S P E C I F I C A T I O N
SYSTEMS AND METHODS FOR COLLECTING AND ANALYZING TEAR FILM OSMOLARITY DATA
RELATED AND PRIORITY APPLICATIONS INFORMATION
This application claims priority to U.S. Patent Application Serial No. 10/800,392, entitled "Systems And Methods For Collecting and Analyzing Tear Film Osmolarity Data", filed on March 12, 2004 and U.S. Patent Application Serial No. 10/823,417, entitled, "Systems and Methods for Delivering a Sample Fluid to a Receiving Substrate", filed on April 12, 2004, each of which is incorporated herein by reference in its entirety as if set forth in full.
BACKGROUND
1. Field of the Inventions
[0001] The field of the invention relates generally to measuring the osmotic pressure of fluids and, more particularly, to systems and methods for collecting and analyzing tear film osmolarity data.
2. Background Information
[0002] Tears fulfill an essential role in maintaining ocular surface integrity, protecting against microbial challenge, and preserving visual acuity. These functions, in turn, are critically dependent upon the composition and stability of the tear film structure, which includes an underlying mucin foundation, a middle aqueous component, and an overlying lipid layer. Disruption, deficiency, or absence of the tear film can severely impact the
eye. If unmanaged with artificial tear substitutes or tear film conservation therapy, these disorders can lead to intractable desiccation of the corneal epithelium, ulceration and perforation of the cornea, an increased incidence of infectious disease, and ultimately pronounced visual impairment and blindness.
[0003] Keratoconjunctivitis sicca (KCS), or "dry eye", is a condition in which one or more of the tear film structure components listed above is present in insufficient volume or is otherwise out of balance with the other components. It is known that the fluid tonicity or osmolarity of tears increases in patients with KCS. KCS is associated with conditions that affect the general health of the body, such as Sjogren's syndrome, agirfg, and androgen deficiency. Therefore, osmolarity of a tear film can be a sensitive and specific indicator for the diagnosis of KCS and other conditions.
[0004] The osmolarity of a sample fluid (e.g., a tear) can be determined by an ex vivo technique called "freezing point depression," in which solutes or ions in a solvent (i.e., water), cause a lowering of the fluid freezing point from what it would be without the ions. In the freezing point depression analysis the freezing point of the ionized sample fluid is found by detecting the temperature at which a quantity of the sample (typically on the order of about several milliliters) first begins to freeze in a container (e.g., a tube). To measure the freezing point, a volume of the sample fluid is collected into a container, such as a tube. Next, a temperature probe is immersed in the sample fluid, and the container is brought into contact with a freezing bath or Peltier cooling device. The sample is continuously stirred so as to achieve a supercooled liquid state below its freezing point. Upon mechanical induction, the sample solidifies, rising to its freezing point due to the thermodynamic heat of fusion. The deviation from the sample freezing
point from 0°C is proportional to the solute level in the sample fluid. This type of measuring device is sometimes referred to as an osmometer.
[0005] Presently, freezing point depression measurements are made ex vivo by removing tear samples from the eye using a micropipette or capillary tube and measuring the depression of the freezing point that results from heightened osmolarity. However, these ex vivo measurements are often plagued by many difficulties. For example, to perform freezing point depression analysis of the tear sample, a relatively large volume must be
collected, typically on the order of 20 microliters (μL) of a tear film. Because no more than about 10 to 100 nanoliters (nL) of tear sample can be obtained at any one time from a KCS patient, the collection of sufficient amounts of fluid for conventional ex vivo techniques requires a physician to induce reflex tearing in the patient. Reflex tearing 'is caused by a sharp or prolonged irritation to the ocular surface, akin to when a large piece of dirt becomes lodged in one's eye. Reflex tears are more dilute, i.e., have fewer solute ions than the tears that are normally found on the eye. Any dilution of the tear film invalidates the diagnostic ability of an osmolarity test for dry eye, and therefore make currently available ex vivo methods prohibitive in a clinical setting. [0006] A similar ex vivo technique is vapor pressure osmometry, where a small, circular piece of filter paper is lodged underneath a patient's eyelid until sufficient fluid is absorbed. The filter paper disc is placed into a sealed chamber, whereupon a cooled temperature sensor measures the condensation of vapor on its surface. Eventually the temperature sensor is raised to the dew point of the sample. The reduction in dew point proportional to water is then converted into osmolarity. Because of the induction of reflex tearing and the large volume requirements for existing vapor pressure osmometers, they are currently impractical for determination of dry eye.
[0007] The Clifton Nanoliter Osmometer (available from Clifton Technical Physics of Hartford, New York, USA) has been used extensively in laboratory settings to quantify the solute concentrations of KCS patients, but the machine requires a significant amount of training to operate. It generally requires hour-long calibrations and a skilled technician in order to generate acceptable data. The Clifton Nanoliter Osmometer is also bulky and relatively expensive. These characteristics seriously detract from its use as a clinical osmometer.
[0008] hi contrast to ex vivo techniques that measure osmolarity of tear samples removed from the ocular surface, an in vivo technique that attempted to measure osmolarity directly on the ocular surface used a pair flexible pair of electrodes that were placed directly underneath the eyelid of the patient. The electrodes were then plugged into an LCR meter to determine the conductivity of the fluid surrounding them. While it has long been known that conductivity is directly related to the ionic concentration, and hence osmolarity of solutions, placing the sensor under the eyelid for half a minute likely induced reflex tearing. Furthermore, these electrodes were difficult to manufacture and posed increased health risks to the patient as compared to simply collecting tears with a capillary.
[0009] It should be apparent from the discussion above that current osmolarity measurement techniques are unavailable in a clinical setting and can't attain the volumes necessary for dry eye patients. Thus, there is a need for an improved, clinically feasible, nanoliter-scale osmolarity measurement. The present invention satisfies this need. SUMMARY OF THE INVENTION [0010] A data collection system is configured to perform an osmolarity measurement of a sample fluid such as a tear film. The data collection system includes a user interface that
allows the clinician to input information regarding the patient. This information can include identifying information such as the patient's name or social security number. The clinician can also input diagnostic information including results from a preliminary physical examination of the patient, a report of the patient's symptoms, and medication that the patient is currently taking. Both the identifying information and the diagnostic information are then transmitted to a base unit. The base unit houses a sample receiving chip that is configured to measure the osmolarity of a sample fluid. Once the measurement is complete, the base unit transmits the identifying information and diagnostic information, including the osmolarity measurement, to a central server. The central server is configured to compile a database of the results from multiple osmolarity tests.
[0011] In another aspect, the data collection system is configured to prevent the central server from accessing the patient names stored on the base unit. Instead, a processing device in the base unit assigns a unique identification tag to each patient. The central server is prevented from recalling the patient name and instead identifies each data set based only on the unique identification tag. Similarly, although the patient name and unique identification tag are stored together on the base unit, the base unit cannot recall a particular unique identification tag associated with a particular patient name. Thus, the system provides the ability to anonymously collect data, a critical requirement for clinical trials.
