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US20200023351A1 - Fluid-tight flow system to isolate biomarkers from a liquid sample - Google Patents

Fluid-tight flow system to isolate biomarkers from a liquid sample Download PDF

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Publication number
US20200023351A1
US20200023351A1 US16/577,031 US201916577031A US2020023351A1 US 20200023351 A1 US20200023351 A1 US 20200023351A1 US 201916577031 A US201916577031 A US 201916577031A US 2020023351 A1 US2020023351 A1 US 2020023351A1
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United States
Prior art keywords
fluid
pump
liquid sample
microfluidic chip
flow system
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Pending
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US16/577,031
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English (en)
Inventor
Rolf Muller
Scott Beach
Judy Muller-Cohn
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BIOFLUIDICA Inc
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BIOFLUIDICA Inc
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Priority to US16/577,031 priority Critical patent/US20200023351A1/en
Assigned to BIOFLUIDICA, INC. reassignment BIOFLUIDICA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MULLER, ROLF, MULLER-COHN, JUDY
Assigned to BIOFLUIDICA, INC. reassignment BIOFLUIDICA, INC. CONFIRMING ASSIGNMENT Assignors: BEACH, Scott
Assigned to BIOFLUIDICA, INC. reassignment BIOFLUIDICA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BEACH, Scott
Publication of US20200023351A1 publication Critical patent/US20200023351A1/en
Priority to US18/631,612 priority patent/US12390805B2/en
Pending legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B01L3/021—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids
    • B01L3/0217—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids of the plunger pump type
    • B01L3/0237—Details of electronic control, e.g. relating to user interface
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
    • G01N35/1011—Control of the position or alignment of the transfer device
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
    • G01N35/1016—Control of the volume dispensed or introduced
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0652—Sorting or classification of particles or molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0668—Trapping microscopic beads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0689—Sealing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/143—Quality control, feedback systems
    • B01L2200/146—Employing pressure sensors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0663—Whole sensors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502753—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1081—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices characterised by the means for relatively moving the transfer device and the containers in an horizontal plane
    • G01N35/109—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices characterised by the means for relatively moving the transfer device and the containers in an horizontal plane with two horizontal degrees of freedom

Definitions

  • the present invention relates generally to a novel fluid-tight flow system and a novel fluid-tight flow system with real-time feedback control.
  • liquid handling systems are used to transport and operate on volumes of liquid.
  • one or more liquid samples may be provided in containers (e.g., microwell plates or vials) in a liquid handling system.
  • the liquid handling system may include one or more pipettors that are used to remove (e.g., by aspirating) portions of the samples from the containers and/or to add (e.g., by dispensing) material to the samples in the containers.
  • Standard pipetting systems only use one pipette at a time to dispense or collect samples.
  • Liquid handlers may be used to directly inject samples from a pipettor into a macro-scale fluidic systems, such as a flow cytometer, (U.S. Pat. No. 7,858,040) in conjunction with a separate pump system, such as the Hamilton PSD3 Servo syringe pump, to control fluid flow.
  • a separate pump system such as the Hamilton PSD3 Servo syringe pump
  • capillary connectors are typically used in conjunction with syringe pumps or separate pressure supply devices to deliver liquid patient samples to microfluidic chips (as in the Elveflow microfluidic flow control system).
  • the presently disclosed subject matter describes a fluid-tight flow system comprising a microfluidic chip comprising an inlet port in fluid communication with an outlet port; a first automated pipetting channel comprising a first pump, and a first pipette tip containing a liquid sample and coupled to the inlet port; a second automated pipetting channel comprising a second pump, and a second pipette tip coupled to the outlet port; and a non-transitory computer readable medium in communication with the first pump and the second pump, and programmed to command the first pump of the first automated pipetting channel and the second pump of the second automated pipetting channel to control flow of the liquid sample through the microfluidic chip.
  • the first pump or the second pump comprises a plunger and a pipetting drive motor.
  • the first pump or the second pump comprises a piston contained within the first pipette tip and a pipetting drive motor.
