Patent Publication Number: US-2006013731-A1

Title: Microfluidic system with feedback control

Description:
CROSS-REFERENCE  
      This application is a continuation-in-part application of application Ser. No. 10/811,446, filed Mar. 26, 2004, which is incorporated herein by reference in its entirety and to which application we claim priority under 35 USC §120. 
    
    
     BACKGROUND OF THE INVENTION  
      1. Field of the Invention  
      The present invention relates, in general, to analytical devices and, in particular, to microfluidic analytical systems.  
      2. Description of the Related Art  
      In analytical devices based on liquid samples (i.e., fluidic analytical devices), the requisite liquid samples should be controlled with a high degree of accuracy and precision in order to obtain reliable analytical results. Such control is especially warranted with respect to “microfluidic” analytical devices that employ liquid samples of small volume, for example, 10 nanoliters to 10 microliters. In such microfluidic analytical devices, the liquid samples are typically contained and transported in micro-channels with dimensions on the order of, for example, 10 micrometers to 500 micrometers.  
      The control (e.g., transportation, position detection, flow rate determination and/or volume determination) of small volume liquid samples within micro-channels can be essential in the success of a variety of analytical procedures including the determination of glucose concentration in interstitial fluid (ISF) samples. For example, obtaining reliable results may require knowledge of liquid sample position and/or volume in order to insure that a sufficient liquid sample has arrived at a detection area before analysis is commenced. The relatively small size of the liquid samples and micro-channels in microfluidic analytical devices can, however, render such control problematic.  
      In the context of analytical systems for blood glucose monitoring, continuous or semi-continuous monitoring systems and methods are advantageous in that they provide enhanced insight into blood glucose concentration trends, the effect of food and medication on blood glucose concentration and a user&#39;s overall glycemic control. A challenge of continuous or semi-continuous glucose monitoring systems is that only small volumes of liquid sample (e.g., an ISF liquid sample of about 250 nanoliters) are generally available for measuring a glucose concentration. In addition, it is difficult to transport small volumes of liquid from a target site to an ex vivo glucose monitor with a controlled flow rate and in such a way that the position and total volume of extracted fluid is known. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
      A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:  
       FIG. 1  is a simplified cross-sectional side view and schematic representation of a microfluidic analytical system according to an exemplary embodiment of the present invention;  
       FIG. 2  is a simplified perspective view of a molded plug of the microfluidic analytical system of  FIG. 1 ;  
       FIG. 3  is a simplified top view of a micro-channel disc of the microfluidic analytical system of  FIG. 1 ;  
       FIG. 4  is a simplified bottom view of a laminate layer of the microfluidic analytical system of  FIG. 1 ;  
       FIG. 5  is a simplified block diagram depicting a microfluidic system for extracting a bodily fluid sample and monitoring an analyte therein, with which embodiments of microfluidic analytical systems according to the present invention can be employed;  
       FIG. 6  is a simplified schematic diagram of the sampling module of  FIG. 5  being applied to a user&#39;s skin layer, with the dashed arrow indicating a mechanical interaction and the solid arrows indicating ISF flow or, when associated with element  228 , the application of pressure;  
       FIG. 7  is a simplified schematic diagram of a position electrode, micro-channel, analyte sensor and meter configuration for use in embodiments of microfluidic analytical systems according to the present invention;  
       FIG. 8A  is a simplified cross-sectional and schematic diagram illustrating a manner in which a position electrode can be exposed to a micro-channel in embodiments of microfluidic analytical systems according to the present invention;  
       FIG. 8B  is a simplified cross-sectional and schematic diagram illustrating a manner in which a position electrode is separated from a micro-channel by an insulating layer in embodiments of microfluidic analytical systems according to the present invention;  
       FIG. 9  is simplified schematic diagram of another position electrode, micro-channel, analyte sensor and meter configuration for use in embodiments of microfluidic analytical systems according to the present invention illustrating a manner by which a position detector can be in electrical communication with an analyte sensor;  
       FIG. 10  simplified schematic diagram of yet another position electrode, micro-channel, analyte sensor and meter configuration for use in embodiments of microfluidic analytical systems according to the present invention showing the use of three position electrodes;  
       FIG. 11  is simplified schematic diagram of a position electrode, main micro-channel, branch micro-channels, analyte sensor and meter configuration for use in embodiments of microfluidic analytical systems according to the present invention;  
       FIG. 12  is simplified schematic diagram of another position electrode, main micro-channel, branch micro-channels, analyte sensor and meter configuration for use in embodiments of microfluidic analytical systems according to the present invention;  
       FIG. 13  is a simplified schematic diagram of a position electrode, micro-channel and meter configuration for use in embodiments of microfluidic analytical systems according to the present invention;  
       FIG. 14  is a simplified schematic diagram of an equivalent electrical circuit for a portion of the configuration of  FIG. 13 ;  
       FIG. 15  is a simplified schematic diagram of a further position electrode, micro-channel and meter configuration for use in embodiments of microfluidic analytical systems according to the present invention;  
       FIG. 16  is a simplified schematic diagram of an equivalent electrical circuit for a portion of the configuration of  FIG. 15 ;  
       FIG. 17  is a simplified schematic diagram of another position electrode, micro-channel and meter configuration for use in embodiments of microfluidic analytical systems according to the present invention;  
       FIG. 18  is a simplified schematic diagram of yet another position electrode, micro-channel and meter configuration for use in embodiments of microfluidic analytical systems according to the present invention;  
       FIG. 19  is a simplified schematic diagram of an equivalent electrical circuit for a portion of the configuration of  FIG. 18 ;  
       FIG. 20  is a simplified schematic diagram of still another a position electrode, micro-channel and meter configuration for use in embodiments of microfluidic analytical systems according to the present invention;  
       FIG. 21  is a graph of admittance versus bolus number; and  
       FIG. 22  is a flow diagram depicting stages in a process for the feedback control of a microfluidic system according to an exemplary embodiment of the present invention.  
