WO2021043013A1 - Automatic micromilling platform for microfluidic devices - Google Patents

Automatic micromilling platform for microfluidic devices Download PDF

Info

Publication number
WO2021043013A1
WO2021043013A1 PCT/CN2020/110716 CN2020110716W WO2021043013A1 WO 2021043013 A1 WO2021043013 A1 WO 2021043013A1 CN 2020110716 W CN2020110716 W CN 2020110716W WO 2021043013 A1 WO2021043013 A1 WO 2021043013A1
Authority
WO
WIPO (PCT)
Prior art keywords
machine
workpiece
micromilling
spindle
control system
Prior art date
Application number
PCT/CN2020/110716
Other languages
French (fr)
Inventor
Yi Ping HO
Hon Fai CHAN
Yuk Wai Lee
Yu Ki NG
Original Assignee
The Chinese University Of Hong Kong
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Chinese University Of Hong Kong filed Critical The Chinese University Of Hong Kong
Publication of WO2021043013A1 publication Critical patent/WO2021043013A1/en

Links

Images

Classifications

    • 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
    • B01L3/502707—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 the manufacture of the container or its components
    • 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

Definitions

  • Microfluidics refers to the manipulation of low volume of fluids in the range of nanoliters and picoliters and has important applications in the fields of invitro diagnostics, pharmaceutical and life science research, drug delivery, advanced therapy and laboratory testing.
  • a major bottleneck in microfluidic research is the huge cost and time invested for design iterations of microfluidic devices because a new mask or mold has to be fabricated for each new design.
  • microfluidic devices are fabricated using different materials such as glass, polydimethylsiloxane (PDMS) , poly (methyl methacrylate) (PMMA) and silicon and their fabrication technologies vary.
  • PDMS polydimethylsiloxane
  • PMMA poly (methyl methacrylate)
  • silicon silicon
  • the fabrication of a PDMS device relies on a soft lithography technique, which includes steps such as mask design, substrate pretreatment, UV exposure and photoresist development.
  • steps such as mask design, substrate pretreatment, UV exposure and photoresist development.
  • techniques such as wet chemical etching/deep reactive ion etching, hot embossing and injection molding are often used.
  • liquid chemicals or etchants such as hydrofluoric acid or dry etchant such as reactive plasma are applied to remove substrate material in specific patterns defined by a mask.
  • a molten polymer is pressed or injected to conform to a mold that contains the template of the desired features.
  • Most of these methods require a pre-formed mask or mold containing the pattern to be fabricated, which requirement lengthens the turnaround time of prototype fabrication and limits the development in the field. For example, in soft-lithography the overall turnaround time for each microchannel chip is at least 2 days.
  • Other methods such as electron beam lithography require very expensive equipment and extremely long production time for large patterning area. Further, the currently available machines cannot be fine-tuned easily and are not versatile to be applied to diverse applications.
  • the instant invention provides a micromachining platform thatis a universal platform for automatic, reliable, and cost-effective production of high-resolution microfluidics devices having microscale channels and/or other specific features for various potential biomedical applications.
  • the micromilling system of the invention comprises a motion control system, a spindle and hanger system, a workpiece carrier, a calibration system, and a bonding machine.
  • the micromilling system of the invention allows direct production of microfluidic devices such as microfluidic chips in a few hours with high-resolution microscale channels and/or other features that can be used in diverse biomedical testing and research applications.
  • FIG. 1 shows the features of a micromilling platform of the invention with (1) control system, (2) spindle with end mill installed, (3) hanger, (4) workpiece carrier, (5) tool calibration sensor, and (6) touch measurement sensor.
  • FIGS. 2A-2D show different views of the microcmilling platform.
  • FIG. 2A shows a front view.
  • FIG. 2B shows a side view.
  • FIG. 2C shows adiagonal view.
  • FIG. 2D shows a top view.
  • FIG. 3 shows the dimensions of theoretical work piece (left) and of a realistic work piece (right) .
  • FIG. 4 shows a block diagram of the control system of the micromilling platform of the invention.
  • Microfluidics refers to the manipulation of low volume of fluids in the range of nanoliters and picoliters and has important applications in the fields of invitro diagnostics, pharmaceutical and life science research, drug delivery, advanced therapy, and laboratory testing.
  • the instant invention addresses this need by providing a micromilling system that can be used with various materials and allows convenient and quick machining of a variety of devices, including microfluidic chips with 3D microscale features.
  • Micromilling is a subtractive manufacturing process that removes material from a surface via a rotating driller and has the potential to address some of the challenges associated with other fabrication methods including soft lithography, wet etching, hot embossing, and electron beam lithography. Micromilling can be used to produce 3D microscale features including positive-relief and negative-relief structures with sub-micron resolution.
  • the instant invention provides embodiments of a micromilling system or machine for fabrication of high-resolution microfluidic devices, which micromilling system or machine comprises a 4-axis direct drive motion system (X-Y-Y-Z) , a spindle, a driller or end mill, a hanger, a sample holder, a tool calibration sensor, and a bonding machine to achieve automatic, reliable, and cost-effective production of microfluidic chips with high resolution microscale channels and/or positive-relief and/or negative-relief structures.
  • “resolution” meansthesmallest feature size that this fabrication process may produce.
  • “High resolution” means a feature size less than 0.1 ⁇ m.
  • the micromilling system of the instant invention allows the direct production, in just a few hours, of microfluidic chips with high resolution microscale channels that can be used in diverse biomedical testing and research applications.
  • the micromilling systemof the invention can also be used to machine a mold for subsequent embossing and injection molding steps and/or engraving microchannels and features directly on a device.
  • the micromilling system of the invention allows the control of thickness and parallelism of a workpiece and, thus, allows a uniform thickness of a microfluidic device and a refinement of positive-relief and/or negative-relief structures to create 3D features on a micrometer scale without the need for any molds. Therefore, the micromilling system can streamline the efficacy and lowerthe cost of microfluidic device production.
  • the micromilling system of the invention can produce a microfluidic device in a matter of a few hours at a fraction of the cost of conventional production methods.
  • the micromilling system of the instant invention comprises a fixturing means such as a mountholding a spindle and a touch measurement sensor and a plate, wherein the mount and the plate are stably connected and the plate comprises affixed to its surface a workpiece carrier, a tool calibration sensor, and a hanger system.
  • the fixturingmeansof the plate comprises a set of multiple rails that are interconnected to each other, connected to the plate, and connected to a non-movable base.
  • the rails of the fixturing means allow a four-axis (X-Y-Y-Z) motion of the plate.
  • the plate further comprises a vacuum pad and mechanical gripper to ensure firm connection of the workpiece to the plate during the machining process.
  • the mountand plate are configured such that the spindle, workpiece, tool calibration sensor, and touch measurement sensor are fixed in a position relative to each other during the milling operation performed by the system.
  • the spindle of the micromilling system comprises a milling tool such as an end mill protruding from the center of the spindle.
  • the mount comprises a moving means that holds the spindle and is configured to move the spindle such that the spindle and workpiece material define a workspace therebetween.
  • the spindle is configured to hold the end mill such that the end mill protrudes from the center of the spindle towards the workspace between the spindle and the workpiece.
  • the touch measurement sensor is affixed to the mount such that the sensor tip protrudes towards a tool calibration sensor affixed to the plate adjacent to the workpiece carrier.
  • the touch measurement sensor is advantageously configured to detect the thickness and parallelism of the workpiece.
  • the micromilling system of the invention comprises 4 axes, each of which has a resolution of 0.1 ⁇ m.
  • the hanger of the micromilling system is positioned on the plate such that it is localized adjacent to the spindle to allow a quick exchange of tools for the fabrication of devices of various features.
  • the spindle and hanger system are configured to automatically change the spindle for the machining of an array of different materials required in different applications. Therefore, the micromilling platform of the invention provides a versatility that allows the micromachining of a large number of different materials for the production of a variety of workpieces for diverse applications.
