Apparatus for forming droplet array on an integrated circuit

Abstract

An apparatus for forming droplets on a patterned integrated circuit (IC) can include a chamber including a fluid reagent intake port configured to apply fluid reagent against a surface of the patterned IC. The patterned IC can include an array of hydrophilic regions spaced apart from each other and each bordered by a hydrophobic region. A manipulator can translate the patterned IC with respect to the held portion of the fluid reagent within the chamber, forming an array of droplets of the fluid reagent on the patterned IC that corresponds with the array of hydrophilic regions.

Description

Docket No. 3867.C76WO1APPARATUS FOR FORMING DROPLET ARRAY ON AN INTEGRATED CIRCUITCLAIM OF PRIORITY

[0001] This application claims priority to and the benefit of U.S. Provisional Application Serial No. 63 / 696,719, filed September 19, 2024, which is hereby incorporated herein by reference, and the benefit of priority of which is claimed herein.BACKGROUND

[0002] Droplet microfluidics provide an approach for conducting biological assays with enhanced precision and control compared to certain well plate-based systems. Certain approaches to assaying biological specimens involve well plates with standardized layouts and pitch of individual fluidic volumes, such as high throughput screening methods involving well plates having about 96, 384, or 1536 wells per plate.BRIEF DESCRIPTION OF THE DRAWINGS

[0003] In the drawings, which are not necessarily drawn to scale, like numerals can describe similar components in different views. Like numerals having different letter suffixes can represent different instances of similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document.

[0004] FIG. 1 A is a side view of an example of an apparatus for forming droplets on a patterned integrated circuit (IC).

[0005] FIG. IB is a top view of an example of an apparatus for forming droplets on a patterned integrated circuit (IC).

[0006] FIG. IC is a top view of an example of an apparatus for forming droplets on a patterned integrated circuit (IC).

[0007] FIG. 2A is a side view of an example of an apparatus for forming droplets on a patterned integrated circuit (IC).

[0008] FIG. 2B is a side view of an example of an apparatus for forming droplets on a patterned integrated circuit (IC).

[0009] FIG. 3 is a flowchart showing a process for automated incident management and report generation.

[0010] FIG. 4 is a block diagram of a machine.DETAILED DESCRIPTIONDocket No. 3867.C76WO1

[0011] This document relates to high throughput screening (HTS) systems for biological specimens, particularly phenotypic screening approaches that can provide higher physiological relevance than certain other target-based screening approaches. Electronic and mechanical phenotypic screening techniques can be particularly valuable for studying diseases involving electrogenic cells, as these approaches can assess electrical properties and mechanical characteristics of biological specimens. For example, biological specimen assaying can involve methodologies for analyzing and processing biological samples in controlled laboratory environments.

[0012] Droplet microarray techniques have been developed to enable screening-based assays at relatively high throughput. However, certain other droplet microarray techniques face significant technical challenges that limit their reliability and effectiveness in generating desired droplet arrays. For example, it can be challenging to accurately create a droplet array on an integrated circuit (IC), e.g., based on small droplet volume (e.g., at or near a nanoliter scale) involved in such applications. For example, it can be especially difficult to achieve consistent droplet formation during assay preparation and maintenance during assaying. Further, an environment in which the droplet array is created can greatly complicate achieving a desired consistency and precision in droplet array creation, e.g., especially in certain other environments (e.g., performed in ambient conditions) where relatively small droplets tend to evaporate quickly. Further, it can be difficult to achieve a desired droplet uniformity across a droplet array. Certain other approaches struggle to produce droplets with consistent size, spacing, and composition, which can be important to facilitate reliable comparative analysis in screening applications. The present inventors have recognized the benefits of an apparatus for forming droplets on a patterned integrated circuit (IC) to address these challenges, e.g., via apparatuses and technique for forming droplets on a patterned integrated circuit (IC) within a precisely controlled environment. Such a technique can facilitate comprehensive control of an end user of the apparatus over the droplet formation process while maintaining desired environmental conditions for biological applications.

[0013] FIG. 1A, FIG. IB, and FIG. IC each depict an example of a droplet array device 102 for forming droplets on an integrated circuit 104. The droplet array device 102 can include a chamber 108 that is fluid-sealed from an external ambient environment. This sealed chamber 108 design can help mitigate certain evaporation issues, such as by creating a controlled microenvironment where environmental parameters can be precisely managed. The droplet array device 102 can include processing circuitry 132 configured to control temperature, relative humidity (RH), and gas content within the chamber.Docket No. 3867.C76WO1

[0014] For certain applications, such as during cell culture, the processing circuitry 132 can control supply of at least one of oxygen (02) or carbon dioxide (CO2) (e.g., received from a source of gas 134) into the chamber at a gas inlet 122 of the chamber based on feedback received from the one or more sensors 114. Further, the processing circuitry 132 can control heating element 112 and a humidifier 110 to maintain specified atmospheric compositions within the chamber 108, such as the about 37°C temperature and controlled 02 and CO2 concentrations needed to mimic certain cellular growing environments similar to those found in laboratory incubators.

