Systems and methods for sample use maximization

Abstract

The present invention provides systems, devices, and methods for point-of-care and/or distributed testing services. The methods and devices of the invention are directed toward automatic detection of analytes in a bodily fluid. The components of the device can be modified to allow for more flexible and robust use with the disclosed methods for a variety of medical, laboratory, and other applications. The systems, devices, and methods of the present invention can allow for effective use of samples by improved sample preparation and analysis.

1 . A method of detecting the presence or concentration of an analyte in a sample fluid contained in a container comprising:
 (a) illuminating the container along a first region having a first path length to yield a first measurement of light intensity transmitted across the first path length;   (b) moving the sample fluid to another region in the container having another path length if the first measurement falls outside a predetermined dynamic range of transmitted light intensity;   (c) illuminating the container along the another region to yield another measurement of light intensity transmitted across the another path length; and optionally   (d) repeating steps (b) and (c) until a measurement of light intensity falls within the predetermined dynamic range, thereby detecting the presence or concentration of the analyte.   
     
     
         2 . The method of  claim 1 , further comprising deconvoluting a line scan of the image, thereby detecting the presence or concentration of an analyte. 
     
     
         3 . The method of  claim 1 , wherein the sample is moved from a first region of the container having a first path length to a second region of the container having another path length by aspirating the sample. 
     
     
         4 . The method of  claim 3  wherein an end of the container is attached to a pipette which is configured to aspirate the sample. 
     
     
         5 . The method of  claim 3  wherein the sample is moved up or down the length of the container. 
     
     
         6 . The method of  claim 1 , wherein the container is a pipette tip. 
     
     
         7 . The method of  claim 1 , wherein the container is conically shaped. 
     
     
         8 . The method of  claim 1 , wherein the container has two open ends. 
     
     
         9 . The method of  claim 8 , wherein a first open end has a greater diameter than a second open end. 
     
     
         10 . The method of  claim 1 , wherein the container has a plurality of distinct widths to permit transmission of light along a plurality of varying path lengths. 
     
     
         11 . The method of  claim 1 , wherein the container volume is less than 100 microliters. 
     
     
         12 . The method of  claim 1 , wherein a plurality of distinct path lengths are imaged simultaneously. 
     
     
         13 . A method of measuring an analyte concentration in a sample fluid comprising:
 (a) providing the sample contained in a container dimensioned with a plurality of distinct widths to permit transmission of light along a plurality of varying path lengths that correspond to the plurality of distinct widths;   (b) illuminating the container along at least one of the plurality of path lengths; and   (c) imaging the container to measure a first light intensity transmitted across said at least one of the plurality of path lengths, for the determination of the concentration of the analyte based on the measured first light intensity.   
     
     
         14 . The method of  claim 13 , further comprising:
 (a) imaging the container to measure a second light intensity transmitted across another path length corresponding to another distinct width of the container;   (b) comparing said first light intensity and the second light intensity;   (c) determining an analyte concentration based on said comparing step.   
     
     
         15 . The method of  claim 13 , further comprising selecting a desired detection path length by one or more of the following: (a) moving a light source relative to the sample, (b) moving a detector relative to the sample, or (c) moving sample within the container relative to the light source. 
     
     
         16 . The method of  claim 13 , wherein the illumination is provided by a light source and the imaging is provided by a detector, wherein the light source and the detector are on opposing sides of the container. 
     
     
         17 . The method of  claim 13 , wherein the illumination is provided by a light source and the imaging is provided by a detector, wherein the light source and the detector are on the same side of the container. 
     
     
         18 . The method of  claim 13 , wherein the plurality of path lengths are orthogonal to the length of the container. 
     
     
         19 . The method of  claim 13 , wherein the container has a first open end and a second open end, wherein the first open end has a smaller width than the second open end. 
     
     
         20 . The method of  claim 19 , wherein the second open end is configured to connect to a fluid handling device. 
     
     
         21 . An automated system for separating one or more components in a biological fluid comprising:
 (a) a pipette tip or closed tube adapted to engage with an aspirator wherein said pipette tip or tube comprises two opposing ends, at least one of which is closed or sealable; and   (b) a centrifuge configured to receive said sealed pipette tip or closed tube to effect said separating of one or more components in a biological fluid.   
     