  • the fluid-tight flow system further comprises closed-loop feedback control wherein the first automated pipetting channel further comprises a first pressure sensor; the second automated pipetting channel further comprises a second pressure sensor; and the non-transitory computer readable medium is further in communication with the first pressure sensor and second pressure sensor; wherein said non-transitory computer readable medium is further programmed to receive data from the first pressure sensor in real-time and data from the second pressure sensor in real-time, and adjust command of at least the first pump of the first automated pipetting channel or the second pump of the second automated pipetting channel to adjust flow through the microfluidic chip using real-time feedback based on said data from the first pressure sensor and the second pressure sensor.
  • the real-time feedback based on said data from the first pressure sensor and the second pressure sensor comprises detection at, above or below a pressure threshold or a flow rate threshold.
  • the liquid sample is a bodily fluid.
  • the bodily fluid is blood, saliva, lymphatic fluid, cells suspended in fluid, synovial fluid, semen, urine, cerebrospinal fluid, or amniotic fluid.
  • the microfluidic chip further comprises a cell selection module, a plasma isolation module, or a solid-phase extraction module in fluid communication with the inlet and the outlet port.
  • the microfluidic chip comprises a cell selection module and said cell selection module comprises a capture bed in fluid communication with the inlet port and the outlet port.
  • the capture bed comprises a plurality of isolation channels configured to isolate biomarker cells from the liquid sample, solid supports configured to bind to biomarker cells, or a filter substrate configured as a size-based separator for biomarker cells.
  • the filter substrate is a microcavity array.
  • the solid supports are pillars, beads, or resins.
  • the plurality of isolation channels are configured to isolate circulating tumor cells or circulating leukemic cells.
  • the liquid sample is blood and the microfluidic chip comprises a plasma isolation module configured to separate plasma from red blood cells and white blood cells.
  • the liquid sample is plasma and the microfluidic chip comprises a solid-phase extraction module configured to extract cfDNA, ctDNA, or exosomes from plasma.
  • the solid-phase extraction module comprises an extraction bed in fluid communication with the inlet port and the outlet port.
  • the extraction bed comprises extraction channels configured to extract cfDNA, ctDNA, or exosomes from plasma; solid supports configured to bind cfDNA, ctDNA, or exosomes; or a filter substrate configured as a size-based separator for exosomes.
  • the solid supports are pillars, beads, or resins.
  • the liquid sample is blood and the microfluidic chip further comprises a plasma isolation module configured to separate plasma from red blood cells and white blood cells and a solid-phase extraction module configured to extract cfDNA, ctDNA, or exosomes from plasma; and each module is in fluid communication with each other module, and the inlet and the outlet port.
  • a plasma isolation module configured to separate plasma from red blood cells and white blood cells
  • a solid-phase extraction module configured to extract cfDNA, ctDNA, or exosomes from plasma
  • the liquid sample is blood and the microfluidic chip further comprises a solid-phase extraction module configured to lyse biomarker cells and capture DNA or RNA released from lysed biomarker cells; and each module is in fluid communication with each other module, and the inlet and the outlet port.
  • a solid-phase extraction module configured to lyse biomarker cells and capture DNA or RNA released from lysed biomarker cells
  • the microfluidic chip further comprises a reaction module in fluid communication with the inlet and the outlet port.
  • the reaction module is a continuous flow thermal reactor.
  • the reaction module is configured for reverse transcription, an enzymatic digestion reaction, or a primer extension reaction.
  • the reaction module is configured for polymerase chain reaction, quantitative polymerase chain reaction, or reverse-transcript polymerase chain reaction.
  • the microfluidic chip further comprises a processing module in fluid communication with the inlet and the outlet port.
  • the processing module is configured to co-encapsulate an individual cell with a barcoded microparticle in a droplet.
  • the processing module is a flow purification module configured to purify target nucleic acid molecules from excess non-target nucleic acid nucleotide components.
  • the processing module is configured for cell lysis, DNA purification, or electrophoresis.
  • the microfluidic chip further comprises a diagnostic module in fluid communication with the inlet and the outlet port.
  • the diagnostic module is a nanosensor module comprising nanotubes configured to detect or identify a single molecule or a nucleotide.
  • the diagnostic module is a hybridization sequencing module configured to expose a nucleotide sequence to probes and detect hybridized probes.
  • the diagnostic module is configured to detect or identify a single molecule or a nucleotide.
  • the diagnostic module is configured for fluorescence in situ hybridization.
