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WO2025081090A1 - Systèmes et procédé de conception microfluidique - Google Patents

Systèmes et procédé de conception microfluidique Download PDF

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Publication number
WO2025081090A1
WO2025081090A1 PCT/US2024/051112 US2024051112W WO2025081090A1 WO 2025081090 A1 WO2025081090 A1 WO 2025081090A1 US 2024051112 W US2024051112 W US 2024051112W WO 2025081090 A1 WO2025081090 A1 WO 2025081090A1
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WIPO (PCT)
Prior art keywords
microfluidic device
design
simulation
electronic processor
component
Prior art date
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PCT/US2024/051112
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English (en)
Inventor
Greg NORDIN
Bruce K. Gale
Brady Goenner
Pierre-Emmanuel Gaillardon
Greg LIDDIARD
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University of Utah Research Foundation Inc
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University of Utah Research Foundation Inc
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Publication of WO2025081090A1 publication Critical patent/WO2025081090A1/fr
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Classifications

    • G—PHYSICS
    • G05—CONTROLLING; REGULATING
    • G05B—CONTROL OR REGULATING SYSTEMS IN GENERAL; FUNCTIONAL ELEMENTS OF SUCH SYSTEMS; MONITORING OR TESTING ARRANGEMENTS FOR SUCH SYSTEMS OR ELEMENTS
    • G05B19/00—Programme-control systems
    • G05B19/02—Programme-control systems electric
    • G05B19/18—Numerical control [NC], i.e. automatically operating machines, in particular machine tools, e.g. in a manufacturing environment, so as to execute positioning, movement or co-ordinated operations by means of programme data in numerical form
    • G05B19/4097—Numerical control [NC], i.e. automatically operating machines, in particular machine tools, e.g. in a manufacturing environment, so as to execute positioning, movement or co-ordinated operations by means of programme data in numerical form characterised by using design data to control NC machines, e.g. CAD/CAM
    • G05B19/4099—Surface or curve machining, making 3D objects, e.g. desktop manufacturing
    • G—PHYSICS
    • G05—CONTROLLING; REGULATING
    • G05B—CONTROL OR REGULATING SYSTEMS IN GENERAL; FUNCTIONAL ELEMENTS OF SUCH SYSTEMS; MONITORING OR TESTING ARRANGEMENTS FOR SUCH SYSTEMS OR ELEMENTS
    • G05B19/00—Programme-control systems
    • G05B19/02—Programme-control systems electric
    • G05B19/04—Programme control other than numerical control, i.e. in sequence controllers or logic controllers
    • G05B19/042—Programme control other than numerical control, i.e. in sequence controllers or logic controllers using digital processors
    • G—PHYSICS
    • G05—CONTROLLING; REGULATING
    • G05B—CONTROL OR REGULATING SYSTEMS IN GENERAL; FUNCTIONAL ELEMENTS OF SUCH SYSTEMS; MONITORING OR TESTING ARRANGEMENTS FOR SUCH SYSTEMS OR ELEMENTS
    • G05B2219/00—Program-control systems
    • G05B2219/30—Nc systems
    • G05B2219/49—Nc machine tool, till multiple
    • G05B2219/49008—Making 3-D object with model in computer memory

Definitions

  • Embodiments herein relate to design of microfluidic devices.
  • Microfluidic devices use small cross-section channels (e.g., one the order of 0.1-500 micrometers (pm)), to perform functions on small volumes of a sample fluid, typically on the order of one microliter (pL) or less.
  • Microfluidic devices are typically fabricated using photolithography techniques similar to those used in microelectronics and microelectromechanical system (MEMS) manufacturing.
  • MEMS microelectromechanical system
  • a mold may be created through lithography techniques that include casting an elastomer (e.g., polydimethylsiloxane (PDMS)).
  • PDMS polydimethylsiloxane
  • Microfluidic devices such as lab-on-a-chip devices, have become a powerful tool in healthcare diagnostics and biology studies, and are used in many applications such as virus and pathogen detection, proteomics, genomics, synthetic biology, and biological disease research.
  • the advantages of microfluidic devices over conventional laboratory techniques include, for example, small sample and reagent volumes, increased testing throughput, reduced contamination, high-sensitivity, and/or high specificity.
  • the system includes: an electronic processor configured to receive, via a user interface, a set of design inputs defining operational requirements of a microfluidic device to be designed, based on the set of design inputs, generate a microfluidic device design by generating an abstracted design of the microfluidic device that includes a machine-readable list of connections and a sequence of liquid processing steps to be performed by the microfluidic device, and based on the abstracted design, generating a layout of the microfluidic device to determine placement and routing of microfluidic device components and connections between components, perform a simulation of the microfluidic device design, wherein results of the simulation indicate at least one selected from a group consisting of an output chemical concentration, an output flow rate, an output pressure, and an output temperature in the microfluidic device design, determine whether the results of the simulation satisfy the operational requirements of the microfluidic device, in response to determining that the results of the simulation do not satisfy the operational requirements, perform an optimization function to automatically modify the layout of the microfluidic device design
  • the electronic processor is further configured to the electronic processor is further configured to, in response to performing an optimization function to automatically modify the layout of the microfluidic device design, repeat simulation of the microfluidic device design.
  • the simulation of the microfluidic device design is performed using an electronic design simulation tool having fluid dynamic disciplines defined therein.
