of the current passing through working electrode  38 . This corresponds to the amperometric circuitry of  FIG. 3 . Selector  31  in this embodiment is a single-pole double-throw switch with selectable sources S 1 , S 2  and a destination D, controlled by control input IN, connected to control line  53 . 
         [0057]    Two-electrode cell  39  may be seen in  FIG. 10 , with electrode  41  serving as combined counter electrode and reference electrode. 
         [0058]    Integrated circuit  50  of  FIG. 10  contains four switches. One of the switches of circuit  50  is a switch  55  at pins  8 ,  6 ,  7  (input  4 , source  4 , and drain  4  respectively). This switch  55  corresponds to switch  44  in  FIG. 3 , and isolates the electrode  41  from the driver of amplifier  35 . When the switch  55  is opened, it is possible to use amplifier  51  as a voltmeter, measuring the voltage between inverting pin  2  and noninverting pin  3 , thereby measuring the voltage between the two electrodes  38 ,  41  of the cell  39 . The voltage at output  52  is proportional to the voltage measured at the inputs of amplifier  51 . 
         [0059]    The opening and closing of the switch  55  is controlled by control line  54 . (It should also be appreciated that with appropriate switching, as discussed below, it is possible to use a smaller number of amplifiers in a way that fulfills the roles of both the amperometric circuitry and the potentiometic circuitry.) 
         [0060]    What is shown in  FIG. 10  is thus a powerful and versatile analysis circuit that permits at some times measuring voltage across the electrodes of an electrochemical cell, and that permits at other times performing amperometric measurements across those same electrodes. This permits an automated means of switching between modes. In this way the apparatus differs from prior-art electrochemical analytic instruments which can operate in a potentiostat (amperometic) mode or in a galvanostat (potentiometic) mode, but which require a human operator to make a manual selection of one mode or the other. 
         [0061]    In addition, it will be appreciated that the apparatus of  FIG. 10  can also monitor voltage during an amperometric measurement if certain switches are closed. In other words, the amperometric and potentiometric measurements need not be at exclusive times. 
         [0062]    It will also be appreciated that the switching between amperometric and potentiometric modes need not be at fixed and predetermined times, but can instead be performed dynamically depending upon predetermined criteria. For example a measurement could initially be an amperometric measurement, with the apparatus switching to potentiometric measurement after detection of some particular event in the course of the amperometric measurement. 
         [0063]    Among the powerful approaches made possible by such a circuit is to use an amperometric mode to generate a chemical potential, which can then itself be measured by potentiometry. 
         [0064]    Turning now to  FIG. 13 , what is shown is a functional block  62  which can be the analysis circuit of any of the previously discussed figures. A voltage input  34  may be seen as well as an output  33  indicative of current in an amperometric measurement. The functional block  62  may comprise a three-terminal reaction cell  39  or a two-terminal reaction cell  39  as described in connection with the previously discussed figures. 
         [0065]    Optionally there may be a voltage output  52  indicative of voltage measured by a voltmeter  42 , omitted for clarity in  FIG. 13 . In such a case, one or two or three switches (also omitted for clarity in  FIG. 13 ) are used to isolate the cell  39  to permit potential (voltage) measurement. 
         [0066]    Importantly in  FIG. 13 , input  34  is connected to a digital-to-analog converter (DAC)  60  which receives a digital input  61 . In the most general case the DAC is a fast and accurate DAC, generating complex waveforms as a function of time at the output  63  which is in turn connected with the input  34  of the block  62 . 
         [0067]    In some cases it may turn out that the DAC can be a less expensive circuit. For example it may turn out that it can be a simple resistor ladder connected to discrete outputs from a controller. As another example it may turn out that a pulse-width-modulated output from a controller can be used to charge or discharge a capacitor, giving rise to a desired output at  63  and thus an input at  34 . Such a circuit may be seen for example in co-pending application number (docket  19 ), which application is incorporated herein by reference for all purposes. 
         [0068]    In this way it is possible to apply time-varying waveforms to reaction cells  39 , for example ramps and sinusoids. 
         [0069]    The benefits of the invention, for example the use of automatically controlled switching between amperometric and potentiometic modes, and the use of time-variant voltage inputs for the amperometric measurements, offer themselves not only for the glucose measurement mentioned above, but for myriad other measurements including blood chemistry and urine chemistry measurements, as well as immunoassays, cardiac monitoring, and coagulation analysis. 
         [0070]    Turning now to  FIG. 11 , what is shown is a perspective view of a test instrument  70 . A display  71  provides information to a user, and pushbuttons  78 ,  79 ,  80  permit inputs by the user. Display  71  is preferably a liquid-crystal display but other technologies may also be employed. Large seven-segment digits  72  permit a large portrayal of an important number such as a blood glucose level. 
         [0071]    Importantly, a rectangular array of low-resolution circles or other areas can show, in a rough way, qualitative information. This may include hematocrit level, a multi-day history trend graph, a filling rate, a temperature, a battery life, or memory/voice-message space remaining. The array can also be used to show “progress bars” which help the human user to appreciate that progress is being made in a particular analysis. The array may be fifteen circles wide and six rows high. 
         [0072]    Thus one way to use the display is to show a very rough bar graph in which the horizontal axis represents the passage of time and in which the vertical axis represents a quantity of interest. For each time interval there may be none, one, two, or three, four, five, or six circles turned on, starting from the bottom of the array. 
         [0073]    Another way to use the display is to show a very rough bar graph with between none and fifteen circles turned on, starting at the left edge of the array. 