  • the diagnostic module is configured for protein crystallization or mass spectrometry.
  • the presently disclosed subject matter also describes a method of isolating biomarker cells from a liquid sample comprising providing a fluid-tight flow system described herein, wherein the non-transitory computer readable medium programmed to command the first pump of the first automated pipetting channel and the second pump of the second automated pipetting channel to control flow of the liquid sample through the microfluidic chip comprises programming to control flow of the liquid sample through the cell selection module; controlling flow of the liquid sample through the cell selection module; and isolating biomarker cells from the liquid sample.
  • biomarker cells are circulating tumor cells.
  • the presently disclosed subject matter also describes a method of extracting cfDNA, ctDNA, or exosomes from plasma comprising providing a fluid-tight flow system described herein wherein the non-transitory computer readable medium programmed to command the first pump of the first automated pipetting channel and the second pump of the second automated pipetting channel to control flow of the liquid sample through the microfluidic chip comprises programming to control flow of the liquid sample through the solid-phase extraction module; controlling flow of plasma through the solid-phase extraction module; and extracting cfDNA, ctDNA, or exosomes from plasma.
  • the presently disclosed subject matter also describes a method of extracting cfDNA, ctDNA, or exosomes from blood comprises providing a fluid-tight flow system described herein wherein the non-transitory computer readable medium programmed to command the first pump of the first automated pipetting channel and the second pump of the second automated pipetting channel to control flow of the liquid sample through the microfluidic chip comprises programming to control flow of the liquid sample through the plasma isolation module and the solid-phase extraction module; controlling flow of blood through the plasma isolation module; separating plasma from red blood cells and white blood cells; controlling flow of plasma through the solid-phase extraction module; and extracting cfDNA, ctDNA, or exosomes from plasma.
  • the presently disclosed subject matter also describes a method of capturing DNA or RNA released from biomarker cells comprises providing a fluid-tight flow system described herein wherein the non-transitory computer readable medium programmed to command the first pump of the first automated pipetting channel and the second pump of the second automated pipetting channel to control flow of the liquid sample through the microfluidic chip comprises programming to control flow of the liquid sample through the cell selection module and the solid-phase extraction module; controlling flow of blood through the isolation channels; isolating biomarker cells from blood; controlling flow of the processed liquid sample comprising the isolated biomarker cells through the solid-phase extraction module; lysing biomarker cells; and capturing DNA or RNA released from lysed biomarker cells.
  • FIG. 1 a is a schematic diagram of an example fluid-tight flow system according to embodiments of the present disclosure, and additional components of real-time feedback control according to embodiments of the present disclosure.
  • FIG. 1 b illustrates an example fluid-tight flow system including a controller, a pipetting instrument, e.g. an automated liquid handler, comprising multiple automated pipetting channels, multiple microfluidic chips each with an inlet port and outlet port, and an instrument deck to support the microfluidic chip, pipette tips, samples, reagents, workstations for sample processing.
  • a pipetting instrument e.g. an automated liquid handler, comprising multiple automated pipetting channels, multiple microfluidic chips each with an inlet port and outlet port, and an instrument deck to support the microfluidic chip, pipette tips, samples, reagents, workstations for sample processing.
  • FIG. 1 c is a perspective view of multiple pipetting channels and microfluidic chips, wherein the pipette tips are coupled to the inlet port and outlet port of the respective microfluidic chip, according to embodiments of the present disclosure.
  • FIG. 2 a on the left, is a perspective view of the pipetting channels and microfluidic chip, wherein the pipette tips are coupled to the inlet port and outlet port of the microfluidic chip, respectively, according to embodiments of the present disclosure; and on the right, is a vertical sectional view of the same according to embodiments of the present disclosure.
  • FIG. 2 b is a cross sectional view of the pipette tips coupled to the inlet port and outlet port of the microfluidic chip, respectively, according to embodiments of the present disclosure.
  • FIG. 2 c is a top view of the base chip of the microfluidic chip according to embodiments of the present disclosure (cover plate not shown).
  • FIG. 3 is the backend software architecture for preparing firmware commands of a Hamilton Microlab STAR line liquid handler according to one embodiment of the present disclosure.
  • FIG. 4 a is a flow chart including exemplary methods according to embodiments of the present invention.