     
         22 . The system of  claim 21 , wherein the one or more components are selected from the group consisting of blood plasma, blood serum, blood cells, and particulates. 
     
     
         23 . The system of  claim 21 , wherein when the pipette tip is engaged with the aspirator to effect a draw of the biological fluid. 
     
     
         24 . The system of  claim 23 , wherein the pipette tip has an open end that forms an airtight seal with the aspirator. 
     
     
         25 . The system of  claim 21 , further comprising
 an imaging device; and   at least one other pipette tip dimensioned to allow dispensing of a liquid into the pipette tip or tube of (a) or to allow the aspiration of a liquid from the pipette tip or tube of (a).   
     
     
         26 . The system of  claim 21 , wherein the pipette tip or closed tube is oriented vertically when the centrifuge is at rest. 
     
     
         27 . The system of  claim 26 , wherein the pipette tip or closed tube is oriented horizontally when the centrifuge is spinning at a predetermined rotational velocity. 
     
     
         28 . A method for isolating components in a sample comprising:
 (a) loading a sample into a pipette tip or a tube comprising two opposing ends, at least one of which is sealable or sealed;   (b) sealing the pipette tip or the tube on the at least one end of the pipette tip;   (c) centrifuging the sealed pipette tip or the tube, thereby forming an interfacial region that separates the sample into a supernatant and a pellet;   (d) imaging the centrifuged pipette tip or the tube to determine the location of the interfacial region; and   (e) automatically aspirating the supernatant based on the location of the interfacial region.   
     
     
         29 . The method of  claim 28 , further comprising determining the location of the supernatant by said imaging step and automatically aspirating the supernatant based on the location of the supernatant. 
     
     
         30 . The method of  claim 29  wherein said determination occurs with the aid of a processor, and said processor provides instructions to an aspirating device which performs the automated aspiration step. 
     
     
         31 . The method of  claim 28  wherein the imaging occurs by use of a camera that is configured to capture the image of the side profile of the pipette tip or the tube. 
     
     
         32 . The method of  claim 28  wherein the supernatant includes one or more of the following: blood plasma or blood serum. 
     
     
         33 . The method of  claim 29  wherein the pellet includes one or more of the following: blood cells or particulates. 
     
     
         34 . A method for characterizing an analyte suspected to be present in a sample comprising:
 (a) obtaining a digital image of the sample, wherein the digital image comprises at least a two-dimensional array of pixels, and wherein each pixel comprises a plurality of intensity values, each of which corresponds to a distinct detection spectral region;   (b) correlating, with the aid of a programmable device, the obtained intensity values with a predetermined set of values that define a dynamic range of each detection spectral region; and   (c) predicting the presence and/or quantity of said analyte in the sample based on said correlating of the obtained intensity values with a predetermine set of values.   
     
     
         35 . The method of  claim 34 , wherein the plurality of intensity values comprise intensity values for red, green, and blue detection spectral regions. 
     
     
         36 . The method of  claim 34  further comprising selecting an illumination wavelength, and illuminating the sample with the selected illumination wavelength prior to and/or concurrently with obtaining the digital image. 
     
     
         37 . The method of  claim 36  further comprising: subsequent to obtaining the digital image, (a) selecting another illumination wavelength; (b) illuminating the sample with the other selected illumination wavelength; (c) obtaining another digital image of the sample, wherein the digital image comprises at least a two-dimensional array of pixels, and wherein each pixel comprises a plurality of intensity values, each of which corresponds to a distinct detection spectral region; and (d) predicting the presence and/or quantity of said analyte in the sample based on the obtained intensity values from the digital image and said another digital image. 
     
     
         38 . A method for characterizing an analyte suspected to be present in a sample of biological fluid comprising:
 (a) providing said sample of biological fluid;   (b) allowing said analyte to react with one or more reagents that specifically react with said analyte to generate an optically detectable signal; and   (c) measuring said optically detectable signal with a plurality of detection spectral regions, wherein the presence of said optically detectable signal within a dynamic range of at least one detection spectral region is indicative of the concentration of said analyte in said sample of biological fluid.   
     
     
         39 . The method of  claim 38 , wherein the plurality of detection spectral regions is selected from the group consisting of red, green, and blue. 
     