[0012] In another aspect, the data collection system is configured to determine a clinician rating. The clinician rating is a quantitative measure of clinician experience, the institution's track record of successful tests, and other measures that indicate the confidence in the abilities ofthe clinic to perform diagnoses commensurate with the test.
[0013] These and other features, aspects, and embodiments ofthe invention are described below in the section entitled "Detailed Description ofthe Preferred Embodiments." BRIEF DESCRIPTION OF THE DRAWINGS [0014] Features, aspects, and embodiments of the inventions are described in conjunction with the attached drawings, in which:
[0015] Figure 1 illustrates an aliquot-sized sample receiving chip for measuring the osmolarity of a sample fluid.
[0016] Figure 2 illustrates an alternative embodiment of a sample receiving chip that includes a circuit region with an array of electrodes imprinted with photolithography techniques.
[0017] Figure 3 illustrates another alternative embodiment ofthe Figure 1 chip, wherein a circuit region includes printed electrodes arranged in a plurality of concentric circles. [0018] Figure 4 is a top view ofthe chip shown in Figure 2. [0019] Figure 5 is a top view ofthe chip shown in Figure 3.
[0020] Figure 6 is a block diagram of an osmolarity measurement system configured in accordance with the present invention.
[0021] Figure 7 is a perspective view of a tear film osmolarity measurement system constructed in accordance with the present invention.
[0022] Figure 8 is a side section of the sample receiving chip showing the opening in the exterior packaging.
[0023] Figure 9 is a calibration curve relating the sodium content of the sample fluid with electrical conductivity.
[0024] Figure 10 illustrates a hinged base unit of the osmometer that utilizes the sample receiving chips described in Figures 1-5.
[0025] Figure 11 illustrates a probe card configuration for the sample receiving chip and processing unit.
[0026] Figure 12 is a flowchart describing an exemplary osmolarity measurement technique in accordance with the invention.
[0027] Figure 13 is a block diagram of a data collection system configured in accordance with one embodiment ofthe present invention.
[0028] Figure 14 is a flow chart illustrating a method for collecting osmolarity data in accordance with one embodiment ofthe present invention.
[0029] Figure 15 is a diagram illustrating an embodiment portable osmolarity measuring device configured in accordance with the invention.
[0030] Figure 16 is a diagram illustrating another embodiment portable osmolarity measuring device configured in accordance with the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [0031] Exemplary embodiments are described for measuring the osmolarity of an aliquot volume of a sample fluid (e.g., tear film, sweat, blood, or other fluids). The exemplary embodiments are configured to be relatively fast, non-invasive, inexpensive, and easy to use, with minimal injury of risk to the patient. Accurate measurements can be provided with as little as nanoliter volumes of a sample fluid. For example, a measuring device configured in accordance with the invention enables osmolarity measurement with no
more than 200μL of sample fluid, and typically much smaller volumes can be successfully measured. In one embodiment described further below, osmolarity measurement accuracy is not compromised by variations in the volume of sample fluid collected, so that osmolarity measurement is substantially independent of collected volume. The sample fluid can include tear film, sweat, blood, or other bodily fluids. It
should be noted, however, that sample fluid can comprise other fluids, such as milk or other beverages.
[0032] Figure 1 illustrates an exemplary embodiment of an osmolarity chip 100 that can be used to measure the osmolarity of a sample fluid 102, such as a tear film sample. In the Figure 1 embodiment, the chip 100 includes a substrate 104 with a sample region having sensor electrodes 108, 109 and circuit connections 110 imprinted on the substrate. The electrodes and circuit connections are preferably printed using well-known photolithographic techniques. For example, current techniques enable the electrodes 108, 109 to have a diameter in the range of approximately one (1) to eighty (80) microns, and spaced apart sufficiently so that no conductive path exists in the absence of sample fluid. Currently available techniques, however, can provide electrodes of less than one micron in diameter, and these are sufficient for a chip constructed in accordance with the invention. The amount of sample fluid needed for measurement is no more than is necessary to extend from one electrode to the other, thereby providing an operative conductive path. The photolithographic scale ofthe chip 100 permits the measurement to be made for aliquot-sized samples in a micro- or nano-scale level. For example, reliable osmolarity measurement can be obtained with a sample volume of less than 20 μL of tear film. A typical sample volume is less than one hundred nanoliters (100 nL). It is expected that it will be relatively easy to collect 10 nL of a tear film sample even from patients suffering from dry eye.
[0033] The chip 100 is configured to transfer energy to the sample fluid 102 and enable detection of the sample fluid energy properties. In this regard, a current source is applied across the electrodes 108, 109 through the connections 110. The osmolarity of the sample fluid can be measured by sensing the energy transfer properties of the sample
fluid 102. The energy transfer properties can include, for example, electrical conductivity, such that the impedance of the sample fluid is measured, given a particular amount of electrical power (e.g., current) that is transferred into the sample through the connections 110 and the electrodes 108, 109.
[0034] If conductivity of the sample fluid is to be measured, then preferably a sinusoidal signal on the order of ten volts at approximately 10 kHz is applied. The real and imaginary parts of the complex impedance of the circuit path from one electrode 108 through the sample fluid 102 to the other electrode 109 are measured. At the frequencies of interest, it is likely that the majority ofthe electrical signal will be in the real half of the complex plane, which reduces to the conductivity of the sample fluid. This electrical signal (hereafter referred to as conductivity) can be directly related to the ion concentration of the sample fluid 102, and the osmolarity can be determined. Moreover, if the ion concentration of the sample fluid 102 changes, the electrical conductivity and the osmolarity of the fluid will change in a corresponding manner. Therefore, the osmolarity is reliably obtained. In addition, because the impedance value does not depend on the volume of the sample fluid 102, the osmolarity measurement can be made substantially independent ofthe sample volume.
[0035] As an alternative to the input signal described above, more complex signals can be applied to the sample fluid whose response will contribute to a more thorough estimate of osmolarity. For example, calibration can be achieved by measuring impedances over, a range of frequencies. These impedances can be either simultaneously (via combined waveform input and Fourier decomposition) or sequentially measured. The frequency versus impedance data will provide information about the sample and the relative performance ofthe sample fluid measurement circuit.