  • the system further includes: a resin flushing system including a pressure and vacuum source fluidically and/or pneumatically connected to a pair of corresponding input and output ports of the microfluidic device, wherein the resin flushing system is configured to control the pressure and vacuum source to automatically flush unpolymerized resin from negative space regions of the microfluidic device.
  • a resin flushing system including a pressure and vacuum source fluidically and/or pneumatically connected to a pair of corresponding input and output ports of the microfluidic device, wherein the resin flushing system is configured to control the pressure and vacuum source to automatically flush unpolymerized resin from negative space regions of the microfluidic device.
  • the electronic processor determines whether the results of the simulation satisfy the operational requirements of the microfluidic device by determining whether a relative error between the simulation results and the operational requirements exceeds a threshold.
  • the electronic processor is configured to generate the layout according to a set of design parameters that includes at least one selected from a group consisting of a wire length coefficient, a bin grid number, a placement penalty, a phi max value, and a component overflow threshold.
  • performing an optimization function to automatically modify the layout of the microfluidic device design includes automatically modifying a selected one of the set of design parameters.
  • the electronic processor is configured to select an initial bin number between 20 and 24.
  • the electronic processor is configured to select the component overflow threshold based on a component density of the layout.
  • the electronic processor is configured to select the phi max value based on the bin grid number.
  • the electronic processor is configured to prioritize, among the set of design parameters, minimizing the wire length coefficient. [0018] In some aspects, the electronic processor generates the layout of the microfluidic device using a modified electronic design automation (EDA) tool.
  • EDA electronic design automation
  • performing the simulation includes parsing and converting the machine-readable list of connections into a SPICE file having inputs and outputs defined by at least selected from a group consisting of a pressure, a flow, a chemical concentration, and a temperature.
  • the electronic processor is further configured to, for each component of the microfluidic device design, generate a set of component files defining layout information of the component, port location of the component, component behavioral information, and component geometric information, and store the set of component files in a memory.
  • the operational requirements include at least one selected from a group consisting of an expected chemical concentration resulting from a mixing operation, an expected fluid pressure, an expected temperature, and an expected flow rate.
  • the set of design inputs includes a natural language input
  • the electronic processor is further configured to parse the natural language input using an artificial intelligence (Al) model to generate a machine-readable translation of the natural language input.
  • Al artificial intelligence
  • the natural language input is a description of an assay protocol.
  • the machine-readable translation includes a netlist.
  • the abstracted design further includes an undirected graph having nodes representing microfluidic device components and vertices representing component connections.
  • the set of design inputs further include printer specifications including total available area and a number of printable layers that can fit a maximum thickness of the microfluidic device.
  • the 3D printer is a stereolithography (SLA) 3D printer.
  • the microfluidic device includes more than two patterned elastomeric layers in a stacked structure.
  • the system further includes: an operating instrument configured to receive the microfluidic device and operate on the microfluidic device, wherein the electronic processor is further configured to in response to determining that the results of the simulation satisfy the operational requirements, generate a set of operating instructions for the operating instrument to operate on the microfluidic device, and transmit the set of operating instructions to the operating instrument.
  • the operating instrument includes a pressure and vacuum system
  • the microfluidic device includes a set of channels pneumatically connectable to the operating instrument via an interface of the operating instrument
  • the set of operating instructions include values of pressure to be applied to selected channels of the microfluidic device.
  • the set of operating instructions further include trigger conditions for applying pressure or vacuum, the trigger conditions including a timing trigger condition and/or a sensed pressure trigger condition.
  • Another example provides a method for automated design of a microfluidic device.
  • the method includes: receiving, via a user interface, a set of design inputs defining operational requirements of a microfluidic device to be designed; based on the set of design inputs, generating, via an electronic processor, a microfluidic device design by generating an abstracted design of the microfluidic device that includes a machine-readable list of connections and a sequence of liquid processing steps to be performed by the microfluidic device, and based on the abstracted design, generating a layout of the microfluidic device to determine placement and routing of microfluidic device components and connections between components; performing a simulation of the microfluidic device design, wherein results of the simulation indicate at least one selected from a group consisting of an output chemical concentration, an output flow rate, an output pressure, and an output temperature in the microfluidic device design; determining whether the results of the simulation satisfy the operational requirements of the microfluidic device; in response to determining that the results of the simulation
  • the method further includes: in response to performing an optimization function to automatically modify the layout of the microfluidic device design, repeating simulation of the microfluidic device design.
  • the simulation of the microfluidic device design is performed using an electronic design simulation tool having fluid dynamic disciplines defined therein.
  • the method further includes: controlling, with a resin flushing system including a pressure and vacuum source fluidically and/or pneumatically connected to a pair of corresponding input and output ports of the microfluidic device, the pressure and vacuum source to automatically flush unpolymerized resin from negative space regions of the microfluidic device.
  • a resin flushing system including a pressure and vacuum source fluidically and/or pneumatically connected to a pair of corresponding input and output ports of the microfluidic device, the pressure and vacuum source to automatically flush unpolymerized resin from negative space regions of the microfluidic device.
  • the layout is generated according to a set of design parameters that includes at least one selected from a group consisting of a wire length coefficient, a bin grid number, a placement penalty, a phi max value, and a component overflow threshold.
  • performing an optimization function to automatically modify the layout of the microfluidic device design includes automatically modifying a selected one of the set of design parameters.
  • the method further includes: selecting an initial bin number between 20 and 24.
  • the method further includes: prioritizing, among the set of design parameters, minimizing the wire length coefficient.