     
         40 . The method of  claim 38 , further comprising the step of quantitating the concentration of said analyte by evaluating the values measured from said at least one detection spectral region. 
     
     
         41 . The method of  claim 38 , wherein the biological fluid is blood, urine, saliva, spinal fluid, or semen. 
     
     
         42 . The method of  claim 38 , wherein the measuring is performed by an imaging device configured to measure a plurality of detection spectral regions. 
     
     
         43 . The method of  claim 42  wherein the imaging device is configured to measure the plurality of detection spectral regions simultaneously. 
     
     
         44 . The method of  claim 42  wherein the imaging device is configured to measure the plurality of detection spectral regions sequentially. 
     
     
         45 . The method of  claim 38 , wherein the sample is measured in a pipette tip. 
     
     
         46 . A method for increasing the accuracy of an assay comprising:
 (a) imaging a sample in a first tip to determine the volume of the first sample;   (b) imaging one or more reagents in a second tip to determine the volume of the one or more reagents;   (c) mixing the sample and the one or more reagents to form a reaction mixture;   (d) imaging the reaction mixture;   (e) calibrating based on said determined volumes of the sample and the one or more reagents; and   (f) calculating a concentration of an analyte using the calibration.   
     
     
         47 . The method of  claim 46 , further comprising imaging the reaction mixture to determine the volume of the reaction mixture. 
     
     
         48 . The method of  claim 46 , wherein said imaging of the sample in the first tip is conducted using a camera configured to capture a side profile of the first tip. 
     
     
         49 . The method of  claim 48 , wherein said imaging of the one or more reagents in the second tip is conducted using a camera configured to capture a side profile of the second tip. 
     
     
         50 . The method of  claim 49 , wherein the height of the sample and the one or more reagents is calculated based on the captured profiles. 
     
     
         51 . The method of  claim 50 , wherein determining the volume is based on the height of the sample and the one or more reagents and the known cross-sectional areas of the sample and the one or more reagents respectively. 
     
     
         52 . The method of  claim 47  wherein the calibration is also based on the determined volume of the reaction mixture. 
     
     
         53 . An automated system for separating one or more components in a biological fluid comprising:
 (a) a centrifuge comprising one or more bucket configured to receive a container to effect said separating of one or more components in a fluid sample; and   (b) the container, wherein the container includes one or more shaped feature that is complementary to a shaped feature of the bucket.   
     
     
         54 . The system of  claim 53  wherein the one or more bucket is a swinging bucket that is at or near a vertical position when the centrifuge is at rest and that is at or near a horizontal position when the centrifuge is spinning. 
     
     
         55 . The system of  claim 54  further comprising a plurality of swinging buckets that are spaced radially symmetrically. 
     
     
         56 . The system of  claim 53  wherein the fluid sample is a biological fluid. 
     
     
         57 . The system of  claim 56  wherein the biological fluid is blood. 
     
     
         58 . The system of  claim 53  wherein the container is configured to contain 100 uL or less of blood. 
     
     
         59 . The system of  claim 53  wherein the container is closed on one end and open at an opposing end. 
     
     
         60 . The system of  claim 53  wherein the container is a centrifugation vessel. 
     
     
         61 . The system of  claim 60  wherein the centrifugation vessel has a rounded end with one or more interior nubs. 
     
     
         62 . The system of  claim 60  further comprising an extraction tip with one or more shaped feature that is complementary to a shaped feature of the centrifugation vessel, and that is configured to fit within the centrifugation vessel. 
     
     
         63 . The system of  claim 53  wherein the shaped feature of the bucket includes one or more shelf upon which a protruding portion of the container is configured to rest. 
     
     
         64 . The system of  claim 53  wherein the bucket is configured to be capable of accepting a plurality of containers having different configurations, and wherein the shaped feature of the bucket includes a plurality of shelves, wherein a first container having a first configuration is configured to rest upon a first shelf, and a second container having a second configuration is configured to rest upon a second shelf. 
     