[0036] Figure 2 illustrates an alternative embodiment of a sample receiving chip 200 that measures osmolarity of a sample fluid 202, wherein the chip comprises a substrate layer 204 with a sample region 206 comprising an imprinted circuit that includes an array of electrodes 208. In the illustrated embodiment of Figure 2, the sample region 206 has a 5- by-5 array of electrodes that are imprinted with photolithographic techniques, with each electrode 208 having a connection 210 to one side of the substrate 204. Not all of the electrodes 208 in Figure 2 are shown with a connection, for simplicity of illustration. The electrodes provide measurements to a separate processing unit, described further below. [0037] The electrode array of Figure 2 provides a means to measure the size of the tear droplet 202 by detecting the extent of conducting electrodes 208 to thereby determine the extent of the droplet. In particular, processing circuitry can determine the number of electrodes that are conducting, and therefore the number of adjacent electrodes that are covered by the droplet 202 will be determined. The planar area of the substrate that is covered by the sample fluid is thereby determined. With a known nominal surface tension ofthe sample fluid, the height ofthe sample fluid volume over the planar area can be reliably estimated, and therefore the volume ofthe droplet 202 can be determined. [0038] Figure 3 illustrates another alternative embodiment of a sample receiving chip 300 on which a sample fluid 302 is deposited. The chip comprises a substrate layer 304, wherein a sample region 306 is provided with electrodes 308 that are configured in a plurality of concentric circles. In a manner similar to the square array of Figure 2, the circular arrangement of the Figure 3 electrodes 308 also provides an estimate of the size ofthe sample fluid volume 302 because the droplet typically covers a circular or oval area of the sample region 302. Processing circuitry can detect the largest (outermost) circle of electrodes that are conducting, and thereby determine a planar area of coverage by the
fluid sample. As before, the determined planar area provides a volume estimate, in conjunction with a known surface tension and corresponding volume height ofthe sample fluid 302. In the Figure 3 illustrated embodiment, the electrodes 308 can be printed using well known photolithography techniques that currently permit electrodes to have a diameter in the range of one (1) to eighty (80) microns. This allows the submicrolifer droplet to substantially cover the electrodes. The electrodes can be printed over an area sized to receive the sample fluid, generally covering 1 mm to 1 cm . [0039] The electrodes and connections shown in Figure 1, Figure 2, and Figure 3 can be imprinted on the respective substrate layers as electrodes with contact pads, using photolithographic techniques. For example, the electrodes can be formed with different conductive metalization such as aluminum, platinum, titanium, titanium-tungsten, and other similar material. In one embodiment, the electrodes can be formed with a dielectric rim to protect field densities at the edges of the electrodes. This can reduce an otherwise unstable electric field at the rim ofthe electrode.
[0040] Top views of the exemplary embodiments ofthe chips 200 and 300 are illustrated in Figure 4 and Figure 5, respectively. The embodiments show the detailed layout of the electrodes and the connections, and illustrate how each electrode can be electrically connected for measuring the electrical properties of a sample droplet. As mentioned above, the layout of the electrodes and the connections can be imprinted on the substrate 100, 200, 300 using well-known photolithographic techniques.
[0041] Figure 6 is a block diagram of an osmometry system 600 configured in accordance with an embodiment of the present invention, showing how information is determined and used in a process that determines osmolarity of a sample fluid. The osmometry system 600 includes a measurement device 604 and a processing device 606. The
measurement device receives a volume of sample fluid from a collection device 608. The collection device can comprise, for example, a micropipette or capillary tube. The collection device 608 collects a sample tear film of a patient, such as by using negative pressure from a fixed-volume micropipette or charge attraction from a capillary tube to draw a small tear volume from the vicinity ofthe ocular surface of a patient. [0042] The measurement device 604 can comprise a system that transfers energy to the fluid in the sample region and detects the imparted energy. For example, the measurement device 604 can comprise circuitry that provides electrical energy in a specified waveform (such as from a function generator) to the electrical path comprising two electrodes bridged by the sample fluid. The processing device 606 detects the energy imparted to the sample fluid and determines osmolarity. The processing device can comprise, for example, a system including an RLC multimeter that produces data relating to the reactance of the fluid that forms the conductive path between two electrodes, and including a processor that determines osmolarity through a table look-up scheme. If desired, the processing device can be housed in a base unit that receives one of the chips described above.
[0043] As mentioned above, a sample sufficient to provide an osmolarity measurement can contain less than 20 microliters (μL) of fluid. A typical sample of tear film in accordance with the invention is collected by a fluid collector such as a capillary tube, which often contains less than one microliter of tear film. Medical professionals will be familiar with the use of micropipettes and capillary tubes, and will be able to easily collect the small sample volumes described herein, even in the case of dry eye sufferers. [0044] The collected sample fluid is expelled from the collection device 608 to the measurement device 604. The collection device can be positioned above the sample
region of the chip substrate either manually by a medical professional or by being mechanically guided over the sample region. In one embodiment, for example, the collection device (e.g., a capillary tube) is mechanically guided into position with an injection-molded plastic hole in a base unit, or is fitted to a set of clamps with precision screws (e.g., a micromanipulator with needles for microchip interfaces). In another embodiment, the guide is a computer-guided feedback control circuitry that holds the capillary tube and automatically lowers it into the proper position. [0045] The electrodes and connections of the chips measure energy properties of the sample fluid, such as conductivity, and enable the measured properties to be received by the processing device 606. The measured energy properties of the sample fluid include electrical conductivity and can also include other parameters, such as both parts of the complex impedance of the sample, the variance of the noise in the output signal, and the measurement drift due to resistive heating of the sample fluid. The measured energy properties are processed in the processing device 606 to provide the osmolarity of the sample. In one embodiment, the processing device 606 comprises a base unit that can accept a chip and can provide electrical connection between the chip and the processing device 606. In another embodiment, the base unit can include a display unit for displaying osmolarity values. It should be noted that the processing device 606 and, in particular, the base unit can be a hand-held unit.
[0046] Figure 7 is a perspective view of a tear film osmolarity measuring system 700 constructed in accordance with the present invention. In the illustrated embodiment 'of Figure 7, the exemplary system 700 includes a measuring unit 701 that comprises a chip, such as one of the chips described above, and a connector or socket base 710, which provides the appropriate measurement output. The system 700 determines osmolarity by
measuring electrical conductivity of the sample fluid: Therefore, the measurement chip 701 comprises a semiconductor integrated circuit (IC) chip with a substrate having a construction similar to that of the chips described above in connection with Figure 1 through Figure 5. Thus, the chip 701 includes a substrate layer with a sample region that is defined by at least two electrodes printed onto the substrate layer (such details are of a scale too small to be visible in Figure 7; see Figure 1 through Figure 5). The substrate and sample region are encased within an inert package, in a manner that will be known to those skilled in the art. h particular, the chip 701 is fabricated using conventional semiconductor fabrication techniques into an IC package 707 that includes electrical connection legs 708 that permit electrical signals to be received by the chip 701 and output to be communicated outside ofthe chip. The packaging 707 provides a casing that makes handling of the chip more convenient and helps reduce evaporation of the sample fluid.
[0047] Figure 8 shows that the measurement chip 701 is fabricated with an exterior opening hole 720 into which the sample fluid 702 is inserted. Thus, the hole 720 can be formed in the semiconductor packaging 707 to provide a path through the chip exterior to the substrate 804 and the sample region 806. The collection device (such as a micropipette or capillary tube) 808 is positioned into the hole 720 such that the sample fluid 702 is expelled from the collection device directly onto the sample region 806 ofthe substrate 804. The hole 720 is sized to receive the tip ofthe collection device. The hole 720 forms an opening or funnel that leads from the exterior of the chip onto the sample region 806 of the substrate 804. In this way, the sample fluid 702 is expelled from the collection device 808 and is deposited directly on the sample region 806 of the substrate 804. The sample region is sized to receive the volume of sample fluid from the collection
device. In Figure 8, for example, the electrodes form a sample region 806 that is generally in a range of approximately 1 mm2 to 1 cm2 in area.
