Devices and methods for multiplexed liquid supply and removal

Abstract

Devices and methods for multiplexed liquid supply and removal from a plurality of containers are generally described. In some embodiments, the plurality of containers may be part of a device described herein. In some embodiments, the plurality of containers may be part of a separate consumable component designed to be compatible with a device described herein such that liquids can be flowed into the plurality of containers and / or wastes can be removed from the plurality of containers via the device. In some embodiments, a device described herein may comprise a device and the plurality of containers. Some of the devices and apparatuses described herein comprise a plurality of ports, valves, pumps and channels which are in fluidic communication in such a configuration as to allow the multiplexed delivery of a liquid and / or removal of a waste from one or more containers in the plurality of containers.

Description

[0001] DEVICES AND METHODS FOR MULTIPLEXED LIQUID SUPPLY AND REMOVAL RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 761,839, filed February 21, 2025, and entitled “Devices and Methods for Multiplexed Liquid Supply and Removal,” which is incorporated herein by reference in its entirety for all purposes.

[0003] FIELD

[0004] Devices for multiplexed liquid supply and removal, and associated methods, are generally described.

[0005] BACKGROUND

[0006] Existing devices and methods for performing cell culture and other experiments involving biological cells exhibit several drawbacks, such as being incompatible with systems for real-time monitoring of experimental conditions, not allowing for high throughput data collection, and limiting experimental parallelization.

[0007] Accordingly, new devices and methods would be beneficial.

[0008] SUMMARY

[0009] The present disclosure generally describes devices and methods. The subject matter described herein involves, in some cases, interrelated products, alternative solutions to a particular problem, and / or a plurality of different uses of one or more devices and / or articles.

[0010] Paragraph 1: In one aspect a device is described. In some embodiments, the device comprises: an apparatus configured to supply liquid to a plurality of containers, the apparatus comprising: an inlet port downstream from and in fluidic communication with a location configured to supply the liquid to the inlet port; a plurality of liquid supply channels downstream from the inlet port, wherein each liquid supply channel in the plurality of liquid supply channels comprises an upstream end and a downstream end, and wherein each upstream end is configured to receive the liquid from the inlet port; a plurality of liquid valves, wherein each liquid valve in the plurality of liquid valves is positioned fluidically between an upstream end of a liquid supply channel in the plurality of liquid supply channels and the inlet port; a plurality of liquid supply ports, wherein each liquid supply port isdownstream from and in fluidic communication with a downstream end of a liquid supply channel in the plurality of liquid supply channels, and where each liquid supply port is configured to supply a container in the plurality of containers with the liquid; a liquid pump configured to pump the liquid from the inlet port, through the liquid valves, through the liquid supply channels, and to the liquid supply ports; a plurality of waste removal channels, wherein each waste removal channel in the plurality of waste removal channels comprises an upstream end and a downstream end; and a plurality of waste removal ports, wherein each waste removal port is upstream from and in fluidic communication with an upstream end of a waste removal channel in the plurality of waste removal channels, and wherein each waste removal port is configured to receive waste from a container in the plurality of containers.

[0011] Paragraph 2: In some embodiments, the device of Paragraph 1 further comprises a waste port upstream from and in fluidic communication with a waste receiving location.

[0012] Paragraph 3: In some embodiments, the device of Paragraph 2 further comprises a plurality of waste valves, wherein each waste valve in the plurality of waste valves is positioned fluidically between a downstream end of a waste removal channel in the plurality of waste removal channels and the waste port.

[0013] Paragraph 4: In some embodiments, the device of Paragraph 3 further comprises a waste pump configured to pump waste from the waste removal ports, through the waste removal channel, and to the waste port.

[0014] Paragraph 5: In some embodiments, the device of Paragraph 3 further comprises a vacuum line configured to transport waste from the waste removal ports, through the waste removal channel, and to the waste port.

[0015] Paragraph 6: In another aspect, a method for supplying a container in a plurality of containers with a liquid is provided. In some embodiments, the method for supplying a container in a plurality of containers with a liquid, comprises: in the device described in any preceding Paragraph: flowing the liquid from a liquid supply source to and through the inlet port; flowing the liquid from the inlet port to and through a liquid valve in the plurality of liquid valves; flowing the liquid from the liquid valve to and through a liquid supply channel in the plurality of liquid supply channels; flowing the liquid from the liquid supply channel to and through a liquid supply port in the plurality of liquid supply ports; and flowing the liquid from the liquid supply port into the container.

[0016] Paragraph 7: In another aspect, a method for removing waste from a container in a plurality of containers is provided. In some embodiments, the method for removing waste from a container in a plurality of containers comprises: in the device described in anypreceding Paragraph: flowing the waste from the container to and through a waste removal port in the plurality of waste removal ports; flowing the waste from the waste removal port to and through a waste removal channel in the plurality of waste removal channels; flowing the waste from the waste removal channel to and through a waste valve in the plurality of waste valves; flowing the waste from the waste valve to and through the waste port; and flowing the waste from the waste port to a waste receiving location.

[0017] Paragraph 8: In another aspect, a substrate is provided. In some embodiments, the substrate comprises: a plurality of containers; a plurality of substrate liquid supply ports, wherein each container in the plurality of containers comprises a substrate liquid supply port; a plurality of substrate waste disposal ports, wherein each container in the plurality of containers comprises a substrate waste disposal port; a liquid supply port connecting region located upstream from and in fluidic communication with a substrate liquid supply port in the plurality of substrate liquid supply ports, wherein the liquid supply port connecting region is configured to connect to a substrate liquid supply port; a waste removal port connecting region located downstream from and in fluidic communication with a substrate waste disposal port in the plurality of substrate waste disposal ports, wherein the waste removal port connecting region is configured to connect to a waste removal port; a plurality of substrate liquid supply channels, wherein each substrate liquid supply channel within the plurality of substrate liquid supply channels is located fluidically between a substrate liquid supply port in the plurality of substrate liquid supply ports and the liquid supply port connecting region, and configured to flow a liquid from the liquid supply port connecting region to the substrate liquid supply port; and a plurality of substrate waste removal channels, wherein each waste removal channel in the plurality of substrate waste removal channels is located fluidically between a substrate waste disposal port in the plurality of substrate waste disposal ports and the waste removal port connecting region, and configured to flow waste from the substrate waste disposal port to the waste removal port connecting region.

[0018] Paragraph 9: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises the plurality of containers.

[0019] Paragraph 10: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the plurality of containers is disposed on a substrate.

[0020] Paragraph 11: In some embodiments, in a device, substrate, or method of any preceding Paragraph, each container in the plurality of containers is a well in a multi-well plate.Paragraph 12: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the device is configured to receive the substrate.

[0021] Paragraph 13: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the device comprises an opening shaped to receive the substrate.

[0022] Paragraph 14: In some embodiments, in a device, substrate, or method of any preceding Paragraph,

[0023] the apparatus is a chip.

[0024] Paragraph 15: In some embodiments, in a device, substrate, or method of any preceding Paragraph, at least a portion of a surface of the substrate is transparent to at least one wavelength of light.

[0025] Paragraph 16: In some embodiments, in a device, substrate, or method of any preceding Paragraph, at least a portion of a surface of the apparatus is transparent to at least one wavelength of light.

[0026] Paragraph 17: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the wavelength of light is greater than or equal to 400 nm and less than or equal to 700 nm.

[0027] Paragraph 18: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the degree of transparency is greater than or equal to 70%.

[0028] Paragraph 19: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the liquid pump and / or waste pump is disposed in and / or on the apparatus.

[0029] Paragraph 20: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the device comprises a microfluidic chip.

[0030] Paragraph 21: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the apparatus is formed of a material that is biocompatible.

[0031] Paragraph 22: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the substrate is formed of a material that is biocompatible.

[0032] Paragraph 23: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the apparatus is formed of a material that is sterilizable.

[0033] Paragraph 24: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the substrate is formed of a material that is sterilizable.

[0034] Paragraph 25: In some embodiments, in a device, substrate, or method of any preceding Paragraph, at least a portion of the liquid pump and / or the waste pump is formed of a material that is sterilizable.Paragraph 26: In some embodiments, in a device, substrate, or method of any preceding Paragraph, at least a portion of each liquid valve and / or each waste valve is formed of a material that sterilizable.

[0035] Paragraph 27: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the apparatus is formed from a plastic.

[0036] Paragraph 28: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the substrate is formed from a plastic.

[0037] Paragraph 29: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the plastic comprises polystyrene, polycarbonate, and / or polypropylene.

[0038] Paragraph 30: In some embodiments, in a device, substrate, or method of any preceding Paragraph, each container in the plurality of containers is a cell culture chamber.

[0039] Paragraph 31: In some embodiments, a device, substrate, or method of any preceding Paragraph comprises a controller configured to direct the flow of the liquid.

[0040] Paragraph 32: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the controller is configured to control the plurality of valves.

[0041] Paragraph 33: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the controller is configured to control the liquid pump and / or the waste pump.

[0042] Paragraph 34: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the device comprises one or more gaskets.

[0043] Paragraph 35: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the pump is a rotary membrane pump, a peristaltic pump, a rotary pump, a piston pump, or a diaphragm pump.

[0044] Paragraph 36: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the pump is a rotary membrane pump.

[0045] Paragraph 37: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the liquid valves are pneumatic valves, turning valves, or rotary membrane valves.

[0046] Paragraph 38: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the waste valves are pneumatic valves, turning valves, or rotary membrane valves.

[0047] Paragraph 39: In some embodiments, in a device, substrate, or method of any preceding Paragraph, each valve in the plurality of liquid valves is configured to be operated independently.Paragraph 40: In some embodiments, in a device, substrate, or method of any preceding Paragraph, each valve in the plurality of waste valves is configured to be operated independently.

[0048] Paragraph 41: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the liquid comprises a pH-adjusting liquid.

[0049] Paragraph 42: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the liquid comprises a cell-culture medium.

[0050] Paragraph 43: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the pH-adjusting liquid comprises a buffer.

[0051] Paragraph 44: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the pH-adjusting liquid comprises an acid.

[0052] Paragraph 45: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the pH-adjusting liquid comprises a base.

[0053] Paragraph 46: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the liquid comprises waste.

[0054] Paragraph 47: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the liquid has a temperature of greater than or equal to 2 °C and less than or equal to 37 °C.

[0055] Paragraph 48: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the liquid is refrigerated.

[0056] Paragraph 49: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the liquid is stored in a refrigerator.

[0057] Paragraph 50: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the liquid reservoir is stored in a refrigerator.

[0058] Paragraph 51: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the inlet port and / or waste port is in fluidic communication with a reservoir.

[0059] Paragraph 52: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the inlet port and / or waste port comprises a luer lock fitting.

[0060] Paragraph 53: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the inlet port and / or waste port comprises a septum.

[0061] Paragraph 54: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the inlet port and / or waste port comprises a foil configured to be punctured when the port is fluidically connected to a reservoir.Paragraph 55: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the inlet port is configured to form a seal with a reagent reservoir.

[0062] Paragraph 56: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the waste port is configured to form a seal with a waste reservoir.

[0063] Paragraph 57: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the inlet port and / or waste port is configured to form a sterile connection with a reservoir.

[0064] Paragraph 58: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the waste port is in fluidic communication with a waste reservoir.

[0065] Paragraph 59: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the inlet port is in fluidic communication with a reagent reservoir.

[0066] Paragraph 60: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the location configured to supply the liquid to the inlet port is a location at which a reagent reservoir is positioned.

[0067] Paragraph 61: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the waste receiving location is a location at which a waste reservoir is positioned.

[0068] Paragraph 62: In some embodiments, in a device, substrate, or method of any preceding Paragraph, each liquid supply port is configured to form a seal with a container in the plurality of containers.

[0069] Paragraph 63: In some embodiments, in a device, substrate, or method of any preceding Paragraph, each waste removal port is configured to form a seal with a container in the plurality of containers.

[0070] Paragraph 64: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the waste receiving location is a waste reservoir.

[0071] Paragraph 65: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the liquid supply source is a liquid reservoir.

[0072] Paragraph 66: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises at least one sensor.

[0073] Paragraph 67: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises performing a measurement using the sensor.

[0074] Paragraph 68: In some embodiments, a device, substrate, or method of any preceding Paragraph, further comprises flowing the liquid into the container in an amount determined based on the sensor measurement.Paragraph 69: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises flowing the liquid into the plurality of containers in an amount determined based on the sensor measurement.

[0075] Paragraph 70: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises flowing the liquid out of the container in an amount determined based on the sensor measurement.

[0076] Paragraph 71: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises flowing the liquid out of the plurality of containers in an amount determined based on the sensor measurement.

[0077] Paragraph 72: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the sensor is a pH sensor.

[0078] Paragraph 73: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises measuring a pH of a liquid contained by the container.

[0079] Paragraph 74: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises flowing the pH-adjusting liquid into the container in an amount and / or at a pH determined based on the measurement of the pH.

[0080] Paragraph 75: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises flowing pH-adjusting liquid into the plurality of containers in an amount and / or at a pH determined based on the measurement of the pH.

[0081] Paragraph 76: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the device comprises two or more sensors.

[0082] Paragraph 77: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the device comprises a sensor for carbon dioxide.

[0083] Paragraph 78: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the device further comprises a sensor for carbon dioxide, cell concentration, cell viability, nutrients, metabolites (such as lactate, glucose), temperature, pressure, humidity, and / or viscosity.

[0084] Paragraph 79: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the device comprises an optical sensor, an electrochemical sensor, and / or an acoustic sensor.

[0085] Paragraph 80: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the device comprises a timer.Paragraph 81: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises flowing a liquid into the container at a predetermined time and / or at predetermined intervals of time.

[0086] Paragraph 82: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises flowing a liquid into the plurality of containers at a predetermined time and / or at predetermined intervals of time.

[0087] Paragraph 83: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises flowing the liquid out of the container at a predetermined time and / or at predetermined intervals of time.

[0088] Paragraph 84: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises flowing the liquid out of the plurality of containers at a predetermined time and / or at predetermined intervals of time.

[0089] Paragraph 85: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the apparatus is positioned inside an instrument.

[0090] Paragraph 86: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the instrument comprises an optical detector.

[0091] Paragraph 87: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the optical detector comprises a microscope.

[0092] Paragraph 88: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the instrument further comprises a light source.

[0093] Paragraph 89: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the light source is a source of fluorescent light.

[0094] Paragraph 90: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises performing an optical measurement.

[0095] Paragraph 91: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the optical measurement is performed on a liquid contained by the container.

[0096] Paragraph 92: In some embodiments, a device, substrate, or method of any preceding Paragraph, further comprises flowing the liquid into the container in an amount determined based on the optical measurement.

[0097] Paragraph 93: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises flowing the liquid into the plurality of containers in an amount determined based on the optical measurement.Paragraph 94: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the device comprises two or more modules, and wherein each module comprises an identical set of components.