  • FIG. 4 b is an exemplary schematic of coordinating commands and firmware parameters to control z-drive motors and pipetting drive motors of pipetting channels 1 and 2 according to embodiments of the present invention.
  • FIG. 4 c is a flow chart including exemplary methods according to embodiments of the present invention.
  • FIG. 4 d is a flow chart including exemplary methods for conducting analysis on the data from the pressure sensors according to embodiments of the present invention.
  • FIG. 4 e is a chart of exemplary real-time feedback control parameters to avoid over-pressure in a microfluidic chip according to embodiments of the present invention.
  • FIG. 4 f is a flow chart including exemplary methods for conducting analysis on the data from the pressure sensors according to embodiments of the present invention.
  • FIG. 1 a is a schematic diagram of an example fluid-tight flow system according to embodiments of the present disclosure, and additional components of real-time feedback control according to embodiments of the present disclosure.
  • FIG. 1 a illustrates an example fluid-tight flow system including a controller 100 , a pipetting instrument 001 comprising two automated pipetting channels 312 and 313 , and a microfluidic chip 400 .
  • the microfluidic chip 400 comprises an inlet port 402 , an outlet port 403 , and a capture bed 406 (shown in FIG. 2 c ).
  • FIG. 1 b illustrates an example fluid-tight flow system including a controller 100 , e.g.
  • FIG. 1 c is a perspective view of multiple pipetting channels, e.g. 312 and 313 , and microfluidic chips, e.g. 400 , wherein the pipette tips, e.g. 316 and 317 , are coupled to the inlet port, e.g. 402 , and outlet port, e.g. 403 , of the respective microfluidic chip, e.g. 400 , according to embodiments of the present disclosure.
  • a first automated pipetting channel 312 comprises a pump 308 (shown in FIG. 2 a ) and a pipette tip 316 that contains a liquid sample (not shown) and is coupled to the inlet port 402 .
  • a second automated pipetting channel 313 comprises a pump 309 (shown in FIG. 2 a ) and a pipette tip 317 that is coupled to the outlet port 403 .
  • the pipette tips 316 and 317 are simultaneously coupled to the inlet port 402 and the outlet port 403 , respectively.
  • the pipette tips 316 and 317 are disposable pipette tips.
  • the two automated pipetting channels 312 and 313 are configured and operative to control fluid flow of a liquid sample from the pipette tip 316 and through the microfluidic chip 400 via the inlet port 402 , capture bed 406 (shown in FIG. 2 c ), and outlet port 403 .
  • the liquid sample may flow through the microfluidic chip into the pipette tip 317 of the second automated pipette 313 or a sample container (not shown).
  • the pipetting instrument 001 may be an automated liquid handling system such as BiomekTM FX from Beckman-Coulter, Inc. (Brea, Calif.), Freedom EVOTM from Tecan Group, Ltd. (Switzerland), and STAR LineTM from Hamilton Company (Reno, Nev.).
  • the pipetting instrument 001 comprises an instrument motherboard 301 that is in communication with a controller 100 , instrument motors (e.g. pipettor arm drive motors such as X- and Y-drive motors; pipetting channel Z-drive motor; and pipetting drive motors 310 , and 311 ), and instrument sensors (e.g. pressure sensors 315 and 315 , tip sensors, capacitive sensors).
  • instrument motors e.g. pipettor arm drive motors such as X- and Y-drive motors; pipetting channel Z-drive motor; and pipetting drive motors 310 , and 311
  • instrument sensors e.g. pressure sensors 315 and 315 , tip sensors, capacitive sensors.
  • the instrument motherboard 301 comprises a communication device, a processing device, and a memory device for storing programs that control the functions of various pipetting instrument 001 components.
  • the pipetting instrument 001 may further comprise an instrument deck 350 to support the microfluidic chip 400 , pipette tips, samples, reagents, workstations for sample processing.
  • the controller 100 is in communication with the instrument motherboard 301 , instrument motors (e.g. pipettor arm drive motors such as X- and Y-drive motors; pipetting channel Z-drive motor; and pipetting drive motors 310 , and 311 ), and instrument sensors (e.g. pressure sensors 315 and 315 , tip sensors, capacitive sensors).