[0048] Returning to Figure 7, the chip 701 can include processing circuitry 704 that comprises, for example, a function generator that generates a signal of a desired waveform, which is applied to the sample region electrodes of the chip, and a voltage measuring device to measure the root-mean-square (RMS) voltage value that is read from the chip electrodes. The function generator can produce high frequency alternating current (AC) to avoid undesirable direct current (DC) effects for the measurement process. The voltage measuring device can incorporate the functionality of an RLC measuring device. Thus, the chip 701 can incorporate the measurement circuitry as well as the sample region electrodes. The processing circuitry can include a central processing unit (CPU) and associated memory that can store programming instructions (such as firmware) and also can store data. In this way, a single chip can include the electrodes and associated connections for the sample region, and on a separate region of the chip, can also include the measurement circuitry. This configuration will minimize the associated stray resistances ofthe circuit structures.
[0049] As noted above, the processing circuitry 70 applies a signal waveform to the sample region electrodes. The processing circuitry also receives the energy property signals from the electrodes and determines the osmolarity value of the sample fluid. For example, the processing unit receives electrical conductivity values from a set of electrode pairs. Those skilled in the art will be familiar with techniques and circuitry for determining the conductivity of a sample fluid that forms a conducting path between two or more electrodes.
[0050] In the Figure 7 embodiment, the processing unit 704 produces signal waveforms at a single frequency, such as 100 kHz and 10 Volts peak-to-peak. The processing circuitry 704 then determines the osmolarity value from the sodium content correlated to the electrical conductivity using a calibration curve, such as the curve shown in Figure '9. In this case, the calibration curve is constructed as a transfer function between the electrical conductivity (voltage) and the osmolarity value (i.e., the sodium content). It should be noted, however, that other calibration curves can also be constructed to provide transfer functions between other energy properties and the osmolarity value. For example, the variance, autocorrelation and drift of the signal can be included in an osmolarity calculation. If desired, the osmolarity value can also be built upon multi- variable correlation coefficient charts or neural network interpretation so that the osmolarity value can be optimized with an arbitrarily large set of measured variables. [0051] In an alternate form ofthe Figure 7 embodiment, the processing unit 704 produces signal waveforms of a predetermined frequency sweep, such as 1 kHz to 100 kHz in 1 kHz increments, and stores the conductivity and variance values received from the set of electrode pairs at each frequency. The output signal versus frequency curve can then be used to provide higher order information about the sample which can be used with the aforementioned transfer functions to produce an ideal osmolarity reading. [0052] As shown in Figure 7, the base socket connector 710 receives the pins 708 of the chip 701 into corresponding sockets 711. The connector 710, for example, can supply the requisite electrical power to the processing circuitry 704 and electrodes ofthe chip. Thus, the chip 701 can include the sample region electrodes and the signal generator and processing circuitry necessary for determining osmolarity, and the output comprising the
osmolarity value can be communicated off the chip via the pins 708 through the connector 710 and to a display readout.
[0053] If desired, the base connector socket 710 can include a Peltier layer 712 located beneath the sockets that receive the pins 708 ofthe chip 701. Those skilled in the art will understand that a Peltier layer comprises an electrical / ceramic junction such that properly applied current can cool or heat the Peltier layer. In this way, the sample chip 701 can be heated or cooled, thereby further controlling evaporation of the sample fluid. It should be apparent that evaporation of the sample fluid should be carefully controlled, to ensure accurate osmolarity values obtained from the sample fluid. [0054] Figure 10 shows an alternative embodiment of an osmometer in which the chip does not include an on-chip processing unit such as described above, but rather includes limited circuitry comprising primarily the sample region electrodes and interconnections. That is, the processing unit is separately located from the chip and can be provided in the base unit.
[0055] Figure 10 shows in detail an osmometer 1000 that includes a base unit 1004, which houses the base connector 710, and a hinged cover 1006 that closes over the base connector 710 and a received measurement chip 701. Thus, after the sample fluid has been dispensed on the chip, the chip is inserted into the socket connector 710 of the base unit 1004 and the hinged cover 1006 is closed over the chip to reduce the rate of evaporation ofthe sample fluid.
[0056] It should be noted that the problem with relatively fast evaporation of the sample fluid can generally be handled in one of two ways. One way is to measure the sample fluid voltage quickly as soon possible after the droplet is placed on the sample region of the chip. Another way is to enable the measuring unit to measure the rate of evaporation
along with the corresponding changes in conductivity values. The processing unit can then post-process the output to estimate the osmolarity value. The processing can be performed in the hardware or in software stored in the hardware. Thus, the processing unit can incorporate different processing techniques such as using neural networks to collect and learn about characteristic of the fluid samples being measured for osmolarity, as well as temperature variations, volume changes, and other related parameters so that the system can be trained in accordance with neural network techniques to make faster and more accurate osmolarity measurements.
[0057] Figure 11 shows another alternative construction, in which the osmolarity system utilizes a sample receiving chip 1102 that does not include IC packaging such as shown in Figure 7. Rather, the Figure 11 measurement chip 1102 is configured as a chip with an exposed sample region comprising the electrodes and associated connections, but the processing circuitry is located in the base unit for measuring the energy properties of the sample fluid. In this alternative construction, a connector similar to the connector socket 710 allows transmission of measured energy properties to the processing unit in the base unit. Those skilled in the art will understand that such a configuration is commonly referred to a probe card structure.
[0058] Figure 11 shows a probe card base unit 1100 that receives a sample chip probe card 1102 that comprises a substrate 1104 with a sample region 1106 on which are formed electrodes 1108 that are wire bonded to edge connectors 1110 of the probe card. When the hinged lid 1112 ofthe base unit is closed down over the probe card, connecting tines 1114 on the underside of the lid come into mating contact with the edge connectors 1110. i this way, the electrodes of the sample region 1106 are coupled to the processing circuitry and measurement can take place. The processing circuitry of the probe card
embodiment of Figure 11 can be configured in either of the configurations described above. That is, the processing to apply current to the electrodes and to detect energy properties of the sample fluid and determine osmolarity can be located on-chip, on the substrate ofthe probe card 1102, or the processing circuitry can be located off-chip, in the base unit 1100.
[0059] hi all the alternative embodiments described above, the osmometer is used by placing a new measurement chip into the base unit while the hinged top is open. Upon placement into the base unit the chip is lowered up and begins monitoring its environment. Recording output signals from the chip at a rate of, for example, 1 kHz, will fully capture the behavior of the system. Placing a sample onto any portion of the electrode array generates high signal-to-noise increase in conductivity between any pair of electrodes covered by the sample fluid. The processing unit will recognize the change in conductivity as being directly related to the addition of sample fluid, and will begin conversion of electronic signals into osmolarity data once this type of change is identified. This strategy occurs without intervention by medical professionals. That is, the chip processing is initiated upon coupling to the base unit and is not dependent on operating the lid ofthe base unit or any other user intervention.