  • the workpiece carrier of the micromilling system of the invention holds a workpiece in a position under the spindle such that the end mill protruding from the spindle can mill the surface of the workpiece in the desired pattern.
  • the plate having affixed to its surface the tool calibration sensor, hanger, and workpiece is affixed to a system of movable rails that together move the plate along the 4 axes (X-Y-Y-Z) and enable a fine tuning of location of the spindle in relation to the workpieceduring the milling operation.
  • the tool calibration sensor is disposed adjacent to the workpiece carrier to ensure maximum precision for tool calibration with a reproducibility of at least 0.01 mm.
  • the end mill of the micromilling system of the invention has a cutting section, the diameter of which can range from about 0.01 mm to about 0.2 mm.
  • the diameter of the cutting section of the end mill can be from about 12 ⁇ m to about 190 ⁇ m; from about 15 ⁇ m to about 180 ⁇ m; from about 20 ⁇ m to about 170 ⁇ m; from about 25 ⁇ m to about 160 ⁇ m; from about 30 ⁇ m to about 150 ⁇ m, and any increments within such ranges.
  • the limits of the channel that can be produced on a workpiece using the micromilling system of the instant invention are based on the diameter of the end mill, the resolution of the axes, and the revolution stability of the spindle. For example, at a size of the mill of about 30 ⁇ m, an axis resolution of about 0.1 ⁇ m, and a spindle stability of about 10 ⁇ m, workpieces with microchannels of a diameter of less than 100 ⁇ m can be produced.
  • the micromilling system of the instant invention further comprises a bonding machine that is configured to assemble multiple fabricated materials for sealing the microfluidic channels.
  • the micromilling system of the invention can be used to produce microfluidic devices using workpiece material including, but not limited to, silicon, glass, ceramic, elastomers including, but not limited to, acrylic, thermoplastic polymers including poly (methyl methacrylate) (PMMA) , poly (dimethylsiloxane) (PDMS) , polystyrene, polyurethane, thermoset polyester, polycarbonate, cyclo-oelfin polymer (COP) , poly (methyl glutarimide) (PGM1) , phenol formaldehyde resin, epoxy-based polymers, polyethylene teraphthalate (PET) , and other polymeric materials.
  • workpiece material including, but not limited to, silicon, glass, ceramic, elastomers including, but not limited to, acrylic, thermoplastic polymers including poly (methyl methacrylate) (PMMA) , poly (dimethylsiloxane) (PDMS) , polystyrene, polyurethane, thermoset polyester, polycarbonate
  • Also provided is a method for micromilling a workpiece comprising placing a workpiece material on the vacuum pad and spring-loaded mechanical gripper of the workpiece carrier; measuring the thickness and parallelism of the workpiece material using the touch measurement sensor; sending the thickness and parallelism data to the control system; setting the height reference point of machining according to the thickness data andcompensating for any misalignment according to the parallelism data; configuring the control system to the desired milling specifications; and micromillingthe workpiece material with the end mill.
  • a method for producing a microfluidic device having various surface features comprising placing a device material on the vacuum pad and mechanical gripper of the workpiece carrier; measuring the thickness and parallelism of the device material using the touch measurement sensor; sending the thickness and parallelism data to the control system, setting the height reference point of machining according to the thickness data and compensating for any misalignment according to the parallelism data; configuring the control system to the desired milling specifications for the device to be fabricated; micromilling the workpiece with a first end mill according to the specifications for a first configuration; exchanging the first spindle/end mill with a second spindle/end mill from the hanger; micromilling the workpiece with the second end mill according to the specifications for a second configuration; exchanging the second spindle/end mill for a third spindle/end mill from the hanger; micromilling the workpiece with the third end mill according to the specifications for a third configuration; and repeating the above steps in a preset order or a random order of spin
  • control system can be set such that the end mill machines or micromills a defined spot on the workpiece material, wherein the end mill is in a fixed position and the workpiece material moves relative to the end mill during the machining operationusing the multiple interconnected railsstably connected to the workpiece-carrying plate. Therefore, the plate carrying the workpiece can be moved along 4 axes relative to the end mill, which motion along the 4 axes is controlled by the motion control system.
  • the micromilling system is configured such that each axis of the system has a resolution of about 0.1 ⁇ m. In some embodiments, the resolution of each axis can be about 0.05 ⁇ m, about 0.06 ⁇ m, about 0.07 ⁇ m, about 0.08 ⁇ m, or about 0.09 ⁇ m.
  • the hanger of the micromilling system is configured to position different end mill configurations with different cutting section diameters adjacent to the spindle such that the end mills with different cutting section diameters can be conveniently and quickly exchanged.
  • This feature allows the micromilling system to produce micromilled devices with different microchannel, positive-relief, and/or negative relief measurements within a matter of hours fullyautomatically. This enhances the efficiency and precision of the machining process and reduces the requirement of human effort, thereby reducing production cost.
  • the micromilling device of the invention is used to produce microfluidic chips that are, e.g., for the handling, separation, control, measurement, and analysis of biological and/or chemical fluids, or biological and/or chemical samples suspended in fluid, particularly biomolecule samples that can have a size in the micron range.
  • the micromilling system of the invention does not need a mold but instead fabricates the desired device from a workpiece directly. Besides saving time and materials, the micromilling system allows the custom design of each device based on the specifications provided by the control system
  • the micromilling system is configured to produce microfluidic devices having a plurality of microchannels, wherein the microchannels are of the same dimensions.
  • the micromilling system is configured to produce microfluidic devices having a plurality of microchannels, wherein the microchannelshave different dimensions.
  • the micromilling system is configured to produce microfluidic devices having a plurality of positive-relief and/or negative-relief features, wherein the positive-and/or negative-relief features are of the same dimensions.
  • the micromilling system is configured to produce microfluidic devices having a plurality of positive-relief and/or negative-relief features, wherein the positive-and/or negative-relief features have different dimensions.
  • the micromilling system can be configured to produce microfluidic devices with microchannelsthat have height differences of as low as 0.05 ⁇ mand width differences of as low as 10 ⁇ m.
  • the micromilling system can be configured to produce microfluidic devices that have positive-relief and/or negative-relief features withheight differences of as low as 0.05 ⁇ m and width differences of as low as 10 ⁇ m, wherein the surface features are homogenous throughout the microfluidic device.
  • the micromilling system can be configured to produce microfluidic devices that have positive-relief and/or negative-relief features with height differences of as low as 0.05 ⁇ m and width differences of as low as 10 ⁇ m, wherein the surface features are non-homogenous throughout the microfluidic device.
  • the surface features of the microfluidic device can be of any pattern known in the art, wherein the control system is configured to produce such patterns.
  • the control system can be configured to produce patterns including, but are not limited to, positive-relief patterns, negative-relief patterns, indentations, through holes, and channels.
  • positive-relief includes raised features, ridges, protrusions, and the like and refers to structures of a fabricated workpiece body, such as a microfluidic chip, where the structural characteristics extend outwards from the core or central mass of the fabricated workpiece body and/or from the primary surface of the body.
  • negative-relief includes inset features, channels, grooves, and the like and refers to structures of a fabricated workpiece body, such as a microfluidic chip, where the structural characteristics extend inwards towards the core or central mass of the fabricated workpiece body and/or from the primary surface of the body.
  • the micromilling system of the invention can be configured to produce a microfluidic device having positive-relief and negative relief features formed during the fabrication process.
  • the micromilling system can be configured to produce a workpiece that has positive-relief features, wherein the height of positive-relief and/or negative-relief featuresor the change in height of positive-relief and/or negative-relief features on the workpiece ranges from about 0.05 ⁇ m to about 50 ⁇ m.