[0098] Paragraph 95: In some embodiments, in a device, substrate, or method of any preceding Paragraph, each module is configured to be operated independently.

[0099] Paragraph 96: In some embodiments, in a device, substrate, or method of any preceding Paragraph, one or more substrates is disposed on the device.

[0100] Paragraph 97: In some embodiments, a device, substrate, or method of any preceding Paragraph, further comprises a second inlet port downstream from and in fluidic communication with a second location configured to supply a second liquid to the second inlet port, wherein the second inlet port upstream from and in fluidic communication with the plurality of liquid valves.

[0101] Paragraph 98: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the second location configured to supply the second liquid to the second inlet port is a location at which a reagent reservoir is positioned.

[0102] Paragraph 99: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises supplying a first liquid to a first plurality of containers and a second liquid to a second plurality of containers.

[0103] Paragraph 100: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises supplying a first liquid to a first plurality of containers in an amount determined based on a first sensor measurement and supplying a second liquid to a second plurality of containers based on a second sensor measurement.

[0104] Paragraph 101: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises supplying a first liquid to a first container in the plurality containers in an amount determined based on a first sensor measurement and supplying a second liquid to a second container in the plurality of containers based on a second sensor measurement.

[0105] Paragraph 102: In some embodiments, a device, substrate, or method of any preceding Paragraph, further comprises supplying a first liquid to a first plurality of containers during a first time period and supplying a second liquid to a second plurality of containers during a second time period.

[0106] Paragraph 103: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises supplying a first pH-adjusting liquid to the first plurality of containers in an amount and / or at a pH determined based on the measurement of the pH inthe first plurality of containers and supplying a second pH-adjusting liquid to the second plurality of containers in an amount and / or at a pH determined based on the measurement of the pH in the second plurality of containers.

[0107] Paragraph 104: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises supplying a first pH-adjusting liquid to a first container in the plurality of containers in an amount and / or at a pH determined based on the measurement of the pH in the first container and supplying a second pH-adjusting liquid to a second container in the plurality of containers in an amount and / or at a pH determined based on the measurement of the pH in the second container.

[0108] Paragraph 105: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises flowing waste out of a first plurality of containers in a first amount and removing waste from a second plurality of containers in a second amount.

[0109] Paragraph 106: In some embodiments, a device, substrate, or method of any preceding Paragraph further comprises flowing waste out of a first container in the plurality of containers in a first amount and removing waste from a second container in the plurality of containers in a second amount.

[0110] Paragraph 107: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the liquid comprises a therapeutic agent.

[0111] Paragraph 108: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the therapeutic agent comprises a small molecule drug, a biologic, an antibody, an antibody fragment, a nucleic acid-based therapeutic, and / or a cell-based therapeutic.

[0112] Paragraph 109: In some embodiments, a device, substrate, or method of any preceding Paragraph comprises performing one or more measurements on the waste.

[0113] Paragraph 110: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the container in the plurality of containers contains a starting liquid, and the method further comprises, prior to flowing the liquid into the container: flowing the starting liquid from the container to and through a waste removal port in the plurality of waste removal ports; flowing the starting liquid from the waste removal port to and through a waste removal channel in the plurality of waste removal channels; flowing the starting liquid from the waste removal channel to and through a waste valve in a plurality of waste valves; flowing the starting liquid from the waste valve to and through a waste port; and flowing the starting liquid from the waste port to a waste receiving location.Paragraph 111: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the liquid comprises cell-culture media and a therapeutic agent.

[0114] Paragraph 112: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the method further comprises incubating the liquid in the container.

[0115] Paragraph 113: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the method further comprises sensing a property of the liquid in the container during the incubation.

[0116] Paragraph 114: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the property is cell viability, cell morphology, impedance, or fluorescence.

[0117] Paragraph 115: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the method further comprises flowing the liquid from the container to and through the waste removal port in the plurality of waste removal ports; flowing the liquid from the waste removal port to and through the waste removal channel in the plurality of waste removal channels; flowing the liquid from the waste removal channel to and through the waste valve in the plurality of waste valves; flowing the liquid from the waste valve to and through the waste port; and flowing the liquid from the waste port to a waste receiving location.

[0118] Paragraph 116: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the method further comprises performing one or more measurements on the liquid after the liquid has been flowed to the waste receiving location.

[0119] Paragraph 117: In some embodiments, in a device, substrate, or method of any preceding Paragraph, the method further comprises flowing a second liquid to and through the inlet port; flowing the second liquid from the inlet port to and through the liquid valve in the plurality of liquid valves; flowing the second liquid from the liquid valve to and through the liquid supply channel in the plurality of liquid supply channels; flowing the second liquid from the liquid supply channel to and through the liquid supply port in the plurality of liquid supply ports; and flowing the second liquid from the liquid supply port into the container.

[0120] Paragraph 118: In some embodiments, in a device, substrate, or method of any preceding Paragraph, wherein flowing the second liquid to the inlet port comprises flowing the second liquid from the liquid supply source to and through the inlet port.

[0121] Paragraph 119: In some embodiments, in a device, substrate, or method of any preceding Paragraph, wherein flowing the second liquid to the inlet port comprises flowing the second liquid from a second liquid supply source to and through the inlet port.Other advantages and novel features of the present invention will become apparent from the following detailed description of various non-limiting embodiments of the invention when considered in conjunction with the accompanying figures. In cases where the present specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control. If two or more documents incorporated by reference include conflicting and / or inconsistent disclosure with respect to each other, then the document having the later effective date shall control.

[0122] BRIEF DESCRIPTION OF THE DRAWINGS

[0123] Non-limiting embodiments of the present invention will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the invention shown where illustration is not necessary to allow those of ordinary skill in the art to understand the invention. In the figures:

[0124] FIG. 1A presents a top-view schematic of a nonlimiting device, according to some embodiments;

[0125] FIG. IB presents a side-view schematic of a nonlimiting channel comprising a bubble-trapping structure, according to some embodiments;

[0126] FIG. 1C presents a top-view schematic of a nonlimiting device and a substrate comprising a plurality of containers, according to some embodiments;

[0127] FIG. ID presents a side-view schematic of a nonlimiting substrate comprising a plurality of containers, according to some embodiments;

[0128] FIG. IE presents a side-view schematic of a nonlimiting substrate comprising a plurality of containers, according to some embodiments;

[0129] FIG. IF presents a top-view schematic of a nonlimiting substrate comprising a plurality of containers, according to some embodiments;

[0130] FIG. 1G presents a side-view schematic of a nonlimiting container within a substrate comprising a plurality of containers, according to some embodiments;

[0131] FIGS. 1H-1K present top-view schematics of nonlimiting containers within a substrate comprising a plurality of containers, according to some embodiments;FIG. 2A presents a top-view schematic of a nonlimiting device, according to some embodiments;

[0132] FIG. 2B presents a top-view schematic of a nonlimiting device and substrates comprising a plurality of containers, according to some embodiments;

[0133] FIG. 3A presents a flowchart of a method for supplying a container within a plurality of containers with a liquid, according to some embodiments;

[0134] FIG. 3B presents a flowchart of a method for removing waste from a container within a plurality of containers, according to some embodiments;

[0135] FIG. 4 presents an angled side-view schematic of a nonlimiting device and substrate comprising a plurality of containers, according to some embodiments;

[0136] FIG. 5 presents a top-view schematic of a nonlimiting device and substrate comprising a plurality of containers, according to some embodiments;

[0137] FIG. 6 shows an angled side-view schematic view of a nonlimiting device and substrate comprising a plurality of containers wherein the substrate is formed from an opaque material, according to some embodiments;

[0138] FIG. 7 shows an angled side-view schematic view of a nonlimiting device and substrate comprising a plurality of containers wherein the substrate is formed from an optically transparent material, according to some embodiments;

[0139] FIG. 8 shows a top-view schematic view of a nonlimiting device and substrate comprising a plurality of containers, according to some embodiments;

[0140] FIG. 9 shows a top-view schematic view detailing the fluidic connections within a nonlimiting device, according to some embodiments; and

[0141] FIG. 10 shows a nonlimiting device and substrates comprising a plurality of containers, and liquid reservoirs, according to some embodiments.

[0142] DETAILED DESCRIPTION

[0143] Devices and methods for multiplexed liquid supply and removal from a plurality of containers are generally described. In some embodiments, the plurality of containers may be part of a device described herein. In some embodiments, the plurality of containers may be part of a separate consumable component designed to be compatible with a device described herein such that liquids can be flowed into the plurality of containers and / or wastes can be removed from the plurality of containers via the device. In some embodiments, a device described herein may comprise a device and the plurality of containers. Some of the devices and apparatuses described herein comprise a plurality of ports (e.g. an inlet port, a wasteport), valves (e.g. liquid valves, waste valves), pumps (e.g. a liquid pump, a waste pump) and channels (e.g. liquid supply channels, waste removal channels) which are in fluidic communication in such a configuration as to allow the multiplexed delivery of a liquid and / or removal of a waste from one or more containers in the plurality of containers. In some embodiments, the devices and apparatuses described herein may comprise a plurality of reservoirs (e.g. a liquid reservoir, a waste reservoir) to store the liquid to be flowed into the plurality of containers and / or the waste to be flowed out of the plurality of containers. In some embodiments, the reservoirs may be part of the device. In other embodiments, the reservoirs may be separate consumable components configured to be and / or capable of being compatible with a port in the device (e.g. an inlet port, a waste port) such as to become fluidically connected to the other components of the device. Methods for operating the devices and apparatuses described herein are also described.

[0144] In some embodiments, the containers in the devices and methods described herein may be cell culture chambers and / or containers used for the performance of experiments involving biological cells. In some such embodiments, the cells may be adherent biological cells. For example, in some embodiments, the containers in the devices and methods described herein may be cell culture chambers and / or containers used for performing experiments involving 2D cell cultures (e.g., monolayer cell cultures) comprising adherent biological cells. In some instances, the devices and methods described herein may offer particular advantages for performing cell culture and / or experiments involving adherent biological cells. For example, in some embodiments, the multiplexed delivery of a liquid and / or removal of waste to one or more containers comprising biological cells may reduce the time and / or effort required to perform several experiments in parallel. In some embodiments, the devices and methods described herein may facilitate the automated delivery of cell culture media, pH-adjusting liquids, or other liquids from one or more of the containers. In some embodiments, the devices and methods described herein may facilitate the automated removal of waste from one or more of the containers. Automating these processes may advantageously reduce human error and reduce human effort required to perform cell culture and / or experiments involving adherent biological cells. In some embodiments, the devices and methods described herein may facilitate real-time sensing of one or more properties of the liquid(s) in one or more of the containers, including one or more properties related to the viability and / or metabolism of biological cells within one or more of the containers. In some embodiments, the devices and methods may facilitate delivering a liquid to and / or removing a waste from one or more of the containers based on one or more real-time sensingmeasurements. This may be particularly advantageous because it may allow for real-time adjustment of conditions in one or more of the containers, which may itself allow for efficient and immediate optimization of conditions within one or more of the containers, and / or by avoiding the human error associated with discrete, human-made measurements and delivery of reagents.

[0145] In some embodiments, the containers in the devices and methods described herein may be cell culture chambers and / or containers used for the performance of experiments involving three-dimensional cell cultures. In some embodiments, the three-dimensional cell cultures comprise multicellular aggregates, spheroids, organoids, tissue-like constructs, and / or other self-organized or engineered three-dimensional structures comprising biological cells. In some embodiments, the three-dimensional cell cultures comprise adherent cells. The three-dimensional cell cultures and / or the biological cells therein may be derived from primary cells, stem cells, and / or one or more cell lines. In some instances, the devices and methods described herein may offer particular advantages for performing cell culture and / or experiments involving three-dimensional cell cultures. For example, in some embodiments, the multiplexed delivery of a liquid to and / or removal of waste from one or more containers comprising biological cells (e.g., biological cells that are part of a three-dimensional cell culture) may reduce the time and / or effort required to perform several experiments in parallel. In some embodiments, the devices and methods described herein may facilitate the automated delivery of cell culture media, pH-adjusting liquids, or other liquids from one or more of the containers. In some embodiments, the devices and methods described herein may facilitate the automated removal of waste from one or more of the containers. Automating these processes may advantageously reduce human error and reduce human effort required to perform cell culture and / or experiments involving three-dimensional cell cultures. In some embodiments, the devices and methods described herein may facilitate real-time sensing of one or more properties of the liquid(s) in one or more of the containers, including one or more properties related to the viability and / or metabolism of biological cells within one or more of the containers. In some embodiments, the devices and methods may facilitate delivering a liquid to and / or removing a waste from one or more of the containers based on one or more real-time sensing measurements. This may be particularly advantageous because it may allow for real-time adjustment of conditions in one or more of the containers, which may itself allow for efficient and immediate optimization of conditions within one or more of the containers, and / or by avoiding the human error associated with discrete, human-made measurements and delivery of reagents. This may be particularly advantageous for three-dimensional cell cultures, which may be fragile and / or particularly sensitive to changes in the conditions within the container.

[0146] In some embodiments, some components of the devices and apparatuses described herein may have advantageously small volumes. For example, in some embodiments, the devices and apparatuses described herein may have a plurality of liquid supply channels and / or waste removal channels with small dead volumes. This may offer particular advantages such as avoiding waste of reagents and / or mitigating the buildup of undesirable contaminants in one or more of the channels and / or containers.

[0147] In some embodiments, the devices and methods described herein may have one or more other advantages. Some such advantages may include allowing for high-throughput biological experiments (and, in some embodiments, thereby facilitating reliable statistical analysis and / or rapid testing of different conditions within the plurality of containers), performing real-time imaging of biological cells and / or other components within the one or more containers, allowing for parallelization of multiple automated experiments, and / or reducing the burden on human researchers by automating time- sensitive and / or high-precision tasks.

[0148] FIG. 1A shows one non-limiting embodiment of a device as described herein. FIG.