[0060] In any of the configurations described above, either the "smart chip" with processing circuitry on-chip (Figure 7), or the electrode-only configuration with processing circuitry off-chip (Figure 10), in a packaged chip (Figure 7 and Figure 10) or in a probe card (Figure 11), the sample receiving chip can be disposed of after each use, so that the base unit serves as a platform for interfacing with the disposable measurement chip. As noted, the base unit can also include relevant control, communication, and display circuits (not shown), as well as software, or such features can be provided off-
chip in the base unit. In this regard, the processing circuitry can be configured to automatically provide sufficient power to the sample region electrodes to irreversibly oxidize them after a measurement cycle, such that the electrodes are rendered inoperable for any subsequent measurement cycle. Upon inserted a used chip into the base unit, the user will be given an indication that the electrodes are inoperable. This helps prevent inadvertent multiple use of a sample chip, which can lead to inaccurate osmolarity readings and potentially unsanitary conditions.
[0061] A secondary approach to ensure that a previously used chip is not placed back into the machine includes encoding serial numbers, or codes directly onto the chip. The base unit will store the used chip numbers in memory and cross-reference them against new chips placed in the base connector. If the base unit finds that the serial number of the used chip is the same as an old chip, then the system will refuse to measure osmolarity until a new chip is inserted. It is important to ensure use of a new chip for each test because proteins adsorb and salt crystals form on the electrodes after evaporation has run its course, which corrupt the integrity of the measuring electrodes.
[0062] Figure 12 is a flowchart describing an exemplary osmolarity measurement technique in accordance with the invention. A body fluid sample, such as a tear film, is collected at box 1200. The sample typically contains less than one microliter. At box 1202, the collected sample is deposited on a sample region of the chip substrate. The energy properties of the sample are then measured at box 1204. The measured energy properties are then processed, at box 1206, to determine the osmolarity of the sample. If the chip operates in accordance with electrical conductivity measurement, then the measurement processing at box 1206 can include the "electrode oxidation" operation
described above that renders the chip electrodes inoperable for any subsequent measuring cycles.
[0063] In the measurement process for a conductivity measuring system, a substantially instantaneous shift is observed from the open circuit voltage to a value that closely represents the state of the sample at the time of collection, upon placement of a sample tear film on an electrode array of the substrate. Subsequently, a drift in the conductivity ofthe sample will be reflected as a continual change in the output. [0064] The output of the measurement chip can be a time-varying voltage that is translated into an osmolarity value. Thus, in a conductivity-based system, more information than just the "electrical conductivity" of the sample can be obtained by measuring the frequency response over a wide range of input signals, which improves the end stage processing. For example, the calibration can be made over a multiple frequencies (e.g., measure ratio of signals at 10, 20, 30, 40, 50, 100 Hz) to make the measurement process a relative calculation. This makes the chip-to-chip voltage drift small. The standard method for macroscale electrode based measurements (i.e., in a pH meter, or microcapillary technique) is to rely upon known buffers to set up a linear calibration curve. Because photolithography is an extremely reproducible manufacturing technique, when coupled to a frequency sweep, calibration can be performed without operator intervention.
[0065] As mentioned above, the processing of the energy properties can be performed in a neural network configuration, where the seemingly disparate measured data points obtained from the energy properties can be used to provide more accurate osmolarity reading than from a single energy property measurement. For example, if only the electrical conductivity of the sample is measured, then the calibration curve can be used
to simply obtain the osmolarity value corresponding to the conductivity. This osmolarity value, however, generally will not be as accurate as the output ofthe neural network. [0066] The neural network can be designed to operate on a collection of calibration curves that reflects a substantially optimized transfer function between the energy properties of the sample fluid and the osmolarity. Thus, in one embodiment, the neural network constructs a collection of calibration curves for all variables of interest, such as voltage, evaporation rate and volume change. The neural network can also construct or receive as an input a priority list that assigns an importance factor to each variable to indicate the importance of the variable to the final outcome, or the osmolarity value. The neural network constructs the calibration curves by training on examples of real data where the final outcome is known a priori. Accordingly, the neural network will be trained to predict the final outcome from the best possible combination of variables. This neural network configuration that processes the variables in an efficient combination 'is then loaded into the processing unit residing in the measurement chip 701 or the base unit. Once trained, the neural network can be configured in software or hardware. [0067] Although the embodiments described above for measuring osmolarity provides substantial advantage over the conventional osmolarity measuring techniques such as a freezing point depression technique, the teachings of the present invention can be used to determine osmolarity of a sample in accordance with the freezing point depression technique. Accordingly, the exemplary osmometry system 600 of Figure 6 can be used to provide an osmolarity value based on the freezing point depression technique. [0068] The freezing point depression system involves collecting and depositing the sample fluid in a similar manner as in the boxes 1200 and 1202 ofthe flowchart in Figure 12. As noted above, however, the osmometer of the osmometer system can include a
cooling device, such as a Peltier cooling device. In the Figure 7 embodiment described above, the Peltier device is disposed on the socket 710 or the chip 701 (see Figure 7) to cool the sample. If desired, the Peltier cooling device can be used to cool the sample fluid to the freezing point ofthe sample fluid. A photo-lithographed metal junction, or p- n junction, known as a thermocouple, can be used to monitor the temperature of aliquot- sized samples. The thermocouple would operate in parallel to the electrode array and Peltier cooling device, where the chip would be cooled below freezing so that the sample becomes a solid. Upon solidification, the electrical conductivity of the sample will drastically change. Because the thermocouple is continually measuring the temperature, the point at which the conductivity spikes can be correlated to the depressed freezing point. Alternatively, the chip could be supercooled immediately prior to sample introduction by the Peltier unit, and then by using the resistive heating inherent to the electrodes, a current can be passed along the solid phase material. Upon melting, the conductivity will again drastically change. In the second measurement technique, it is likely that evaporation will be less of a factor. Thus, the present invention permits freezing point depression to be performed at significantly smaller volumes of sample fluid than previously possible.
[0069] The systems and methods described above can, as explained, be used to obtain very accurate data related to osmolarity, such as tear film osmolarity. This type of accurate data can be extremely useful when aggregated in a database for a plurality of patients over a plurality of measurements. For example, taking the tear film osmolarity situation, having highly accurate tear film osmolarity measurement data for a plurality of patients over a plurality of measurements can be extremely useful for analyzing the effect of certain treatments and treatment methodologies on the disease. Thus, aggregating
measurement data made using the systems and methods described above into a patient database and making that patient database available, e.g., to clinicians and other individuals or entities that can take advantage of the data can be an extremely useful exercise.