  • the height or change in height can be from about 0.06 ⁇ m to about 45 ⁇ m, from about 0.07 ⁇ m to about 40 ⁇ m, from about 0.08 ⁇ m to about 35 ⁇ m, from about 0.09 ⁇ m to about 30 ⁇ m, from about 0.1 ⁇ m to about 25 ⁇ m, from about 0.2 ⁇ m to about 20 ⁇ m, from about 0.3 ⁇ m, about 15 ⁇ m, from about 0.4 ⁇ m to about 10 ⁇ m, from about 0.5 ⁇ mto about 8 ⁇ m, from about 0.6 ⁇ m to about 6 ⁇ m, from about 0.7 ⁇ m to about 5 ⁇ m, from about 0.8 ⁇ m to about 4 ⁇ m, from about 0.9 ⁇ m to about 3 ⁇ m, from about 1 ⁇ m to about 2.5 ⁇ m, from about 1.5 ⁇ m to about 2 ⁇ m, and any increments within such ranges.
  • the micromilling system comprising a 4-axis motion system can be configured to rotate the workpiece during the micromillingoperation to also allow the formation of angulated features including angulated walls and valleys and other features.
  • micromilling system can also be combined with conventional techniques including, but not limited to, laser etching, iron etching, 3D printing, depositions, and sputter deposition to generate additional positive-relief and/or negative-relief features on the produced device.
  • the micromilling system can be configured to produce a microfluidic device having an array, a plurality, and/or a network of microchannels and/or an array, a plurality, and/or a network of positive-relief and/or negative-relief features.
  • the limits of the microchannelsof a device produced using the micromilling system of the invention are determined by the diameter of the end mill, the resolution of the axes, and the revolution stability of the spindle.
  • the end mill of the spindle can have a size of 30 ⁇ m
  • the axes of the motion system can have a resolution of 0.1 ⁇ m
  • the spindle can have a stability ofabout 10 ⁇ m such that the microchannels produced have a diameter of less than 100 ⁇ m.
  • the microchannels produced can have a diameter of less than 100 ⁇ m in any dimension, e.g., in width/length or depth.
  • the microchannels can have dimensions from about 50 ⁇ m to about 1000 ⁇ m inclusive of any increment or gradient within such ranges.
  • the microchannels can have a width and/or length of about 60 ⁇ m to about 900 ⁇ m; from about 80 ⁇ m to about 800 ⁇ m; from about 100 ⁇ m to about 700 ⁇ m, from about 150 ⁇ m to about 600 ⁇ m; from about 200 ⁇ m to about 500 ⁇ m; from about 250 ⁇ m to about 400 ⁇ m; and from about 300 ⁇ m to about 350 ⁇ m; and any increments within such ranges.
  • the control system of the micromilling system of the invention comprises a user instrumentation interface or other such control mechanism to set or guide the micromilling process.
  • the control system can be electrically coupled to a microprocessor or other non- transitory computer readable medium by wires or by wireless means.
  • the control system can thereby send control or sensory data signals to the microprocessor.
  • the coupled microprocessor can collect sensory data from the control system and can further relay collected information to other non-transitory computer readable media, and/or run calculations on collected data and relay the calculated results to a user-operable and/or user-readable display.
  • the sensory data captured by the control system can come, among others, from the touch measurement sensor and can be evaluated according to computer program instructions controlling the microprocessor either through hardware or software.
  • the control system is further configured to control the operation of the spindle/end mill, the hanger and the workpiece carrier as well as the tool calibrator to ensure proper functioning of the separate elements and concerting of the separate elements for proper workpiece processing.
  • the control system comprises a processing device that controls the operation of the spindle/end mill instrumentation.
  • the processing device can be communicatively coupled to a non-volatile memory device via a bus.
  • the non-volatile memory device may include any type of memory device that retains stored information when powered off.
  • the memory device can include, but is not limited to, electrically erasable programmable read-only memory ( “ROM” ) , flash memory, or any other type of non-volatile memory.
  • some of the memory device can include a non-transitory medium or memory device form which the processing device can read instructions.
  • a computer-readable medium can includeelectronic, optical, magnetic, or other storage devices capable of providing the processing device with computer-readable instructions or other program code.
  • a non-transitory computer-readable medium can include, but is not limited to, magnetic disk (s) , memory chip (s) , ROM, random-access memory ( “RAM” ) , an Application-Specific Integrated Circuit (ASIC) , a configured processor, optical storage, and/or any other medium from which a computer processor can read instructions.
  • the instructions may include processor-specific instructions, generated by a compiler and/or an interpreter from code written in any suitable computer-programming language.
  • the micromilling system of the invention comprises a four-axis (X-Y-Y-Z) motion and control system (1) that comprises a multitude of rails thatare connected to each other, a non-movable base, and the plate carrying the workpiece, tool calibration sensor, and hanger such that the plate can be moved along 4 axes (X-Y-Y-Z) .
  • the system has an open configuration to allow in-process visual inspection of the workpiece.
  • the micromilling system further comprises a spindle with end mill installed (2) , ahanger (3) , a workpiece carrier (4) , and a tool calibration sensor (5) .
  • Each axis of the multiple rails of the fixturing system can have a resolution of 0.1 ⁇ m.
  • the end mill can have a diameter ranging from 0.03mm to 0.2mm.
  • a hanger can be installed to allow quick change of tools for fabricating microchannels of various diameters.
  • a vacuum pad and spring-loaded mechanical gripper are equipped on the workpiece carrier to ensure the workpiece is firmly located during the machining process.
  • a tool calibration sensor can be set up next to the workpiece carrier to ensure maximum precision for tool calibration with a reproducibility of 0.01mm.
  • a touch measurement sensor (6) can be equipped to detect the thickness and the parallelism of the workpiece.
  • the touch measurement sensor is advantageously configured to detect the thickness and parallelism of the workpiece.
  • the control system comprises a machine controller and a motion controller (FIG. 4) .
  • the motion controller receives input information from each of the X-axis, the Y-axis, the Y-axis, and the Z-axis of the fixturing system and controls the movement of the workpiece carrying platform in each of the X-axis, the Y-axis, the Y-axis, and Z-axis, respectively.
  • the motion controller is configured to be in two-way communication with the machine controller.
  • the machine controller is further configured to be in two-way communication with the spindle drive and a human-machine interface.
  • the machine controller is also configured to control a valve that controls a vacuum workpiece holder and a tool exchange.
  • the machine controller is further configured to receive information from the calibration sensor and the touch measurement sensor so as to use the integrated information input to generate an output to the spindle drive to machine the workpiece according to instructions obtained through the human-machine interface.
  • Embodiment 1 A machine for generating high resolution microfluidic channels on microfluidic chips, the machine comprising:
  • Embodiment 2 The machine of Embodiment 1, wherein the motion control system comprises a motion controller and a machine controller, wherein the motion controller is operably linked to the machine controller.
  • Embodiment 3 The machine of Embodiment 2, wherein the machine controller is further operably linked to a spindle drive and a human-machine interface.
  • Embodiment 4 The machine of Embodiment 1, wherein the calibration system comprises a touch measurement sensor and/or a calibration sensor, each of which is operably linked to the machine controller.
  • Embodiment 5 The machine of Embodiment 4, wherein the touch measurement sensor is configured to detect the thickness and parallelism of a workpiece and transmit said detected thickness and parallelism information to the machine controller.
  • Embodiment 6 The machine of Embodiment 1, wherein the spindle and hanger system is configured to automatically change the spindle.
  • Embodiment 7 The machine of Embodiment 1, wherein the workpiece carrier and calibration system are configured to position a workpiece with a resolution of 0.1 ⁇ m along each axis of the motion control system for fully-automated microdrilling and/or micromilling of the workpiece.
  • Embodiment 8 The machine of Embodiment 1, wherein the bonding machine is configured to assemble multiple fabricated workpieces for sealing microfluidic channels.
  • Embodiment 9 A method of using a machine according to Embodiment 1 to produce a microfluidic chip, the method comprising:
  • Embodiment 10 The method of Embodiment 9, further comprising stacking and bonding multiple fabricated workpieces.
  • Embodiment 11 The method of Embodiment 10, wherein the stacking and bonding is performed in an automatic manner.
  • Embodiment 12 The method of Embodiment 9, wherein the workpiece comprises a material selected from the group consisting of silicon, glass, ceramic, elastomers optionally polydimethylsiloxane (PDMS) , thermoset polyester, thermoplastic polymers optionally poly (methyl methoacrylate) (PMMA) , polystyrene and polyurethane, and composite materials optionally cyclin-olefin copolymer (COC) .
  • PDMS polydimethylsiloxane
  • PMMA methyl methoacrylate
  • PMMA poly (methyl methoacrylate)
  • COC cyclin-olefin copolymer