[0149] 1A shows a device 100a comprising an apparatus 101 configured to supply a liquid to and / or remove waste from a plurality of containers and / or capable of supplying a liquid and / or removing a waste from a plurality of containers. The apparatus 101 may comprise a variety of components, such as ports, valves, channels, and pumps. For example, in the non-limiting embodiment shown in FIG. 1A, the apparatus 101 comprises an inlet port 102, which is upstream from and in fluidic communication with a plurality of liquid supply channels 103 having an upstream end and a downstream end. In the embodiment of FIG. 1 A, the apparatus 101 comprises a plurality of liquid valves 104, each of which is positioned fluidically between the upstream end of a liquid supply channel in the plurality of liquid supply channels 103 and the inlet port. In this embodiment, the apparatus 101 comprises a plurality of liquid supply ports 105, each of which is downstream from and in fluidic communication with the downstream end of a liquid supply channel in the plurality of liquid supply channels. In this embodiment, the apparatus 101 comprises a liquid pump 106, which may be configured to pump and / or capable of pumping liquid from the inlet port 102, through the liquid supply channels 103, through the liquid valves 104, and to the liquid supply ports 105. In the embodiment shown in FIG. 1A, the apparatus 101 also comprises a plurality of waste removal ports 112, which are located upstream from and in fluidic communication with aplurality of waste removal channels 113 having an upstream end and a downstream end. In this exemplary embodiment, the apparatus 101 comprises a plurality of waste valves 114, each of which is located fluidically between the upstream end and the downstream end of a waste removal channel in the plurality of waste removal channels. In this embodiment, the apparatus 101 comprises a waste removal port 115, which is located downstream from and in fluidic communication with the downstream end of the plurality of waste removal channels 113. The apparatus shown in FIG. 1A comprises a waste pump 116, which may be configured to pump and / or capable of pumping waste from the plurality of waste removal ports 112, through the plurality of waste removal channels 113, through the waste valves 114, and to the waste port 115. In some embodiments, the apparatus may comprise a chip.

[0150] In the embodiment shown in FIG. 1A, the device 100a does not comprise the plurality of containers. In some embodiments, the plurality of containers may be part of a separate component which is configured to be and / or capable of being compatible with the apparatus such that the apparatus 101 can supply a liquid to and / or remove waste from the plurality of containers. For example, in some embodiments, the apparatus 101 may comprise a cavity having a shape such that the component comprising the plurality of containers can be placed in the cavity. For example, in some embodiments, the component comprising the plurality of containers may have a certain size. In such embodiments, the apparatus may comprise a cavity having a certain size, wherein the size of the cavity is chosen such that the component comprising the plurality of containers may fit within the cavity. In some embodiments, the apparatus 101 may comprise one or more fittings. In some embodiments, the component comprising the plurality of containers may comprise one or more mating fittings, such that the plurality of containers may become fluidically connected to the apparatus 101 when the fittings of the apparatus and the mating fittings of the plurality of containers are joined. In some embodiments, the device may comprise the plurality of containers.

[0151] In some embodiments, the apparatus comprises an inlet port 102. In some embodiments, the inlet port 102 may be downstream from and in fluidic communication with a location configured to supply and / or capable of supplying a liquid to the inlet port. In some embodiments, the location configured to supply and / or capable of supplying a liquid to the inlet port may be a liquid reservoir and / or a liquid supply source as described elsewhere herein. In some embodiments, the liquid reservoir may be part of the device 100a. In other embodiments, the liquid reservoir may be a separate component configured to be and / or capable of being compatible with the inlet port such that it may become reversibly fluidically connected to the inlet port. In some embodiments, the inlet port may comprise a luer lock. Insome embodiments, the luer lock may be configured to be and / or capable of being compatible with a complementary luer lock fitting on a liquid reservoir, wherein the liquid reservoir is configured to become and / or capable of becoming fluidically connected to the inlet port upon the connection of the luer lock and complementary luer lock fitting. In some embodiments, the inlet port may comprise a septum. In some embodiments, the septum may be configured to be and / or capable of being compatible with a septum-piercing member on a liquid reservoir, wherein the liquid reservoir is configured to become and / or capable of becoming fluidically connected to the inlet port when the septum-piercing member of the liquid reservoir pierces the septum of the inlet port. In some embodiments, the inlet port may comprise a foil configured to be punctured and / or capable of being punctured by a foilpuncturing member of a liquid reservoir, wherein the liquid reservoir is configured to become and / or capable of becoming fluidically connected to the inlet port when the foil-puncturing member punctures the foil of the inlet port.

[0152] In some embodiments, an inlet port having any of the above-described configurations may be configured to form and / or capable of forming a sterile connection with a reservoir. In some embodiments, the inlet port may be configured to form and / or capable of forming an aseptic connection with a reservoir. For example, in some embodiments, the inlet port may comprise an inlet port which is sealed and which may be configured to become and / or capable of becoming unsealed (i.e., can allow fluidic communication therethrough) only when an appropriate connection is made. The appropriate connection may be a connection that does not introduce non-sterile components into the reservoir (e.g., via the connection itself or via an environment that the connection allows fluidic communication to therethrough). In some embodiments, for example, the inlet port may comprise a rubber septum which is configured to allow and / or capable of allowing fluidic communication with a liquid reservoir sealed thereby with an environment external to the liquid reservoir only when the rubber septum is broken by a needle. In some embodiments, the inlet port may comprise a silicone luer lock which is configured to allow and / or capable of allowing fluidic communication with a liquid reservoir sealed thereby with an environment external to the liquid reservoir only when a complementary luer lock fitting is connected to the inlet port.

[0153] In some embodiments, the apparatus 101 comprises a plurality of liquid supply channels 103. In some embodiments, each liquid supply channel in the plurality of liquid supply channels may comprise an upstream end and a downstream end. In some embodiments, each upstream end may be configured to receive and / or capable of receiving aliquid from the inlet port 102. For example, in some embodiments, each upstream end may be in fluidic communication with the inlet port 102.

[0154] In some embodiments, a liquid supply channel within a plurality of liquid supply channels may have one or more advantageous features. For example, in some embodiments, the liquid supply channel comprises a bubble-trapping structure. In some embodiments, as shown in FIG. IB, the bubble-trapping structure 150 comprises a cavity positioned above and fluidically connected to the liquid supply channel 152. In some embodiments, a bubble 154 may rise within the liquid supply channel 152 when a liquid containing the bubble 154 is flowed past the bubble-trapping structure 150, thereby entering the bubble-trapping structure and being removed from the flowing liquid. This may advantageously reduce the bubble content of a liquid delivered to a container via the liquid supply channel.

[0155] In some embodiments, the apparatus 101 comprises a plurality of liquid valves 104. In some embodiments, each liquid valve in the plurality of liquid valves is positioned fluidically between the upstream end of a liquid supply channel in the plurality of liquid supply channels and the inlet port. In some embodiments, the plurality of liquid valves may comprise any of a variety of suitable types of valves. Non-limiting examples of suitable valves include pneumatic valves, turning valves, rotary membrane valves, pinch valves, solenoid valves, and shape-memory alloy valves.

[0156] In some embodiments, each valve in the plurality of liquid valves may be configured to be and / or capable of being operated independently. For example, in some embodiments, it is possible that one or more valves in the plurality of liquid valves may be in an open position while one or more other valves in the plurality of liquid valves may be in a closed position. In some embodiments, it is possible that one or more liquid valves in the plurality of liquid valves may be throttled while one or more other liquid valves in the plurality of liquid valves are not throttled and / or one or more other liquid valves in the plurality of liquid valves are throttled to a different level. In some embodiments, all liquid valves in the plurality of liquid valves are configured to be and / or capable of being operated simultaneously. In some embodiments, the position of each valve in the plurality of liquid valves may be modified independently and / or in concert with one or more other valves in the plurality of liquid valves. In some embodiments, the position of each valve in the plurality of liquid valves may be modified based on information from a sensor which may be internal and / or external to the device. Further discussion of how sensors may be used to inform the modification of valve positions is included below.In some embodiments, the apparatus 101 may comprise a plurality of liquid supply ports 105. In some embodiments, each liquid supply port in the plurality of liquid supply ports may be downstream from and in fluidic communication with the downstream end of a liquid supply channel in the plurality of the liquid supply channels. In some embodiments, each liquid supply port is configured to supply and / or capable of supplying a container within the plurality of containers with the liquid. In some embodiments, each liquid supply port may comprise a fitting. In some embodiments, the fitting may be configured to form and / or capable of forming a connection with an opening and / or complementary fitting in a container in the plurality of containers.

[0157] In some embodiments, the apparatus 101 may comprise a liquid pump 106. In some embodiments, the liquid pump 106 may be configured to pump and / or capable of pumping liquid from the inlet port, through the liquid valves, through the liquid supply channels, and to the liquid supply ports. Other flow paths are also possible. For example, in the nonlimiting embodiment shown in FIG. 1A, the liquid pump 106 may be configured to pump and / or capable of pumping the liquid from the inlet port 102, through the liquid pump 106, splitting and flowing the liquid through the plurality of liquid supply channels 103, through the plurality of liquid valves 104, and to the plurality of liquid supply ports 105.

[0158] In some embodiments, the liquid pump 106 may be disposed on the apparatus 101. In some embodiments, the liquid pump 106 may be removable from the apparatus 101. The liquid pump may be one of any of a variety of suitable pumps. Non-limiting examples of suitable pumps include rotary membrane pumps, peristaltic pumps (e.g., tubing pumps), rotary pumps, piston pumps, diaphragm pumps, motor pumps (e.g., syringe pump-like motor pumps), and roller pumps. In some embodiments, the liquid pump may be a reversible pump (i.e., it may be capable of and / or configured to pump liquids therethrough in opposing directions). It is also possible for the liquid pump to be a one-way pump (i.e., it may be capable of and / or configured to pump liquids therethrough in only one direction).

[0159] In some embodiments, a liquid pump may have a minimum dispensing volume of less than 5 pL.

[0160] A liquid pump may be configured to handle and / or capable of handling any of a variety of suitable flow rates. For example, in some embodiments, the liquid pump may be configured to handle and / or capable of handling flow rates of greater than or equal to 0.1 pL / min, greater than or equal to 0.5 pL / min, greater than or equal to 1.0 pL / min, greater than or equal to 1.5 pL / min, greater than or equal to 2.0 pL / min, greater than or equal to 2.5 pL / min, greater than or equal to 3.0 pL / min, or greater than or equal to 3.5 pL / min. In someembodiments, the liquid pump may be configured to handle and / or capable of handling less than or equal to 4.0 pL / min, less than or equal to 3.5 pL / min, less than or equal to 3.0 pL / min, less than or equal to 2.5 pL / min, less than or equal to 2.0 pL / min, less than or equal to 1.5 pL / min, less than or equal to 1.0 pL / min, or less than or equal to 0.5 pL / min.

[0161] Combinations of these ranges are also possible (e.g., in some embodiments, the liquid pump may be configured to handle and / or capable of handling greater than or equal to 0.1 pL / min and less than or equal to 4.0 pL / min, greater than or equal to 0.1 pL / min and less than or equal to 3.5 pL / min, or greater than or equal to 0.5 pL / min and less than or equal to 3.5 pL / min). Other ranges are also possible.

[0162] In some embodiments, a liquid pump may have any of a variety of suitable internal volumes. In some embodiments, it may be particularly advantageous for the liquid pump to have a small internal volume. For example, in some embodiments, the liquid pump may have an internal volume of less than or equal to 30 pL.

[0163] In some embodiments, a liquid pump may be controllable with a custom control protocol. For example, in some embodiments, the liquid pump may be electrically controllable. In some embodiments, the liquid pump may support an electrical connection interface. In some embodiments, the electrical connection interface may be a Micro-USB, inter-integrated circuit (I2C), serial peripheral interface (SPI), universal asynchronous receiver / transmitter (UART), general purpose input / output GPIO, and / or pulse width modulation (PWM) electrical connection interface.

[0164] In some embodiments, a liquid pump may have a small footprint. For example, in some embodiments, the liquid pump may have a footprint of less than or equal to 63.8 mm (width) x 85.4 mm (length) x 45 mm (depth). In some embodiments, the liquid pump may have additional space surrounding the liquid pump which is not occupied by other components. For example, in some embodiments, the liquid pump may have additional space surrounding the liquid pump which is not occupied by other components which extends at least 10 mm in each direction.

[0165] In some embodiments, a liquid pump may have a relatively high accuracy. For example, in some embodiments, the liquid pump may have an error rate of less than or equal to 5%.

[0166] In some embodiments, a liquid pump may be mounted to a device using any of a variety of suitable connections. For example, in some embodiments, the liquid pump may be mounted to the device using a downmount connection and / or a tube connection. In someembodiments, the liquid pump may be mounted to the device by a tube connection which has a tubing volume of less than or equal to 5 pL.

[0167] In some embodiments, a liquid pump may be configured to operate and / or capable of operating at any of a variety of suitable operating pressures. For example, the liquid pump may be capable of operating at a variety of operating pressures without generating bubbles and / or encountering mechanical failures due to bubble generation.

[0168] In some embodiments, a liquid pump may be compatible with fluids having any of a variety of compositions and / or properties. For example, in some embodiments, the liquid pump may be compatible with fluids comprising greater than or equal to 10 wt% ethanol. In some embodiments, the liquid pump may be compatible with fluids comprising greater than or equal to 70 wt% cell culture medium.

[0169] In some embodiment, a liquid pump may be compatible with fluids having any of a variety of pH values. For example, in some embodiments, the liquid pump may be compatible with a fluid having a pH of greater than or equal to 6, greater than or equal to 6.5, greater than or equal to 7, or greater than or equal to 7.5. In some embodiments, the liquid pump may be compatible with a fluid having a pH of less than or equal to 8, less than or equal to 7.5, less than or equal to 7, or less than or equal to 6.5. Combinations of these ranges are also possible (e.g., in some embodiments, the liquid pump may be compatible with fluids having a pH of greater than or equal to 6 and less than or equal to 8). Other ranges are also possible.

[0170] In some embodiments, a liquid pump as described herein may be relatively robust. For example, in some embodiments, the liquid pump may be operational for greater than or equal to one year without experiencing significant failures.

[0171] In some embodiments, the apparatus 101 may comprise a plurality of waste removal channels 113. In some embodiments, each waste removal channel in the plurality of waste removal channels may have an upstream end and a downstream end.

[0172] In some embodiments, the apparatus 101 may comprise a plurality of waste removal ports. In some embodiments, each waste removal port in the plurality of waste removal ports may be upstream from and in fluidic communication with the upstream end of a waste removal channel in the plurality of waste removal channels. In some embodiments, each waste removal port in the plurality of waste removal ports may be configured to receive and / or capable of receiving waste from a container in the plurality of containers. Any of the waste removal ports in the plurality of waste removal ports may have any of the propertiesand characteristics described above for liquid supply ports (e.g. any of the waste removal ports may comprise a fitting, etc.).

[0173] In some embodiments, the apparatus 101 may comprise a waste port 115 upstream from and in fluidic communication with a location configured to receive and / or capable of receiving waste. In some embodiments, the location configured to receive and / or capable of receiving waste is a waste reservoir. The waste port may have any of the properties and characteristics described above for the inlet port (e.g. the waste port may comprise a luer lock, etc.). The waste reservoir may have any of the properties and characteristics described above for the liquid reservoir (e.g. the waste reservoir may comprise a complementary luer lock fitting, etc.).

[0174] In some embodiments, the apparatus 101 may comprise a plurality of waste valves 114. In some embodiments, each waste valve in the plurality of waste valves is positioned fluidically between a downstream end of a waste removal channel in the plurality of waste removal channels and the waste port. The waste valves may have any of the properties and characteristics described above for liquid valves (e.g. the waste valves may be configured to be and / or capable of being operated independently, etc.).