[0070] Accordingly, as measurements are made using the systems and methods described above a database can be formed that comprises the results of those measurements. For example, a base unit, such as one described above, can include memory into which the measurement results of a plurality of measurements are loaded. The base unit would therefore need to have some mechanism by which the measurements can be associated with a patient so that the measurement data can be later stored in the database and correlated with specific individuals and specific treatments. Thus, a user interface can be built into such a base unit that allows the clinician or user to input the necessary identifying information. Alternatively, some form of user interface device can be interfaced with such a base unit and such information can be input through the user interface device. Some specific examples of such a user interface device and configuration are described in more detail below.
[0071] Once data is obtained for a plurality of patients across the plurality of measurements, the information can then be coπelated and used to identify trends, effectiveness, deficiencies and treatment programs, etc. For example, the data obtained may indicate that when a certain type of synthetic tear is used to treat dry eye the results are positive, whereas the use of a different type of synthetic tear does not produce positiye results. As another example, the data once correlated might indicate that it takes a certain number of treatments before sufficiently effective reduction in dry eye are achieved.
These are just some examples of the types of conclusions and analysis that can be performed once such a database of information is generated.
[0072] It is known that obtaining such information in a clinical setting can be extremely time-consuming and costly and is often inefficient or incomplete. Thus, the ability to aggregate large amounts of highly accurate data can be extremely useful in a clinical setting. Such information can also be useful to monitor the effectiveness, or adherence to, prescribed treatment plans or the ability of doctors to accurately diagnose and treat a disease as dry eye.
[0073] When patients are treated, patient information, such as age, weight, symptoms, etc. are often gathered and kept in a patient history file or database. Thus, such patient history information can be used to correlate the data obtained using the measurement methods and systems described herein. Accordingly, it can be preferable that the information obtained using the measurement system described above be combined with such patient history information. In one embodiment, for example, the patient history information can be accessed by or loaded into a base unit such as the base units described above. The user interface can then be provided to allow a clinician or user to pull up the patient history information for a patient about to be tested and to associate any measurement results with that patient history information. Alternatively, a user interface device, such as one described below, can be used to pull up the patient history infomiation and associate the measurement information, or to load the patient history infoπnation into the base unit so that the measurement information can be associated appropriately. Once a database of measurement information is obtained and associated with the requisite patient history information, access to the database can be provided at a fee. For example, clinicians desiring access to the database can pay a fee based on how
much data is provided, how often the database is accessed, on a monthly basis as long as access is needed, etc. Certain precautions can need to be put in place to maintain anonymity of the patients from whom the measurement data was taken; however, it may be necessary to provide demographic information such as age, weight, symptoms, etc. It will be apparent, however, that the availability of such information can be extremely valuable to a variety of entities and for a variety of purposes.
[0074] Figure 13 illustrates one embodiment of data collection system 1300 that includes sample receiving chip 1302. Data collection system 1300 can, for example, be used to perform enhanced clinical research and clinical trials, which are notoriously expensive due to the enormous premium on controlling the collection and protection ofthe integrity of the resulting data. For a specific market, i.e., clinical tear film osmolarity, sample receiving chip 1302 can be secured in a base unit 1304 and implemented to perform a simple, automated test while maintaining a high level of accuracy as described above. [0075] In one embodiment, data collection system 1400 includes user interface 1306. User interface device 1306 can include a device such as a handheld personal digital assistant (PDA), an embedded computer, a laptop computer, or a desktop computer system. User interface device 1306 can be configured to be in communication with base unit 1304 through either a wireless or direct connection. In one embodiment, the clinician, or other user, can initiate a measurement by entering a password into user interface device 1306 that is unique to the user. The clinician can then be presented with a screen filled with items for establishing patient history data. In one embodiment, user interface device 1306 is connected to a clinic's internal patient database 1308 and user interface device 1306 displays the patient history in a form that is familiar to the user.
[0076] In another embodiment, user interface device 1306 can be configured to also allow the user to enter or supplement data about the patient before beginning a test. User interface device 1306 can therefore be configured to supplant conventional methods of patient history taking that is performed before every clinical procedure, e.g., where information such as gender, age, current medications, and symptoms are recorded and stored.
[0077] In one specific embodiment, data collection system 1300 can be configured to perform and analyze tear film osmolarity data for patients who are potentially suffering from dry eye. Thus, user interface device 1306 can be configured to prompt the clinician to ask the patient questions regarding his or her symptoms. Question such as, "Do your eyes every feel dry?" and "If so, how often?" will be dynamically prompted on the screen of the device and given check boxes for the discretized values and possible answers. The set of questions can, depending on the embodiment, be easily changed depending on the nature ofthe test and the interest ofthe company sponsoring the test. [0078] In one embodiment, prior to collection of the tear sample, the clinician can open base unit 1304 and position a new, disposable sample receiving chip 1302 for performing the measurement. Sample receiving chip 1302 can be in the form of any of the embodiments that have been described above. The clinician then uses a collection device, such as a capillary tube, to collect a sample of tear film from a patient. The capillary tube can then be delivered to the sample receiving chip 1304 through either a manual or automated delivery system. The delivery system can be configured to accurately deliver the sample fluid to sample receiving chip 1304 and engage the test, which will initiate the requisite electrical signals that interact with the fluid and collect the necessary endpoint. In another embodiment, after the patient history is complete, the
user input on user interface device 1306 communicates with base unit 1304, indicating that the sample fluid has been introduced to sample receiving chip 1302 and the test should begin.
[0079] During the initiation of testing, the patient history data can be entered into user interface device 1306, including any data that was pulled-off of the clinic's internal patient database 1308, can be uploaded to base unit 1304.
[0080] Once the test is initiated, the clinic's internal patient database 1308 can be updated with a complete record of the events of the current test and Base unit 1304 can be configured to print out a form that matches the clinics internal filing system and includes the requisite information. This print out can then be signed and physically clipped to the patient's chart as proof that the test was performed.
[0081] Further, depending on the embodiment, either base unit 1304 or user interface device 1306 can be configured to remove all patient identification information from the test data in compliance with the Health Insurance Portability and Accountability Act (HIPP A) and any other federal guidelines that govern the fair use of patient data. Following the removal of identifying information, the remaining data can, for example, simply comprise the age, gender, medications, and osmolarity of the patient, as these are, e.g., critical data points in the progression of Dry Eye disease. More importantly, these data points are likely to be the data that a company sponsoring the clinical test is most interested in receiving. In another embodiment, the data might be so extensive as to include everything on the patient's chart that is within the anonymity guidelines, such as HIPP A, including the physician's diagnosis of the symptoms, date of the test, other associated Dry Eye tests, and similar information.
[0082] Base unit 1304 can, for example, be connected to the Internet, e.g., through a phone line/modem, or through a wireless access point on a nearby network, so that as soon as the osmolarity test is complete, the anonymous profile of the patient and any other related information, can be uploaded to a central server 1310 that can be configured to collect data from a plurality of base units.