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
       FIGS. 1-4  depict a microfluidic analytical system  100  for determining an analyte (e.g., detecting the analyte and/or measuring the concentration of the analyte) in a liquid sample according to an exemplary embodiment of the present invention.  
      Microfluidic analytical system  100  includes an analysis module  102  with a micro-channel  104  for receiving and transporting a liquid sample (e.g., an ISF sample extracted from a dermal tissue target site of a user&#39;s body), an analyte sensor  106  (e.g., an electrochemical analyte sensor or photometric analyte sensor) for measuring an analyte (e.g., glucose) in the liquid sample, and first and second position electrodes  108  and  110 . In the embodiment of  FIGS. 1-4 , micro-channel  104  includes a pre-sensor micro-channel portion  104   a  and a post-sensor micro-channel portion  104   b . Microfluidic analytical system  100  also includes a sensor chamber  105 , within which analyte sensor  106  is disposed.  
      Microfluidic analytical system  100  further includes a meter  112  for measuring impedance between first position electrode  108  and second position electrode  110 , with the measured impedance being dependent on the position of a liquid sample (not shown in  FIGS. 1-4 ) in micro-channel  104 .  
      In general, measuring impedances, or ohmic resistances, between position electrodes in embodiments of the present invention can be accomplished by applying a voltage therebetween and measuring the resulting current. Either a constant voltage or an alternating voltage can be applied between the position electrodes and the resulting direct current (DC) or alternating current (AC), respectively, measured. The resulting DC or AC current can then be used to calculate the impedance or ohmic resistance. Furthermore, one skilled in the art will recognize that measuring an impedance can involve measuring both an ohmic drop (i.e., resistance [R] in Ohms or voltage/current) and measuring capacitance (i.e., capacitance in Farads or coulombs/volt). In practice, impedance can be measured, for example, by applying an alternating current to the position electrode(s) and measuring the resulting current. At different frequencies of alternating current, either resistive or capacitive effects prevail in determining the measured impedance. The pure resistive component can prevail at lower frequencies while the pure capacitive component can prevail at higher frequencies. To distinguish between the resistive and capacitive components, the phase difference between the applied alternating current and the measured resulting current can be determined. If there is zero phase shift, the pure resistive component is prevailing. If the phase shift indicates that the current lags the voltage, then the capacitive component is significant. Therefore, depending on the frequency of an applied alternating current and position electrode configuration, it can be beneficial to measure either resistance or a combination of resistance and capacitance.  
      In the embodiment of  FIGS. 1-4 , impedance measurements can be performed by, for example, applying an alternating voltage between first position electrode  108  and second position electrode  110  and measuring the resulting alternating current. Since first position electrode  108  and second position electrode  110  are a portion of a capacitor (along with any substance [e.g., air or a liquid sample] within micro-channel  104  between the first and second position electrodes and any layers that may be separating the position electrodes from direct contact with the substance), the measured current can be used to calculate the impedance. The presence or absence of a liquid sample in micro-channel  104  between the first and second position electrodes will affect the measured current and impedance.  
      The frequency and amplitude of the alternating voltage applied between the first and second position electrodes can be predetermined such that the presence of a liquid sample between the first and second position electrodes can be detected by a significant increase in measured current.  
      With respect to the measurement of impedance or resistance, the magnitude of the applied voltage can be, for example, in range from about 10 mV to about 2 volts for the circumstance of an ISF liquid sample and carbon-based or silver-based ink position electrodes. The lower and upper limits of the applied voltage range are dependent on the onset of electrolysis or electrochemical decomposition of the liquid sample. In the circumstance that an alternating voltage is employed, the alternating voltage can be applied, for example, at a frequency that results in a negligible net change in the liquid sample&#39;s properties due to any electrochemical reaction. Such a frequency range can be, for example, from about 10 Hz to about 100 kHz with a voltage waveform symmetrical around 0 Volts (i.e., the RMS value of the alternating voltage is approximately zero).  
      As depicted in a simplified manner in  FIG. 1 , analyte sensor  106 , first position electrode  108  and second position electrode  110  are each in operative communication with micro-channel  104 . It should be noted that position electrodes employed in embodiments of the present invention can be formed of any suitable conductive material known to those skilled in the art, including conductive materials conventionally used as analytical electrode materials and, in particular, conductive materials known as suitable for use in flexible circuits, photolithographic manufacturing techniques, screen printing techniques and flexo-printing techniques. Suitable conductive materials include, for example, carbon, noble metals (e.g., gold, platinum and palladium), noble metal alloys, conductive potential-forming metal oxides and metal salts. Position electrodes can be formed, for example, from conductive silver ink, such as the commercially available conductive silver ink Electrodag 418 SS.  
      In the embodiment of  FIGS. 1-4 , analysis module  102  further includes a molded plug  114 , a micro-channel disc  116  and a laminate layer  118  (depicted individually in  FIGS. 2, 3  and  4 , respectively). Analysis module  102  can be constructed by, for example, interfacing micro-channel disc  116  with laminate layer  118  and molded plug  114 .  