[0175] In some embodiments, the apparatus 101 may comprise a waste pump 116 configured to pump and / or capable of pumping waste from the waste removal port, through the waste removal channel, and to the waste port. Other flow paths are also possible. For example, in the non-limiting embodiment shown in FIG. 1A, the waste pump 116 may be configured to pump and / or capable of pumping the waste from the plurality of waste removal ports 112, through the plurality of waste removal channels 113, through the plurality of waste valves 114, through the waste pump 116, and to the waste port 115. In some embodiments, the waste pump 116 may be disposed on the apparatus 101. The waste pump may have any of the properties and characteristics described above for the liquid pump.

[0176] In some embodiments, the apparatus 101 may comprise a vacuum line configured to transport and / or capable of transporting waste from the waste removal port, through the waste removal channel, and to the waste port. In some embodiments, the same alternative flow paths as described above for an apparatus comprising a waste pump may also be possible for an apparatus comprising a vacuum line.

[0177] In some embodiments, any and / or all of the components of the apparatus 101 described above (e.g. any of the inlet port, liquid supply channels, liquid valves, liquid supply ports, the liquid pump, the waste pump, waste removal ports, waste removal channels, waste valves, and / or waste port) may be formed from and / or comprise materials having somedesirable properties. For example, in some embodiments, any and / or all of the components of the apparatus 101 may be formed from and / or comprise a material that is biocompatible. Biocompatibility may be assessed in any of a variety of suitable ways. In some embodiments, an apparatus has a biocompatibility such that the viability of cells cultured in a medium comprising a liquid that has passed through any of the components of the apparatus 101 formed from and / or comprising the material may be assessed. The degree of viability of such cells can be measured by dye (e.g., trypan blue). Other indicators of viability include cells exhibiting adhesion to and / or proliferation in a cell-culture chamber, and / or displaying cellular markers and / or proteins associated with cell health and function upon immunofluorescence staining.

[0178] In some embodiments, any of the components of the apparatus 101 may be formed from and / or comprise a material that is sterilizable. In some embodiments, any of the components of the apparatus may be sterilizable via an autoclave, dry heat sterilization, exposure to gamma radiation, exposure to X-ray radiation, and / or by chemical exposure (e.g. to ethylene oxide, bleach, alcohol, and / or hydrogen peroxide vapor). Any of the components of the apparatus 101 may change color and / or deform (or not change color and / or deform) during sterilization.

[0179] In some embodiments, any of the components of the apparatus 101 may be formed from and / or comprise any of a variety of suitable materials. In some embodiments, any of the components of the apparatus may be formed from and / or comprise a plastic. In some embodiments, the plastic may comprise polystyrene, polypropylene, and / or polycarbonate. In some embodiments, any of the components of the apparatus may be formed from and / or comprise a 3-D printed resin. In some embodiments, any of the components of the apparatus may comprise glass.

[0180] In some embodiments, any of the components of the apparatus may be formed from and / or comprise a material that is optically transparent to at least one wavelength of light (e.g., a transparent pathway may exist between an external surface of the component and an interior of the component). When present, this surface may extend across the entirety of the component or extend across only one or more portions thereof. In some embodiments, the apparatus as a whole may be formed from and / or comprise one or more materials which are transparent to at least one wavelength of light.

[0181] In some embodiments, the material may be optically transparent to light having any of a variety of suitable wavelengths. In some embodiments, the material is optically transparent to light having a wavelength of greater than or equal to 400 nm, greater than or equal to 450nm, greater than or equal to 500 nm, greater than or equal to 550 nm, greater than or equal to 600 nm, or greater than or equal to 650 nm. In some embodiments, the material is optically transparent to light having a wavelength of less than or equal to 700 nm, less than or equal to 650 nm, less than or equal to 600 nm, less than or equal to 550 nm, less than or equal to 500 nm, or less than or equal to 450 nm. Combinations of these ranges are also possible (e.g. the material may be optically transparent to light having a wavelength of greater than or equal to 400 nm and less than or equal to 700 nm, greater than or equal to 450 nm and less than or equal to 650 nm, or greater than or equal to 500 nm and less than or equal to 600 nm). Other ranges are also possible. In some embodiments, the material may be transparent to all wavelengths of light within one or more of the above-referenced ranges.

[0182] In some embodiments, the material may be optically transparent to a wavelength of light in one or more of the above-referenced ranges with a transparency of greater than or equal to 70%, greater than or equal to 80%, greater than or equal to 90%, greater than or equal to 95%, greater than or equal to 99%, or greater than or equal to 99.9%. In some embodiments, the material is optically transparent to a wavelength of light in one or more of the above-referenced ranges with a transparency of less than or equal to 100%, less than or equal to 99.9%, less than or equal to 99%, less than or equal to 95%, less than or equal to 90%, or less than or equal to 80%. Combinations of the above-referenced ranges are also possible (e.g., the material is optically transparent to a wavelength of light in one or more of the above-referenced ranges with a transparency of greater than or equal to 70% and less than or equal to 100%, greater than or equal to 80% and less than or equal to 99.9%, or greater than or equal to 90% and less than or equal to 99%). Other ranges are also possible. In some embodiments, the material is 100% transparent to one or more wavelengths of light in one or more of the ranges in the preceding paragraph. Transparency may be assessed by UV-vis spectroscopy.

[0183] In some embodiments, a device is described. In some embodiments, the device may comprise the apparatus described above. In some embodiments, the device comprises a microfluidic chip. The microfluidic chip may make up one or more components of the apparatus as described above (e.g., one or more of the liquid supply ports, liquid supply channels, waste ports, and / or waste channels may be part of a microfluidic chip). It is also possible for one or more of the components of the apparatus described above (e.g., one or more of the liquid supply ports, liquid supply channels, waste ports, and / or waste channels) to be disposed on a microfluidic chip.In some embodiments, a device described herein comprises the apparatus and further comprises a plurality of containers. As shown in FIG. 1C, a non-limiting exemplary device 100b comprises all the components of the apparatus 101 as shown in FIG. 1A. In some embodiments, the device 100b further comprises a plurality of containers 202.

[0184] The containers within a plurality of containers may have any of a variety of suitable configurations. For example, in some embodiments, one or more containers within the plurality of containers is a round-bottom (e.g., U-bottom) container. In some embodiments, one or more containers within the plurality of containers is a conical-bottom (e.g., V-bottom) container.

[0185] In some embodiments, one or more containers within a plurality of containers may comprise a coating. For example, one or more of the containers may comprise a coating disposed on an interior surface of the container (e.g., a bottom surface of the container, a side wall of the container, etc.). The coating may be disposed on the interior surface such that a liquid contained within the container will come into contact with the coating.

[0186] In some embodiments, one or more containers within the plurality of containers comprises a coating having any of a variety of suitable properties. For example, the coating may comprise an adhesion-promoting coating, an antifouling coating, and / or a selective capture coating. The adhesion-promoting coating may comprise fibronectin, poly-L-lysine (PLL), solubilized basement membrane matrix (e.g., Matrigel), vitronectin, and / or collagen. In some embodiments, the antifouling coating may comprise a PEGylated coating, a zwitterionic polymer, polyacrylamide, dextran, and / or hyaluronic acid. In some embodiments, the selective capture coating comprises an antibody. In some embodiments, the antibody may be configured to capture and / or capable of capturing a cell surface marker (e.g., a cell surface marker of a target cell type).

[0187] In some embodiments, the device may comprise a substrate 201, wherein the substrate comprises the plurality of containers 202. In some embodiments, each container in the plurality of containers is a well in a multi-well plate. In some embodiments, each container in the plurality of containers is a cell culture chamber. In some embodiments, one or more containers in the plurality of containers of the substrate may have any of the properties and / or characteristics described above (e.g., one or more of the containers may be a round-bottom container, and / or one or more of the containers may comprise a coating disposed on at least a portion of an internal surface thereof). In some embodiments, each of the containers in the plurality of containers of the substrate may have any of the properties and / or characteristics described above (e.g., each of the containers may be a round-bottom container, and / or each ofthe containers may comprise a coating disposed on at least a portion of an internal surface thereof).

[0188] In some embodiments, the substrate 201 comprising the plurality of containers 202 may be configured to be and / or capable of being added to and / or removed from the apparatus 101. In some embodiments, the apparatus 101 may be configured to receive and / or capable of receiving the substrate 201. In some embodiments, the apparatus 101 may comprise an opening shaped to receive the substrate 201. In some embodiments, the substrate 201 may be configured such that when the substrate 201 is added to the apparatus, the plurality of containers 202 become fluidically connected to the liquid supply ports 105 and / or waste removal ports 112 of the apparatus. For example, in some embodiments, each container in the plurality of containers may comprise an opening configured to form and / or capable of forming a connection with a liquid supply port in the plurality of liquid supply ports. In some embodiments, each container in the plurality of containers may comprise a fitting configured to form and / or capable of forming a connection with a liquid supply port and / or a portion of a liquid supply port comprising a fitting.

[0189] FIG. ID shows a non-limiting side-view schematic of a substrate 321 comprising a plurality of containers 322. In some embodiments, the substrate 321 is a multi- well plate. In some embodiments, the multi-well plate has a plate lid 323. The substrate may comprise additional components (e.g. fluidic components). For example, in the non-limiting embodiment shown in FIG. ID, each container in the plurality of containers 322 is in fluidic communication with a substrate liquid supply port in the plurality of substrate liquid supply ports 324 and a substrate waste disposal port in the plurality of substrate waste disposal ports 331. In some embodiments, the substrate may further comprise a gasket 325. In some embodiments, each port in the plurality of substrate liquid supply ports and / or plurality of substrate waste disposal ports may be configured to flow and / or capable of flowing a liquid into and / or flowing a waste from a container in the plurality of containers (e.g., via a channel and / or one or more other fluidic components placing such ports in fluidic communication with the containers).

[0190] In some embodiments, each port in the plurality of substrate liquid supply ports and / or the plurality of substrate waste disposal ports may be in fluidic communication with other components of the substrate. For example, FIG. IE shows an additional non-limiting sideview schematic view from a different perspective, showing two containers in the plurality of containers 322. In this exemplary embodiment, each container in the plurality of containers 322 is fluidically connected to a substrate liquid supply channel in the plurality of substrateliquid supply channels 326 via a substrate liquid supply port in the plurality of substrate liquid supply ports 324, and to a substrate waste removal channel in the plurality of substrate waste removal channels 332 via a substrate waste disposal port in the plurality of substrate waste disposal ports 331. In this exemplary embodiment, each container in the plurality of containers 322 is configured to become and / or capable of becoming fluidically connected to a liquid supply port in the plurality of liquid supply ports 105 and / or a waste removal port in the plurality of waste removal ports 112 in the apparatus 101, as shown in FIG. 1A. This may happen in any of a variety of ways. For example, in the non-limiting embodiment shown in FIG. IE, the substrate may comprise a liquid supply port connecting region 341, which is configured to connect and / or capable of connecting to (e.g. becoming in fluidic communication with) a liquid supply port in the plurality of liquid supply ports 105 in the apparatus 101, and a waste removal port connecting region 342, which is configured to connect and / or capable of connecting to (e.g. becoming in fluidic communication with) a waste removal port in the plurality of waste removal ports 112 in the apparatus 101. An additional top-view schematic drawing of a substrate comprising a plurality of containers is shown in FIG. IF.

[0191] As noted above, in some embodiments, each container in a plurality of containers may be configured to become and / or capable of becoming fluidically connected to a substrate liquid supply port and / or a substrate waste disposal port. The container may be configured to become and / or capable of becoming fluidically connected to a substrate liquid supply port and / or a substrate waste disposal port via any of a variety of suitable configurations. For example, the non-limiting embodiment shown in FIG. IE, each container in the plurality of containers 322 is configured to become and / or capable of becoming fluidically connected with a substrate liquid supply port in the plurality of substrate liquid supply ports 324, where the plurality substrate liquid supply ports 324 are positioned such that a liquid may be delivered to the containers from a position below the containers. In some embodiments, each container 322 is configured to become and / or capable of becoming fluidically connected with a substrate waste disposal port in the plurality of substrate waste disposal ports 331, where the plurality of substrate waste disposal ports 331 are positioned such that a waste may be removed from the containers 322 from a position below the containers.

[0192] FIG. 1G shows a cross-sectional schematic of a non-limiting configuration of a container within a plurality of containers. The cross-section through which FIG. 1G is taken includes the direction parallel to gravity (i.e., the top of the cross-section shown in FIG. 1G corresponds to the top of the container and the bottom of the cross-section shown in FIG. 1Gcorresponds to the bottom of the container). In some embodiments, as shown in FIG. 1G, a container 351 in a plurality of containers may be configured to become and / or capable of becoming fluidically connected with a substrate liquid supply port 352 in a plurality of substrate liquid supply ports, where the liquid delivery port 352 is positioned such that a liquid may be delivered to the container from a position adjacent the bottom of the container. In some embodiments, the container 351 is configured to become and / or capable of becoming fluidically connected to a waste disposal port 353 in a plurality of waste disposal ports, where the waste disposal port 353 is positioned such that a waste may be removed from the container 351 from a position adjacent to the top of the container.

[0193] FIG. 1H shows a top-view schematic of a non-limiting configuration of a container within a plurality of containers. In some embodiments, as shown in FIG. 1H, a container 361 in a plurality of containers may be configured to become and / or capable of becoming fluidically connected with a substrate liquid supply port 362 in a plurality of substrate liquid supply ports, where the substrate liquid supply port 362 is positioned such that a liquid may be delivered to the container from a position below the container and at and / or near the center of a bottom surface of the container. In some embodiments, the container 361 is configured to become and / or capable of becoming fluidically connected with one or more substrate waste disposal ports 363 in a plurality of substrate waste disposal ports, where the one or more substrate waste disposal ports are positioned such that a waste may be removed from the container from a position below the container and at and / or near a side wall of the container.

[0194] FIG. II shows a top- view schematic of a non-limiting configuration of a container within a plurality of containers. In some embodiments, as shown in FIG. II, a container 371 in a plurality of containers may be configured to become and / or capable of becoming fluidically connected with a substrate liquid supply port 372 in a plurality of substrate liquid supply ports and a substrate waste disposal port 373 within a plurality of substrate waste disposal port, where the substrate liquid supply port 372 and the substrate waste disposal port 373 are positioned tangentially to the container 371 (e.g., the substrate liquid supply port 372 and the substrate waste disposal port 373 may be disposed in one or more sidewalls thereof and be oriented such that liquid supplied thereby to the container 381 enters the container in a direction parallel to such sidewall(s)). In some embodiments, as shown in FIG. II, the substrate liquid supply port 372 and the substrate waste disposal port 373 are positioned on opposing sides of the container 371 (e.g., on opposing side walls of the container 371, or on opposite sides of a single, cylindrical side wall of the container 371). In some suchembodiments, the container 371 is configured to become and / or capable of becoming fluidically connected with the substrate delivery port 372 such that a liquid may be delivered to the container from a position adjacent the top of the container, adjacent the bottom of the container, and / or at a side of the container. In some embodiments, the container 371 is configured to become and / or capable of becoming fluidically connected with the substrate waste disposal port 373 such that a waste may be removed from the container from a position adjacent the top of the container, adjacent the bottom of the container, and / or at a side of the container. In some embodiments, the substrate liquid supply port and the substrate waste disposal port being positioned on opposing sides of the container may advantageously induce gentle swirling and / or mixing of a liquid contained within the container when a liquid is delivered to the container (e.g., via the substrate liquid supply port 372) and / or when a waste is removed from the container (e.g., via the substrate waste disposal port 373).