[0015] The droplet array device 102 operates with a patterned integrated circuit 104 that includes an array of hydrophilic regions, spaced apart from each other and each bordered by a hydrophobic region. Such a surface patterning provides specific nucleation sites for droplet formation while preventing unwanted spreading of the fluid reagent. The hydrophilic regions can serve as preferential wetting sites where droplets naturally form and are retained, while the hydrophobic regions can act as barriers that define droplet boundaries and prevent coalescence between adjacent droplets, promoting consistent droplet positioning and size control across the array.

[0016] The droplet array device 102 can include a fluid reagent intake reagent loading port 120 configured to apply liquid reagent 130 against a surface of the integrated circuit 104. The droplet array device 102 can also include a fluid retainer 118 configured to hold at least a portion of the fluid reagent received at the fluid reagent intake port, wherein a held portion of the fluid reagent is held in a fixed linear position with respect to the chamber. The fluid retainer 118 can include a reagent reservoir configured to hold the fluid reagent substantially stationary with respect to the integrated circuit 104. This stationary reservoir design can create a "mother droplet" atop the integrated circuit 104 which serves as a continuous source of reagent for droplet formation on the surface of the integrated circuit 104. For example, the mother droplet can maintain a fixed position within the chamber, providing a consistent interface for the dewetting process that creates individual droplets.

[0017] The droplet array device 102 can be implemented with computer-controlled operation (e.g., including the processing circuitry 132) through a non-transitory computer-readable storage medium containing instructions for positioning the patterned IC, controlling fluid reagent flow, managing translation movement, and maintaining environmental conditions. This automated control capability enables precise, repeatable operation and allows for integration with larger laboratory automation systems. In an example., the processing circuitry 132 can manage a plurality of aspects of the droplet formation process, including environmental parameter adjustment, motion control, and real-time monitoring of systemDocket No. 3867.C76WO1 performance, e.g., via feedback from the one or more sensors 114 (e.g., humidity, temperature, gas sensors, optical sensors, etc.) or via feedback from a functionalized region of the integrated circuit 104.

[0018] In an example, the droplet array device 102 can include a manipulator 106 configured to translate the integrated circuit 104 with respect to the held portion of the liquid reagent 130 within the chamber. Such a translation (e.g., during which the fluid retainer 118 holds the mother droplet substantially in place) can facilitate forming an array of droplets of the fluid reagent on the integrated circuit 104, according to and corresponding with the array of hydrophilic regions on the integrated circuit 104.

[0019] In an example, the manipulator 106 includes a chip carrier configured to translate the integrated circuit 104 along a path to form the array of droplets. For example, by moving the integrated circuit 104 (e.g., rather than the reagent delivery system), a top plate 138 of the chamber can remain transparent and free of complex mechanical components that might obstruct optical access. For example, where the top plate 138 is transparent, imaging can be performed from above the droplet array device 102, such as microscopic imaging or monitoring.

[0020] As shown in the progression from FIG. IB and FIG. 1C , the droplet array device 102 (e.g., including the processing circuitry 132) can facilitate controlled dewetting following covering the integrated circuit 104 with the mother droplet, e.g., where the patterned IC is moved through the stationary mother droplet at a specified, constant speed (e.g., within a range of about 0.01 meters per second (m / s) and about 0.5 m / s). As the chip slides through the mother droplet, the dewetting process can cause small daughter droplets to be left behind in the hydrophilic spots on the patterned surface. The speed of translation can be controlled to affect the volume of these daughter droplets, providing precise control over final droplet characteristics. Such a wetting / dewetting approach can facilitate consistent droplet formation across the entire array while maintaining uniform droplet spacing and size. The controlled movement speed allows for optimization of droplet volume and ensures complete coverage of the hydrophilic regions without unwanted reagent deposition in hydrophobic areas.