Abstract

A universal micromilling platform to fabricate microfluidic devices has a motion control system (1), a spindle (2) and a hanger system (3), a workpiece carrier (4), a calibration system, and a bonding machine. Advantageously, the micromilling platform allows direct production of microfluidic devices such as microfluidic chips in a few hours with high-resolution microscale channels and/or other features that can be used in diverse biomedical testing and research applications.

Description

AUTOMATIC MICROMILLING PLATFORM FOR MICROFLUIDIC DEVICES
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of U.S. Provisional Patent Application Serial No. 62/896,180, filed September 5, 2019, which is hereby incorporated by reference in its entirety including any tables, figures, or drawings.
BACKGROUND OF THE INVENTION
Microfluidics refers to the manipulation of low volume of fluids in the range of nanoliters and picoliters and has important applications in the fields of invitro diagnostics, pharmaceutical and life science research, drug delivery, advanced therapy and laboratory testing.
A major bottleneck in microfluidic research is the huge cost and time invested for design iterations of microfluidic devices because a new mask or mold has to be fabricated for each new design.
Currently, microfluidic devices are fabricated using different materials such as glass, polydimethylsiloxane (PDMS) , poly (methyl methacrylate) (PMMA) and silicon and their fabrication technologies vary. For example, the fabrication of a PDMS device, one of the most widely employed materials, relies on a soft lithography technique, which includes steps such as mask design, substrate pretreatment, UV exposure and photoresist development. In addition, techniques such as wet chemical etching/deep reactive ion etching, hot embossing and injection molding are often used. For etching, liquid chemicals or etchants such as hydrofluoric acid or dry etchant such as reactive plasma are applied to remove substrate material in specific patterns defined by a mask. For hot embossing and injection molding, a molten polymer is pressed or injected to conform to a mold that contains the template of the desired features. Most of these methods require a pre-formed mask or mold containing the pattern to be fabricated, which requirement lengthens the turnaround time of prototype fabrication and limits the development in the field. For example, in soft-lithography the overall turnaround time for each microchannel chip is at least 2 days. Other methods such as electron beam lithography require very expensive equipment and extremely long production time for large patterning area. Further, the currently available machines cannot be fine-tuned easily and are not versatile to be applied to diverse applications.
Therefore, there is a need for producingmicrofluidic devices directly to simplify and expedite the production process and reduce costs.
BRIEF SUMMARY OF THE INVENTION
The instant invention provides a micromachining platform thatis a universal platform for automatic, reliable, and cost-effective production of high-resolution microfluidics devices having microscale channels and/or other specific features for various potential biomedical applications.
The micromilling system of the invention comprises a motion control system, a spindle and hanger system, a workpiece carrier, a calibration system, and a bonding machine. Advantageously, the micromilling system of the invention allows direct production of microfluidic devices such as microfluidic chips in a few hours with high-resolution microscale channels and/or other features that can be used in diverse biomedical testing and research applications.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1shows the features of a micromilling platform of the invention with (1) control system, (2) spindle with end mill installed, (3) hanger, (4) workpiece carrier, (5) tool calibration sensor, and (6) touch measurement sensor.
FIGS. 2A-2Dshow different views of the microcmilling platform. FIG. 2A shows a front view. FIG. 2Bshows a side view. FIG. 2Cshows adiagonal view. FIG. 2D shows a top view.
FIG. 3 shows the dimensions of theoretical work piece (left) and of a realistic work piece (right) .
FIG. 4shows a block diagram of the control system of the micromilling platform of the invention.
DETAILED DISCLOSURE OF THE INVENTION
This invention provides a universal micromilling platform to fabricate microfluidic devices. Microfluidics refers to the manipulation of low volume of fluids in the range of nanoliters and picoliters and has important applications in the fields of invitro diagnostics,  pharmaceutical and life science research, drug delivery, advanced therapy, and laboratory testing. Currently, no universal technique is available for the production of microfluidic devices that is applicable to various materials andprovides an expedited and cost-effective way of producing microfluidic devices.
The instant invention addresses this need by providing a micromilling system that can be used with various materials and allows convenient and quick machining of a variety of devices, including microfluidic chips with 3D microscale features.
Micromilling is a subtractive manufacturing process that removes material from a surface via a rotating driller and has the potential to address some of the challenges associated with other fabrication methods including soft lithography, wet etching, hot embossing, and electron beam lithography. Micromilling can be used to produce 3D microscale features including positive-relief and negative-relief structures with sub-micron resolution.
The instant invention provides embodiments of a micromilling system or machine for fabrication of high-resolution microfluidic devices, which micromilling system or machine comprises a 4-axis direct drive motion system (X-Y-Y-Z) , a spindle, a driller or end mill, a hanger, a sample holder, a tool calibration sensor, and a bonding machine to achieve automatic, reliable, and cost-effective production of microfluidic chips with high resolution microscale channels and/or positive-relief and/or negative-relief structures. As used herein, “resolution” meansthesmallest feature size that this fabrication process may produce. “High resolution” means a feature size less than 0.1 μm.
Advantageously, the micromilling system of the instant invention allows the direct production, in just a few hours, of microfluidic chips with high resolution microscale channels that can be used in diverse biomedical testing and research applications. In some embodiments, the micromilling systemof the invention can also be used to machine a mold for subsequent embossing and injection molding steps and/or engraving microchannels and features directly on a device.
The micromilling system of the invention allows the control of thickness and parallelism of a workpiece and, thus, allows a uniform thickness of a microfluidic device and a refinement of positive-relief and/or negative-relief structures to create 3D features on a micrometer scale without the need for any molds. Therefore, the micromilling system can streamline the efficacy and lowerthe cost of microfluidic device production. Advantageously, the micromilling system  of the invention can produce a microfluidic device in a matter of a few hours at a fraction of the cost of conventional production methods.
According to embodiments of the invention, the micromilling system of the instant invention comprises a fixturing means such as a mountholding a spindle and a touch measurement sensor and a plate, wherein the mount and the plate are stably connected and the plate comprises affixed to its surface a workpiece carrier, a tool calibration sensor, and a hanger system. The fixturingmeansof the plate comprises a set of multiple rails that are interconnected to each other, connected to the plate, and connected to a non-movable base. The rails of the fixturing meansallow a four-axis (X-Y-Y-Z) motion of the plate. The plate further comprises a vacuum pad and mechanical gripper to ensure firm connection of the workpiece to the plate during the machining process.