[0083] An important caveat to the anonymity, a requirement that is critical to conform with regulations that govern clinical trials, is that on base unit 1304, a few gigabytes of local memory can be provided to will house the entire history of the clinical tests. In one embodiment, each patient can then be given a unique identification tag. When a patient returns for a follow up visit, his or her profile can be recalled instantly, saving the user time and money. However, the name and ID tag only reside on the local memory of base unit 1304. To ensure anonymity, the patient's name cannot be recalled by central server 1310, and the patient's unique ID cannot be recalled by the local machine, even though the data is housed together. In this manner, the downstream central server 1310 can track individuals over time, and the relative efficacy of treatments can be recorded, while patient anonymity is preserved. .
[0084] The end result of the process can first be an anonymous database with a large amount of clinical data that can be used for product development and correlation of signs to symptoms in an unbiased, quantitative manner. Currently, tens of millions of dollars are spent on clinical trials involving a few hundred people, and the largest clinical databases house tens of thousands of data points. With the automated data collection system described herein, hundreds of thousands, or millions of data points can be collected to the benefit of everyone involved.
[0085] In another embodiment, data collection system 1300 can also be configured to determine clinician ratings. The clinician rating can be a quantitative measure of clinician experience, the institution's track record of successful tests, and other measures that indicate the confidence in the abilities of the clinic to perform diagnoses commensurate with the test.
[0086] Key to these data points will be the statistical bias of the symptomology that the physician presents. In one embodiment, the mean severity of symptoms shall be recorded over time for each clinician who uses data collection system 1300. The physician's individual bias, in the form of a moving average, mean, variance, etc., for each symptom of record will be attached to the osmolarity data so that the bias may be accounted for downstream if necessary. In another embodiment, a set of people, or photographs of people with Dry Eye disease, will be diagnosed by the physician to establish their symptomology bias ahead of time, rather than mathematically assuming that every physician's patient population is mean squared convergent. In yet another embodiment, the combination of human standards and statistical bias calculations are coupled with the osmolarity data for downstream consideration.
[0087] The average gender, age, ethnicity, etc., of the patients can also be tracked to remove geographical bias in cases where the Dry Eye patient population is skewed in one way or another. This information also forms part of the institution's performance score. Further, semi-quantitative measurements ofthe quality ofthe institution and physician are added. These data can take the form of years of experience, prescription profile, e.g., in terms of preference of pharmaceutical brand, and similar information. [0088] Figure 14 is a flow chart illustrating one embodiment of a method of data collection in accordance with the systems and methods described herein. First, in step
1402, the clinician inputs information through a user interface device 1306, such as a PDA or other computer. The information can include identifying information such as the patient's name, as well as diagnostic information such as the severity and duration of symptoms and current medications that the patient is taking.
[0089] In step 1404, the identifying information and the diagnostic information -is communicated to a base unit 1304. The infomiation can be transmitted through either a direct connection or a wireless connection to the base unit, hi step 1406, a processing device can be confirmed to assign a unique identification tag to the patient's identifying information and diagnostic information. The unique identification tag cab provide patient anonymity that is critical to clinical trials and is discussed further below. In step 1408, the osmolarity of a sample fluid, such as a tear film, can be measured with a sample receiving chip as described above. The base unit can then transmits the diagnostic information and the osmolarity measurement to a central server in step 1410. Tliis transmission can be accomplished through an Internet connection via a phone line and modem, or through a wireless access point on a nearby network.
[0090] In step 1412, in the central server 1310 can be configured to prevent the central server from accessing the patient's identifying information that is stored on the local base unit. In this manner, the anonymity of the trial is maintained as the central server cannot recall a patient's name. Instead, the central server can be configured to correlate a set of data with the unique identification tag that has been assigned by the processing device in the base unit.
[0091] Similarly, in step 1414, the base unit is configured to prevent the base unit from recalling a unique identification tag and displaying the identification tag on the user interface. All interaction at the clinical level occurs via the patient's actual name.
Although the patient's name and the correlating unique identification tag are stored on the same base unit, the base unit is configured to prevent the base unit from recalling a particular identification tag for a particular patient. In this manner, anonymity of the clinical trial is maintained.
[0092] In another embodiment, the method at figure 14 can be used to determine clinician rating. As described, the clinician rating can be a quantitative measure of clinician experience, the institution's track record of successful tests, and other measures that indicate the confidence in the abilities of the clinic to perform diagnoses commensurate with the test.
[0093] hi addition, because the systems and methods described above provide for a compact osmolarity measuring devices and circuits, the devices and circuits described herein can be incorporated into portable, volume-independent osmolarity measuring devices that can be used in a variety of applications. For example, such a portable device can be a handheld device that is used to sample osmolarity of various fluids along a manufacturing or production line, e.g., a beverage mixing line or a milk pasteurization line, ha such embodiments, osmolarity can be coπelated with certain properties in order to determine whether the process is proceeding accordingly. A portable device, configured as described herein, can then be used to sample fluids at various steps in the process to ensure that the relevant properties are within desired ranges. [0094] In other embodiments, a portable, e.g., handheld device can be used to test the osmolarity of various bodily fluids, such as blood, urine, sweat, tears, etc. Such a portable device can make collection and testing easier both on site, e.g., at a clinic, doctor's office, hospital, etc. and offsite, e.g., field testing.
[0095] It should also be noted that while some portable device embodiments described herein are clearly intended for a mobile environment, e.g., handheld embodiments, in other embodiments, the portable device can be positioned in a fixed location. In other words, the portable nature of the device allows for optimal locations, e.g., along a manufacturing line, or in a hospital or clinic, to be identified and a device positioned accordingly. As needs changed, new positions, or locations, can be identified and the device can be easily repositioned due to its portable nature.
[0096] In some embodiments, a portable device configured according to the systems and methods described herein has two components: a portable base unit and a receiving substrate. In one embodiment, depicted in Figure 15, a portable device configured in accordance with the systems and methods described herein can be a handheld comprising a personal data assistant ("PDA") base unit 1520, with an extension 1524 to interface with a receiving substrate 1522, such as the substrates described above. In some embodiments, extension 1524 can be configured to perform the electrical measurements described above, and to send the resulting data to the handheld 1520 to be processed. [0097] In other words, extension 1524 can be configured to supply the required signals to receiving substrate 1522 and to receive the corresponding signals in response. The resulting signals can then be sent to handheld device 1520 before, or after being processed by extension 1524.