      Molded plug  114  includes an inlet channel  120  and a registration pole  122 . Micro-channel disc  116  is configured to define (along with laminate layer  118 ) a liquid sample waste reservoir  124 , as well as the aforementioned micro-channel  104  and sensor chamber  105 . In addition, micro-channel disc  116  includes a registration hole  126  (see, for example,  FIG. 3 ).  
      Laminate layer  118  includes an access hole  128 , a membrane valve  130 , and in the embodiment of  FIGS. 1-4 , the aforementioned analyte sensor  106  and first and second position electrodes  108  and  110 .  
      Micro-channel  104  has cross-sectional dimensions perpendicular to a direction of fluid flow (i.e., height and width) in the range of about 10 micrometers to about 500 micrometers. Typical liquid sample volumes to be handled in a micro-channel(s) of embodiments of the present invention are on the order of about 10 nanoliters to about 10 microliters. In this respect, the term “handled” is in reference to the transportation and control of various liquid sample volumes including, but not limited to, isolated liquid sample volumes extracted from a target site (e.g., isolated volumes in the range of 50 nl to 250 nl), the minimum liquid sample volume required by an analyte sensor (for example, 50 nl), and the total liquid sample volume that is conducted through a micro-channel throughout the useful lifetime of a microfluidic analytical system (for example, a total volume of approximately 10 micro-liters).  
      Registration pole  122  of molded plug  114  is employed during manufacturing of microfluidic analytical system  100  to ensure adequate alignment (i.e., registration) of molded plug  114  and micro-channel disc  116 . For example, such alignment must insure that analyte sensor  106  is operatively aligned with sensor chamber  105  and that first and second position electrodes  108  and  110  are aligned with post-sensor micro-channel channel  104   b . During manufacturing, laminate layer  118  can be aligned with micro-channel disc  116  using registration features included in laminate layer  118  and/or micro-channel disc  116  (not shown) or by optical verification.  
      Registration hole  126  of micro-channel disc  116  is depicted as having a half circle shape and extending entirely through micro-channel disc  116 . Registration pole  122  has a shape and size that are complementary to registration hole  126 , thus providing for micro-channel disc  116  to securely interface with the molded plug  114 , as depicted in  FIG. 1 . The use of half circle shapes for both registration hole  126  and registration pole  122  beneficially limits the rotational freedom of a combined molded plug  114  and micro-channel disc  116 . It should be noted that alternative shapes other than a half circle can also be used.  
      Although not depicted in  FIGS. 1-4 , laminate layer  118  includes electrical connections to electrically connect analyte sensor  106  to external apparatus (such as a local controller module as described with respect to  FIG. 5  below) and to connect first and second position electrodes  108  and  110  to meter  112 . Such electrical connections can include, for example, conductive traces and electrical contact pads.  
      It is contemplated that a liquid sample (e.g., an ISF sample) will be transported to inlet channel  120  by suitable means, such as a sampling module as described below with respect to  FIG. 5 . Flow of liquid sample through inlet channel  120  is controlled by membrane valve  130 . It should be noted that other types of valves, besides membrane valves, can be used and are well know to one skilled in the art.  
      In an embodiment of  FIG. 1 , membrane valve  130  is deformable and made of an elastomeric material in a dome shape. When membrane valve  130  is an undeformed condition, a liquid sample may flow past membrane valve  130  and fill pre-sensor micro-channel portion  104   a . However, when membrane valve  130  is initially deformed (for example, by the application of pressure via access hole  128 ), it occludes inlet channel  120  and prevents liquid sample from flowing therethrough. In addition, further deformation of membrane valve  130  pushes liquid sample through pre-sensor micro-channel portion  104   a  and into sensor chamber  105 . The movement of liquid sample past membrane valve  130  (i.e., from inlet channel  120  to pre-sensor micro-channel portion  104   a ) can be controlled by the amount of pressure applied in deforming membrane valve  130 . Typical liquid sample flow rates into micro-channel  104  are in the range of about 10 nanoliters per minute to about 1000 nanoliters per minute.  
      First and second position electrodes  108  and  110 , along with meter  112 , can be used to determine the liquid sample position within micro-channel  104 , the flow rate of a liquid sample and/or the volume of an extracted liquid sample to help control the depression of membrane valve  130 . For example, upon determination of the liquid sample position, knowledge of elapsed time and micro-channel volume can be employed to calculate the flow rate and/or volume of the liquid sample. One skilled in the art will recognize, therefore, that, in general, position electrode(s) electrical characteristics (such as impedance and resistance) measured by meter  112  are indicative of liquid sample position, liquid sample flow rate and liquid sample volume.  
      In addition, meter  112  can optionally include an integrated feedback controller (e.g., a feedback controller that includes suitable microprocessors and/or other electronic circuits) configured to provide a feedback control loop that places membrane valve  130  in a deformed or undeformed condition depending on the flow rate, position or volume of liquid sample within microchannel  104 . In other words, such a feedback control loop serves to occlude (close) or open inlet channel  120  to the flow of liquid sample therethrough. Once apprised of the present disclosure, one skilled in the art can readily ascertain suitable feedback controllers for providing such a feedback control loop.  
      The use of a feedback controller has the benefit of enabling the collection of the minimal volume of liquid sample required to perform an accurate measurement of the analyte and in doing so, to minimize measurement time across varying sampling conditions.  