  • generating the layout of the microfluidic device is performed using a modified electronic design automation (EDA) tool.
  • EDA electronic design automation
  • performing the simulation includes parsing and converting the machine-readable list of connections into a SPICE file having inputs and outputs defined by at least selected from a group consisting of a pressure, a flow, a chemical concentration, and a temperature.
  • the method further includes: for each component of the microfluidic device design, generating a set of component files defining layout information of the component, port location of the component, component behavioral information, and component geometric information, and storing the set of component files in a memory.
  • the operational requirements include at least one selected from a group consisting of an expected chemical concentration resulting from a mixing operation, an expected fluid pressure, an expected temperature, and an expected flow rate.
  • the set of design inputs includes a natural language input
  • the method further includes parsing the natural language input using an artificial intelligence (Al) model to generate a machine-readable translation of the natural language input.
  • Al artificial intelligence
  • the natural language input is a description of an assay protocol.
  • the machine-readable translation includes a netlist.
  • the abstracted design further includes an undirected graph having nodes representing microfluidic device components and vertices representing component connections.
  • the set of design inputs further includes printer specifications including total available area and a number of printable layers that can fit a maximum thickness of the microfluidic device.
  • the 3D printer is a stereolithography (SLA) 3D printer.
  • the microfluidic device includes more than two patterned elastomeric layers in a stacked structure.
  • the method further includes: in response to determining that the results of the simulation satisfy the operational requirements, generating a set of operating instructions for an operating instrument to operate on the microfluidic device, and transmitting the set of operating instructions to the operating instrument.
  • the operating instrument includes a pressure and vacuum system
  • the microfluidic device includes a set of channels pneumatically connectable to the operating instrument via an interface of the operating instrument
  • the set of operating instructions include values of pressure to be applied to selected channels of the microfluidic device.
  • the set of operating instructions further include trigger conditions for applying pressure or vacuum, the trigger conditions including a timing trigger condition and/or a sensed pressure trigger condition.
  • FIG. 1 illustrates a microfluidic design automation system, according to some examples.
  • FIG. 2A illustrates a method for performing automated microfluidic design, according to some examples.
  • FIG. 2B illustrates a continuation of the method for performing automated microfluidic design, according to some examples.
  • FIG. 3A illustrates a layout of a microfluidic chip, according to some examples.
  • FIG. 4 illustrates an instrument that operates on a manufactured microfluidic device, according to some examples.
  • FIG. 6 illustrates a perspective view of a microfluidic device, according to some examples.
  • FIG. 8 illustrates a perspective view of an interface device that connects to a microfluidic device, according to some examples.
  • FIG. 9 illustrates a perspective view of an interface device that connects to a microfluidic device, according to some examples.
  • FIG. 10 illustrates a cross-sectional view of an interface device that connects to a microfluidic device, according to some examples.
  • FIG. 11 illustrates an expanded cross-sectional view of an interface device that connects to a microfluidic device, according to some examples.
  • the terms “first”, “second”, and “third” may be used interchangeably to distinguish one component from another and are not intended to signify location or importance of the individual components.
  • the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise.
  • the terms “coupled,” “fixed,” “attached to,” and the like refer to both direct coupling, fixing, or attaching, as well as indirect coupling, fixing, or attaching through one or more intermediate components or features, unless otherwise specified herein.
  • the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having” or any other variation thereof, are intended to cover a non-exclusive inclusion.
  • a process, method, article, or apparatus that comprises a list of features is not necessarily limited only to those features but may include other features not expressly listed or inherent to such process, method, article, or apparatus.
  • “or” refers to an inclusive- or and not to an exclusive- or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
  • FIG. 1 illustrates a microfluidic design automation (MFD A) system 100 for designing, simulating, and manufacturing microfluidic devices, according to some embodiments.
  • the MFD A system 100 includes a computing device 104 having an electronic processor 108 (e.g., at least one electronic processor 108) communicatively connected to a user interface 112 (e.g., at least one user interface 112), a communication interface 116 (e.g., at least one communication interface 116), and a memory 120 (e.g., at least one memory 120).
  • a computing device 104 having an electronic processor 108 (e.g., at least one electronic processor 108) communicatively connected to a user interface 112 (e.g., at least one user interface 112), a communication interface 116 (e.g., at least one communication interface 116), and a memory 120 (e.g., at least one memory 120).
  • the memory 120 stores, among other things, program data for causing the electronic processor 108 to perform some or all of the methods described herein.
  • the memory 120 may store MFDA program data 124 for generating and simulating layouts of microfluidic devices, MFDA libraries 128 associated with the MFDA program data 124, and a simulation engine 130 for evaluating designs generated using the MFDA Program Data.
  • the memory 120 may also store 3D model generation program data 132 for generating 3D models of microfluidic devices based on layouts generating using the MFDA program data 124.
  • EDA design tools are responsible for automating integrated circuit (IC) design to produce a set of masks and manufacturing instructions for fabrication of ICs.
  • the computing device 104 is communicatively connected to a 3D printer 136, for example via the communication interface 116.
  • the 3D printer may be, for example, a stereolithography (SLA) 3D printer.
  • the system 100 may also include a resin flushing system 140, described in greater detail below.
  • the computing device 104 is also communicatively connected (e.g., via the communication interface 116) to an instrument 400 that operates on a manufactured microfluidic device, described in greater detail below with respect to FIGS. 4-11.