[0021] FIG. 2A and FIG. 2B are each side view of respective examples of a droplet array device 102 for forming droplets on an integrated circuit 104. The system provides multiple actuation options for controlling the translation movement. In one implementation, the manipulator 106 includes or uses a linear stage 204 actuator, e.g., magnetically couplable to the chip carrier to control translation of the chip carrier. Such magnetic coupling approachDocket No. 3867.C76WO1 can facilitate precise motion control while maintaining the sealed integrity of the chamber108.

[0022] Alternatively, the manipulator 106 can include or use a pump 206, fluidly coupled to a channel 208 of the chamber 108 and configured to control translation of the chip carrier based on a change in pressure supplied by the pump 206. This pneumatic or hydraulic actuation technique can provide controlled translation while maintaining chamber isolation.

[0023] FIG. 3 is a flowchart showing a process 300 for automated incident management and report generation.

[0024] At 302, the process 300 includes receiving the patterned IC within a chamber, fluid- sealed from an external ambient environment. In an example, a liquid reagent can be held substantially stationary, via a fluid retainer, with respect to the patterned IC during translation of the patterned IC, via a chip carrier, along a path to form the array of droplets.

[0025] At 304, the process 300 includes receiving fluid reagent at an intake port to apply fluid reagent against a surface of the patterned IC. Here, the patterned IC can include an array of hydrophilic regions, spaced apart from each other and each bordered by a hydrophobic region. In an example, the chamber can include or use a fluid retainer arranged to hold at least a portion of the fluid reagent received at the fluid reagent intake port in a fixed linear position with respect to the chamber.

[0026] At 306, the process 300 can include translating, via a manipulator, the patterned IC with respect to the held portion of the fluid reagent within the chamber, to form an array of droplets of the fluid reagent on the patterned IC. The array of droplets corresponding (e.g., about 1 : 1) with the array of hydrophilic regions.

[0027] In an example, the process 300 can further include controlling a temperature, relative humidity (RH), and gas content within the chamber, e.g., to promote cell growth or based feedback received from one or more sensors embedded withing the chamber or received from the IC.

[0028] FIG. 4 illustrates generally an example of a block diagram of a machine 401 upon which any one or more of the techniques (e.g., methodologies) discussed herein may perform in accordance with some examples. In alternative embodiments, the machine 401 may operate as a standalone device or may be connected (e.g., networked) to other machines. In a networked deployment, the machine 401 may operate in the capacity of a server machine, a client machine, or both in server-client network environments. In an example, the machine 401 may act as a peer machine in peer-to-peer (P2P) (or other distributed) network environment. The machine 401 may be a personal computer (PC), a tablet PC, a set -top boxDocket No. 3867.C76WO1(STB), a personal digital assistant (PDA), a mobile telephone, a web appliance, a network router, switch or bridge, or any machine capable of executing instructions (sequential or otherwise) that specify actions to be taken by that machine. Further, while only a single machine is illustrated, the term “machine” shall also be taken to include any collection of machines that individually or jointly execute a set (or multiple sets) of instructions to perform any one or more of the methodologies discussed herein, such as cloud computing, software as a service (SaaS), other computer cluster configurations.

[0029] Examples, as described herein, may include, or may operate on, logic or a number of components, modules, or mechanisms. Modules are tangible entities (e.g., hardware) capable of performing specified operations when operating. A module includes hardware. In an example, the hardware may be specifically configured to carry out a specific operation (e.g., hardwired). In an example, the hardware may include configurable execution units (e.g., transistors, circuits, etc.) and a computer readable medium containing instructions, where the instructions configure the execution units to carry out a specific operation when in operation. The configuring may occur under the direction of the executions units or a loading mechanism. Accordingly, the execution units are communicatively coupled to the computer readable medium when the device is operating. In this example, the execution units may be a member of more than one module. For example, under operation, the execution units may be configured by a first set of instructions to implement a first module at one point in time and reconfigured by a second set of instructions to implement a second module.

[0030] Machine (e.g., computer system) 401 may include a hardware processor 402 (e.g., a central processing unit (CPU), a graphics processing unit (GPU), a hardware processor core, or any combination thereof), a main memory 403 and a static memory 404, some or all of which may communicate with each other via an interlink (e.g., bus) 405. The machine 401 may further include a display unit 406, an alphanumeric input device 407 (e.g., a keyboard), and a user interface (UI) navigation device 408 (e.g., a mouse). In an example, the display unit 406, alphanumeric input device 407 and ui navigation device 408 may be a touch screen display. The machine 401 may additionally include a storage device (e.g., drive unit) 409, a signal generation device 410 (e.g., a speaker), a network interface device 411, and one or more sensors 412, such as a global positioning system (GPS) sensor, compass, accelerometer, or other sensor. The machine 401 may include an output controller 416, such as a serial (e.g., universal serial bus (USB), parallel, or other wired or wireless (e.g., infrared (IR), near field communication (NFC), etc.) connection to communicate or control one or more peripheral devices (e.g., a printer, card reader, etc.).Docket No. 3867.C76WO1