The mountand plate are configured such that the spindle, workpiece, tool calibration sensor, and touch measurement sensor are fixed in a position relative to each other during the milling operation performed by the system.
The spindle of the micromilling system comprises a milling tool such as an end mill protruding from the center of the spindle. The mount comprises a moving means that holds the spindle and is configured to move the spindle such that the spindle and workpiece material define a workspace therebetween. The spindle is configured to hold the end mill such that the end mill protrudes from the center of the spindle towards the workspace between the spindle and the workpiece.
The touch measurement sensor is affixed to the mount such that the sensor tip protrudes towards a tool calibration sensor affixed to the plate adjacent to the workpiece carrier. In reality, the work piecesare never perfectly in parallelism, which maylimit the precision of manufacturing process or deformation. On the other hand, the operational errors caused by the operators and/or operational procedures may also impede the parallelism of work pieces to the axis. To this end, the touch measurement sensor is advantageously configured to detect the thickness and parallelism of the workpiece. By calculating the measurements of the dimensions of the work piece (see, e.g., FIG. 3, X 1…X 4) , both the thickness and parallelism of the workpiece can be identified and sent to the control system such that the control system can set the height reference point and compensate for misalignment.
The micromilling system of the invention comprises 4 axes, each of which has a resolution of 0.1 μm.
The hanger of the micromilling system is positioned on the plate such that it is localized adjacent to the spindle to allow a quick exchange of tools for the fabrication of devices of various features.
The spindle and hanger system are configured to automatically change the spindle for the machining of an array of different materials required in different applications. Therefore, the micromilling platform of the invention provides a versatility that allows the micromachining of a large number of different materials for the production of a variety of workpieces for diverse applications.
The workpiece carrier of the micromilling system of the invention holds a workpiece in a position under the spindle such that the end mill protruding from the spindle can mill the surface of the workpiece in the desired pattern. The plate having affixed to its surface the tool calibration sensor, hanger, and workpiece is affixed to a system of movable rails that together move the plate along the 4 axes (X-Y-Y-Z) and enable a fine tuning of location of the spindle in relation to the workpieceduring the milling operation.
The tool calibration sensor is disposed adjacent to the workpiece carrier to ensure maximum precision for tool calibration with a reproducibility of at least 0.01 mm.
The end mill of the micromilling system of the invention has a cutting section, the diameter of which can range from about 0.01 mm to about 0.2 mm. For example, the diameter of the cutting section of the end mill can be from about 12μm to about 190μm; from about 15μm to about 180μm; from about 20μm to about 170μm; from about 25μm to about 160μm; from about 30μm to about 150μm, and any increments within such ranges.
The limits of the channel that can be produced on a workpiece using the micromilling system of the instant invention are based on the diameter of the end mill, the resolution of the axes, and the revolution stability of the spindle. For example, at a size of the mill of about 30μm, an axis resolution of about 0.1μm, and a spindle stability of about 10μm, workpieces with microchannels of a diameter of less than 100μm can be produced.
The micromilling system of the instant invention further comprises a bonding machine that is configured to assemble multiple fabricated materials for sealing the microfluidic channels.
The micromilling system of the invention can be used to produce microfluidic devices using workpiece material including, but not limited to, silicon, glass, ceramic, elastomers including, but not limited to, acrylic, thermoplastic polymers including poly (methyl methacrylate) (PMMA) , poly (dimethylsiloxane) (PDMS) , polystyrene, polyurethane, thermoset polyester, polycarbonate, cyclo-oelfin polymer (COP) , poly (methyl glutarimide) (PGM1) , phenol formaldehyde resin, epoxy-based polymers, polyethylene teraphthalate (PET) , and other polymeric materials.
Also provided is a method for micromilling a workpiece, the method comprising placing a workpiece material on the vacuum pad and spring-loaded mechanical gripper of the workpiece carrier; measuring the thickness and parallelism of the workpiece material using the touch measurement sensor; sending the thickness and parallelism data to the control system; setting the height reference point of machining according to the thickness data andcompensating for any misalignment according to the parallelism data; configuring the control system to the desired milling specifications; and micromillingthe workpiece material with the end mill.
Further provided is a method for producing a microfluidic device having various surface features, the method comprising placing a device material on the vacuum pad and mechanical gripper of the workpiece carrier; measuring the thickness and parallelism of the device material using the touch measurement sensor; sending the thickness and parallelism data to the control system, setting the height reference point of machining according to the thickness data and compensating for any misalignment according to the parallelism data; configuring the control system to the desired milling specifications for the device to be fabricated; micromilling the workpiece with a first end mill according to the specifications for a first configuration; exchanging the first spindle/end mill with a second spindle/end mill from the hanger; micromilling the workpiece with the second end mill according to the specifications for a second configuration; exchanging the second spindle/end mill for a third spindle/end mill from the hanger; micromilling the workpiece with the third end mill according to the specifications for a third configuration; and repeating the above steps in a preset order or a random order of spindle/end mill combinations according to the specifications provided by the control system. An example of a block diagram showing the control system of the invention is shown in FIG. 4.
Advantageously, the control system can be set such that the end mill machines or micromills a defined spot on the workpiece material, wherein the end mill is in a fixed position  and the workpiece material moves relative to the end mill during the machining operationusing the multiple interconnected railsstably connected to the workpiece-carrying plate. Therefore, the plate carrying the workpiece can be moved along 4 axes relative to the end mill, which motion along the 4 axes is controlled by the motion control system.
In some embodiments, the micromilling system is configured such that each axis of the system has a resolution of about 0.1 μm. In some embodiments, the resolution of each axis can be about 0.05 μm, about 0.06 μm, about 0.07μm, about 0.08μm, or about 0.09μm.
The hanger of the micromilling system is configured to position different end mill configurations with different cutting section diameters adjacent to the spindle such that the end mills with different cutting section diameters can be conveniently and quickly exchanged. This feature allows the micromilling system to produce micromilled devices with different microchannel, positive-relief, and/or negative relief measurements within a matter of hours fullyautomatically. This enhances the efficiency and precision of the machining process and reduces the requirement of human effort, thereby reducing production cost.
In some embodiments, the micromilling device of the invention is used to produce microfluidic chips that are, e.g., for the handling, separation, control, measurement, and analysis of biological and/or chemical fluids, or biological and/or chemical samples suspended in fluid, particularly biomolecule samples that can have a size in the micron range.
