Devices, cartridge, and sensors for controlling liquid movement and analyzing biological samples

Abstract

Described herein are cartridges and devices for operating said cartridges for analyzing a biological sample, such as a blood or saliva sample. Also described herein is an impedance sensor for analyzing a biological sample. Further described herein are methods of determining a cell count or detecting an analyte in a biological sample, which can include transporting the biological sample through a sensor comprising a channel or pore; applying an electrical current or voltage to the channel or pore; detecting an impedance within the channel or pore; and determining a cell count or detecting the analyte based on the detected impedance. Also described herein is an electrowetting electrode array that is configured to transport aqueous solutions using low voltage, such as about 50 volts or less. Further described herein are methods of transporting an aqueous liquid using electrowetting electrodes.

What is claimed is: 
     
         1 . A cartridge for analyzing a biological sample, comprising:
 a sample receiving port configured to receive the biological sample;   a sensor configured to analyze the biological sample;   a cartridge space in fluid communication with the biological sample receiving port and the sensor;   a plurality of electrowetting electrodes configured to transport the biological sample in the cartridge space and combine the biological sample with one or more reagents; and   a device interface configured to receive power from and communicate with a cartridge interface on a device, wherein the sensor and the plurality of electrowetting electrodes are in electrical communication with the device interface.   
     
     
         2 . The cartridge of  claim 1 , wherein the sensor is an impedance sensor. 
     
     
         3 . The cartridge of  claim 1  or  2 , wherein the sensor is configured to detect a protein or measure an amount of the protein. 
     
     
         4 . The cartridge of  claim 1 , wherein the sensor is a channel sensor, comprising:
 a first channel segment,   a second channel segment,   a pore or channel fluidly connecting the first channel segment and the second channel segment, and   an electrode pair configured to apply an electrical current to the pore or channel, and to detect impedance within the pore or channel.   
     
     
         5 . The cartridge of  claim 4 , wherein the sensor is configured to differentiate between different types of cells. 
     
     
         6 . The cartridge of  claim 5 , wherein the sensor is configured to differentiate between red blood cells, white blood cells, and platelets. 
     
     
         7 . The cartridge of  claim 5  or  6 , wherein the sensor is configured to differentiate between eosinophils, basophils, neutrophils, monocytes, and lymphocytes. 
     
     
         8 . The cartridge of  claim 4 , wherein the electrical current is a multiplexed current comprising a plurality of alternating current components at different frequencies. 
     
     
         9 . The cartridge of  claim 8 , wherein the electrical current is a multiplexed current comprising a (1) a direct current component or a low-frequency alternating current, and (2) a plurality of alternating current components at different frequencies. 
     
     
         10 . The cartridge of any one of  claims 4 - 9 , wherein the electrode pair is configured to detect a real impedance component and an imaginary impedance component within the pore or channel. 
     
     
         11 . The cartridge of any one of  claims 1 - 10 , wherein the plurality of electrowetting electrodes is configured to transport the biological sample using a voltage of less than about 50 volts. 
     
     
         12 . A system for analyzing a biological sample, comprising:
 the cartridge of any one of  claims 1 - 11 ; and   a device comprising a cartridge interface configured to interface with the cartridge, the device configured to power and operate the cartridge.   
     
     
         13 . The system of  claim 12 , wherein the device further comprises one or more processors and a non-transitory computer-readable storage medium storing one or more programs configured to be executed by the one or more processors, the one or more programs comprising instructions for (a) operating the plurality of electrowetting electrodes in the cartridge to transport the biological sample within the cartridge, and (b) operating the sensor. 
     
     
         14 . A method of analyzing a biological sample, comprising:
 depositing a biological sample into a cartridge;   transporting the biological sample within the cartridge using a plurality of electrowetting electrodes;   analyzing the biological sample using one or more sensors within the cartridge to generate analytical data; and   transmitting the analytical data from the cartridge.   
     
     
         15 . The method of  claim 14 , wherein analyzing the biological sample comprises counting a number of cells in the biological sample, wherein the analytical data is indicative of the number of cells. 
     