      It can be beneficial to determine liquid sample position in order to, for example, ascertain when a minimum amount of liquid sample has entered analysis module  102  in order to initiate analyte determination. It can also be beneficial to determine liquid sample flow rate and/or the total amount of liquid sample that has entered microfluidic analytical system  100  in order to control membrane valve  130  in a manner that facilitates semi-continuous stopped flow measurements (i.e., measurements taken with liquid sample flow momentarily halted and that result in a predetermined number of measurements per unit time [typically in the range of 4 to 10 measurements per hour] rather than a continuous measurement) over predetermined time periods. In addition, determining liquid sample flow rate and the total amount of liquid sample enables sensor lag compensation. Furthermore, analyte sensor  106  may be sensitive to flow rate. Therefore, the use of first and second position electrodes  108  and  110 , along with meter  112 , allows system  100  to more accurately determine an analyte over an extended period of time such as, for example, about 8 hours. As described above, membrane valve  130  can be controlled by a feedback controller to facilitate the aforementioned semi-continuous stopped flow measurements.  
      In the embodiment of  FIGS. 1-4 , analyte sensor  106  is disposed within sensor chamber  105 . Analyte sensor  106  can be any suitable sensor known to one skilled in the art. For the circumstance where the analyte of interest is glucose, analyte sensor  106  can be an electrochemical glucose sensor that measures a current proportional to glucose concentration. More particularly, analyte sensor  106  can be, for example, an electrochemical glucose sensor that measures current under stopped flow conditions (i.e., flow rates at or near zero during measurement) and with glucose being consumed within sensor chamber  105 . Examples of analyte sensors that may be used in embodiments of the present invention include, but not limited to, electrochemical-based and photometric-based analyte sensors. Electrochemical-based analyte sensors include, for example, amperometric, potentiometric and coulometric analyte sensors. Photometric-based analyte sensors include, for example, transmission, reflectance, colorimetric, fluorometric, scattering and absorbance analyte sensors.  
      After an analyte in a liquid sample has been determined by analyte sensor  106 , the liquid sample is transported to post-sensor micro-channel portion  104   b.    
      One skilled in the art will recognize that analyte monitoring systems according to embodiments of the present invention can be employed, for example, as a subsystem in a variety of devices. For example, embodiments of the present invention can be employed as an analysis module of microfluidic system  200  depicted in  FIG. 5 . Microfluidic system  200  is configured for extracting a bodily fluid sample (e.g., an ISF sample) and monitoring an analyte (e.g., glucose) therein. System  200  includes a disposable cartridge  212  (encompassed within the dashed box), a local controller module  214  and a remote controller module  216 . It should be noted that in  FIG. 5 , the arrows indicate direction of transfer for both liquid sample and electrical signals as the appropriate circumstances dictate.  
      In system  200 , disposable cartridge  212  includes a sampling module  218  for extracting the bodily fluid sample (namely, an ISF sample) from a body (B, for example, a user&#39;s skin layer) and an analysis module  200  for measuring an analyte (i.e., glucose) in the bodily fluid. Sampling module  218  can be any suitable sampling module known to those of skill in the art, while analysis module  220  can be a microfluidic analytical system according to embodiments of the present invention. Examples of suitable sampling modules are described in International Application PCT/GB01/05634 (published as WO 02/49507 A1 on Jun. 27, 2002) and U.S. patent application Ser. No. 10/653,023, which is hereby fully incorporated herein by reference. However, in system  200 , sampling module  218  is configured to be disposable since it is a component of disposable cartridge  212 .  
      As depicted in  FIG. 6 , the sampling module  218  of system  200  is an ISF sampling module that includes a penetration member  222  for penetrating a target site (TS) of body B and extracting an ISF sample, a launching mechanism  224  and at least one pressure ring  228 . Sampling module  218  is adapted to provide a continuous or semi-continuous flow of ISF to analysis module  220  for the monitoring (e.g., concentration measurement) of an analyte (such as glucose) in the ISF sample.  
      During use of system  200 , penetration member  222  is inserted into the target site (i.e., penetrates the target site) by operation of launching mechanism  224 . For the extraction of an ISF sample from a user&#39;s skin layer, penetration member  222  can be inserted to a maximum insertion depth in the range of, for example, 1.5 mm to 3 mm. In addition, penetration member  222  can be configured to optimize extraction of an ISF sample in a continuous or semi-continuous manner. In this regard, penetration member  222  can include, for example, a 25 gauge, thin-wall stainless steel needle (not shown in  FIG. 5  or  6 ) with a bent tip, wherein a fulcrum for the tip bend is disposed between the needle&#39;s tip and the needle&#39;s heel. Suitable needles for use in penetration members are described in U.S. patent application Ser. No. 10/185,605 (published as U.S. 2003/0060784 A1 on Mar. 27, 2003). Furthermore, further details regarding system  200  are in U.S. patent application Ser. No. 10/718,818.  
      Once penetration member  222  has penetrated target site TS, pressure ring(s)  228  can be employed to apply pressure (i.e., apply force) to the user&#39;s skin layer in the vicinity of the target site (indicated by the downward pointing arrows of  FIG. 6 ). Such pressure serves to create a sub-dermal interstitial fluid (ISF) pressure gradient in the vicinity of the target site. This sub-dermal ISF pressure gradient induces a flow of ISF through penetration member  222  and sampling module  218  to analysis module  220  (as indicated by the curved and upward pointing arrows of  FIG. 6 ).  