Advantageously, the micromilling system of the invention does not need a mold but instead fabricates the desired device from a workpiece directly. Besides saving time and materials, the micromilling system allows the custom design of each device based on the specifications provided by the control system
In some embodiments, the micromilling system is configured to produce microfluidic devices having a plurality of microchannels, wherein the microchannels are of the same dimensions.
In other embodiments, the micromilling system is configured to produce microfluidic devices having a plurality of microchannels, wherein the microchannelshave different dimensions.
In some embodiments, the micromilling system is configured to produce microfluidic devices having a plurality of positive-relief and/or negative-relief features, wherein the positive-and/or negative-relief features are of the same dimensions.
In other embodiments, the micromilling system is configured to produce microfluidic devices having a plurality of positive-relief and/or negative-relief features, wherein the positive-and/or negative-relief features have different dimensions.
Advantageously, the micromilling system can be configured to produce microfluidic devices with microchannelsthat have height differences of as low as 0.05 μmand width differences of as low as 10 μm.
In some embodiments, the micromilling system can be configured to produce microfluidic devices that have positive-relief and/or negative-relief features withheight differences of as low as 0.05 μm and width differences of as low as 10 μm, wherein the surface features are homogenous throughout the microfluidic device.
In other embodiments, the micromilling system can be configured to produce microfluidic devices that have positive-relief and/or negative-relief features with height differences of as low as 0.05 μm and width differences of as low as 10 μm, wherein the surface features are non-homogenous throughout the microfluidic device.
The surface features of the microfluidic device can be of any pattern known in the art, wherein the control system is configured to produce such patterns. For example, the control system can be configured to produce patterns including, but are not limited to, positive-relief patterns, negative-relief patterns, indentations, through holes, and channels.
As used herein, unless otherwise indicated, the term “positive-relief” includes raised features, ridges, protrusions, and the like and refers to structures of a fabricated workpiece body, such as a microfluidic chip, where the structural characteristics extend outwards from the core or central mass of the fabricated workpiece body and/or from the primary surface of the body.
As used herein, unless otherwise indicated, the term “negative-relief” includes inset features, channels, grooves, and the like and refers to structures of a fabricated workpiece body, such as a microfluidic chip, where the structural characteristics extend inwards towards the core or central mass of the fabricated workpiece body and/or from the primary surface of the body.
The micromilling system of the invention can be configured to produce a microfluidic device having positive-relief and negative relief features formed during the fabrication process.
The micromilling system can be configured to produce a workpiece that has positive-relief features, wherein the height of positive-relief and/or negative-relief featuresor the change in height of positive-relief and/or negative-relief features on the workpiece ranges from about  0.05μm to about 50 μm. For example, the height or change in height can be from about 0.06μm to about 45μm, from about 0.07μm to about 40μm, from about 0.08μm to about 35μm, from about 0.09μm to about 30μm, from about 0.1μm to about 25μm, from about 0.2μm to about about 20 μm, from about 0.3μm, about 15μm, from about 0.4μm to about 10μm, from about 0.5μmto about 8μm, from about 0.6μm to about 6μm, from about 0.7μm to about 5μm, from about 0.8 μm to about 4μm, from about 0.9μm to about 3μm, from about 1μm to about 2.5μm, from about 1.5 μm to about 2μm, and any increments within such ranges.
The micromilling system comprising a 4-axis motion system can be configured to rotate the workpiece during the micromillingoperation to also allow the formation of angulated features including angulated walls and valleys and other features.
The micromilling system can also be combined with conventional techniques including, but not limited to, laser etching, iron etching, 3D printing, depositions, and sputter deposition to generate additional positive-relief and/or negative-relief features on the produced device.
The micromilling system can be configured to produce a microfluidic device having an array, a plurality, and/or a network of microchannels and/or an array, a plurality, and/or a network of positive-relief and/or negative-relief features.
The limits of the microchannelsof a device produced using the micromilling system of the invention are determined by the diameter of the end mill, the resolution of the axes, and the revolution stability of the spindle. For example, the end mill of the spindle can have a size of 30 μm, the axes of the motion system can have a resolution of 0.1 μm and the spindle can have a stability ofabout 10 μm such that the microchannels produced have a diameter of less than 100 μm.The microchannels produced can have a diameter of less than 100 μm in any dimension, e.g., in width/length or depth. In some embodiments, the microchannels can have dimensions from about 50 μm to about 1000 μm inclusive of any increment or gradient within such ranges. For example, the microchannels can have a width and/or length of about 60μm to about 900 μm; from about 80 μm to about 800 μm; from about 100 μm to about 700 μm, from about 150μm to about 600 μm; from about 200 μm to about 500 μm; from about 250μm to about 400 μm; and from about 300 μm to about 350 μm; and any increments within such ranges.
The control system of the micromilling system of the invention comprises a user instrumentation interface or other such control mechanism to set or guide the micromilling process. The control system can be electrically coupled to a microprocessor or other non- transitory computer readable medium by wires or by wireless means. The control system can thereby send control or sensory data signals to the microprocessor. The coupled microprocessor can collect sensory data from the control system and can further relay collected information to other non-transitory computer readable media, and/or run calculations on collected data and relay the calculated results to a user-operable and/or user-readable display.
The sensory data captured by the control system can come, among others, from the touch measurement sensor and can be evaluated according to computer program instructions controlling the microprocessor either through hardware or software.
The control system is further configured to control the operation of the spindle/end mill, the hanger and the workpiece carrier as well as the tool calibrator to ensure proper functioning of the separate elements and concerting of the separate elements for proper workpiece processing.
In some embodiments, the control system comprises a processing device that controls the operation of the spindle/end mill instrumentation. The processing device can be communicatively coupled to a non-volatile memory device via a bus. The non-volatile memory device may include any type of memory device that retains stored information when powered off. The memory device can include, but is not limited to, electrically erasable programmable read-only memory ( “ROM” ) , flash memory, or any other type of non-volatile memory.