  • FIG. 2A-2B illustrate an example method 200 for performing, using the electronic processor 108 in conjunction with other components of the system 100, automated microfluidic design, according to some embodiments.
  • the method 200 includes receiving a set of inputs defining, for example, hardware and operational requirements of the microfluidic device (at block 202).
  • the electronic processor 108 may receive the user inputs via the user interface 112, via the memory 120 (e.g., as data from the MFDA libraries 128), from an external device via the communication interface 116, or a combination thereof.
  • the user inputs may describe a bio-assay and/or chemical assay protocol for the microfluidic device and expected operational specifications of the microfluidic.
  • Expected operational specifications of the microfluidic device may include, for example, expected chemical concentration results for mixing operations, expected fluid pressures, expected temperatures, expected flow rates, and/or the like.
  • the set of inputs also include printer specifications associated with the particular 3D printer (e.g., the printer 136) with which the microfluidic device will be manufactured.
  • the electronic processor 108 receives one or more inputs in a natural language format.
  • the electronic processor 108 may receive a text-based natural language description of the assay protocol, a text-based natural language description of the operational specifications, or the like.
  • the computing device 104 may include an artificial intelligence (Al) model (e.g., a natural language model) to parse the natural language inputs and generate a translation of the natural language inputs into machine readable code.
  • the machine-readable code generated by the electronic processor 108 may include, for example, a configuration file, a netlist (e.g., a Verilog netlist), or other machine-readable code for comparing device simulation results to the operational specifications.
  • the electronic processor 108 may receive an assay flowchart, a step-by-step assay protocol, and/or data associated with a known assay implementation system that describes the assay.
  • the computing device 104 may include a program to convert the assay protocol into machine readable code that would then be processed as in the Al situation.
  • the electronic processor 108 Based on the inputs received at block 202, the electronic processor 108 generates a high-level, abstracted design of a microfluidic device (at block 204), and generates a physical design of the microfluidic device (at block 208). Generating the abstracted design (at block 204) may include tasks that do not take into account the physical details (e.g., individual component locations) of the microfluidic device, such as, for example, generating a sequence of liquid processing steps intended to be performed by the microfluidic device.
  • Abstracted features of the microfluidic devices include, for example, operation-level abstracted, otherwise referred to as behavior-level abstractions, and netlist-level abstractions, otherwise referred to as structural-level abstractions.
  • the purpose of the abstracted design in the method 200 is to synthesize a microfluidic design for a set of processes and specifications, and algorithmically build the details of the microfluidic chip to meet these specifications.
  • generating a structural -level abstraction of the microfluidic device may include preplacement and routing operations to produce a netlist, an application graph (e.g., an undirected graph having nodes that represent components and vertices representing component connections), and/or other abstractions.
  • Generating behavioral-level abstractions may include generating a step-by-step list of processes, or operations, that are to be performed on the microfluidic device, such as fluid movement operations, mixing operations, heating operations, sensing operations, and/or the like.
  • the electronic processor 108 may generate (e.g., at block 204) one or more of the device abstractions using a description language tailored to assay-level abstraction of microfluidic devices, such as Biocoder or Aqua. In such instances, the electronic processor 108 parses the language and creates a directional graph that represents the assay steps of the microfluidic device. In this manner, the electronic processor 108 programs the flow of operations of the microfluidic chip by identifying each step and any corresponding dependencies of the step. [0088] The electronic processor 108 generates the physical design (a block 208) using the netlist generated, for example, at block 204 (e.g., as part of the structural-level abstraction). Based on the netlist, the electronic processor 108 generates a physical layout of the microfluidic chip that identifies placement of all components, inputs, outputs, and/or component routing of the microfluidic chip.
  • a description language tailored to assay-level abstraction of microfluidic devices such as Biocoder or Aqua.
  • the electronic processor 108 may generate the physical design using a set of configuration files (e.g., stored in the memory 120) that adapt an EDA software package (e.g., OpenROAD or another EDA tool) to perform placement and routing of microfluidic components.
  • the electronic processor 108 may use these configuration files to match the printer specifications of the printer 136.
  • the configuration files may describe a feature size, a total available area for the layout or a particular feature, a number of printable layers that can fit a maximum thickness of the device, and/or the like.
  • the electronic processor 108 may prioritize certain design parameters that would not otherwise be prioritized in a traditional EDA layout.
  • the physical design parameters prioritized by the electronic processor 108 may include initial wire length coefficient, bin grid number, initial placement penalty, phi max value, and component overflow threshold, each described in greater detail below.
  • Bins are a sub-unit of area within the area of the microfluidic device (e.g., a microfluidic chip).
  • the bin grid number determines the number of rectangular grid sub areas that are used in the placement optimization.
  • the electronic processor 108 may place the components according to a determination that optimal bin grid numbers for minimizing channel length are 8, 16, 24, 28, 32, 64, 68, and 128. In some instances, the electronic processor 108 automatically selects 20 or 24 as the initial bin value.
  • the placement penalty parameter is used to maintain a density in each grid area below a threshold while also minimizing the wire length (e.g., channel length) of the placement solution.
  • the placement penalty spreads out components, while the wirelength coefficient pulls the components together for their respective functions.
  • electronic processor 108 places the components such that a placement density penalty of the components is below 2, and the initial wirelength coefficient is approximately le-3. For example, the electronic processor 108 may automatically set an initial placement density to 1 for the layout.