[0195] In some embodiments, the container may be configured to become and / or capable of becoming fluidically connected with two or more liquid delivery ports. FIG. 1 J shows a topview schematic of one such non-limiting configuration of a container within a plurality of containers. In some embodiments, as shown in FIG. 1J, a container 381 in a plurality of containers may be configured to become and / or capable of becoming fluidically connected with two or more substrate liquid supply ports 382a and 382b in a plurality of substrate liquid supply ports, where the one or more substrate liquid supply ports 382a and 382b are positioned tangentially to the container 381. In some such embodiments, the container 381 is configured to become and / or capable of becoming fluidically connected with the substrate delivery ports 382a and 382b such that a liquid may be delivered to the container from a position adjacent the top of the container, adjacent the bottom of the container, and / or at a side of the container. In some embodiments, the container 381 may be configured to become and / or capable of becoming fluidically connected with a substrate waste disposal port 383 in a plurality of substrate waste disposal ports, where the substrate waste disposal port 383 is positioned such that a waste can be removed from the container 381 to a position to a side of the container (e.g., the substrate waste disposal port may be positioned tangentially or otherwise and have this property). In some embodiments, the container 381 is configured to become and / or capable of becoming fluidically connected with the substrate waste disposal port 383 such that a waste may be removed from the container from a position adjacent the top of the container, adjacent the bottom of the container, and / or at a side of the container.

[0196] The position at which a container is configured to become and / or capable of becoming fluidically connected with a substrate liquid supply port(s) and / or a substrate wastedisposal port(s) may be chosen and / or adjusted based on a desired fluid flow within the container when a liquid is flowed into the container via the substrate liquid supply port and / or when a waste is flowed out of the container via the substrate waste disposal port. For example, FIG. IK shows a top-view schematic of a first non-limiting configuration 395a of a container 391 within a plurality of containers and a second non-limiting configuration 395b of a container 391 within a plurality of containers. In some embodiments, as shown in first configuration 395a and second configuration 395b, a container 391 in a plurality of containers may be configured to become and / or capable of becoming fluidically connected with a substrate liquid supply port 392 in a plurality of substrate liquid supply ports, where the substrate liquid supply port 392 is positioned such that a liquid may be delivered to the containers from a position below the containers, and the container 391 may be configured to become and / or capable of becoming fluidically connected with a substrate waste disposal port 393, where the substrate waste disposal port 393 is positioned such that a waste may be removed from the container 391 from a position below the container. The substrate liquid supply port 392 and the substrate waste disposal port 393 may be positioned at any of a variety of positions relative to each other; for example, the substrate liquid supply port 392 and the substrate waste disposal port 393 are located closer together in first configuration 395a than in second configuration 395b. Other configurations are also possible.

[0197] In some embodiments, the substrate 201 may have any or all of the properties as described for the apparatus above (e.g. biocompatibility, sterilizability, optical transparency, formed of and / or comprising a plastic, etc.).

[0198] In some embodiments, the device 100b may comprise a liquid reservoir. In some embodiments, the liquid reservoir may be in fluidic communication with the inlet port 102 of the apparatus 101. In some embodiments, the liquid reservoir may be configured to form and / or capable of forming a sterile and / or aseptic connection with the inlet port 102. In some embodiments in which the inlet port comprises a luer lock, the liquid reservoir may comprise a luer lock fitting configured to form and / or capable of forming a fluidic connection with an inlet port comprising a luer lock. In some embodiments in which an inlet port comprises a foil, the liquid reservoir may comprise a foil-puncturing member configured to puncture and / or capable of puncturing the foil and a component configured to form and / or capable of forming a fluidic connection with the inlet port. In some embodiments, in which the inlet port comprises a septum, the liquid reservoir may comprise a septum-puncturing member configured to puncture and / or capable of puncturing the septum and a component configured to form and / or capable of forming a fluidic connection with the inlet port. In someembodiments, the liquid reservoir may be configured to be and / or capable of being detached from the inlet port. In some embodiments, the liquid reservoir may be disposable.

[0199] The liquid reservoir may be configured to supply and / or capable of supplying any of a variety of suitable liquids. For example, in some embodiments, the liquid may comprise a pH-adjusting liquid. In some embodiments, the pH-adjusting liquid may comprise an acid, a base, and / or a buffer. In some embodiments, the liquid may comprise a cell culture media. The liquid may comprise other reagents. In some embodiments, a liquid reservoir that comprises one or more reagents is referred to herein as a reagent reservoir. In some embodiments, the liquid comprises one or more therapeutic agents. In some embodiments, the one or more therapeutic agents comprise a small molecule drug, a biologic, an antibody, an antibody fragment, a nucleic acid-based therapeutic, and / or a cell-based therapeutic. In some embodiments, the liquid comprises cell culture media and a therapeutic agent (e.g., any one of or any combination of the therapeutic agents described herein). It is also possible for the liquid to comprise cell-culture media (e.g., in addition to a therapeutic agent).

[0200] In some instances, the liquid may be chosen based on a desired application. As discussed in further detail below, in some embodiments, the liquid may be chosen in order to facilitate the automation of a particular experiment and / or cell-culture application.

[0201] A liquid (e.g., present in a liquid reservoir and / or supplied by a liquid reservoir) may have any of a variety of suitable temperatures. For example, in some embodiments, the liquid has a temperature of greater than or equal to 0 °C, greater than or equal to 2 °C, greater than or equal to 5 °C, greater than or equal to 10 °C, greater than or equal to 15 °C, greater than or equal to 20 °C, greater than or equal to 25 °C, greater than or equal to 30 °C, greater than or equal to 35 °C, or greater than or equal to 37 °C. In some embodiments, the liquid has a temperature of less than or equal to 40 °C, less than or equal to 37 °C, less than or equal to 35 °C, less than or equal to 30 °C, less than or equal to 25 °C, less than or equal to 20 °C, less than or equal to 15 °C, less than or equal to 10 °C, less than or equal to 5 °C, or less than or equal to 2 °C. Combinations of these ranges are also possible (for example, in some embodiments, the liquid may have a temperature of greater than or equal to 2 °C and less than or equal to 37 °C. In some embodiments, the liquid may have a temperature of greater than or equal to 0 °C and less than or equal to 40 °C, or greater than or equal to 5 °C and less than or equal to 35 °C). Other ranges are also possible.

[0202] In some embodiments, a liquid may be stored in a particular location or in particular conditions (e.g., at a particular temperature). For example, in some embodiments, the liquid may be refrigerated (e.g., the liquid may be stored in a refrigerator). In some embodiments, aliquid reservoir may be refrigerated and / or stored in a refrigerator. In some embodiments, a liquid may be stored in a refrigerator and / or a temperature-controlled environment in order to maintain a temperature which is any of the temperatures listed above and / or to maintain a temperature with a range of any of the temperatures listed above.

[0203] In some embodiments, the device 100b may comprise a waste reservoir. In some embodiments, the waste reservoir may be in fluidic communication with the waste port 115 of the apparatus 101. In some embodiments, the waste reservoir may be configured to form and / or capable of forming a sterile and / or aseptic connection with the waste port 115. In some embodiments in which the waste port comprises a luer lock, the waste reservoir may comprise a luer lock fitting configured to form and / or capable of forming a fluidic connection with a waste port comprising a luer lock. In some embodiments in which a waste port comprises a foil, the waste reservoir may comprise a foil-puncturing member configured to puncture and / or capable of puncturing the foil and a component configured to form and / or capable of forming a fluidic connection with the waste port. In some embodiments, in which the waste port comprises a septum, the waste reservoir may comprise a septum-puncturing member configured to puncture and / or capable of puncturing the septum and a component configured to form and / or capable of forming a fluidic connection with the waste port. In some embodiments, the waste reservoir may be configured to be and / or capable of being detached from the waste port. In some embodiments, the waste reservoir may be disposable.

[0204] In some embodiments, the device comprises one or more sensors. Such sensors may be positioned in one or more locations in which it may be desirable to sense a property of the device and / or a property of a liquid present in the device. For instance, sensors may be present in one or more of the containers in the plurality of containers, in one or more of the liquid supply channels in the plurality of liquid supply channels, and / or in one or more of the waste removal channels in the plurality of waste removal channels. One or more sensors may also be positioned in a location in fluidic communication with one or more such locations. In such embodiments, liquid may be removed from the relevant portion of the device and supplied to the location comprising the sensor.

[0205] In some embodiments, one or more sensors may be placed external and / or adjacent to the device. For example, in some embodiments, an optical sensor may be placed external and / or adjacent to the device and configured to visually monitor and / or capable of visually monitoring the device.

[0206] Non-limiting examples of sensors that may be included in the devices described herein include pH sensors, dissolved oxygen sensors, dissolved carbon dioxide sensors,sensors configured to detect and / or capable of detecting cell viability, cell concentration, humidity, pressure, temperature, and / or viscosity. In some embodiments, one or more sensors may be configured to measure and / or capable of measuring the concentrations of any of a variety of nutrients and / or metabolites (e.g. lactate sensors, glucose sensors). In some embodiments, the one or more sensors may comprise an optical, electrochemical, and / or acoustic sensor. In some embodiments, the device may comprise a timer. In some embodiments, the device may comprise two or more sensors. In some embodiments, two or more of the sensors may be of the same type (e.g. the device may comprise two or more pH sensors or two or more temperature sensors, etc.). In some embodiments, two or more of the sensors may be of different types (e.g. the device may comprise one or more pH sensors and one or more temperature sensors, etc.).

[0207] pH sensors may be optical sensors and / or electrochemical sensors (e.g., ion-sensitive field-effect transistors, solid-state polymer membranes, capacitive sensors, sensors comprising carbon nanotubes, and / or enzymatic sensors). Optical sensors may measure the pH by measuring the optical properties of a pH- sensitive indicator dye and calculating the pH therefrom. Electrochemical sensors may measure the pH by measuring the potential, current, and / or capacitance of a liquid and calculating the pH therefrom. In some embodiments, a pH sensor is capable of and / or configured to measure and / or capable of measuring a pH value in a particular range (e.g., between 5.5 and 8.5).

[0208] Dissolved-oxygen sensors may comprise optical sensors (e.g. fluorescence sensors, colorimetric sensors, and / or surface plasmon resonance sensors) and / or electrochemical sensors (e.g., microfabricated Clark-type electrodes, thin-film platinum electrodes, screen-printed electrodes, and / or polymer electrolyte-based electrodes). Optical sensors may measure the dissolved-oxygen content by measuring the absorption, fluorescence, and / or refractive index of a liquid and calculating the dissolved oxygen content therefrom.

[0209] Electrochemical sensors may measure the dissolved oxygen content by measuring the potential, current, and / or capacitance of a liquid and calculating the dissolved oxygen content therefrom. In some embodiments, a dissolved-oxygen sensor is capable of and / or configured to measure and / or capable of measuring a dissolved-oxygen value in a particular range (e.g., between 0% and 100%).

[0210] Sensors for carbon dioxide may comprise optical and / or electrochemical sensors (e.g., potentiometric and / or amphoteric sensors, ion-sensitive field-effect transistors, solid-state electrolyte sensors, and / or enzymatic sensors). Optical sensors may measure the carbon dioxide content by measuring the absorption, fluorescence, and / or refractive index of a liquidand calculating the carbon dioxide content therefrom. Electrochemical sensors may measure the carbon dioxide content by measuring the potential, current, and / or capacitance of a liquid and calculating the carbon dioxide content therefrom.

[0211] Sensors for cell concentration may comprise optical (e.g., optical density sensors, bioreflectance sensors, fluorescence sensors, and / or near-infrared spectroscopy sensors), electrical (e.g., electrical impedance sensors, dielectric spectroscopy sensors, RF impedance sensors, and / or capacitance-based sensors), and / or acoustic sensors (e.g., surface acoustic wave sensors, bulk acoustic wave sensors). Such sensors may measure the optical, electrical, and / or acoustic properties of the liquid and calculate the cell concentration therefrom.

[0212] Sensors for cell viability may comprise optical (e.g., fluorescence, reflectance) and / or electrical (e.g., electrical impedance sensors, capacitance-based sensors, potentiometric sensors, and / or conductivity sensors). Such sensors may measure the optical and / or electrical properties of the liquid and calculate the cell concentration therefrom.

[0213] Sensors for nutrients and metabolites may comprise optical (e.g., fluorescent NADH sensors and / or fluorescent NADPH sensors) and / or electrochemical (e.g., ion-selective electrodes, conductivity sensors, amperometric glucose sensors, and / or amperometric and / or potentiometric lactate sensors). Such sensors may measure the optical and / or electrochemical properties of the liquid and calculate the amount of a nutrient and / or metabolite therein therefrom.

[0214] Sensors for biological products may comprise optical (e.g., surface plasmon resonance sensors, fluorescence sensors, surface-enhanced Raman scattering sensors, interferometric sensors, colorimetric sensors, and / or luminescence sensors) and / or electrical (e.g., field-effect transistors, electrochemical impedance spectroscopy sensors, dielectric spectroscopy sensors, capacitive sensors, electrical impedance sensors, and / or sensors comprising carbon nanotubes) sensors. Such sensors may measure the optical and / or electrical properties of the liquid and calculate the amount of a cell product therein therefrom.

[0215] Temperature sensors may comprise optical (e.g., fluorescence sensors and / or luminescence sensors) and / or electrical (e.g., resistance temperature detectors) sensors. Such sensors may measure the optical and / or electrical properties of the liquid and calculate the temperature therefrom.

[0216] Pressure sensors may comprise optical (e.g., optical pressure sensors) and / or electrical (e.g., capacitive pressure sensors) sensors.Humidity sensors may comprise optical (e.g., absorbance sensors and / or reflectionbased sensors) and / or electrical (e.g., capacitive sensors, resistance sensors, conductivity sensors, and / or dielectric sensors).

[0217] Viscosity sensors may comprise electrical sensors (e.g., capacitance-based sensors and / or electrical impedance sensors).

[0218] Further examples of sensors that may be employed to sense one or more properties of a liquid media include optical sensors (e.g., transmittance sensors and / or reflectance sensors) and electrical sensors (e.g., conductivity sensors and / or capacitance-based sensors).