In some embodiments, some of the memory device can include a non-transitory medium or memory device form which the processing device can read instructions. A computer-readable medium can includeelectronic, optical, magnetic, or other storage devices capable of providing the processing device with computer-readable instructions or other program code. For example, a non-transitory computer-readable medium can include, but is not limited to, magnetic disk (s) , memory chip (s) , ROM, random-access memory ( “RAM” ) , an Application-Specific Integrated Circuit (ASIC) , a configured processor, optical storage, and/or any other medium from which a computer processor can read instructions. The instructions may include processor-specific instructions, generated by a compiler and/or an interpreter from code written in any suitable computer-programming language.
All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.
Following are examples that illustrate procedures for practicing the invention. These examples should not be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.
EXAMPLE 1-DESIGN OF THE MICROMILLLING SYSTEM
The different elements of the overall platform design are shown in FIGS. 1 and 2A-2D. Specifically, the micromilling system of the invention comprises a four-axis (X-Y-Y-Z) motion and control system (1) that comprises a multitude of rails thatare connected to each other, a non-movable base, and the plate carrying the workpiece, tool calibration sensor, and hanger such that the plate can be moved along 4 axes (X-Y-Y-Z) . The system has an open configuration to allow in-process visual inspection of the workpiece.
The micromilling system further comprises a spindle with end mill installed (2) , ahanger (3) , a workpiece carrier (4) , and a tool calibration sensor (5) . Each axis of the multiple rails of the fixturing system can have a resolution of 0.1μm. The end mill can have a diameter ranging from 0.03mm to 0.2mm. A hanger can be installed to allow quick change of tools for fabricating microchannels of various diameters. A vacuum pad and spring-loaded mechanical gripper are equipped on the workpiece carrier to ensure the workpiece is firmly located during the machining process. A tool calibration sensor can be set up next to the workpiece carrier to ensure maximum precision for tool calibration with a reproducibility of 0.01mm. A touch measurement sensor (6) can be equipped to detect the thickness and the parallelism of the workpiece.
Work pieces are in reality never perfectly in parallelism with the workpiece carrier, which may limit the manufacturing process or result in deformation of the resulting product. Furthermore, operational errors by the operators and/or operational procedures may also impede the parallelism of workpieces to the axes of the micromilling system of the invention. Therefore, the touch measurement sensor is advantageously configured to detect the thickness and parallelism of the workpiece. By calculating the measurements X 1….. X 4 of the workpiece (see, FIG. 3) , both thickness and parallelism of the workpiece can be identified and sent to the control system such that the control system can set the height reference point and compensate for misalignment.
The control system comprises a machine controller and a motion controller (FIG. 4) . The motion controller receives input information from each of the X-axis, the Y-axis, the Y-axis, and  the Z-axis of the fixturing system and controls the movement of the workpiece carrying platform in each of the X-axis, the Y-axis, the Y-axis, and Z-axis, respectively.
The motion controller is configured to be in two-way communication with the machine controller. The machine controller is further configured to be in two-way communication with the spindle drive and a human-machine interface. The machine controller is also configured to control a valve that controls a vacuum workpiece holder and a tool exchange. The machine controller is further configured to receive information from the calibration sensor and the touch measurement sensor so as to use the integrated information input to generate an output to the spindle drive to machine the workpiece according to instructions obtained through the human-machine interface.
EXEMPLARY EMBODIMENTS
Embodiment 1. A machine for generating high resolution microfluidic channels on microfluidic chips, the machine comprising:
a motion control system,
a spindle and hanger system,
a workpiece carrier,
a calibration system, and
a bonding machine.
Embodiment 2. The machine of Embodiment 1, wherein the motion control system comprises a motion controller and a machine controller, wherein the motion controller is operably linked to the machine controller.
Embodiment 3. The machine of Embodiment 2, wherein the machine controller is further operably linked to a spindle drive and a human-machine interface.
Embodiment 4. The machine of Embodiment 1, wherein the calibration system comprises a touch measurement sensor and/or a calibration sensor, each of which is operably linked to the machine controller.
Embodiment 5. The machine of Embodiment 4, wherein the touch measurement sensor is configured to detect the thickness and parallelism of a workpiece and transmit said detected thickness and parallelism information to the machine controller.
Embodiment 6. The machine of Embodiment 1, wherein the spindle and hanger system is configured to automatically change the spindle.
Embodiment 7. The machine of Embodiment 1, wherein the workpiece carrier and calibration system are configured to position a workpiece with a resolution of 0.1 μm along each axis of the motion control system for fully-automated microdrilling and/or micromilling of the workpiece.
Embodiment 8. The machine of Embodiment 1, wherein the bonding machine is configured to assemble multiple fabricated workpieces for sealing microfluidic channels.
Embodiment 9. A method of using a machine according to Embodiment 1 to produce a microfluidic chip, the method comprising:
providing a machine according to Embodiment 1;
providing a workpiece;
positioning the workpiece in the workpiece carrier;
receiving instructions from the human-machine interface for micromilling and/or microdrilling high resolution microchannels;
microdrilling and/or micromilling the workpiece according to the instruction; and
removing the workpiece comprising high resolution microchannels from the machine.
Embodiment 10. The method of Embodiment 9, further comprising stacking and bonding multiple fabricated workpieces.
Embodiment 11. The method of Embodiment 10, wherein the stacking and bonding is performed in an automatic manner.
Embodiment 12. The method of Embodiment 9, wherein the workpiece comprises a material selected from the group consisting of silicon, glass, ceramic, elastomers optionally polydimethylsiloxane (PDMS) , thermoset polyester, thermoplastic polymers optionally poly (methyl methoacrylate) (PMMA) , polystyrene and polyurethane, and composite materials optionally cyclin-olefin copolymer (COC) .
It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application. In addition, any elements or limitations of any invention or embodiment thereof disclosed herein can be combined with any and/or all other elements or limitations (individually or in any combination) or any other invention or embodiment thereof disclosed herein, and all such combinations are contemplated with the scope of the invention without limitation thereto.
REFERENCES
1. X. Ma, M.L. Jepsen, A. Ivarsen, B.R. Knudsen, and Y.P. Ho*, “Molecular and functional assessment of multicellular cancer spheroids produced in double emulsions enabled by efficient airway resistance based selective surface treatment, ” Journal of Micromechanics and Microengineering, 27 (9) , 095014, 2017.
2. H.F. Chan*, S. Ma*, J. Tian, K.W. Leong, “High-throughput screening of microchip-synthesized genes in programmable double-emulsion droplets” Nanoscale, 9 (10) , 3485-3495, 2017
3. H.F. Chan, Y. Zhang, K.W. Leong, “Efficient one-step production of microencapsulated hepatocyte spheroids with enhanced functions” Small, 12 (20) , 2720-2730, 2016
4. Y.L. Chiu, H.F. Chan, K.K.L. Phua, Y. Zhang, S. Juul, B.R. Knudsen, K.W. Leong*, Y.P. Ho*, “Synthesis of Fluorosurfactants for Emulsion-Based Biological Applications, ” ACS Nano, 8 (4) : 3913-3920, 2014.
5. H.F. Chan, Y. Zhang, Y.L. Chiu, Y.P. Ho, Y. Jung, and K.W. Leong, “Rapid formation of multicellular spheroids in double-emulsion droplets with controllable microenvironment, ” Scientific Reports, 3: 3462, 2013.