  • the electronic processor 108 may place the components using a tool that minimizes the wire length between components and generates a solution for mixed-size placement of developed components, such as, for example, the OpenROAD RePl Ace tool.
  • RePl Ace is an EDA tool that performs component placement.
  • RePlAce represents each component as an electric charge to spread out components.
  • the electronic processor 108 controls the tool to iterates through solutions moving components based on the repulsion of neighboring components until overlap is below an overflow threshold.
  • the electronic processor 108 then uses a detailed placer to move the components to legal position with no overlap.
  • the physical dimensions of channels in a microfluidic device impact pressure and flow rate of the working fluid.
  • the primary goal of physical design generation e.g., placement and routing of components
  • the primary goal of physical design generation is to minimize the wire routing lengths of the device based on the assumption that with the microfluidic chip will be manufactured according to the netlist (e.g., the abstract design) generated at block 204.
  • operations performed by the microfluidic chip such as mixing operations, may be dependent on resistances within the microfluidic chip. These resistances are often dependent on the channel length of the routing path. Due to the nature of parallel resistances and the multiplicative scaling of tolerances, some microfluidic channels are much more sensitive to changes in lengths than others. Therefore, the electronic processor 108 may assume the additional wire lengths in the microfluidic chip in order to improve simulation results.
  • the overflow is a value between 0 and 1 that represents the amount of total component overlap.
  • the value specified by the overflow threshold is the limit that the placement tool needs to meet for completing placement.
  • the electronic processor 108 may dynamically set the initial overflow threshold based on a number of components and/or a density of components to be included in the layout. For example, for sparse layouts (e.g., layouts having a number of components of component density below a density threshold), the electronic processor 108 may automatically set the overflow threshold to a value of 0.1 or less (e.g., 0 to 0.1).
  • the electronic processor 108 may automatically set the overflow threshold to a value of 2.0 or less (e.g., 0 to 2.0, 0.1 to 2.0, 1.5 to 2.0, or the like).
  • the phi value is an adaptive parameter for movement of components.
  • the electronic processor 108 clamps the phi value at predetermined bounds (e.g., phi max value). In some instances, the electronic processor 108 selects the phi max value based on the selected bin grid number. For example, the electronic processor 108 may set the initial phi max value such that the initial phi max value does not exceed 1.04. In some instances, for bin values above a bin threshold (e.g., a bin value of 32 or larger), the electronic processor 108 may automatically set the initial phi max value to 1.02.
  • a bin threshold e.g., a bin value of 32 or larger
  • generating the physical design (e.g., the layout) (at block 208) also includes generating a 3D model (e.g., a CAD model) of the microfluidic design according to the generated layout.
  • a 3D model e.g., a CAD model
  • FIG. 3A illustrates an example layout 304 of a microfluidic chip generated by the electronic processor 108
  • FIG. 3B illustrates a corresponding 3D model 308 of the layout 304.
  • the electronic processor 108 generates the layout 304 and the 3D model 308 of the microfluidic device to include a standardized interface for connecting to the resin flushing system 140.
  • the electronic processor 108 may generate the 3D model using, for example, a custom software package (e.g., stored in the memory 120) to translate the layout generated using the EDA tool (e.g., an output of, for example, OpenROAD) into a 3D model readable by a CAD software (e g., SCAD), for example, using a SolidPython library or other module for generating CAD code.
  • a custom software package e.g., stored in the memory 120
  • the layout generated using the EDA tool e.g., an output of, for example, OpenROAD
  • CAD software e.g., SCAD
  • SolidPython library or other module for generating CAD code for example, using a SolidPython library or other module for generating CAD code.
  • the electronic processor 108 may also generate a component library (e.g., to be included in the MFDA libraries 128) for the reuse of developed components in other microfluidic devices, or for future optimization of the microfluidic device being designed in the method 200.
  • a component library e.g., to be included in the MFDA libraries 1228 for the reuse of developed components in other microfluidic devices, or for future optimization of the microfluidic device being designed in the method 200.
  • the electronic processor 108 may abstract the respective components of the microfluidic device into a ID model that can be represented as pressure and fluid flow rate through a path of components of the fluid system based on the current state of the inputs of the device.
  • Each component may have a defined system of equations and/or a black box model that is based on equations that fit experimental or interpolated data.
  • Modules of each component are included in the component library to be loaded, when needed, by the simulation engine 130.
  • Each generated component may be associated with a set of files that contain the layout information of the component.
  • the layout information may include layout sizes (e.g., device chip size and/or component size), port location, component behavioral information (e.g., fluidic resistance and/or mixing relation from inputs to outputs), geometric information (e.g., CAD information), or a combination thereof.
  • the set of files associated with each respective component may include library extensible format (LEF) files, Verilog-AMS files or other EDA file type, a CAD file (e.g., a SCAD file), or a combination thereof.
  • LEF library extensible format
  • Verilog-AMS files or other EDA file type e.g., Verilog-AMS files
  • CAD file e.g., a SCAD file
  • Automatic generation of these files for each component improves modularity of device features by enabling the device components to be uploaded and accessed by engineers to efficiently implement new microfluidic applications with little effort.
  • 3D printing and system-level simulations as will be described in greater detail below, these new applications and designs can be quickly iterated through and optimized.