[0031] The storage device 409 may include a machine readable medium 413 that is non- transitory on which is stored one or more sets of data structures or instructions 414 (e.g., software) embodying or utilized by any one or more of the techniques or functions described herein. The instructions 414 may also reside, completely or at least partially, within the main memory 403, within static memory 404, or within the hardware processor 402 during execution thereof by the machine 401. In an example, one or any combination of the hardware processor 402, the main memory 403, the static memory 404, or the storage device 409 may constitute machine readable media.

[0032] While the machine readable medium 413 is illustrated as a single medium, the term “machine readable medium” may include a single medium or multiple media (e.g., a centralized or distributed database, or associated caches and servers) configured to store the one or more instructions 414.

[0033] The term “machine readable medium” may include any medium that is capable of storing, encoding, or carrying instructions for execution by the machine 401 and that cause the machine 401 to perform any one or more of the techniques of the present disclosure, or that is capable of storing, encoding or carrying data structures used by or associated with such instructions. Non-limiting machine-readable medium examples may include solid-state memories, and optical and magnetic media. Specific examples of machine-readable media may include: non-volatile memory, such as semiconductor memory devices (e.g., Electrically Programmable Read-Only Memory (EPROM), Electrically Erasable Programmable Read- Only Memory (EEPROM)) and flash memory devices; magnetic disks, such as internal hard disks and removable disks; magneto-optical disks; and CD-ROM and DVD-ROM disks.

[0034] The instructions 414 may further be transmitted or received over a communications network 415 using a transmission medium via the network interface device 411 utilizing any one of a number of transfer protocols (e.g., frame relay, internet protocol (IP), transmission control protocol (TCP), user datagram protocol (UDP), hypertext transfer protocol (HTTP), etc.). Example communication networks may include a local area network (LAN), a wide area network (WAN), a packet data network (e.g., the Internet), mobile telephone networks (e.g., cellular networks), Plain Old Telephone (POTS) networks, and wireless data networks (e.g., Institute of Electrical and Electronics Engineers (IEEE) 802.11 family of standards known as Wi-Fi®, IEEE 802.16 family of standards known as WiMax®), IEEE 802.15.4 family of standards, peer-to-peer (P2P) networks, among others. In an example, the network interface device 411 may include one or more physical jacks (e.g., Ethernet, coaxial, or phone jacks) or one or more antennas to connect to the communications network 415. In an example, the network interface device 411 may include a plurality of antennas to wirelessly communicateDocket No. 3867.C76WO1 using at least one of single-input multiple-output (SIMO), multiple-input multiple-output (MIMO), or multiple-input single-output (MISO) techniques. The term “transmission medium” shall be taken to include any intangible medium that is capable of storing, encoding or carrying instructions for execution by the machine 401, and includes digital or analog communications signals or other intangible medium to facilitate communication of such software.

Claims

Docket No. 3867.C76WO1CLAIMSWhat is claimed is:

1. An apparatus for forming droplets on a patterned integrated circuit (IC), the apparatus comprising: a chamber, fluid-sealed from an external ambient environment; a fluid reagent intake port, configured to apply fluid reagent against a surface of the patterned IC, wherein the patterned IC includes an array of hydrophilic regions, spaced apart from each other and each bordered by a hydrophobic region; a fluid retainer configured to hold at least a portion of the fluid reagent received at the fluid reagent intake port, wherein a held portion of the fluid reagent is held in a fixed linear position with respect to the chamber; a manipulator to translate the patterned IC with respect to the held portion of the fluid reagent within the chamber, the translating forming an array of droplets of the fluid reagent on the patterned IC, the array of droplets corresponding with the array of hydrophilic regions; and processing circuitry configured to control a temperature, relative humidity (RH), and gas content within the chamber.

2. The apparatus of claim 1, wherein the fluid retainer includes a reagent reservoir configured to hold the fluid reagent substantially stationary with respect to the patterned IC, wherein the manipulator includes a chip carrier configured to translate the patterned IC along a path to form the array of droplets.

3. The apparatus of claim 2, wherein the manipulator includes a linear actuator stage magnetically couplable to the chip carrier to control translation of the chip carrier.