  • instrument motors e.g. pipettor arm drive motors such as X- and Y-drive motors; pipetting channel Z-drive motor; and pipetting drive motors 310 , and 311
  • instrument sensors e.g. pressure sensors 315 and 315 , tip sensors, capacitive sensors.
  • the controller 100 is integrated into the pipetting instrument 001 or with the instrument motherboard 301 .
  • the controller 100 generally comprises a communication device, a processing device, and a memory device.
  • the processing device is operatively coupled to the communication device and memory device.
  • the processing device uses the communication device to communicate with the instrument motherboard 301 , and as such the communication device generally comprises a modem, server, or other device for communicating with the instrument motherboard 301 .
  • the controller 100 may comprises a non-transitory computer readable medium, stored in the memory device, and programmed to command the first pump of the first automated pipetting channel and the second pump of the second automated pipetting channel to control flow of the liquid sample through the microfluidic chip.
  • the controller 100 may be embodied in one or more computers, microprocessors or microcomputers, microcontrollers, programmable logic controllers, field programmable gate arrays, or other suitably configurable or programmable hardware components.
  • the controller 100 may comprise control software, firmware, hardware or other programming instruction sets programmed to receive user inputs, and control instrument motors (e.g. pipettor arm drive motors such as X- and Y-drive motors; pipetting channel Z-drive motor; and pipetting drive motors 310 , and 311 ); as well as provide for real-time feedback control according to embodiments of the present disclosure.
  • control instrument motors e.g. pipettor arm drive motors such as X- and Y-drive motors; pipetting channel Z-drive motor; and pipetting drive motors 310 , and 311 .
  • the controller 100 may comprise a non-transitory computer readable medium, stored in the memory device, and programmed to receive data from the first pressure sensor in real-time and data from the second pressure sensor in real-time, and adjust command of at least the first pump of the first automated pipetting channel or the second pump of the second automated pipetting channel to adjust a flow rate within the microfluidic chip using real-time feedback based on said data from the first pressure sensor and second pressure sensor.
  • the controller 100 may comprise control software, firmware, hardware or other programming instruction sets programmed to receive data from instrument sensors (e.g. pressure sensors 314 and 315 ), receive user inputs, conduct analyses based on pressure data, and adjust control of the pump(s) of the automated pipetting channel(s).
  • the controller 100 may control parameters of the pipetting instrument 001 such as, timing of movement and X, Y, Z positions of instrument arms 302 and 303 , timing and control of pipetting drive motors 310 and 311 such as to control fluid flow rates of a liquid sample through a microfluidic chip.
  • the controller 100 can transmit control signals or other instructions to electrical or electromechanical system components (e.g. such as motors or drives, servos, actuators, racks and pinions, gearing mechanisms, and other interconnected or engaging dynamic parts) via communication technologies to enable data communication (e.g.
  • USB Universal Serial Bus
  • IEEE Institute of Electrical and Electronics Engineers
  • RF radio frequency
  • FIG. 2 a on the left, is a perspective view of the pipetting channels 312 and 313 and microfluidic chip 400 , wherein the pipette tips 316 and 317 are coupled to the inlet port 402 and outlet port 403 of the microfluidic chip 400 , respectively, according to embodiments of the present disclosure; and on the right, is a vertical sectional view of the same according to embodiments of the present disclosure. Accordingly, the pipetting channels 312 and 313 comprising the pipette tips 316 and 317 , respectively, are in fluid communication with the channels of the microfluidic chip.
  • the pipette tips 316 and 317 are coupled to the inlet port 402 and outlet port 403 of the microfluidic chip 400 via a friction fit, thereby creating a hermetic (or air-tight) seal and a leak-tight seal.
  • fluid-tight means air-tight and leak-tight.
  • the pumps of the automated pipetting channels are pistons or plungers 308 and 309 in communication with pipetting drive motors 310 and 311 and pressure sensors 314 and 315 .
  • the pressure sensors 314 and 315 are integrated into the pipetting channels 312 and 313 .
  • FIG. 2 b is a cross sectional view of the pipette tips 316 and 317 coupled to the inlet port 402 and outlet port 403 of the microfluidic chip 400 , respectively, according to embodiments of the present disclosure.
  • the inlet port 402 or outlet port 403 has a tapered shape.