[0219] In some embodiments, the device may comprise a timer. In some embodiments, the timer may be configured to provide and / or capable of providing a signal at a particular time interval. In some embodiments, the time interval may be set by a user.

[0220] In some embodiments, the device further comprises a controller. In some embodiments, the controller provides and / or receives signals (e.g. electrical signals) from the device. In some embodiments, the controller provides and / or receives signals from one or more locations external and / or adjacent to the device. In some embodiments, the controller receives signals from one or more sensors in the device. In some embodiments, the controller directs the flow of liquid and / or waste within the device based on one or more signals received from the one or more sensors. In some embodiments, the controller directs the flow of a liquid and / or waste within the device by providing a signal to one or more locations in the device (e.g. providing a signal to a pump, a valve, etc.).

[0221] In some embodiments, the controller controls one or more pumps within the device (e.g. the liquid pump, the waste pump). In some embodiments, the controller may increase and / or decrease the flow rate of the liquid pump and / or the waste pump. In some embodiments, the controller may increase and / or decrease the flow rate of the liquid pump and / or the waste pump based on one or more signals received from the one or more sensors. In some embodiments, the controller may turn the liquid pump and / or the waste pump on and / or off. In some embodiments, the controller may turn the liquid pump and / or the waste pump on and / or off based on one or more signals received from the one or more sensors. Further discussion of how the controller may increase and / or decrease the flow rate based on one or more signals from one or more sensors is included below.

[0222] In some embodiments, the controller controls one or more valves within the device (e.g. one or more valves in the plurality of liquid valves, one or more valves in the plurality of waste valves). In some embodiments, the controller may change the configuration of one or more valves in response to one or more signals received from one or more sensors in thedevice. In some embodiments, the controller may open one or more valves. In some embodiments, the controller may close one or more valves. In some embodiments, the controller may throttle one or more valves. Further discussion of how the controller may alter the configuration of the valves based on one or more signals from one or more sensors is included below.

[0223] In some embodiments, an apparatus as described herein may comprise two or more inlet ports and / or two or more waste ports. These ports may have any of the characteristics of inlet ports and / or waste ports as described above. In some embodiments, each waste port may be in fluidic communication with a location configured to receive and / or capable of receiving waste. In some locations, the location configured to receive and / or capable of receiving waste may be a waste reservoir. In some embodiments, each inlet port may be in fluidic communication with a location configured to supply and / or capable of supplying a liquid. In some embodiments, the location configured to supply and / or capable of supplying a liquid may be a liquid reservoir and / or a liquid supply source as described elsewhere herein. In some embodiments, the two or more inlet ports may be configured to supply and / or capable of supplying liquids to a container in the plurality of containers. In some embodiments, the two or more inlet ports may be configured to supply and / or capable of supplying the same liquid to the container. In some embodiments, the two or more inlet ports may be configured to supply and / or capable of supplying different liquids to the container. In some embodiments, each inlet port may be in fluidic communication with a liquid reservoir containing different liquids. In some embodiments, each inlet port may be in fluidic communication with a liquid reservoir containing the same liquid. In some embodiments, in which there are more than two inlet ports, two or more inlet ports may be in fluidic communication with a liquid reservoir containing a first liquid and one or more other ports may be in fluidic communication with a liquid reservoir containing a second liquid. The inlet ports may have any of the properties and characteristics of inlet ports as described above (e.g. the inlet ports may comprise a luer lock, etc.). The liquid reservoirs may have any of the properties and characteristics of liquid reservoirs as described above (e.g. the liquid reservoirs may comprise a luer lock fitting, etc.).

[0224] In some embodiments, the two or more inlet ports may be configured to provide a liquid to the same liquid supply channel and / or plurality of liquid supply channels. As a nonlimiting example, the apparatus may comprise a first inlet port, a second inlet port, and a plurality of liquid supply channels comprising an upstream end and a downstream end. In some embodiments, each supply channel in the plurality of liquid supply channels may bedownstream from and in fluidic communication with both the first inlet port and the second inlet port. In some embodiments, the first inlet port and the second inlet port may each be in fluidic communication with a different plurality of liquid supply channels (e.g. the first inlet port may be in fluidic communication with a first plurality of liquid supply channels, the second inlet port may be in fluidic communication with a second plurality of supply channels).

[0225] In some embodiments, the apparatus may comprise one or more input valves. In some embodiments, each input valve maybe positioned fluidically between each of the one or more inlet ports and a plurality of liquid supply channels. In some embodiments, each input valve in the plurality of input valves may be configured to direct and / or capable of directing a liquid from one of the inlet ports to one or more liquid supply channels in a plurality of liquid supply channels. The input valves may direct liquid therefrom to a liquid supply channel via a component that fluidically connects the two (e.g., via a channel to a liquid valve upstream from the liquid supply channel). Use of a liquid pump to apply pressure that causes downstream flow may cause liquid to flow from the input valve through any such components (e.g., through a channel fluidically connecting the input port to a liquid valve, and through the liquid valve) to the liquid supply channel. When any valves in such a flow path are open, application of such pressure may cause liquid to flow therethrough (e.g., when both an input valve and a liquid valve are open, liquid may flow from an inlet port, through the input valve, to the liquid valve, and through the liquid valve to a liquid supply channel).

[0226] In some embodiments in which an apparatus described herein comprises two or more inlet ports and a plurality of liquid supply channels, the apparatus may comprise two or more input valves configured to direct and / or capable of directing the liquid from each inlet port to the plurality of liquid supply channels. Such input valves each may be fluidically connected to the liquid supply channels and / or one or more components upstream from the liquid supply channels (e.g., liquid valves upstream from the liquid supply channels). This fluidic connection may be via, e.g., channels connecting the input valves to the liquid supply channels or the components upstream therefrom. When an input valve is open, application of pressure via a liquid pump may cause liquid to flow from the input valve to the liquid supply channel and / or a liquid valve upstream therefrom. The identity of the inlet port(s) supplying any particular liquid supply channel may accordingly be controlled by opening and closing the input valves and the liquid valve upstream therefrom.

[0227] In some embodiments, an apparatus as described herein may comprise two or more modules. In some embodiments, the apparatus may be configured to supply and / or capableof supplying a liquid to two or more separate pluralities of containers, wherein each plurality of containers is in fluidic communication with one of the modules. For example, FIG. 2A shows a device 200a comprising an apparatus 101a configured to supply and / or capable of supplying liquid to two separate pluralities of containers. In some embodiments, the apparatus 101a may comprise a chip. In some embodiments, the apparatus 101a may be configured to supply and / or capable of supplying a liquid to two or more separate pluralities of containers. In some embodiments, as shown in FIG. 2 A, the apparatus may comprise a first inlet port 102a and a second inlet port 102b. In some embodiments, the first inlet port 102a may be configured to supply and / or capable of supplying a liquid to the first plurality of containers and the second inlet port 102b may be configured to supply and / or capable of supplying a liquid to the second plurality of containers. In some embodiments, the first and second plurality of containers may not be part of the device 200a. In some embodiments, the first and second plurality of containers may each be part of a separate component which is configured to be and / or capable of being compatible with the apparatus such that the apparatus can supply a liquid to and / or remove a waste from each plurality of containers. In some embodiments, the apparatus may comprise the plurality of containers. In some embodiments, the first inlet port 102a may be in fluidic communication with a location configured to supply and / or capable of supplying a first liquid. In some embodiments, the second inlet port 102b may be in fluidic communication with a location configured to supply and / or capable of supplying a second liquid. Either or both such locations may be a liquid supply source as described elsewhere herein. In some embodiments, the first liquid and the second liquid are different liquids. In some embodiments, the first liquid and the second liquid are the same liquid. The first inlet port and the second inlet port may have any of the properties and characteristics of inlet ports as described above (e.g. the first inlet port and the second inlet port may comprise a luer lock, etc.).

[0228] In some embodiments, each module may comprise any of the apparatus and / or device components described above. For example, in some embodiments, the apparatus 101a may comprise a first plurality of liquid supply channels and a second plurality of liquid supply channels. In FIG. 2 A, as described in further detail below, these liquid supply channels are positioned fluidically between the liquid valves and the liquid supply ports. They are covered by the upper surface of the apparatus 101a in FIG. 2A, but are present therebeneath. In some embodiments, each liquid supply channel in each plurality of liquid supply channels may comprise an upstream end and a downstream end. In some embodiments, the upstream end of each liquid supply channel in the first plurality of liquid supply channels may beconfigured to receive and / or capable of receiving a liquid from the first inlet port 102a. In some embodiments, the upstream end of each liquid supply channel in the second plurality of liquid supply channels may be configured to receive and / or capable of receiving a liquid from the second inlet port 102b. In some embodiments, each liquid supply channel in each plurality of liquid supply channels may have a relatively small dead volume. For example, in some embodiments, each liquid supply channel in each plurality of liquid supply channels may have a dead volume as described above for the liquid supply channels of the apparatus as shown in FIG. 1A.

[0229] It should be noted that the inlet ports 102a and 102b shown in FIG. 2 A are covered by liquid supply sources (and, in FIG. 2A, taking the form of liquid reservoirs). Therefore, it should be understood that FIG. 2A depicts liquid supply sources disposed on and covering the inlet ports 102a and 102b, which are not visible in FIG. 2A.

[0230] In some embodiments, the apparatus 101a comprises a first plurality of liquid valves 104a and a second plurality of liquid valves 104b. In some embodiments, each liquid valve in the first plurality of liquid valves is positioned fluidically between the upstream end of a liquid supply channel in the first plurality of liquid supply channels and the first inlet port. In some embodiments, each liquid valve in the second plurality of liquid valves is positioned fluidically between the upstream end of a liquid supply channel in the second plurality of liquid supply channels and the second inlet port. In some embodiments, each plurality of liquid valves may have any of the properties and characteristics of liquid valves as described above.

[0231] In some embodiments, each valve in each plurality of liquid valves may be configured to be and / or capable of being operated independently. For example, in some embodiments, one or more valves in the first plurality of liquid valves may be in an open position while one or more other valves in the first plurality of liquid valves may be in a closed position. In some embodiments, one or more liquid valves in the first plurality of liquid valves may be throttled while one or more other liquid valves in the first plurality of liquid valves are not throttled and / or one or more other liquid valves in the first plurality of liquid valves are throttled to a different level. In some embodiments, all liquid valves in the first plurality of liquid valves are configured to be and / or capable of being operated simultaneously. In some embodiments, the position of each valve in the first plurality of liquid valves may be modified independently and / or in concert with one or more other valves in the first plurality of liquid valves. In some embodiments, the position of each valve in the first plurality of liquid valves may be modified based on information from a sensor whichmay be internal and / or external to the device and may be used by the controller to modify the position of the valve. In some embodiments, one or more valves in the second plurality of liquid valves may be in an open position while one or more other valves in in the second plurality of liquid valves may be in a closed position. In some embodiments, one or more liquid valves in the second plurality of liquid valves may be throttled while one or more other liquid valves in the second plurality of liquid valves are not throttled and / or one or more other liquid valves in the second plurality of liquid valves are throttled to a different level. In some embodiments, all liquid valves in the second plurality of liquid valves are configured to be and / or capable of being operated simultaneously. In some embodiments, the position of each valve in the second plurality of liquid valves may be modified independently and / or in concert with one or more other valves in the second plurality of liquid valves. In some embodiments, the position of each valve in the second plurality of liquid valves may be modified based on information from a sensor which may be internal and / or external to the device and may be used by the controller to modify the position of the valve. Further discussion of how sensors may be used to inform the modification of valve positions is included below.

[0232] In some embodiments, the valves in the first plurality of liquid valves may be operated independently from the valves in the second plurality of liquid valves. In some embodiments, the valves in the first plurality of liquid valves may be operated simultaneously with the valves in the second plurality of liquid valves.

[0233] In some embodiments, there may be additional valves located fluidically between the upstream end of a liquid supply channel in the plurality of liquid supply channels and the inlet port. For example, in some embodiments, there may be additional ports and / or valves located fluidically between the upstream end of a liquid supply channel in each plurality of liquid supply channels and the inlet port. A non-limiting example of such a configuration can be seen in FIG. 2A, in which additional inlet ports 120a and selector valves 130a are positioned fluidically between the liquid valves 104a and the inlet port 102a and additional inlet ports 120b and selector valves 130b are positioned fluidically between the liquid valves 104b and the inlet port 102b. In some embodiments, there may be additional valves located fluidically between the upstream end of a liquid supply channel and an inlet port. Such valves may have any of the properties or characteristics as described for the liquid valves above (e.g. such valves may be turning valves, etc.).

[0234] In some embodiments, the apparatus 101a may comprise one or more pluralities of liquid supply ports. In some embodiments, each liquid supply port in a first plurality ofliquid supply ports may be downstream from and in fluidic communication with the downstream end of a liquid supply channel in the first plurality of liquid supply channels. In some embodiments, each liquid supply port in a second plurality of liquid supply ports may be downstream from and in fluidic communication with the downstream end of a liquid supply channel in the second plurality of liquid supply channels. In some embodiments, each liquid supply port is configured to supply and / or capable of supplying a container within the plurality of containers with a liquid. For example, in some embodiments, each liquid supply port in the first plurality of liquid supply ports is configured to supply and / or capable of supplying a container within a first plurality of containers with a liquid, and each liquid supply port in the second plurality of liquid supply ports is configured to supply and / or capable of supplying a container in the second plurality of containers with a liquid. In some embodiments, each liquid supply port may comprise a fitting. In some embodiments, the fitting may be configured to form and / or capable of forming a connection with an opening and / or complementary fitting in a container in the plurality of containers.

[0235] In some embodiments, the apparatus 101a may comprise one or more liquid pumps. For example, in FIG. 2 A, the apparatus 101a comprises a first liquid pump 106a and a second liquid pump 106b. In some embodiments, the first liquid pump 106a may be configured to pump and / or capable of pumping a liquid from the first inlet port, through the first plurality of liquid valves, through the first plurality of liquid supply channels, and to the first plurality of liquid supply ports. In some embodiments, the second liquid pump 106b may be configured to pump and / or capable of pumping a liquid from the second inlet port, through the second plurality of liquid valves, through the second plurality of liquid supply channels, and to the second plurality of liquid supply ports. In some embodiments, the first liquid pump 106a and / or the second liquid pump 106b may be disposed on the apparatus 101a. In some embodiments, the first liquid pump 106a and / or the second liquid pump 106b may be removable from the apparatus 101a. The first liquid pump and / or the second liquid pump may have any of the properties and characteristics of liquid pumps as described above.

[0236] In some embodiments, the apparatus 101a may comprise a first plurality of waste removal channels and a second plurality of waste removal channels. In FIG. 2A, as described in further detail below, waste removal channels are positioned fluidically between the waste removal ports and the waste valves. They are covered by the upper surface of the apparatus 101a in FIG. 2 A, but are present therebeneath. In some embodiments, each waste removal channel in each plurality of waste removal channels may have an upstream end and a downstream end. In some embodiments, each waste removal channel in the plurality ofwaste removal channels may have a relatively small dead volume. For example, in some embodiments, each waste removal channel in the plurality of waste removal channels may have a dead volume as described above for a waste removal channel in apparatus 101 as shown in FIG. 1A.