  • the electronic processor 108 In response to generating the abstract design and the physical design (e.g., at blocks 204 and 208, respectively), the electronic processor 108 generates a simulation of the microfluidic chip to evaluate the performance of the chip, for example using the simulation engine 130 (at block 212). Conventionally, device optimization cannot evaluate higher-level device behaviors when optimizing the design of the microfluidic chip beyond an assumed operation time. The simulation engine 130 therefore bridges the MFDA design tools of the system 100, ensuring that the generated design meets user-defined design constraints.
  • the simulation environment of the simulation engine 130 may be based on, for example, a simulation program with integrated circuit emphasis (SPICE) simulator (e.g., HSPICE, PSPICE, LTSPICE etc.) and Verilog-AMS used in analog electronic design.
  • SPICE simulation program with integrated circuit emphasis
  • the simulation engine 130 has flexible programmability to include microfluidic fluidic behaviors, allowing the software to evaluate and relate the flow and pressure behaviors of the microfluidic device on a continuum.
  • the electronic processor 108 uses the SPICE simulator to solve the system of equations that define the microfluidic chip. Models of the microfluidic components are coded in, for example, Verilog-AMS or another language that allows non-electrical disciplines to be defined.
  • the electronic processor 108 defines additional fluid dynamic disciplines that follow the same abstractions of Verilog-AMS (e.g., potential and flow variables), which are analogous to the conservation of energy equations in fluid dynamics.
  • the electronic processor 108 may use a compatible Verilog-AMS files and a parser to convert the netlist into SPICE files for the simulation engine 130 having inputs and outputs that include, for example, pressure, flow, and/or chemical concentrations.
  • the simulation engine 130 uses physics-based models for its components for systemlevel simulations that applies fluid resistive equations together with physical design. These simulations can be used to quickly evaluate the critical steps and their interaction modeling of various properties throughout the microfluidic system, such as flow rate, pressure, and/or chemical concentration. In some instances, unlike computation fluid dynamic (CFD) simulations, the simulation engine 130 does not collect the same granular level of detail from the meshing of microfluidics components.
  • CFD computation fluid dynamic
  • the electronic processor 108 verifies whether mixing ratios or other measured outputs of the microfluidic chip meet the operational specifications defined at block 202.
  • the electronic processor 108 codes the chemical concentrations at each input of the microfluidic chip, as well as pressures and flows within the chip, into the netlist of the program to be run by the simulation engine 130.
  • the electronic processor 108 uses the chemical concentrations at the output node or output nodes of the microfluidic chip to evaluate the function of the current design of the microfluidic device. For example, the electronic processor 108 may determine a relative error (e.g., compared to an expected output) in the chemical concentrations of the proposed layout solution of the microfluidic chip (e.g., generated at block 208). The electronic processor 108 uses the relative error to determine whether the microfluidic chip designed at blocks 204 and 208 requires modifications, or is suitable for manufacturing.
  • a relative error e.g., compared to an expected output
  • Table 1 provides sample output data from a simulation performed for a steady state system.
  • the electronic processor 108 may collect data corresponding to device convergences for flow and mixing concentrations.
  • the electronic processor 108 uses an average added length to estimate additional routing to chip when designing the microfluidic device, which may result in the large pre-routing error shown in Table 1 but an otherwise low overall error for the simulated device.
  • the electronic processor 108 presents the simulation results to the user using the user interface 112, and optimizes the design in response to receiving a command from the user via the user interface 112 to proceed with optimization.
  • the electronic processor 108 may also store the simulation results in the memory 120 for later review.
  • the electronic processor 108 determines whether the results of the simulation satisfy the operational specifications for the microfluidic design (at block 216). For example, in response to determining that a relative error of one or more simulation outputs (e.g., chemical concentration, temperature, pressure, flow rate, etc.) is greater than a threshold (NO at block 216), the electronic processor 108 automatically optimizes, as part of an interactive loop, the design parameters of the microfluidic device (at block 220).
  • a relative error of one or more simulation outputs e.g., chemical concentration, temperature, pressure, flow rate, etc.
  • the relative error threshold may be, for example, approximately a 5% error threshold, approximately a 10% error threshold, approximately a 15% error threshold, or the like. In some instances, the relative error threshold is a user-selected threshold received with the set of inputs at block 202.
  • the electronic processor 108 may modify one or more of the wire length coefficient, bin grid number, the placement penalty, the phi max value, the component overflow threshold, component placements, and/or another design parameter of the device.
  • Optimizing the design may include updating the component libraries and/or generating an updated 3D CAD model of the design.
  • the electronic processor 108 again performs a simulation on the optimized design (at block 216).
  • the electronic processor In response to determining that the relative errors of the simulation outputs are less than or equal to the threshold error or errors (YES at block 216), the electronic processor generates instructions for manufacturing (e.g., 3D printing) the designed microfluidic device (at block 224). For example, the electronic processor 108 may generate one or more STL files corresponding to the microfluidic device model, slices the model, and transmits printing commands to the 3D printer 136 for printing the microfluidic chip (at block 228).
  • the electronic processor 108 generates the manufacturing instructions in response to receiving a command from the user via the user interface 112 to proceed with manufacturing the microfluidic device. In some instances, the electronic processor 108 does not generate the 3D CAD model of the microfluidic device until after the design passes simulation (e.g., after block 216). In such instances, generating the manufacturing instructions may also include generating the 3D model of the device.
  • the electronic processor 108 may have access to many of the low-level and high- level functions of the 3D printers via an MFDA-specific application programming interface (API) that enables more a rapid exploration of exposure and layer thickness parameters for fabricating complex high-resolution components. For example, layer thickness may have an impact on channel sidewall smoothness, but smaller layer thicknesses may result in longer 3D print times. Therefore, the electronic processor 108 may transmit print commands to the 3D printer 136 such that only a region adjacent to channels have thinner layers, rather than having thinner layers throughout the entire device.