  • the inlet port 402 and outlet port 403 have a tapered shape and are thus configured to receive and couple to pipette tips are varying sizes.
  • FIG. 2 c is a top view of the base chip of the microfluidic chip according to embodiments of the present disclosure (cover plate not shown).
  • the microfluidic chip 400 comprises an inlet port 402 , a feeder channel 408 , a capture bed 406 , an exit channel 408 , and an outlet port 403 ; wherein the capture bed 406 comprises a plurality of isolation channels, the feeder channel intersects with the isolation channels, and the exit channel intersects with the isolation channels.
  • the capture bed comprises a plurality of isolation channels configured to isolate circulating tumor cells, circulating leukemic cells, cfDNA, or exosomes.
  • FIG. 3 is the backend software architecture for preparing firmware commands of a Hamilton Microlab STAR line liquid handler according to one embodiment of the present disclosure.
  • FIG. 4 a is a flow chart including exemplary methods according to embodiments of the present invention. The method may be implemented by controller 100 in communication with other components of the presently disclosed system; for example, by sending commands and receiving data via the instrument motherboard 301 , which is in communication with instrument motors or instrument sensors.
  • a computer readable medium may be encoded with data and instructions for controlling flow of a liquid sample through a microfluidic chip; such as data and instructions to: command the X- and Y-drive motors of the pipetting arm to position pipetting channel 1 and 2 , each comprising a pipette tip, over the inlet and outlet ports of a microfluidic chip (step 520 ), command the z-drive motors to move pipetting channel 1 and 2 down to engage the pipette tips with the inlet and outlet ports of the microfluidic chip, respectively (step 522 ), command pressure sensors of pipetting channels 1 and 2 to activate (step 524 ), collect data from pressure sensors, preferably at regular time intervals (step 526 ), and command a) pipetting drive motor of pipetting channel 1 to move plunger down or up at a defined speed (step 600 ) and b) pipetting drive motor of pipetting channel 2 to move plunger up or down at a defined speed (step 602 ) and coordinate these commands
  • FIG. 4 b is an exemplary schematic of coordinating commands and firmware parameters to control z-drive motors and pipetting drive motors of pipetting channels 1 and 2 to control flow from the pipette tip of pipetting channel 1 , through a microfluidic chip, and into the pipette tip of pipetting channel 2 , according to embodiments of the present invention.
  • the fluid-tight flow system reduces the loss of biomaterial by using automated pipetting channels comprising pipette tips coupled to the inlet and outlet ports of a microfluidic chip, removing extraneous components such as capillary connectors and directly introducing a liquid sample into a microfluidic chip for isolation.
  • the automated pipetting channels comprising pipette tips coupled to the inlet and outlet ports of a microfluidic chip creates a fluid-tight flow system that enables coordinated use of the pipetting channels in novel way to control flow of a liquid sample from one pipette tip, through a microfluidic chip, and into the other pipette tip to collect the liquid sample.
  • pistons or plungers of automated pipetting channels are configured to aspirate or dispense when the pipette tip is in contact with a liquid sample.
  • the fluid-tight flow system described herein enables use of the pipetting channels as synchronized pumps to control flow of a liquid sample through a microfluidic chip, including use of a pipetting channel to aspirate or pull a liquid sample that is not in contact with the pipette tip or dispense or push a liquid sample that is no longer in contact with the pipette tip (i.e. when the liquid sample has completely entered the microfluidic chip).
  • the systems and methods disclosed herein enable control of flow rates at low to extremely low flow rates through microfluidic chips; thus, providing advantages in capture and isolation of rare biomarkers (e.g. DNA, RNA, exosomes).
  • FIG. 4 c is a flow chart including exemplary methods according to embodiments of the present invention. The method may be implemented by controller 100 in communication with other components of the presently disclosed system; for example, by sending commands and receiving data via the instrument motherboard 301 , which is in communication with instrument motors or instrument sensors.