[0237] In some embodiments, the apparatus 101a may comprise one or more pluralities of waste removal ports. In some embodiments, each waste removal port in a first plurality of waste removal ports may be upstream from and in fluidic communication with the upstream end of a waste removal channel in the first plurality of waste removal channels. In some embodiments, each waste removal port in the second plurality of waste removal ports may be upstream from and in fluidic communication with the upstream end of a waste removal channel in the second plurality of waste removal channels. In some embodiments, each waste removal port in the first plurality of waste removal ports may be configured to receive and / or capable of receiving waste from a container in the first plurality of containers. In some embodiments, each waste removal port in the second plurality of waste removal ports may be configured to receive and / or capable of receiving waste from a container in the second plurality of containers. Any of the waste removal ports in the plurality of waste removal ports may have any of the properties and characteristics described above for liquid supply ports (e.g. any of the waste removal ports may comprise a fitting, etc.).

[0238] In some embodiments, the apparatus 101a may comprise a waste port 115a upstream from and in fluidic communication with a location configured to receive and / or capable of receiving waste. In some embodiments, the location configured to receive and / or capable of receiving waste is a waste reservoir. The waste port may have any of the properties and characteristics described above for the inlet port (e.g. the waste port may comprise a luer lock, etc.). The waste reservoir may have any of the properties and characteristics described above for the liquid reservoir (e.g. the waste reservoir may comprise a complementary luer lock fitting, etc.).

[0239] In some embodiments, the apparatus 101a may comprise one or more waste valves. In some embodiments, the apparatus comprises a first waste valve 114a and a waste valve 114b. In some embodiments, the first waste valve 114a is positioned fluidically between a downstream end of each waste removal channel in the first plurality of waste removal channels and the waste port 115a. In some embodiments, the second waste valve is positioned fluidically between a downstream end of each waste removal channel in the second plurality of waste removal channels and the waste port 115a. In some embodiments, the apparatus 101a may comprise a second waste port. In some embodiments, the secondwaste valve 114b may be positioned fluidically between a downstream end of each waste removal channel in the plurality of waste removal channels and the second waste port. In some embodiments, the apparatus 101a may comprise a plurality of waste valves. In some embodiments, the apparatus 101a may comprise a first plurality of waste valves, in which each waste valve is positioned fluidically between an upstream end of a waste removal channel in the plurality of waste removal channels and the waste port. In some embodiments, the apparatus 101a may comprise a second plurality of waste valves, in which each waste valves is positioned fluidically between an upstream end of a waste removal channel in the plurality of waste removal channels and the waste port. The waste valves may have any of the properties and characteristics described above for liquid valves (e.g. the waste valves may be configured to be and / or capable of being operated independently, etc.).

[0240] In some embodiments, the apparatus 101a may comprise one or more waste pumps. For example, in FIG. 2 A, the apparatus 101a comprises a first waste pump 116a configured to pump and / or capable of pumping waste from a waste removal port in the first plurality of waste removal ports, through a waste removal channel in the first plurality of waste removal channels, through the first waste valve waste valve, and to the waste port. The apparatus 101a may comprise a second waste pump 116b configured to pump and / or capable of pumping waste from a waste removal port in the second plurality of waste removal ports, through a waste removal channel in the second plurality of waste removal channels, through the second waste valve and to the waste port. In some embodiments, the first waste pump 116a and / or the second waste pump 116b may be disposed on the apparatus 101a. Each waste pump may have any of the properties and characteristics described above for the liquid pump. Each waste pump and each liquid pump may each have different volumes per pump cycle and / or maximum flow rates within the above-referenced ranges. Each waste pump and each liquid pump may have the same volume per pump cycle and / or maximum flow rate within the above-referenced ranges.

[0241] In some embodiments, a device is described. In some embodiments, the device may comprise the apparatus 101a in FIG. 2A, described above. For example, in some embodiments, the device comprises the apparatus and further comprises one or more pluralities of containers. As shown in FIG. 2B, a non-limiting exemplary device 200b comprises all the components of the device 200a as shown in FIG. 2A. In some embodiments, the device 200b further comprises a first plurality of containers 202a and a second plurality of containers 202b. In some embodiments, the device may comprise a first substrate 201a, wherein the substrate comprises the first plurality of containers 202a, and asecond substrate 201b, wherein the substrate comprises the second plurality of containers 202b. In some embodiments, each container in the first plurality of containers and / or each container in the second plurality of containers is a well in a multi-well plate. In some embodiments, each container in the first plurality of containers and / or each container in the second plurality of containers is a cell culture chamber.

[0242] In some embodiments, the first substrate 201a comprising the first plurality of containers 202a and / or the second substrate 201b comprising the second plurality of containers 202b may be configured to be and / or capable of being added to and / or removed from the apparatus 101a. In some embodiments, the apparatus may be configured to receive and / or capable of receiving the first substrate 201a and / or the second substrate 201b. In some embodiments, the apparatus may comprise an opening shaped to receive the first substrate 201a and / or an opening shaped to receive the second substrate 201b. In some embodiments, the first substrate 201a may be configured such that when the first substrate 201a is added to the apparatus, the first plurality of containers 202a become fluidically connected to the first plurality of liquid supply ports 105a and / or the first plurality of waste removal ports 112a of the apparatus. In some embodiments, the second substrate 201b may be configured such that when the second substrate 201b is added to the apparatus, the second plurality of containers 202b become fluidically connected to the second plurality of liquid supply ports 105b and / or the second plurality of waste removal ports 112b of the apparatus. For example, in some embodiments, each container in the first plurality of containers may comprise an opening configured to form and / or capable of forming a connection with a liquid supply port in the first plurality of liquid supply ports and / or each container in the second plurality of containers may comprise an opening configured to form and / or capable of forming a connection with a liquid supply port in the second plurality of liquid supply ports. In some embodiments, each container in the second plurality of containers may be configured to form and / or capable of forming a connection with a waste removal port in the first plurality of waste removal ports and / or each container in the second plurality of containers may comprise an opening configured to form and / or capable of forming a connection with a waste removal port in the second plurality of the waste removal ports. In some embodiments, each opening in each plurality of containers may be configured to form and / or capable of forming a connection with a liquid supply port and / or a waste removal port may comprise a fitting.

[0243] In some embodiments, such as the non-limiting embodiment as shown in FIG. 10, a device as described herein may comprise an apparatus 101a, one or more substratescomprising a plurality of containers (e.g. the plurality of containers 202a), and one or more liquid reservoirs (for example, the liquid reservoir 301a).

[0244] The devices and apparatuses as described herein may be used for a variety of applications. For example, in some embodiments, any the devices and methods may be used for cell culture and / or for performing any of a variety of experiments on biological cells. Cell culture may comprise growing cells in a device described herein. For instance, cells may be present in a cell-culture medium in a device described herein and one or more properties of the device may be selected to promote cell growth. The cells being cultured may be adherent (e.g., to a component of a device described herein). In some embodiments, the cells may be part of an adherent monolayer (e.g., 2D monolayer). In some embodiments, as noted above, the cells may be part of a three-dimensional cell culture (e.g., a multicellular aggregate, a spheroid, an organoid, a tissue-like construct, and / or another self-organized or engineered three-dimensional structure comprising biological cells). In some embodiments, the containers may comprise cell-culture chambers. In some embodiments, the substrate comprising the chambers (e.g. the substrate 201 comprising containers 202 in FIG. IB) may be a multi-well plate comprising a plurality of cell culture chambers.

[0245] In some embodiments, the devices and apparatuses described herein may be configured to be and / or capable of being used as part of a larger experimental platform comprising other components. For example, in some embodiments, any of the devices or apparatuses described herein may be configured to be and / or capable of being used as part of a larger cell culture device. In some embodiments, the devices and apparatuses described herein may be configured to be and / or capable of being used as part of an incubator. In some embodiments, the devices and apparatuses described herein may be placed within a larger experimental platform, such as an incubator.

[0246] In some embodiments, the devices and apparatuses described herein may be positioned within an instrument. In some embodiments, the instrument may comprise an optical detector. In some embodiments, the optical detector may comprise a microscope, a light source, and / or a fluorescent light source. In some embodiments, the optical detector may be configured to provide and / or capable of providing a signal (e.g. an electrical signal) to the controller in the device. In some embodiments, the instrument may comprise other detectors and / or sensors. In some embodiments, the other detectors and / or sensors may be configured to provide and / or capable of providing a signal to the controller in the device.

[0247] In some embodiments, methods for operating the devices disclosed above are described. In some embodiments, a method for supplying a liquid to a container in a pluralityof containers is described. A non-limiting exemplary method is shown in FIG. 3A. In some embodiments, a method for supplying a container in the plurality of containers with a liquid comprises, in any of the devices described above, flowing the liquid from a liquid supply source to and through the inlet port (step 403), flowing the liquid from the inlet port to and through a liquid valve in the plurality of liquid valves (step 404), flowing the liquid from the liquid valve to and through a liquid supply channel in the plurality of liquid supply channels (step 405), flowing the liquid from the liquid supply channel to and through a liquid supply port in the plurality of liquid supply ports (step 406), and flowing the liquid from the liquid supply port into the container in the plurality of containers (step 407).

[0248] In some embodiments, the liquid supply source may comprise a liquid reservoir, which may have any of the properties of a liquid reservoir as described above.

[0249] In some embodiments, in which the device comprises at least one sensor, the method for supplying a liquid to a container in the plurality of containers may comprise performing one or more measurements using one or more sensors (optional step 408) and / or obtaining a measurement from a sensor (optional step 401). In some embodiments, the method further comprises flowing the liquid into a container in the plurality of containers in an amount determined based on the one or more signals generated by the one or more sensor measurements. In some embodiments, one or more sensors in the device may send a signal to a controller (optional step 409). In some embodiments, the controller may use the one or more signals to determine an amount by which to change the flow rate of the liquid pump (optional step 402). In some embodiments, the controller may use the one or more signals to determine a way in which to alter the configuration of one or more valves in the plurality of liquid valves (optional step 402). In some embodiments, the method further comprises flowing a liquid to a container in the plurality of containers in an amount based on one or more sensor measurements. In some embodiments, the method may comprise flowing a liquid to two or more containers in the plurality of liquid containers based on one or more sensor measurements. In some embodiments, flowing the liquid to one or more containers in the plurality of containers may be achieved by the controller modifying the flow rate through the pump and / or the configuration of one or more valves in the plurality of liquid valves.

[0250] In some methods, one or more steps are performed prior to flowing a liquid into a container in a plurality of containers. For instance, in some embodiments, the container contains a starting liquid that it would be desirable to remove therefrom prior to flowing the liquid thereinto. In such embodiments, prior to flowing the liquid into the container, the starting liquid may be flowed to a waste receiving location. This may be effected by flowingthe starting liquid from the container to and through a waste removal port in the plurality of waste removal ports, flowing the starting liquid from the waste removal port to and through a waste removal channel in the plurality of waste removal channels, flowing the starting liquid from the waste removal channel to and through a waste valve in a plurality of waste valves, flowing the starting liquid from the waste valve to and through a waste port, and, finally, flowing the starting liquid from the waste port to a waste receiving location. The starting liquid may be any of a variety of liquids, one non-limiting example of which is cell-culture media (e.g., cell-culture media employed to grow cells and / or perform experiments prior to the use of the container for containing the liquid), and another non-limiting example of which is a buffer (e.g., phosphate-buffered saline employed to store, wash, and / or transport cells and / or perform experiments prior to the use of the container for containing the liquid).

[0251] In some embodiments, one or more steps are performed after flowing a liquid into a container in a plurality of containers. As one example, some methods comprise incubating the liquid in the container. During such incubation, one or more properties of the liquid (e.g., cell viability, cell morphology, impedance, fluorescence) may be sensed.

[0252] In some embodiments, in which the device comprises two or more pluralities of containers and one or more sensors, the method may further comprise supplying a first liquid to a first plurality of containers in an amount determined based on a first sensor measurement and supplying a second liquid to a second plurality of containers based on a second sensor measurement. In some embodiments, the first liquid and the second liquid comprise the same liquid. In some embodiments, the first liquid and the second liquid comprise different liquids. In some embodiments, the method may comprise supplying a first liquid to a container in the first plurality of containers in an amount determined based on a first sensor measurement and supplying a second liquid to a container in the second plurality of containers based on a second sensor measurement. In some embodiments, the first sensor measurement and the second sensor measurement may be the same sensor measurement. In some embodiments, the first sensor measurement and the second sensor measurement may be different sensor measurements. In some embodiments, the one or more sensors in the device may send a signal to a controller. In some embodiments, the controller may use the one or more signals to determine an amount by which to change the flow rate of a first liquid pump and / or a second liquid pump. In some embodiments, the controller may use the one or more signals to determine a way in which to alter the configuration of one or more valves in a first plurality of liquid valves and / or a second plurality of liquid valves.The liquid may be any of a variety of suitable liquids. For example, in some embodiments, the liquid may be a cell culture media and / or a pH-adjusting liquid (e.g. an acid, a base, a buffer). In some embodiments, the liquid may comprise a therapeutic agent (e.g., a small-molecule drug, a biologic, an antibody, an antibody fragment, a nucleic acidbased therapeutic, and / or a cell-based therapeutic, as described above) and / or cell-culture media. The sensor measurements in any of the methods described above may comprise measurements made by any of a variety of suitable sensors. The sensors may comprise any of the sensors described above (e.g. a pH sensor, a carbon dioxide sensor, etc.). In some embodiments, the sensor may comprise an optical detector. In some embodiments, the sensor (e.g. the optical detector) may be external to the device. In some embodiments, the sensor measurements in any of the methods described above may comprise measurements made by two or more different types of sensors and / or two or more of the same type of sensors.

[0253] In some embodiments, wherein at least one sensor is a pH sensor and at least one sensor measurement is a pH measurement, the method may comprise performing at least one pH measurement. In some embodiments, the liquid comprises a pH-adjusting liquid (e.g. an acid, a base, a buffer). In some embodiments, the method further comprises flowing the pH-adjusting liquid into a container in the plurality of containers in an amount determined based on the one or more signals generated by the pH measurement. In some embodiments, the pH sensor may send a signal to a controller. In some embodiments, the amount of liquid to be delivered to the container may be determined by the pH measurement. In some embodiments, the controller may use the one or more signals to determine an amount by which to change the flow rate of the liquid pump. In some embodiments, the controller may use the one or more signals to determine a way in which to alter the configuration of one or more valves in the plurality of liquid valves. In some embodiments, the method may comprise flowing a pH-adjusting liquid to two or more containers in the plurality of containers based on one or more pH measurements. In some embodiments, flowing the pH-adjusting liquid to one or more containers in the plurality of containers may be achieved by the controller modifying the flow rate through the pump and / or the configuration of one or more valves in the plurality of liquid valves.