[0098] Handheld device 1520 can, therefore, contain the necessary electronics to perform the osmolarity measurement as described above. In other embodiments, handheld device 1520 can be configured to store the data so that it can be downloaded to a computing device that would compute the osmolarity measurement for each data point. In still another embodiment, extension 1524 can be configured to perform osmolarity
measurements with the results being stored in handheld device 1520 for subsequent download to a computing device. Once downloaded, the data can be coπelated and used, e.g., to track trends in the data such as described above. The ability to track trends in the osmolarity data can be very important, because it can allow a production line operator, for example, to predict problems and address them before they occur. The ability to be proactive in this manner can improve production results and eliminate downtime. [0099] Extension 1524 can be configured such that it can interface with or hold measuring device 1522, which can for example can be a measuring chip 701 as described in relation to figure 7. Thus, extension 1524 can comprise the sockets and connectors required to interface with such a chip. Extension 1524 can also comprise the appropriate interface for interfacing with handheld device 1520. Such an interface can be a custom interface or an industry standard interface depending on the embodiment. [0100] Extension 1520 can also comprise the requisite circuits to generate the signals described above for performing osmolarity measurement of a sample fluid placed on the receiving substrate of measuring device 1522. Thus, extension 1524 can house oscillators capable of producing alternating cuπent ("AC") sine waves in the 10-100 kHz range, multimeter capabilities, such as sampling data capability, and an auto-balancing bridge circuit, or simple voltage divider, across which the sample fluid analyte is placed. [0101] In certain embodiments, extension 1524 can be configured to communicate root mean squared impedance data for the sample fluid to handheld device 1520. In such embodiments, handheld device 1520 can be configured to provide both analysis software and the user interface for viewing and interacting with the data. As mentioned, in other embodiments, handheld device 1520 can be configured to store the data so that the data
can be downloaded to a device loaded with the analysis software and comprising a user interface as required.
[0102] In certain embodiments, the analysis software, whether loaded on device 1520 or a separate device to which the data is downloaded, can be configured to remove corruptive signals before determining the final value ofthe osmolarity.
[0103] Extension 1524 can be configured to receive simple electrode cartridge, comprising, for example, a housing, possibly fabricated from plastic, and two or more micro-electrodes patterned at the base of the housing. In such an embodiment, the cartridge can function as a receiving substrate. The user can snap such a cartridge into a holder on extension 1524 and then can place a sample of fluid into the cartridge for analysis. In other words, measuring device 1522 can comprise a cartridge that snaps into extension 1524. The cartridge can act both as a basin to receive a sample fluid and as the substrate for performing the measurements described above.
[0104] In other embodiments, the cartridge can be implemented as a capillary tube with microelectrodes imprinted at the entrance of the capillary. This type of cartridge can, for example, be used with very small samples of fluid or to collect samples from a small opening in an industrial or biological setting. The user can collect such fluid by touching the capillary to the sample. The capillary should "sip up" a small amount of fluid from the sample. Even a very small sample should be sufficient complete the circuit across the microelectrodes and initiate measurement.
[0105] In still other embodiments, extension 1524 can be configured to receive an inverted cartridge, with electrodes placed outside the cartridge casing. In such an embodiment, the cartridge can simply be touched to the sample to complete the circuit and to perform the measurement.
[0106] In certain embodiments, measuring device 1522 can be disposable. Such a disposable measuring device can be discarded after use and replaced by a new device 1522. This replacement will enable the operator to make successive measurements easily and quickly using a extension 1524 and handheld device 1520. This method ensures that no cross contamination or residual salts will corrupt sequential measurements. In other embodiments, such as that depicted in Figure 16, a handheld device configured in accordance with the systems and methods described herein can be a self-contained device 1602 with an integrated extension 1606 with all of the above capabilities. In certain embodiments, extension 1606 can be fused, or otherwise coupled, to the housing of device 1602 at a convenient place, e.g., in the center of device 1602, to allow for counterbalanced insertion of a measuring device or circuit 1604, which may be configured in any manner described above.
[0107] It should be noted that the requirements for handheld device 1520 can be made simpler, potentially allowing the use or design of a simpler device 1520, by configuring device 1520 such that it can receive an entirely self contained extension 1524, e.g., and extension configured to act as a "lab-on-a-chip." In such embodiments, most if not all required functionality for osmolarity measuring and processing is contained on extension 1524. The entire extension 1524 can then be made to be disposable after one or more measurements. By moving the osmolarity functionality to extension 1524, handheld device 1520 can be made far smaller. For example, handheld device 1520 can be configured to simply comprise communication capability.
[0108] In certain embodiments, such a simplified handheld device 1520 can be configured to comprise some limited additional features or capabilities. For example, such a simplified handheld device 1520 can be configured to comprise some embedded
software look up tables to enable conversion from conductivity to osmolarity for different analytes. Such tables can be interchangeable if, for example, a user is measuring multiple different fluids, e.g., blood and then urine in short succession. By including the tables in handheld device 1520, the ability to quickly change tables, or load new tables can be facilitated.
[0109] In any of the handheld embodiments described above, handheld device 1520 can be configured to receive removable memory. For example, a receptacle or interface for a flash memory, a memory stick, Universal Serial Bus (USB) memory device, etc., can be integrated into the housing of the device. In fact, a self contained, "lab-on-a-chip" extension 1524 can be design to resemble a USB key memory. In one embodiment, for example, such an extension 1524 can comprise a display, such as a LCD screen, and can be configured to receive a "lab-on-a-chip" cartridge on one end, while the other end can comprise a USB comiector. Such a cartridge can then be configured to display the osmolarity on the LCD.
[0110] Further, any of the handheld, or portable, embodiments described can be paired with wireless communication capabilities to permit real-time transmission of data regarding sample fluid osmolarity, e.g., as related to steps in an industrial process. This data can, for example, be transmitted to another portable base unit or to any device with wireless communication capabilities. Such communication would permit the monitoring of osmolarity by any employee of the given factory, and can allow annotations and osmolarity data to be shared in real-time, i other words, a technician making measurements with a handheld device 1520 can not only transmit the osmolarity data, e.g., to a supervisor or consultant, but handheld device can also comprise a user interface that can allow the technician to input annotations or comments to be sent as well.
[0111] It may be advantageous to fit a portable base unit with legs for increased stability. Increased stability could be achieved in a variety of ways, hi some embodiments, device 1520 can have screw mounts for a tripod. Device 1524 can then be attached to and removed from a tripod in a manner similar to a camera. In other embodiments, the device 1520 can have legs on the underside, which may be implemented as sticky rubber hemispheres or telescopically folding legs. Such folding legs would form the device's own tripod or quadropod, which would be shorter than a typical camera tripod. [0112] Devices to be used in a doctor's office can, for example, be mounted upright against a wall with the extension receptacle pointing straight up. Adjustable mounting brackets would allow planar rotation of device 1520.
[0113] In industrial settings, device 1520 can be fitted to existing piping such that the inverted electrode or capillary sampler would be placed adjacent to the wall ofthe lumen of the pipe. Device 1520 can then rest on the outside of the piping and would be separated from the electrode or capillary sampler by a seal to prevent direct fluidic contact. Quadropod legs could be attached magnetically, adhesively, or via screw plates to the exterior of the piping. Accordingly, device 1520 can reside in one place for an extended period of time, continuously displaying or broadcasting the osmolarity, until it became necessary to move the unit.
[0114] While certain embodiments of the inventions have been described above, it will be understood that the embodiments described are by way of example only. Accordingly, the inventions should not be limited based on the described embodiments. Rather, the scope of the inventions described herein should only be limited in light of the claims that follow when taken in conjunction with the above description and accompanying drawings.