  • a computer readable medium may be encoded with data and instructions for controlling flow of a liquid sample through a microfluidic chip; such as data and instructions to: command the X- and Y-drive motors of the pipetting arm to position pipetting channel 1 and 2 , each comprising a pipette tip, over the inlet and outlet ports of a microfluidic chip (step 520 ), command the z-drive motors to move pipetting channel 1 and 2 down to engage the pipette tips with the inlet and outlet ports of the microfluidic chip, respectively (step 522 ), command pressure sensors of pipetting channels 1 and 2 to activate (step 524 ), collect data from pressure sensors, preferably at regular time intervals (step 526 ), command a) pipetting drive motor of pipetting channel 1 to move plunger down or up at a defined speed (step 700 ) and b) pipetting drive motor of pipetting channel 2 to move plunger up or down at a defined speed (step 702 ) and coordinate these commands to
  • a pressure sensor monitors pressure in the air space between a liquid sample and a plunger in a pipetting channel. Accordingly, any real-time feedback in current liquid handling pipetting systems with pressure sensors (e.g. Dynamic Device real-time closed loop pipetting systems) is limited to detection of errors related to functions of a pipette tip (e.g. clogging in a pipette tip, flow rate of aspirating into a pipette tip, flow rate of dispensing from a pipette tip, volumetric monitoring of liquid dispensed or aspirated) apart from any fluidic system and thus requiring separate pressure sensors to monitor pressure in a fluidic system. Pressure data and movement of the plunger can be correlated to calculate a standard curve (pressure v.
  • Deviations from this standard curve can detect errors related to functions of pipette tip, such as a clogged tip during aspiration based on a pressure threshold for clots and incomplete aspiration of a liquid sample into a pipette tip based on a pressure threshold for insufficient liquid in a pipette tip.
  • the systems and methods including real-time feedback control and disclosed herein are novel and have unique advantages in controlling flow in a microfluidic chip.
  • the automated pipetting channels comprising pressure sensors and pipette tips coupled to the inlet and outlet ports of a microfluidic chip creates a fluid-tight flow system that enables monitoring pressure in a fluidic system and determining flow rate without additional sensor components, and adjusting flow rate with real-time feedback controls.
  • Real-time feedback based on pressure data in the systems disclosed herein comprises detection of clogging in the microfluidic chip, detection of a pressure level at or above a pressure threshold to avoid over-pressure in a microfluidic chip, and detection of flow rate at or above a flow rate threshold for a liquid sample.
  • FIG. 4 d is a flow chart including exemplary methods for conducting analysis on the data from the pressure sensors according to embodiments of the present invention.
  • the step of conducting analysis on the data from the pressure sensors can include the following steps, and a computer readable medium may further be encoded with data and instructions to: determine pressure in the channels of a microfluidic chip, preferably at regular timed intervals (step 10 ), monitor pressure in channels of a microfluidic chip (step 11 ), and detect pressure in the channels of a microfluidic chip at, above, or below a pressure threshold (step 12 ).
  • a pressure threshold that correlates to detection of clogging in a microfluidic chip can be determined by 1) comparison between a standard curve (pressure v. time), based on pressure data and movement of the plunger(s), that represents successful flow of a liquid sample through a microfluidic chip and a curve (pressure v. time), based on pressure data and movement of the plunger(s), that represents clogging in a microfluidic chip and 2) selection of a pressure level as a pressure threshold.
  • a pressure threshold that correlates to maximum pressure in a microfluidic chip can be determined by 1) comparison between a standard curve (pressure v.
  • a computer readable medium may further be encoded with data and instructions to receive user input of a pressure threshold, or to determine any of the foregoing pressure thresholds.
  • a computer readable medium may further be encoded with data and instructions to repeat adjustments in commands in steps 700 and 702 and analysis (step 704 ) in order to control flow of a liquid sample through a microfluidic chip with real-time feedback.
  • FIG. 4 e is a chart of exemplary real-time feedback control parameters to avoid over-pressure in a microfluidic chip according to embodiments of the present invention. As shown schematically in this chart, steps 10 - 12 (with respect to a pressure threshold that correlates to maximum pressure in a microfluidic chip), 700 , and 702 are repeated over time as fluid flow through a microfluidic chip is adjusted. Pressure thresholds to avoid over-pressure in a microfluidic chip may be defined by user, or a computer readable medium may further be encoded with data and instructions to determine a pressure threshold to avoid over-pressure in a microfluidic chip.
  • FIG. 4 f is a flow chart including exemplary methods for conducting analysis on the data from the pressure sensors according to embodiments of the present invention.