      Pressure ring  228  can be referred to as being in a “deployed” state when pressure ring  228  is applying pressure on the user&#39;s skin layer in the vicinity of the target site as described above. Furthermore, pressure ring  228  can be referred to as being in a “retracted” state when pressure ring  228  is not applying pressure to the user&#39;s skin layer in the vicinity of the target site, although the penetration member can continue to reside in the user&#39;s skin layer. In such a retracted state, fluid flow through penetration member  222  is effectively stopped.  
      Therefore, placing pressure ring  228  in a deployed or retracted state can serve to control (e.g., start, stop or otherwise adjust) the flow of liquid sample (e.g., ISF sample) through sampling module  218  and into analysis module  220 . Placing pressure ring  228  into a deployed and/or retracted state can be accomplished via a feedback controller adapted to control the flow of bodily fluid sample through the microfluidic system based on an electrical characteristic (such as impedance or resistance) measured by the meter. Such a feedback controller can, therefore, be employed to, for example, facilitate semi-continuous stopped flow measurements.  
      In the embodiment of  FIGS. 1-4 , first and second position electrodes  108  and  110  and meter  112  are configured such that both the first and second position electrodes are “downstream” of analyte sensor  106  with respect to micro-channel  104 . However, other suitable configurations can be employed. For example,  FIG. 7  is a simplified schematic diagram of a position electrode, micro-channel, analyte sensor and meter configuration  300  for use in embodiments of microfluidic analytical systems according to the present invention. Configuration  300  includes first position electrode  302 , second position electrode  304 , electrical impedance meter  306 , timer  308 , micro-channel  310  and analyte sensor  312 . In the configuration of  FIG. 7 , wavy lines depict a liquid sample (e.g., an ISF, blood, urine, plasma, serum, buffer or reagent liquid sample) within micro-channel  310 .  
      Configuration  300  can be used to determine the position or flow rate of a liquid sample in micro-channel  310 . In the configuration of  FIG. 7 , analyte sensor  312  is located in-between first position electrode  302  and second position electrode  304 . Electrical impedance meter  306  is adapted for measuring an electrical impedance between first position electrode  302  and second electrode  304 . Such a measurement can be accomplished by, for example, employing a voltage source to impose either a continuous or alternating voltage between first position electrode  302  and second position electrode  304  such that an impedance resulting from a conducting path formed by a liquid sample within micro-channel  310  and between first position electrode  302  and second position electrode  304  can be measured, yielding a signal indicative of the presence of the liquid sample.  
      Furthermore, when electrical impedance meter  306  measures a change in impedance due to the presence of a liquid sample between the first and second position electrodes, a signal can be sent to timer  308  to mark the time at which liquid is first present between the first and second position electrodes. When the measured impedance indicates that the liquid sample has reached the second position electrode, another signal can be sent to timer  308 . The difference in time between when a liquid sample is first present between the first and second position electrodes and when the liquid sample reaches the second position electrode can be used to determine liquid sample flow rate (given knowledge of the volume of micro-channel  310  between the first and second position electrodes). Furthermore, knowledge of liquid sample flow rate and/or liquid sample position can be used to determine total liquid sample volume. In addition, a signal denoting the point in time at which a liquid sample arrives at second position electrode  304  can also be sent to a local controller module (e.g., local controller module  214  of  FIG. 5 ) for use in determining the proper deformed state for membrane valve  130  and/or determining the retracted or deployed state of a sampling module&#39;s pressure ring. Therefore, such a local controller module can optionally include a feedback controller as described herein.  
      It can be desirable to collect a pre-determined minimum volume of ISF liquid sample before making an analytical measurement. Such a predetermined minimum volume may be in the range of, for example, from about 25 nanoliters to about 500 nanoliters, and preferably may range from about 100 nanoliters to about 250 nanoliters. In this regard, a sampling module pressure ring (such as pressure ring  228  of  FIG. 5 ) can be placed in a deployed state for a duration of time such that the pre-determined volume of liquid is collected. Once first position electrode  302  and second position electrode  304  indicate that the pre-determined volume of liquid has been collected, a feedback controller within local controller module  214  can be employed to place the pressure ring(s) in a retracted state that essentially stops flow through the sampling module. It should be noted that under certain biological conditions, fluid may still flow through a sampling module even though pressure ring(s)  228  is in a retracted state. However, such flow is relatively insignificant in magnitude and typically ranges from, for example, 0 nanoliters per minute to 50 nanoliters per minute. If desired, the feedback controller can be employed to subsequently place the pressure ring(s) in a deployed state and, thus, restart liquid sample flow.  
      In an alternative embodiment to this invention, first position electrode  302  and second position electrode  304  may be used to measure flow rate instead of volume. In this case, local controller module  214 , can employ a feedback controller that deploys or retracts pressure ring(s) based on flow rate.  
       FIG. 8A  is a simplified cross-sectional and schematic diagram illustrating a manner in which a position electrode can be in operative communication with a micro-channel in embodiments of microfluidic analytical systems according to the present invention.  FIG. 8A  depicts a micro-channel  350  (in cross-section), a micro-channel disc  352 , a position electrode  354 , a laminate layer  356  and a meter  358 . In the configuration of  FIG. 8A , position electrode  354  is in operative communication with the micro-channel  350  such that a surface  360  of position electrode  354  is exposed to liquid sample (depicted by the wavy lines in  FIG. 8A ) in micro-channel  350 .  