  • API application programming interface
  • Designing microfluidics typically include the design of both a control layer and flow layer.
  • conventional fabrication processes e.g., lithography or micro-milling
  • separate placement and routing of the control and flow layers is needed to reduce the interaction between layers.
  • microfluidic devices Due to the increased difficulty of aligning thin elastomeric layers, microfluidic devices conventionally do not include more than two patterned layers. The use of an SLA printer with access to low-level printer functions therefore enables microfluidic chips to be printed with more than two stacked layers and/or in a stacked structure.
  • the negative space regions of the printed microfluidic device are filled with unpolymerized liquid resin. These negative space regions encode the microfluidic functionality of the device, and therefore the resin must be cleared before post-print curing of the device (at block 232).
  • removal, or flushing, of unpolymerized resin is performed manually using a pressure and/or vacuum source sequentially applied to each port of the device.
  • the system 100 may also include a flushing system 140 for automated resin flushing in the device.
  • the resin flushing system 140 includes, for example, a pressure and/or vacuum source fluidically and/or pneumatically connectable to a pair of corresponding input and output ports of the manufactured microfluidic device.
  • the resin flushing system 140 is configured to control the pressure and/or vacuum sources to automatically flush unpolymerized resin from negative space regions of the microfluidic device.
  • the method 200 may further include generating operating instructions for a device that operates on the manufactured microfluidic device (at block 236), and transmitting the operating instructions to an operating instrument that operates on the microfluidic device (at block 240).
  • the electronic processor 108 generates the operating instructions in response to determining that the simulation results satisfy the operational specifications for the microfluidic design (e.g., at block 216).
  • the electronic processor 108 generates the operating instructions after completion of the manufacturing of the microfluidic device.
  • the electronic processor 108 may determine the operating instructions based on, for example, the abstracted design generated at block 204 of the method 200 (e.g., based on an assay protocol for the microfluidic device).
  • FIG. 4 schematically illustrates an example instrument 400 that operates on a microfluidic device 404 manufactured according to, for example, the method 200 described above.
  • the operating instrument 400 may include an electronic processor 408 (e.g., one or more electronic processors 408), a pressure and/or vacuum system 412, a user interface 414 (e.g., one or more user interfaces 414), and a communication interface 416.
  • the operating instrument 400 also includes a reagent source 418 (e.g., one or more reagent sources 418) for storing chemical reagents to be mixed or otherwise operated on by the microfluidic device 404.
  • a reagent source 418 e.g., one or more reagent sources 4128 for storing chemical reagents to be mixed or otherwise operated on by the microfluidic device 404.
  • the operating instrument 400 may further include port interfaces 420 configured to couple with input and output ports of the microfluidic device 404.
  • the operating instrument 400 applies pressure and/or vacuum (e.g., using the pressure and/or vacuum system 412) to the microfluidic device 404 via the port interfaces 420 to drive reagents e.g., provide via the reagent source 418) through the channels of the microfluidic device 404 to perform an assay (e.g., the assay specified by the inputs received at block 202 of the method 200) or other functions.
  • the pressure and/or vacuum system 412 may include one or more pressure and/or vacuum sources, pressure and/or vacuum regulators, one or more pressure sensors, and/or one or more pneumatic valve banks connected to the port interfaces 420.
  • the user interface 414 may include one or more buttons, switches, display screens (e.g., touch screens), and/or indicators for receiving control commands and outputting data related to an operation being performed on the microfluidic device 404.
  • the operating instrument 400 receives (e.g., via the communication interface 416 and/or the user interface 414) the set of instructions for operating on the microfluidic device 404 from the computing device 104.
  • the set of operating instructions may define values of pressure and/or vacuum to be applied, using the pressure and/or vacuum system 412, to selected channels of the microfluidic device 404 (e.g., using the port interfaces 420).
  • the set of instructions may further define trigger conditions for applying the pressure or vacuum, for example, timing triggers or sensed pressure triggers. Pressure triggers may be detected using one or more pressure sensors in the pressure and/or vacuum system 412 or the microfluidic device 404.
  • the components of the operating instrument 400 are distributed between a control device 504 and a base device 508.
  • the control device 504 may include the electronic processor 408 (e.g., at least one electronic processor 408) and the pressure and/or vacuum system 412.
  • the base device 508, otherwise referred to at the interface device 508, may include, for example, the port interfaces 420.
  • the base device 508 is connected to the pressure and/or vacuum system of the control device 504, and interfaces with the manufactured microfluidic device 404.
  • FIG. 6 illustrates a perspective view of an example microfluidic device 404 connectable to the example operating instrument 400 (e.g., connectable to the interface device 508 of the operating instrument 400).
  • the microfluidic device 404 includes a set of channel ports 512, otherwise referred to as input and output ports 512, connectable to corresponding port interfaces 420 of the interface device 508.
  • the channel ports 512 enable, for example, pressure to be applied to the channels within the microfluidic device 404 by the operating instrument 400.
  • the channel ports 512 may each have a standardized diameter (e.g., approximately 1.5 mm, approximately 1.7 mm, approximately 1.9 mm, etc.), and adjacent ones of the respective channel ports 512 may each be located a standardized distance apart (e.g., approximately 2.0 mm center-to center, approximately 2.2 mm center-to-center, approximately 2.4 mm center-to-center, etc.).