4. The apparatus of any of claims 2-3, wherein the manipulator includes a pump, fluidly coupled to a channel of the chamber and configured to control translation of the chip carrier based on a change in pressure supplied by the pump.

5. The apparatus of any of claims 1-4, comprising a humidifier, a heating element, and one or more sensors arranged within the chamber.

6. The apparatus of claim 5, wherein the processing circuitry is configured to control a parameter of at least one of the humidifier or heating element based on at least one of temperature or RH feedback received from the one or more sensors.Docket No. 3867.C76WO17. The apparatus of any of claims 5-6, wherein the processing circuitry is configured to control supply of at least one of oxygen (O2) or carbon dioxide (CO2) into the chamber at a gas inlet of the chamber based on feedback received from the one or more sensors.

8. A method for forming droplets on a patterned integrated circuit (IC), the method comprising: receiving the patterned IC within a chamber, wherein the chamber is fluid-sealed from an external ambient environment; receiving fluid reagent at an intake port to apply fluid reagent against a surface of the patterned IC, wherein the patterned IC includes an array of hydrophilic regions, spaced apart from each other and each bordered by a hydrophobic region; holding at least a portion of the fluid reagent received at the fluid reagent intake port, via a fluid retainer, in a fixed linear position with respect to the chamber; translating, via a manipulator, the patterned IC with respect to the held portion of the fluid reagent within the chamber, to form an array of droplets of the fluid reagent on the patterned IC, the array of droplets corresponding with the array of hydrophilic regions; and controlling a temperature, relative humidity (RH), and gas content within the chamber.

9. The method of claim 8, comprising holding, via the fluid retainer, a reagent substantially stationary with respect to the patterned IC during translation of the patterned IC, via a chip carrier, along a path to form the array of droplets.

10. The method of claim 9, comprising magnetically manipulating the chip carrier to control translation of the IC along the path.

11. The method of any of claims 9-10, comprising at least one of pneumatically or hydraulically manipulating the chip carrier to control translation of the IC along the path.

12. The method of any of claims 8-11, comprising controlling a parameter of at least one of a humidifier or a heating element arranged within the chamber, based on at least one of temperature or RH feedback received from one or more sensors arranged within the chamber.

13. The method of claim 12, comprising controlling a supply of at least one of oxygen (O2) or carbon dioxide (CO2) into the chamber at a gas inlet of the chamber based on feedback received from the one or more sensors.Docket No. 3867.C76WO114. A non-transitory computer-readable storage medium, the computer-readable storage medium including instructions that when executed by a computer, cause the computer to: position the patterned IC within a chamber, fluid-sealed from an external ambient environment; cause fluid reagent to flow into the chamber through an intake port to cause the fluid reagent to be applied to a surface of the patterned IC, wherein the patterned IC includes an array of hydrophilic regions, spaced apart from each other and each bordered by a hydrophobic region, wherein the chamber includes a fluid retainer arranged to hold at least a portion of the fluid reagent received at the fluid reagent intake port in a fixed linear position with respect to the chamber; translate, via a manipulator, the patterned IC with respect to the held portion of the fluid reagent within the chamber, to form an array of droplets of the fluid reagent on the patterned IC, the array of droplets corresponding with the array of hydrophilic regions; and control a temperature, relative humidity (RH), and gas content within the chamber.

15. The computer-readable storage medium of claim 14, wherein the computer-readable storage medium includes instructions that when executed by the computer, cause the computer to operate the fluid retainer to hold a reagent substantially stationary with respect to the patterned IC during translation of the patterned IC, via a chip carrier, along a path to form the array of droplets.

16. The computer-readable storage medium of claim 15, wherein the computer-readable storage medium includes instructions that when executed by the computer, cause the computer to magnetically manipulate the chip carrier to control translation of the IC along the path.

17. The computer-readable storage medium of any of claims 15-16, wherein the computer- readable storage medium includes instructions that when executed by the computer, cause the computer to at least one of pneumatically or hydraulically manipulate the chip carrier to control translation of the IC along the path.

18. The computer-readable storage medium of any of claims 14-17, wherein the computer- readable storage medium includes instructions that when executed by the computer, cause the computer to control a parameter of at least one of a humidifier or heating element arranged within the chamber, based on at least one of temperature or RH feedback received from one or more sensors arranged within the chamber.Docket No. 3867.C76WO119. The computer-readable storage medium of claim 18, wherein the computer-readable storage medium includes instructions that when executed by a computer, cause the computer to control a supply of at least one of oxygen (O2) or carbon dioxide (CO2) into the chamber at a gas inlet of the chamber based on feedback received from the IC indicating cell health or growth.

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