      In the embodiment of  FIG. 8A  (and other embodiments of the present invention), micro-channel disc  352  and laminate layer  356  are made of electrically insulating material such as, for example, polymeric insulating materials (e.g., polystyrene, silicone rubber, PMMA, polycarbonate or PEEK) and non-polymeric insulating materials such as, for, example, glass.  
       FIG. 8B  is a simplified cross-sectional and schematic diagram (employing the same labeling numerals as  FIG. 8A ) illustrating another manner by which a position electrode can be in operative communication with a micro-channel in embodiments of microfluidic analytical systems according to the present invention.  FIG. 8B  depicts a micro-channel  350  (in cross-section), a micro-channel disc  352 , a position electrode  354 , a laminate layer  356  and a meter  358 . In the configuration of  FIG. 8   b , position electrode  354  is in operative communication with the micro-channel  350  but separated from micro-channel  350  by an insulating layer, namely a portion of laminate layer  356 . A benefit of the manner depicted in  FIG. 8B  is that there is no direct contact between liquid sample in micro-channel  350  and position electrode  354  and, consequently, no electrolysis or electrochemical decomposition of the liquid sample due to position electrode  354  can occur.  
       FIG. 9  is simplified schematic diagram of another micro-channel, analyte sensor and position electrode configuration  400  for use in embodiments of microfluidic analytical systems according to the present invention. Configuration  400  includes first position electrode  402 , second position electrode  404 , electrical impedance meter  406 , timer  408 , micro-channel  410  and analyte sensor  412 . In the configuration of  FIG. 9 , wavy lines depict a liquid sample (e.g., an ISF, blood, urine, plasma, serum, buffer or reagent liquid sample) within micro-channel  410 .  
      In the embodiment of  FIG. 9 , both first position electrode  402  and analyte sensor  412  are in operative communication with local controller module  214 . In this manner first position electrode can serve both as a position electrode and as a reference electrode for analyte sensor  412  (assuming that analyte sensor  412  is an electrochemical-based analyte sensor). Furthermore, it should be noted that electrical impedance meter  406  and timer  408  may be incorporated into local controller module  214 .  
      An advantage of the configuration of  FIG. 9  is a reduced complexity that is achieved by using the first position electrode as both a position electrode and a reference electrode for analyte sensor  412 . In the configuration of  FIG. 9 , first position electrode  402  can, for example, be manufactured of a material that results in a stable electrical potential between the first position electrode and the liquid sample. In the circumstance that the liquid sample is an ISF liquid sample, the first position electrode can be formed of chlorinated silver (Ag/AgCl).  
       FIG. 10  is a simplified schematic diagram of yet another position electrode, micro-channel, analyte sensor and meter configuration  450  for use in embodiments of microfluidic analytical systems according to the present invention. Configuration  450  includes first, second and third position electrodes  452 ,  454  and  456 , respectively, an analyte sensor  458 , an electrical impedance meter  460 , timer  462 , and micro-channel  464 . Electrical impedance meter  460  is configured to measure the electrical impedance between any two of the first, second and third position electrodes.  
      Configuration  450  differs from configurations  300  and  400  in that configuration  450  includes three position electrodes. The inclusion of three position electrodes provides for an improved ability to accurately detect the position and flow rate of a liquid sample within micro-channel  464 . For example, the use of two position electrodes enables the detection of a single bolus (i.e., the volume contained in a micro-channel between the two position electrodes). However, the use of three (or more) position electrodes enables the detection of multiple boluses as the liquid sample sequentially passes the three (or more) position electrodes.  
       FIG. 11  is simplified schematic diagram of a position electrode, micro-channel (comprised of a main micro-channel and two branch micro-channels), analyte sensor and meter configuration  500  for use in embodiments of microfluidic analytical systems according to the present invention. Configuration  500  includes a micro-channel comprised of main micro-channel  502 , first branch micro-channel  504  and second branch micro-channel  506 . Configuration  500  also includes first position electrode  508  (in operative communication with main micro-channel  502 ), second position electrode  510  (in operative communication with first branch micro-channel  504 ) and third position electrode  512  (in operative communication with second branch micro-channel  506 ).  
      Furthermore, configuration  500  includes a first analyte sensor  514  (in operative communication with first branch micro-channel  504 ) and a second analyte sensor  516  (in operative communication with second branch micro-channel  506 ), a meter  518  and timer  520 . Meter  518  is configured to measure an electrical characteristic (e.g., impedance) between the first position electrode and either of the second and third position electrodes.  
      It is envisioned that configuration  500  will be employed in a device that includes liquid handling means for selectively directing a liquid sample from main micro-channel  502  to either of first and second branch micro-channels  504  and  506 . Examples of such liquid handling means include, but are not limited to, active valves, passive valves, capillary breaks, air pressure barriers and hydrophobic patches.  
      Configuration  500  can be employed to detect the position of a liquid sample in either first branch micro-channel  504  (by employing meter  518  to measure an electrical characteristic between first position electrode  508  and second position electrode  510 ) or second branch micro-channel  506  (by employing meter  518  to measure an electrical characteristic between first position electrode  508  and third position electrode  512 ). Such detection(s) can be employed to control liquid sample flow and the determination of an analyte in the liquid sample by either first analyte sensor  514  or second analyte sensor  516 .  
       FIG. 11  is simplified schematic diagram of another position electrode, micro-channel (comprised of a main micro-channel and two branch micro-channels), analyte sensor and meter configuration  550  for use in embodiments of microfluidic analytical systems according to the present invention. Configuration  550  includes a micro-channel comprised of main micro-channel  552 , first branch micro-channel  554  and second branch micro-channel  556 . Configuration  550  also includes first and second position electrodes  558  and  560  (in operative communication with first branch micro-channel  554 ), and third and fourth position electrodes  562  and  564  (in operative communication with second branch micro-channel  556 ).  