     
         16 . The method of  claim 14  or  15 , wherein analyzing the biological sample comprises comprising differentiating two or more different cell types. 
     
     
         17 . The method of any one of  claims 14 - 16 , wherein analyzing the biological sample comprises applying an electrical current to the biological sample and recording a multiplexed impedance of the electrical current. 
     
     
         18 . The method of any one of  claims 14 - 17 , wherein analyzing the biological sample comprises determining a concentration of an analyte or a protein within the biological sample. 
     
     
         19 . The method of  claim 18 , wherein determining the concentration of the analyte or the protein within the biological sample comprises:
 binding the analyte or the protein to an affinity moiety bound to an electrode within one of the sensors, and   measuring an impedance change resulting from the analyte or the protein binding to the affinity moiety.   
     
     
         20 . A system, comprising
 (a) a cartridge configured to analyze a biological sample, the cartridge comprising:
 (i) a sensor comprising:
 a first channel segment; 
 a second channel segment; 
 a pore or a channel fluidly connecting the first channel segment and the second channel segment; 
 an electrode pair configured apply a multiplexed electrical current or voltage to the pore or channel; and 
 an electrode pair configured to detect impedance at a plurality of frequencies within the pore or channel, wherein the electrode pair configured to apply the multiplexed electrical current and the electrode pair configured to detect the impedance are the same electrode pair or different electrode pairs; and 
 
 (ii) a device interface electrically connected to the sensor; and 
   (b) a device configured to interface with and operate the cartridge, comprising one or more processors and a non-transitory computer-readable storage medium storing one or more programs configured to be executed by the one or more processors, the one or more programs comprising instructions for determining a cell count or an analyte concentration based on the detected impedance, wherein the detected impedance comprises at least a first multivariate impedance pattern at a first frequency and a second multivariate impedance pattern at a second frequency.   
     
     
         21 . The system of  claim 20 , wherein the electrode pair configured to apply the multiplexed electrical current and the electrode pair configured to detect the impedance are the same electrode pair. 
     
     
         22 . The system of any one of  claim 20  or  21 , wherein the first multivariate impedance pattern and the second multivariate impedance pattern each comprise a real component and an imaginary component of the impedance. 
     
     
         23 . The system of any one of  claims 20 - 22 , wherein the first multivariate impedance pattern and the second multivariate impedance pattern each comprise a magnitude component and phase imaginary component of the impedance. 
     
     
         24 . The system of any one of  claims 20 - 23 , wherein the first multivariate impedance pattern and the second multivariate impedance pattern comprises one or more of an impedance peak height, an impedance peak width, an impedance peak area, or an impedance peak half-width peak height. 
     
     
         25 . The system of any one of  claims 20 - 24 , wherein the sensor is configured to differentiate between different types of cells. 
     
     
         26 . The system of  claim 25 , wherein the sensor is configured to differentiate between red blood cells, white blood cells, and platelets. 
     
     
         27 . The system of  claim 25  or  26 , wherein the sensor is configured to differentiate between eosinophils, basophils, neutrophils, monocytes, and lymphocytes. 
     
     
         28 . A method of determining a cell count in a biological sample, comprising:
 transporting the biological sample through a sensor comprising a channel or pore;   applying a multiplexed electrical current or voltage to the channel or pore;   detecting a multiplexed impedance within the channel or pore, the multiplexed impedance comprising at least a first multivariate impedance pattern at a first frequency and a second multivariate impedance pattern at a second frequency; and   determining a cell count based on the detected multiplexed impedance.   
     
     
         29 . The method of  claim 28 , wherein the first multivariate impedance pattern and the second multivariate impedance pattern each comprise a real component and an imaginary component. 
     
     
         30 . The method of  claim 28 , wherein the first multivariate impedance pattern and the second multivariate impedance pattern each comprise a magnitude component and a phase component. 
     
     
         31 . The method of any one of  claims 28 - 30 , comprising differentiating between two or more different types of cells. 
     