Claims (12)

  1. A machine for generating high resolution microfluidic channels on microfluidic chips, the machine comprising:
    a motion control system,
    a spindle and hanger system,
    a workpiece carrier,
    a calibration system, and
    a bonding machine.
  2. The machine of claim 1, wherein the motion control system comprises a motion controller and a machine controller, wherein the motion controller is operably linked to the machine controller.
  3. The machine of claim 2, wherein the machine controller is further operably linked to a spindle drive and a human-machine interface.
  4. The machine of claim 1, wherein thecalibration system comprises a touch measurement sensor and/or a calibration sensor, eachof which is operably linked to the machine controller.
  5. The machine of claim 4, wherein the touch measurement sensor is configured to detect the thickness and parallelism of a workpiece and transmit said detected thickness and parallelism information to the machine controller.
  6. The machine of claim 1, wherein the spindle and hanger system is configured to automatically change the spindle.
  7. The machine of claim 1, wherein the workpiece carrier and calibration system are configured toposition a workpiece with a resolution of 0.1 μm along each axis of the motion control system for fully-automated microdrilling and/or micromillingof the workpiece.
  8. The machine of claim 1, wherein the bonding machine is configured to assemble multiple fabricated workpieces for sealing microfluidic channels.
  9. A method of using a machine according to claim 1 to produce a microfluidic chip, the method comprising:
    providinga machine according to claim 1;
    providing a workpiece;
    positioning the workpiece in the workpiece carrier;
    receiving instructions from the human-machine interface for micromilling and/or microdrilling high resolution microchannels;
    microdrilling and/or micromilling the workpieceaccording to the instruction; and
    removing the workpiece comprising high resolution microchannels from the machine.
  10. The method of claim 9, further comprising stacking and bonding multiple fabricated workpieces.
  11. The method of claim10, wherein the stacking and bonding is performed in an automatic manner.
  12. The method of claim 9, wherein the workpiece comprises a material selected from the group consisting of silicon, glass, ceramic, elastomers optionally polydimethylsiloxane (PDMS) , thermoset polyester, thermoplastic polymers optionally poly (methyl methoacrylate) (PMMA) , polystyrene and polyurethane, and composite materials optionallycyclin-olefin copolymer (COC) .
PCT/CN2020/110716 2019-09-05 2020-08-24 Automatic micromilling platform for microfluidic devices WO2021043013A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201962896180P 2019-09-05 2019-09-05
US62/896,180 2019-09-05

Publications (1)

Publication Number Publication Date
WO2021043013A1 true WO2021043013A1 (en) 2021-03-11

Family

ID=74853019

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/110716 WO2021043013A1 (en) 2019-09-05 2020-08-24 Automatic micromilling platform for microfluidic devices

Country Status (1)

Country Link
WO (1) WO2021043013A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN201430723Y (en) * 2009-07-02 2010-03-24 黄介军 Digital control engraving machine
CN102442633A (en) * 2010-10-14 2012-05-09 北京华凯瑞微流控芯片科技有限责任公司 Numerically controlled processing instrument for microfluidic chip
CN204583216U (en) * 2015-03-19 2015-08-26 华南理工大学 A kind of micro-fluidic chip of microfluid spontaneous vasomotion and priming device
US20160118265A1 (en) * 2012-09-28 2016-04-28 The Board Of Trustees Of The University Of Illinois Spectrally and Temporally Engineered Processing using Photoelectrochemistry
CN108161567A (en) * 2017-12-27 2018-06-15 北京百奥芯科技有限公司 A kind of new CNC machine Z-axis presetting cutter method
CN108706542A (en) * 2018-05-25 2018-10-26 辽宁工业大学 A kind of micro-fluidic chip digital control processing instrument

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN201430723Y (en) * 2009-07-02 2010-03-24 黄介军 Digital control engraving machine
CN102442633A (en) * 2010-10-14 2012-05-09 北京华凯瑞微流控芯片科技有限责任公司 Numerically controlled processing instrument for microfluidic chip
US20160118265A1 (en) * 2012-09-28 2016-04-28 The Board Of Trustees Of The University Of Illinois Spectrally and Temporally Engineered Processing using Photoelectrochemistry
CN204583216U (en) * 2015-03-19 2015-08-26 华南理工大学 A kind of micro-fluidic chip of microfluid spontaneous vasomotion and priming device
CN108161567A (en) * 2017-12-27 2018-06-15 北京百奥芯科技有限公司 A kind of new CNC machine Z-axis presetting cutter method
CN108706542A (en) * 2018-05-25 2018-10-26 辽宁工业大学 A kind of micro-fluidic chip digital control processing instrument

Similar Documents

Publication Publication Date Title
Scott et al. Fabrication methods for microfluidic devices: An overview
Hwang et al. Microchannel fabrication on glass materials for microfluidic devices
Guckenberger et al. Micromilling: a method for ultra-rapid prototyping of plastic microfluidic devices
Gross et al. Recent advances in analytical chemistry by 3D printing
Jain et al. Micromanufacturing: a review—part I
Jain et al. Micromanufacturing processes
Martynova et al. Fabrication of plastic microfluid channels by imprinting methods
Khan Malek Laser processing for bio-microfluidics applications (part II)
Trotta et al. Flexible micro manufacturing platform for the fabrication of PMMA microfluidic devices
CN105347298B (en) A kind of method using AFM probe nanometer delineation processed complex three-dimensional micro-nano structure
Mecomber et al. Enhanced machining of micron-scale features in microchip molding masters by CNC milling
Ding et al. Microfluidic impact printer with interchangeable cartridges for versatile non-contact multiplexed micropatterning
WO2021043013A1 (en) Automatic micromilling platform for microfluidic devices
Hamed et al. Applications, materials, and fabrication of micro glass parts and devices: An overview
Ching et al. Techniques and materials for the fabrication of microfluidic devices
Hoople et al. Comparison of microscale rapid prototyping techniques
CN104140077A (en) Atomic force microscope based five-axis machining device and method for machining micro-nano structure on micro thin-wall spherical surface
Channon et al. Additive manufacturing for electrochemical (micro) fluidic platforms
Khalid et al. Meso scale component manufacturing: a comparative analysis of non-lithography and lithography-based processes
Picot‐Clémente Laser technologies for micro and nanofluidics systems: new opportunities for the biological and chemical industries
Jain et al. Micromanufacturing: an introduction
Yi et al. Overview of polymer micro/nanomanufacturing for biomedical applications
Phaneuf et al. Direct, high-speed milling of polymer microchamber arrays
Huang et al. Pin-plate micro assembly by integrating micro-EDM and Nd-YAG laser
Hou et al. Decreasing Surface Roughness of Microchannels CO 2 Laser Cut into Polystyrene (PS) to Produce Microfluidic Chips by Optimizing Operating Parameters.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20861060

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20861060

Country of ref document: EP

Kind code of ref document: A1