      Furthermore, configuration  550  includes a first analyte sensor  566  (in operative communication with first branch micro-channel  554 ) and a second analyte sensor  568  (in operative communication with second branch micro-channel  556 ), a meter  570  and timer  572 . Meter  570  is configured to measure an electrical characteristic (e.g., impedance) between either of the first and second position electrodes and the third and fourth position electrodes.  
      It is envisioned that configuration  550  will be employed in a device that includes liquid handling means for selectively directing a liquid sample from main micro-channel  552  to either of first and second branch micro-channels  554  and  556 . Examples of such liquid handling means include, but are not limited to, active valves, passive valves, capillary breaks, air pressure barriers and hydrophobic patches.  
      Configuration  550  can be employed to detect the position of a liquid sample in either first branch micro-channel  554  (by employing meter  570  to measure an electrical characteristic between first position electrode  558  and second position electrode  560 ) or second branch micro-channel  556  (by employing meter  570  to measure an electrical characteristic between third position electrode  562  and fourth position electrode  564 ). Such detection(s) can be employed to control liquid sample flow and the determination of an analyte in the liquid sample by either first analyte sensor  566  or second analyte sensor  568 . A benefit of configuration  550  is that the first and second position electrodes (as well as the third and fourth position electrodes) can be positioned relatively close together to enable accurate measurements of relatively high electrical characteristics (e.g., relatively high impedances) therebetween.  
       FIG. 13  is a simplified schematic diagram of a position electrode, micro-channel and meter configuration  600  for use in embodiments of microfluidic analytical systems according to the present invention.  FIG. 14  is a simplified schematic diagram of an equivalent electrical circuit for a portion of configuration  600  of  FIG. 13 .  
      Configuration  600  includes a first position electrode  602  and a second position electrode  604  in an interdigitated configuration. Configuration  600  also includes a micro-channel  606  and a meter  608 . First and second position electrodes  602  and  604  each having a plurality of electrode portions that are placed substantially parallel to, and in alternating succession with, each other (e.g., in an alternating, “finger-like” pattern as depicted in  FIG. 13 ). For explanatory purposes, four electrode portions for first and second position electrodes  602  and  604  ( 602   a  and  604   a , respectively) are illustrated in  FIG. 13 . The interdigitated electrode portions are also referred to as “fingers.” 
      The position electrodes of embodiments of the present invention and the spacing therebetween can be of any suitable dimension. Advantageously, an interdigitated configuration can be employed with dimensions (e.g., dimensions W g  and W e  of  FIG. 13 ) that allow for the measurement of electrical properties of a relatively small liquid sample.  
      In configuration  600 , each “finger” can independently have a width We in the range of, for example, from about 1 micrometers to about 1500 micrometers. The separation between electrode “fingers” (W g ) can be, for example, in the range between about 0.1 millimeters and about 15 millimeters. The thickness of the position electrodes is sufficient to support a desired electric current. Exemplary thicknesses are, for example, in the range from about 1 micrometers to about 100 micrometers.  
      Interdigitated configurations such as configuration  600  can have any number of “fingers” that are sufficient to provide utility, e.g., providing contact with a liquid sample and to measure an electrical characteristic. An interdigitated configuration can have, for example, from 2 to about 100 “fingers.” 
      Configuration  600  can be employed to detect a liquid sample bolus(es) flowing through micro-channel  606 . With such boluses having a pre-determined volume (such as for example 250 nanoliters) defined by the height and width of micro-channel  606  and the distance W g . For example, if micro-channel  606  has a height and width that are both about 250 microns, W e  is about 0.5 millimeters and W g  is about 4 millimeters, then when there is no liquid sample bridging between any finger of position electrode  602  and position electrode  604 , the resistance between first electrode  602  and second electrode  604  is essentially infinity. However, if an ISF liquid sample bridges (fills) micro-channel  606  between the first finger of the first position electrode and the first finger of the second position electrode (a circumstance depicted by wavy lines in FIG.  13 ), a measured total resistance R T  decreases to a liquid resistance R I  of about 37 KOhm.  
      It should be noted that in configuration  600 , the resistance of each finger R e  is much less than R I  by at least about a factor of ten. As micro-channel  606  fills further with a liquid sample, the measured total resistance R T  between first position electrode  602  and second position electrode  604  further decreases. The decrease in total measured total resistance R T  can characterized by the equation  
           R   T     =       R   I     n       ,       
 
 where n=the number fingers “bridged” by the liquid sample. Configuration  600  is particularly useful when R e  is much less than R I . 
 
      In configuration  600 , micro-channel  606  is depicted as passing (i.e., coming into operative communication with) each electrode finger  602   a  one time. However, micro-channel  606  could alternatively have a serpentine configuration such that micro-channel  606  passes each electrode finger  602   a  a plurality of times. Such a configuration can enhance the ability to easily resolve relatively small liquid sample volumes (e.g., liquid sample volumes of less than 5 nl).  
       FIG. 15  is a simplified schematic diagram of a position electrode, micro-channel and meter configuration  650  for use in embodiments of microfluidic analytical systems according to the present invention.  FIG. 16  is a simplified schematic diagram of an equivalent electrical circuit for a portion of configuration  600  of  FIG. 15 .  