     
         65 . A setup, comprising:
 a vessel configured to accept and confine a sample, wherein the vessel comprises an interior surface, an exterior surface, an open end, and an opposing closed end; and   a tip configured to extend into the vessel through the open end, wherein the tip comprises a first open end and second open end, wherein the second open end is inserted into the vessel,   wherein the vessel or the tip further comprises a protruding surface feature that prevents the second open end of the tip from contacting the bottom of the interior surface of the closed end of the vessel.   
     
     
         66 . The setup of  claim 65 , wherein the surface feature is integrally formed on the bottom interior surface of the vessel. 
     
     
         67 . The setup of  claim 65 , wherein the surface feature comprises a plurality of bumps on the bottom interior surface of the vessel. 
     
     
         68 . The setup of  claim 65 , wherein the protruding surface feature is at or near the closed end. 
     
     
         69 . A sample processing apparatus comprising:
 a sample preparation station, assay station, and/or detection station;   a control unit having computer-executable commands for performing a point-of-service service at a designated location with the aid of at least one of said sample preparation station, assay station and detection station; and   at least one centrifuge configured to perform centrifugation of a sample from a fingerstick.   
     
     
         70 . The apparatus of  claim 69 , wherein the centrifuge is contained within the sample preparation station and/or the assay station. 
     
     
         71 . The apparatus of  claim 70 , wherein the computer-executable commands are configured to perform the point-of-service service at a site selected from the group consisting of a retailer site, the subject's home, or a health assessment/treatment location. 
     
     
         72 . A method for dynamic feedback, said method comprising:
 taking an initial measurement of a sample within a container using a detection mechanism;   based on said initial measurement, determining, using a processor, whether the sample concentration falls into a desired range, and determining, using a processor, (a) a degree of dilution to be performed if the sample concentration is higher than the desired range or (b) a degree of concentration to be performed if the sample concentration is lower than the desired range; and   adjusting the sample concentration according to the determined degree of dilution or the determined degree of concentration.   
     
     
         73 . The method of  claim 72  further comprising taking a subsequent measurement of the sample within the container. 
     
     
         74 . The method of  claim 73  further comprising, based on the subsequent measurement determining, using a processor, whether the sample concentration falls into a desired range. 
     
     
         75 . The method of  claim 74  wherein the subsequent measurement is made using the detection mechanism. 
     
     
         76 . The method of  claim 73  further comprising determining a characteristic of the sample based on the subsequent measurement. 
     
     
         77 . The method of  claim 76  wherein the characteristic is selected from one or more of the following: the presence or concentration of an analyte, the presence or concentration of a cell, and the morphology of the cell. 
     
     
         78 . The method of  claim 77  wherein the subsequent measurement is made using a separate detection mechanism from the initial detection mechanism. 
     
     
         79 . The method of  claim 73  wherein the initial measurement provides a crude cell concentration measurement of the sample. 
     
     
         80 . The method of  claim 79  wherein the subsequent measurement provides a measurement of cell concentration of the sample of greater resolution than the initial measurement. 
     
     
         81 . The method of  claim 72  wherein the initial measurement is taken by imaging the sample. 
     
     
         82 . The method of  claim 72  wherein the adjusting of the sample concentration permits detection of analyte that would otherwise fall outside the desired range. 
     
     
         83 . A method for providing quality control, said method comprising:
 capturing an image of conditions under which a detection mechanism measures a characteristic of a sample; and   determining, using a processor, based on the image whether there are undesirable conditions under which the detection mechanism is operated.   
     
     
         84 . The method of  claim 83  wherein the undesirable conditions includes the presence of one or more undesirable materials. 
     
     
         85 . The method of  claim 84  wherein the undesirable materials includes one or more of the following: bubbles, particles, fibers, debris, and precipitates that interfere with the measurement of the characteristic of the sample. 
     
     
         86 . The method of  claim 83  wherein the detection mechanism is a different mechanism from a mechanism used to capture the image. 
     
     
         87 . The method of  claim 83  wherein the image is captured using a camera. 
     
     
         88 . The method of  claim 83  further comprising providing an alert if an undesirable condition is detected. 
     
     
         89 . The method of  claim 83  further comprising adjusting the sample if an undesirable condition is detected. 
     
     
         90 . The method of  claim 83  wherein the image includes an image of the sample. 
     
     
         91 . The method of  claim 90  wherein the image includes an image of one or more of the following: the sample container or the detection mechanism.