  • the step of conducting analysis on the data from the pressure sensors can include the following steps, and a computer readable medium may further be encoded with data and instructions to: determine flow rate of a liquid sample in the channels of a microfluidic chip, preferably at regular timed intervals (step 20 ), monitor the flow rate of a liquid sample in channels of a microfluidic chip (step 21 ), and detect a flow rate in the channels of a microfluidic chip at, above, or below a flow rate threshold (step 22 ).
  • a flow rate threshold that correlates to optimized flow to isolate a given biomarker can be determined by 1) comparison between a standard curve (flow rate v. time), based on pressure data and movement of the plunger(s), that represents successful flow of a liquid sample through a microfluidic chip and a curve (flow rate v. time), based on pressure data and movement of the plunger(s), that represents an optimized flow rate for a class of liquid samples through a microfluidic chip and 2) selection of a flow rate as a flow rate threshold.
  • a computer readable medium may further be encoded with data and instructions to receive user input of a flow rate threshold, or to determine a flow rate threshold.
  • a computer readable medium may further be encoded with data and instructions to repeat adjustments in commands in steps 700 and 702 and analysis (step 704 ) in order to control flow of a liquid sample through a microfluidic chip with real-time feedback.
  • the controller 100 comprises a decision engine 102 and a flow control rules server 104 .
  • a computer readable medium may be encoded with data and instructions to command a) pipetting drive motor of pipetting channel 1 to move plunger down or up at a defined speed (step 700 ) and b) pipetting drive motor of pipetting channel 2 to move plunger up or down at a defined speed (step 702 ) and coordinate these commands to control flow of a liquid sample through a microfluidic chip (and ultimately into the pipette tip of pipetting channel 2 ).
  • the flow control rules server 104 comprises rules for coordinating commands to the pipetting drive motors of the pipetting channels to control flow of a liquid sample through a microfluidic chip. Exemplary rules are set forth in Table 1:
  • the flow control rules server 104 may comprise rules for determining a pressure threshold.
  • the flow control rules server 104 may comprise rules for determining a flow rate threshold.
  • the decision engine 102 is configured to determine which rules of the flow control rules server to apply to coordinate commands to the the pipetting drive motors of the pipetting channels to control flow of a liquid sample through a microfluidic chip. In one embodiment, the decision engine 102 is configured to determine which rules of the flow control rules server to apply in response to detection of pressure at, above, or below a pressure threshold. In one embodiment, the decision engine 102 is configured to determine which rules of the flow control rules server to apply in response to detection of a flow rate at, above, or below a flow rate threshold.
  • controller device 100 shown in FIG. 1 a may include suitable hardware, software, or combinations thereof configured to implement the various techniques described herein.
  • the methods and system of the disclosed embodiments, or certain aspects or portions thereof, may take the form of program code (i.e., instructions) embodied in tangible media, such as floppy diskettes, CD-ROMs, hard drives, or any other machine-readable storage medium, wherein, when the program code is loaded into and executed by a machine, such as a computer, the machine becomes an apparatus for practicing the presently disclosed subject matter.
  • the computer will generally include a processor, a storage medium readable by the processor (including volatile and non-volatile memory and/or storage elements), at least one input device and at least one output device.
  • One or more programs are preferably implemented in a high level procedural or object oriented programming language to communicate with a computer system.
  • the program(s) can be implemented in assembly or machine language, if desired.
  • the language may be a compiled or interpreted language, and combined with hardware implementations.
  • the described methods and components of the system may also be embodied in the form of program code that is transmitted over some transmission medium, such as over electrical wiring or cabling, through fiber optics, or via any other form of transmission, wherein, when the program code is received and loaded into and executed by a machine, such as an EPROM, a gate array, a programmable logic device (PLD), a client computer, a video recorder or the like, the machine becomes an apparatus for practicing the presently disclosed subject matter.
  • a machine such as an EPROM, a gate array, a programmable logic device (PLD), a client computer, a video recorder or the like
  • PLD programmable logic device
  • client computer a client computer
  • video recorder or the like
  • the program code When implemented on a general-purpose processor, the program code combines with the processor to provide a unique apparatus that operates to perform the processing of the presently disclosed subject matter.

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