  • the microfluidic device 404 includes thirty-two channel ports 512. However, the microfluidic device 404 may be designed and manufactured to include more than thirty -two channel ports 512 or less than thirty-two channel ports 512. In some instances, the number of channel ports 512 are defined by the inputs received at block 202 of the method 200. In some instances, the number of channel ports 512 are determined by the electronic processor 108 based on a received assay protocol (e.g., determined at block 204 of the method 200). As shown in FIG. 6, in some instances, each channel port 512 includes a seal ring 514 (e.g., a rubber seal ring 514) for sealing or otherwise further securing a pneumatic connection between the microfluidic device 404 and the interface device 508.
  • a seal ring 514 e.g., a rubber seal ring 514
  • the microfluidic device 404 further includes reagent ports 516, or fluid wells 516, for receiving chemical reagents to be, for example, mixed or otherwise operated on in the microfluidic device 404.
  • the microfluidic device includes 6 reagent ports 516 located at an upper surface of the microfluidic device 404.
  • the location and number of the reagent ports 516 may vary according to the microfluidic device design generated using the method 200.
  • Each reagent port 516 may have, for example, an approximately 40 microliter capacity.
  • each reagent port 516 may be approximately 2.5 mm in diameter and 2 mm in depth.
  • chemical reagents may be added to the reagent ports 516 of the microfluidic device 404 using a pipette, such as the pipette 520 illustrated in FIG. 7.
  • the reagent ports 516 are fluidically connectable to the operating instrument 400 (e.g., using the interface device 508) and supplied by a reagent source 418.
  • FIG. 8 illustrates a perspective view of the interface device 508 and the microfluidic device 404 in an unclamped, or unsecured, position, in accordance with some embodiments.
  • the interface device 508 includes thirty-two pneumatic port interfaces 420 connectable to corresponding channel ports 512 of the microfluidic device 404.
  • the number of port interfaces 420 may vary according to implementation.
  • the interface device 508 may further include an adjustable clamp 524 for securing the channel ports 512 of the microfluidic device 404 to the corresponding port interfaces 420 of the interface device 508.
  • FIG. 9 illustrates a perspective view of the interface device 508 with the microfluidic device 404 in a clamped, or secured position.
  • the interface device 508 may further include pneumatic signal pins 528 that enable quick disconnection between selected port interfaces 420 and corresponding channel ports 512 of the microfluidic device.
  • the pneumatic signal pins 528 may have a standardized tubing size, for example, approximately 2 millimeter (mm) tubing.
  • FIG. 10 illustrates a cross-sectional view of the example interface device 508 and the microfluidic device 404, in accordance with some embodiments.
  • the port interfaces 420 define respective port tubes extending within an interior of the interface device 508 to connect to and apply pneumatic pressure to the corresponding channel ports 512 of the microfluidic device 404.
  • FIG. 11 illustrates an expanded portion of the cross-section shown in FIG. 10, according to some examples.
  • the interface device 508 may include a tapered portion 532 for guiding the insertion of the microfluidic device 404 to the interface device 508 (e.g., during tightening of the clamp 524).
  • the electronic processor 108 links steps such as component placement and routing, system-level evaluation and validation, 3D printing preparation, and manufacturing preprocessing and postprocessing steps into a complete process.

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  • Engineering & Computer Science (AREA)
  • Manufacturing & Machinery (AREA)
  • Human Computer Interaction (AREA)
  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Automation & Control Theory (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)

Abstract

Selon des exemples, l'invention concerne un système de conception d'un dispositif microfluidique. Le système comprend un processeur électronique configuré pour recevoir un ensemble d'entrées de conception définissant des exigences matérielles et opérationnelles d'un dispositif microfluidique à concevoir. Sur la base de l'ensemble d'entrées de conception, le processeur électronique génère une conception de dispositif microfluidique par génération d'une conception abstraite du dispositif microfluidique, qui comprend une liste de liaisons lisible par machine et une séquence d'étapes de traitement de liquide à effectuer par le dispositif microfluidique, et, sur la base de la conception abstraite, génération d'une disposition du dispositif microfluidique pour déterminer le placement de composants du dispositif microfluidique et le routage de liaisons entre des composants. Le processeur électronique effectue une simulation de la conception de dispositif microfluidique, les résultats de la simulation indiquant une concentration chimique de sortie, un débit de sortie, une pression de sortie et/ou une température de sortie dans la conception de dispositif microfluidique.
PCT/US2024/051112 2023-10-13 2024-10-11 Systèmes et procédé de conception microfluidique Pending WO2025081090A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200401670A1 (en) * 2019-06-18 2020-12-24 International Business Machines Corporation Platform for Design and Prototyping of Micro Paper Based Devices
US20210229091A1 (en) * 2020-01-28 2021-07-29 Rn Technologies, Llc Additive manufacturing of devices from assemblies of discretized component voxel elements
IN202141030041A (fr) * 2021-08-25 2022-09-02

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200401670A1 (en) * 2019-06-18 2020-12-24 International Business Machines Corporation Platform for Design and Prototyping of Micro Paper Based Devices
US20210229091A1 (en) * 2020-01-28 2021-07-29 Rn Technologies, Llc Additive manufacturing of devices from assemblies of discretized component voxel elements
IN202141030041A (fr) * 2021-08-25 2022-09-02

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