      Configuration  650  includes a single comb-shaped position electrode  652  with eight “fingers”  652   a , a micro-channel  654  and a meter  656 . Electrode fingers  652   a  serve to define electrode segments therebetween with each segment having a resistance R e  (as depicted in  FIG. 16 ). It should be noted that the dimensions W g  and W e  of  FIG. 16  can be the same as described previously with respect to configuration  600 .  
      When there is no liquid sample in micro-channel  654  between any of the eight fingers  652   a , a measured total resistarice of position electrode  652  is the summation of the resistance for each electrode segment R e  (i.e., the resistance of all electrode elements together). However, once a liquid sample begins to fill micro-channel  654  between any of fingers  652   a , the measured total resistance R T  decreases since resistance R I  is created in parallel to R e  (see  FIG. 16 ). It should be noted that with respect to configuration  650 , the resistance of each electrode segment R e  is significantly greater than R I , preferably by about a factor of ten or greater.  
       FIG. 17  is a simplified schematic diagram of a position electrode, micro-channel and meter configuration  700  for use in embodiments of microfluidic analytical systems according to the present invention. Configuration  700  includes a single serpentine-shaped position electrode  702 , a micro-channel  704  and a meter  706 .  
      It should be noted that the dimensions W g  and W e  of  FIG. 16  can be the same as described previously with respect to configuration  600 .  
       FIG. 18  is a simplified schematic diagram of a position electrode, micro-channel and meter configuration  750  for use in embodiments of microfluidic analytical systems according to the present invention.  FIG. 19  is a simplified schematic diagram of an equivalent electrical circuit for a portion of configuration  750  of  FIG. 18 .  
      Configuration  750  includes a position electrode  752 , micro-channel  754 , bypass electrode  756 , and meter  758 . Position electrode  752  is a single comb-shaped position electrode with eight electrode “fingers”  752   a . Electrode fingers  752   a  serve to define electrode segments therebetween with each segment having a resistance R e  (as depicted in  FIG. 18 ). It should be noted that the dimensions W g  and W e  of  FIG. 18  can be the same as described previously with respect to configuration  600 .  
      In the absence of any liquid sample, bypass electrode  756  is electrically floating. However, when a liquid sample is present between two consecutive electrode fingers  752   a , bypass electrode  756  becomes a part of the circuit depicted in  FIG. 19  and is characterized by resistance R b .  
      Assuming that R b  is significantly less than R I ′ (i.e., the resistance of a liquid sample between an electrode finger and a bypass electrode), more current will flow through the bypass electrode than the liquid sample. Therefore, configuration  750  is beneficial when used in combination with high-resistive liquid samples since bypass electrode  756  effectively reduces the R T , as shown schematically in  FIG. 19 . Furthermore, once apprised of the present disclosure, one skilled in the art will recognize that a bypass electrode(s) can be similarly disposed between position electrodes or between electrode fingers in a variety of electrode configurations (for example, the configurations of FIGS.  7 ,  9 - 13  and  17 ) to reduce total measured resistance in the presence of a relatively high-resistive liquid sample.  
       FIG. 20  is a simplified schematic diagram of a position electrode, micro-channel and meter configuration  800  for use in embodiments of microfluidic analytical systems according to the present invention. Configuration  800  includes a position electrode  802 , micro-channel  804  and meter  806 . Meter  806  is configured to measure a continually changing electrical characteristic of position electrode  802  as a liquid sample (depicted by the wavy lines in  FIG. 20 ) passes through micro-channel  804 .  
     EXAMPLE  
      An interdigitated configuration similar to that of  FIG. 13  was tested by employing a phosphate buffer solution as a liquid sample. The first and second position electrodes of the configuration were formed from Ag/AgCl using a screen printing technique. In addition, the first position electrode and second position electrode were separated by a distance W g  of 4 millimeters.  
      A potential waveform was applied between the first and second position electrodes with a frequency of 0.25 MHz, an amplitude of +/−0.1 volts, and a RMS of 0 volt. Based on the resulting current between the first and second position electrodes, measured total resistance R T  and total measured admittance were calculated (it should be noted that A T =1/R T ).  FIG. 21  shows that the measured total admittance A T  increases linearly as successive liquid sample boluses pass each of the electrode fingers of the configuration.  
       FIG. 21  illustrates that each successive bolus was detected as a change in admittance. Therefore, boluses can be counted by, for example, monitoring for spikes in the derivative of a measured impedance signal versus time.  
       FIG. 22  is a flow diagram depicting stages in a method  900  for the feedback control of a microfluidic system. Method  900  includes measuring an electrical characteristic (such as impedance or resistance) of at least one position electrode of a microfluidic system with a meter of the microfluidic system, as set forth in step  910 . One skilled in the art will recognize that such a microfluidic system can be any suitable microfluidic system embodiment described herein including, but not limited to, the embodiments described with respect to  FIG. 5  and related figures.  
      At step  920 , the feedback controller is employed to control the flow of bodily fluid sample through the microfluidic system based on the electrical characteristic measured by the meter. As discussed above with respect to embodiments of microfluidic systems and microfluidic analytical systems according to the present invention, such control can be accomplished by (i) placing a pressure ring in a retracted state or a deployed state or (ii) by placing a membrane valve in a deformed or undeformed state. In addition, the control can be based on electrical characteristics that are indicative of a liquid sample&#39;s position, flow rate and/or volume. Furthermore, the flow can be controlled to facilitate semi-continuous stopped flow measurements.  
      It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.