         [0074]    In this way, at minimal expense, a modest number of circles (in this case, ninety circles) may be used in a flexible way to show quantitative information in two different ways. The circles are preferably addressed individually by means of respective traces to a connector at an edge of the liquid-crystal display. Alternatively they may addressed by row and column electrodes. 
         [0075]    The number of circles in a row may be fifteen. 
         [0076]    Turning now to  FIG. 9 , what is shown is a test instrument  70  in side view. A test strip  90 , containing an electrochemical cell  39  (omitted for clarity in  FIG. 9 ), is inserted into the test instrument  70  by means of movement to the right in  FIG. 9 . 
         [0077]    It will be appreciated that the user of the test instrument  70  may have difficulty inserting the test strip  90  into the instrument  70 . This may happen because the user has limited hand-eye coordination or limited fine-motor control. Alternatively, this may happen because the user is in a place that is not well lit, for example while camping and at night. In either case, the user can benefit from a light-emitting diode (LED)  91  which is used to light up the area of the test strip  90 . There is a connector  93  into which the strip  90  is inserted, and the LED  91  is preferably illuminated before the strip  90  is inserted. 
         [0078]    In one prior art instrument there is an LED at a connector like the connector  93 , but it only can be turned on after the strip like strip  90  is inserted. As such it is of no help in guiding the user in insertion of the strip. 
         [0079]    Importantly, then, with the apparatus of  FIG. 9 , the user can illuminate the LED before inserting the strip. This may be done by pressing a button, for example. This may cast light along path  92 , illuminating the tip of the strip. It may also cast light upon the connector  93 , or both. 
         [0080]    It may also be helpful to illuminate the tip of the strip in a different way. The strip  90  as shown in  FIG. 12  may have the ability (due to being partly or largely transparent) to serve as an optical waveguide. For example many adhesives usable in the manufacture of such strips are transparent. Light can pass along the length of the strip as shown at  95 , emitted at the end as shown at  96 . In this way it is possible to illuminate the lanced area (the area that has been pricked to produce a drop of blood) so that the tip of the strip  90  can be readily guided to the location of the drop of blood. 
         [0081]    The light-transmitting section of the strip  90  may be substantially transparent, or may be fluorescent or phosphorescent, so that the strip lights up and is easy to see. 
         [0082]    Experience with users permits selecting an LED color that is well suited to the task. For example a blue LED will offer very good contrast when the user is trying to find a drop of red blood, working better than a red LED. 
         [0083]    Turning now to  FIG. 14 , a circuit requiring only two operational amplifiers  122 ,  137  is shown. Central to the circuit is reaction cell  130  having a working electrode  120  and a counter electrode  121 . Operational amplifier  122  serves as a unity-gain amplifier (buffer) applying voltage V 2  to the working electrode  120 . Pulse-width-modulated control line  123  turns transistors  124 ,  125  on and off to develop some desired voltage through low-pass filter network  126 . This developed voltage V 2  is measured at line  127 , which in a typical case goes to an analog-to-digital converter for example at a microcontroller, all omitted for clarity in  FIG. 14 . 
         [0084]    The manner of operation of the pulse-width-modulated line  123  is described in more detail in copending application number XX, (docket number AGAM.P019,) entitled “Method and apparatus for providing stable voltage to analytical system”, filed contemporaneously herewith, which application is hereby incorporated herein by reference for all purposes. 
         [0085]    During the amperometric phase of analysis, switch  133  is open and switches  134  and  132  are closed. A reference voltage VREF at  136  develops a voltage V 1  ( 135 ) which is measured, preferably by means of an analog-to-digital converter omitted for clarity in  FIG. 14 . This voltage is provided to an input of amplifier  137 , and defines the voltage presented to the electrode  121 . The voltage developed at  128  is, during this phase, indicative of the current through the reaction cell  130 . 
         [0086]    During the potentiometric phase of analysis, switch  133  is closed and switches  134  and  132  are opened. In this way the potential at the electrode  121  is made available to the amplifier  137  and from there to the sense line  128 . The voltage developed at line  128  is indicative of the voltage at the electrode  121 , and the voltage at electrode  120  is defined by the voltage at  127 , and in this way it is possible to measure the potential difference between the electrodes  120 ,  121 . 
         [0087]    Describing the apparatus differently, what is seen is an apparatus used with a reaction cell having a first electrode and a second electrode. A voltage source provides a controllable voltage to the first electrode and a voltage sensor senses voltage provided to the first electrode. An amplifier is coupled with the second electrode by way of a switch means. The switch means is switchable between first and second positions, the switch means in the first position disposing the amplifier to measure current through the second electrode, thereby measuring current through the reaction cell. The switch means in the second position disposes the amplifier to measure voltage present at the second electrode. The switch means in an exemplary embodiment comprises first, second, and third analog switches, the first analog switch connecting the second electrode and an inverting input of the amplifier, the second analog switch connecting the second electrode and a non-inverting input of the amplifier, the third analog switch connecting the non-inverting input of the amplifier and a reference voltage. The first position is defined by the first and third switches being closed and the second switch being open, while the second position is defined by the first and third switches being open and the second switch being closed. 
         [0088]    Returning to  FIG. 14 , a low-pass filter  129  is provided to smooth the signal at line  128 . 
         [0089]    It will be appreciated that if amplifiers suitable for use in this analysis are expensive, and if analog switches suitable for use at  132 ,  133 ,  134  are inexpensive, then it is desirable to employ a circuit such as is shown here to permit minimizing the number of amplifiers needed. 
         [0090]    Those skilled in the art will have no difficulty devising myriad obvious improvements and variations upon the embodiments of the invention without departing from the invention, all of which are intended to be encompassed by the claims which follow.