     
         32 . A method of detecting an analyte in a biological sample, comprising:
 transporting the biological sample through a sensor comprising a channel or pore, the biological sample comprising an analyte bound to an affinity moiety;   applying an electrical current or voltage to the channel or pore;   detecting an impedance within the channel or pore; and   detecting the analyte based on the detected impedance.   
     
     
         33 . The method of  claim 32 , wherein the analyte is a protein or an electrolyte. 
     
     
         34 . The method of  claim 32  or  33 , wherein the affinity moiety is a multivalent affinity moiety. 
     
     
         35 . The method of any one of  claims 32 - 34 , wherein the affinity moiety comprises an aptamer, an antibody, or an antibody fragment. 
     
     
         36 . The method of any one of  claims 35 - 35 , wherein detecting the analyte based on the detected impedance comprises distinguishing between an affinity moiety bound to the analyte and an unbound affinity moiety. 
     
     
         37 . An electrowetting electrode array, comprising:
 a plurality of coplanar electrowetting electrodes coated with and spaced by an insulating layer;   wherein the electrowetting array comprises a hydrophobic liquid contact surface, and wherein the electrowetting array is configured to transport an aqueous liquid using a voltage of about 50 volts or less.   
     
     
         38 . The electrowetting electrode array of  claim 37 , wherein the insulating layer comprises the hydrophobic liquid contact surface. 
     
     
         39 . The electrowetting electrode array of  claim 38 , wherein the insulating layer comprises a nanostructured surface. 
     
     
         40 . The electrowetting electrode array of  claim 37 , wherein the insulating layer is coated with a hydrophobic layer comprising the hydrophobic liquid contact surface. 
     
     
         41 . The electrowetting electrode array of any one of  claims 37 - 40 , wherein the plurality of electrowetting electrodes is configured to transport the aqueous liquid using a voltage of about 0.5 volts to about 50 volts. 
     
     
         42 . The electrowetting electrode array of any one of  claims 37 - 41 , wherein the insulating layer has a dielectric constant of about 3.9 or higher. 
     
     
         43 . The electrowetting electrode array of any one of  claims 37 - 42 , wherein the insulating layer has a thickness of about 1 nm to about 5 μm. 
     
     
         44 . The electrowetting electrode array of any one of  claims 37 - 43 , wherein the electrowetting electrodes are separated from the hydrophobic liquid contact surface by about 1 nm to about 25 μm. 
     
     
         45 . A cartridge for analyzing a biological sample, comprising:
 a sample receiving port configured to receive the biological sample;   a sensor configured to analyze the biological sample;   a cartridge space in fluid communication with the biological sample receiving port and the sensor, the cartridge space comprising the electrowetting electrode array of any one of  claims 37 - 44 ; and   a device interface configured to receive power from and communicate with a cartridge interface on a device, wherein the sensor and the plurality of electrowetting electrodes are in electrical communication with the device interface.   
     
     
         46 . A system for analyzing a biological sample, comprising:
 the cartridge of  claim 45 ; and   a device comprising a cartridge interface configured to interface with the cartridge, the device configured to operate the electrowetting electrode array.   
     
     
         47 . A method of transporting a liquid, comprising:
 positioning an aqueous liquid on a first hydrophobic liquid contact surface above an inactivated first electrowetting electrode; and   activating a second electrowetting electrode by applying a voltage of about 50 volts or less to the second electrowetting electrode, thereby transporting the aqueous liquid from the first hydrophobic liquid contact surface to a second hydrophobic liquid contact surface above the second electrowetting electrode;   wherein the first electrowetting electrode and the second electrowetting electrode are coated with and separated by an insulating layer.   
     
     
         48 . A metal oxide semiconductor capacitor (MOSCap) sensor, comprising:
 a first sensor segment comprising a first electrode and a first semiconductor layer;   a second sensor segment comprising a second electrode and a second semiconductor layer; and   a space between the first sensor segment and the second sensor segment configured to allow liquid flow;   wherein the first sensor segment, second sensor segment, and the space are in a stacked configuration.