[0254] In some embodiments, in which the device comprises two or more pluralities of containers, the method may comprise flowing a pH-containing liquid into one or more containers in each plurality of containers based on the measurement of one or more pH sensors. In some embodiments, the method may further comprise supplying a first pH-adjusting liquid to a first plurality of containers in an amount determined based on a first pHsensor measurement and supplying a second pH-adjusting liquid to a second plurality of containers based on a second pH sensor measurement. In some embodiments, the first pH-adjusting liquid and the second pH-adjusting liquid comprise the same liquid (e.g., the first pH adjusting liquid and the second pH-adjusting liquid may both be the same acid). In some embodiments, the first pH-adjusting liquid and the second pH-adjusting liquid comprise different liquids (e.g., the first pH-adjusting liquid may be a base and the second pH-adjusting liquid may be an acid). In some embodiments, the method may comprise supplying a first pH-adjusting liquid to a container in the first plurality of containers in an amount determined based on a first pH measurement and supplying a second pH-adjusting liquid to a container in the second plurality of containers based on a second pH measurement. In some embodiments, the one or more pH sensors in the device may send a signal to a controller. In some embodiments, the controller may use the one or more signals to determine an amount by which to change the flow rate of a first liquid pump and / or a second liquid pump. In some embodiments, the controller may use the one or more signals to determine a way in which to alter the configuration of one or more valves in a first plurality of liquid valves and / or a second plurality of liquid valves.

[0255] In some embodiments, wherein the device comprises a timer, the method of delivering a liquid to a container in the plurality of containers may comprise delivering a liquid to the container at a predetermined time and / or interval of time. In some embodiments, the liquid comprises cell culture media. In some embodiments, the liquid comprises a therapeutic agent (e.g., any of the therapeutic agents described elsewhere herein). For example, in some embodiments, the timer may send a signal to a controller at a predetermined time and / or interval of time. In some embodiments, the controller may use the one or more signals to determine an amount by which to change the flow rate of the liquid pump. In some embodiments, the controller may use the one or more signals to determine a way in which to alter the configuration of one or more valves in the plurality of liquid valves. In some embodiments, the method further comprises flowing a liquid to a container in the plurality of containers in an amount based on the signal from the timer. In some embodiments, the method comprises flowing a liquid into a container in the plurality of containers in a predetermined amount based on the signal from the timer. In some embodiments, the method comprises flowing a liquid into a container in the plurality of containers in an amount based on the signal from one or more other sensors in the device at the predetermined time and / or interval of time determined by the timer. In some embodiments, the method may comprise flowing a liquid to two or more containers in the plurality of liquid containers based on thesignal from the timer, in a predetermined amount based on the signal from the timer, and / or in an amount determined based on signals from one or more other sensors. In some embodiments, flowing the liquid to one or more containers in the plurality of containers may be achieved by the controller modifying the flow rate through the pump and / or the configuration of one or more valves in the plurality of liquid valves.

[0256] In some embodiments (e.g., in some embodiments in which the liquid comprises a therapeutic agent), the method may comprise delivering a first liquid to a container in a plurality of containers at a first predetermined time and / or interval of time and a second liquid to the container in the plurality of containers at a second predetermined time and / or interval of time. In some embodiments, the first liquid and / or the second liquid may be delivered to the container in an amount determined based on a signal from one or more sensors in the device at the predetermined time and / or interval of time determined by a timer. In some embodiments, the first liquid comprises a first therapeutic agent and the second liquid comprises a second therapeutic agent that is different from the first therapeutic agent. In some embodiments, the first liquid and the second liquid comprise the same therapeutic agent. In some embodiments, the first liquid and the second liquid comprise the same therapeutic agent in different amounts (e.g., different dosages).

[0257] In some embodiments (e.g., in some embodiments in which the liquid comprises a therapeutic agent), the method may comprise delivering a first liquid to a container in a plurality of containers at a first time and / or interval of time determined based on a signal from one or more sensors, and delivering a second liquid to the container in the plurality of containers at a second time and / or interval of time determined based on a signal from one or more sensors. In some embodiments, the first liquid and / or the second liquid may be delivered to the container in an amount determined based on a signal from one or more sensors in the device at the time and / or interval of time determined by one or more sensors in the device (e.g., a signal the same sensor(s) or different sensor(s) than the sensor(s) whose signal is used to determine the time and / or interval of time). In some embodiments, the first liquid comprises a first therapeutic agent and the second liquid comprises a second therapeutic agent that is different from the first therapeutic agent. In some embodiments, the first liquid and the second liquid comprise the same therapeutic agent. In some embodiments, the first liquid and the second liquid comprise the same therapeutic agent in different amounts (e.g., different dosages).

[0258] In some embodiments in which a liquid comprising a therapeutic agent is delivered to a container within a plurality of containers, biological cells may be present within thecontainer. In some such embodiments, one or more effects of the therapeutic agent on the cells may be measured and / or monitored (e.g., using one or more sensors) after the delivery of the therapeutic agent to the container. For example, in some embodiments, the effect of the therapeutic agent on the viability of the cells, cell death, cell proliferation, metabolic activity of the cells, gene or protein expression within the cells, signaling pathway activation within the cells, differentiation state of the cells, and / or a morphological change of the cell may be measured and / or monitored after the delivery of the liquid comprising the therapeutic agent to the container comprising the biological cells. One or more of these effects may be measured using any of a variety of suitable sensors and / or devices. For example, one or more of the effects mentioned above may be measured and / or monitored by observing the cells using brightfield and / or fluorescence microscopy. In some embodiments, one or more dyes, antibodies, and / or genetically encoded reporters may be provided to the cells (e.g., via a liquid delivered to the container as described above) and / or already present in and / or with the cells in the container, and position and / or intensity of a signal from the dyes, antibody, and / or genetically encoded reporter may be measured and / or monitored (e.g., via brightfield and / or fluorescence microscopy). Other measurements, such as pH measurements and / or dissolved oxygen (DO) measurements may also be used.

[0259] In some embodiments, in which the device comprises two or more pluralities of containers and one or more timers, the method may further comprise supplying a first liquid to a first plurality of containers at a first predetermined time and / or interval of time and supplying a second liquid to a second plurality of containers at a second predetermined time and / or interval of time. In some embodiments, the first liquid and the second liquid comprise the same liquid. In some embodiments, the first liquid and the second liquid comprise different liquids. In some embodiments, the first liquid and / or the second liquid comprise cell culture media. In some embodiments, the first liquid and / or the second liquid may comprise a therapeutic agent (e.g., any of the therapeutic agents described elsewhere herein). In some embodiments, the first liquid comprises a first therapeutic agent and the second liquid comprises a second therapeutic agent that is different from the first therapeutic agent. In some embodiments, the first liquid and the second liquid comprise the same therapeutic agent. In some embodiments, the first liquid and the second liquid comprise the same therapeutic agent in different amounts (e.g., in different dosages). In some embodiments, the first predetermined time and / or interval of time is the same as the second predetermined time and / or interval of time. In some embodiments, the first predetermined time and / or interval of time is different from the second predetermined time and / or interval of time. In someembodiments, the method may comprise supplying a first liquid to a container in the first plurality of containers in a predetermined amount and / or in an amount determined based on a first sensor measurement at a first predetermined time and / or interval of time and supplying a second liquid to a container in the second plurality of containers in a predetermined amount and / or in an amount based on a second sensor measurement at a predetermined time and / or interval of time. In some embodiments, the first sensor measurement and the second sensor measurement may be the same sensor measurement. In some embodiments, the first sensor measurement and the second sensor measurement may be different sensor measurements. In some embodiments, the timer and / or the one or more sensors in the device may send a signal to a controller. In some embodiments, the controller may use the one or more signals to determine an amount by which to change the flow rate of a first liquid pump and / or a second liquid pump. In some embodiments, the controller may use the one or more signals to determine a way in which to alter the configuration of one or more valves in a first plurality of liquid valves and / or a second plurality of liquid valves.

[0260] In some embodiments, a method for removing waste from a container in a plurality of containers is described. In some embodiments, such a method may be performed in combination with a method for supplying a liquid to a container in a plurality of containers (e.g., a method comprising some or all of the steps shown in FIG. 3A). For example, as described above, waste may be removed from a container prior to supplying a liquid thereto. As another example, a liquid initially supplied to a container may generate waste and / or become waste, and such waste may be removed therefrom. It is also possible for a method to comprise several cycles in which a liquid is supplied to a container and then waste is removed from the container.

[0261] A non-limiting exemplary embodiment of a method for removing waste from a container in a plurality of containers is shown in FIG. 3B. In some embodiments, removing waste from a container in a plurality of containers comprises flowing the waste from the container to and through a waste removal port in the plurality of waste removal ports (step 455), flowing the waste from the waste removal port to and through a waste removal channel in the plurality of waste removal channels (step 456), flowing the waste from the waste removal channel to and through a waste valve in the plurality of waste valves (step 457), flowing the waste from the waste valve to and through the waste port (step 458), and flowing the waste from the waste port to a waste receiving location (step 459).

[0262] In some embodiments, the waste receiving location may comprise a waste reservoir, which may have any of the properties of a waste reservoir as described above.In some embodiments, in which the device comprises at least one sensor, the method for removing a waste from a container in the plurality of containers may comprise performing a measurement on the liquid in the container using one or more sensors (optional steps 451 and 452). This measurement may be performed during incubation of the liquid in the container. In some embodiments, the method further comprises flowing the waste out of a container in the plurality of containers in an amount determined based on the one or more signals from the one or more sensors. In some embodiments, the method may comprise removing waste from two or more containers in the plurality of liquid containers based on one or more sensor measurements. In some embodiments, one or more sensors in the device may send a signal to a controller (optional step 453). In some embodiments, the controller may use the one or more signals to determine an amount by which to change the flow rate of the waste pump (optional step 454). In some embodiments, the controller may use the one or more signals to determine a way in which to alter the configuration of one or more valves in the plurality of waste valves (optional step 454).

[0263] In some embodiments, in which the device comprises two or more pluralities of containers and two or more sensors, the method may further comprise removing waste from a first plurality of containers in an amount determined based on a first sensor measurement and removing waste from a second plurality of containers based on a second sensor measurement. In some embodiments, the first sensor measurement and the second sensor measurement may be the same sensor measurement. In some embodiments, the first sensor measurement and the second sensor measurement may be different sensor measurements. In some embodiments, the one or more sensors in the device may send a signal to a controller. In some embodiments, the controller may use the one or more signals to determine an amount by which to change the flow rate of a first waste pump and / or a second waste pump. In some embodiments, the controller may use the one or more signals to determine a way in which to alter the configuration of one or more valves in a first plurality of waste valves and / or a second plurality of waste valves.

[0264] In some embodiments, wherein the device comprises a timer, the method of removing waste from a container in the plurality of containers may comprise removing waste from the container at a predetermined time and / or interval of time. For example, in some embodiments, the timer may send a signal to a controller at a predetermined time and / or interval of time. In some embodiments, the controller may use the one or more signals to determine an amount by which to change the flow rate of the waste pump. In some embodiments, the controller may use the one or more signals to determine a way in which toalter the configuration of one or more valves in the plurality of waste valves. In some embodiments, the method comprises removing waste from a container in the plurality of containers in an amount based on the signal from the timer. In some embodiments, the method comprises removing waste from a container in the plurality of containers in a predetermined amount based on the signal from the timer. In some embodiments, the method comprises removing waste from a container in the plurality of containers in an amount based on the signal from one or more other sensors in the device at the predetermined time and / or interval of time determined by the timer. In some embodiments, the method may comprise removing waste from two or more containers in the plurality of liquid containers based on the signal from the timer, in a predetermined amount based on the signal from the timer, and / or in an amount determined based on signals from one or more other sensors. In some embodiments, removing waste from one or more containers in the plurality of containers may be achieved by the controller modifying the flow rate through the waste pump and / or the configuration of one or more valves in the plurality of waste valves.

[0265] In some embodiments, in which the device comprises two or more pluralities of containers and one or more timers, the method may further comprise removing waste from a first plurality of containers at a first predetermined time and / or interval of time and removing waste from a second plurality of containers at a second predetermined time and / or interval of time. In some embodiments, the first predetermined time and / or interval of time is the same as the second predetermined time and / or interval of time. In some embodiments, the first predetermined time and / or interval of time is different from the second predetermined time and / or interval of time. In some embodiments, the method may comprise removing waste from a container in the first plurality of containers in a predetermined amount and / or in an amount determined based on a first sensor measurement at a first predetermined time and / or interval of time and removing waste from a container in the second plurality of containers in a predetermined amount and / or in an amount based on a second sensor measurement at a predetermined time and / or interval of time. In some embodiments, the first sensor measurement and the second sensor measurement may be the same sensor measurement. In some embodiments, the first sensor measurement and the second sensor measurement may be different sensor measurements. In some embodiments, the timer and / or the one or more sensors in the device may send a signal to a controller. In some embodiments, the controller may use the one or more signals to determine an amount by which to change the flow rate of a first waste pump and / or a second waste pump. In some embodiments, the controller mayuse the one or more signals to determine a way in which to alter the configuration of one or more valves in a first plurality of waste valves and / or a second plurality of waste valves.

[0266] The sensor measurements in any of the methods described above may comprise measurements made by any of a variety of suitable sensors. The sensors may comprise any of the sensors described above (e.g. a pH sensor, a carbon dioxide sensor, etc.). In some embodiments, the sensor may comprise an optical detector. In some embodiments, the sensor (e.g. the optical detector) may be external to the device.

[0267] In some embodiments, a method as described herein may comprise performing one or more measurements on a waste removed from a container in the plurality of containers. For example, in some embodiments, the waste removed from the container may be analyzed using a sensor (e.g., any of the sensors described above).

[0268] As described above, in some embodiments, a method comprises flowing a liquid into a container in a plurality of containers subsequent to removing waste or another liquid from a container in a plurality of containers. In some embodiments, after removing a liquid (e.g., a liquid that has become waste) from a container in a plurality of containers, a second liquid is supplied to that container. The supply of the second liquid to that container may be performed as described above with respect to the supply of the liquid to that container. For instance, it may comprise flowing the second liquid to and through the inlet port (e.g., from the liquid supply source or a second liquid supply source that is different from the liquid supply source), flowing the second liquid from the inlet port to and through the liquid valve in the plurality of liquid valves, flowing the second liquid from the liquid valve to and through the liquid supply channel in the plurality of liquid supply channels, flowing the second liquid from the liquid supply channel to and through the liquid supply port in the plurality of liquid supply ports, and / or flowing the second liquid from the liquid supply port into the container.

[0269] In some embodiments, the controller is configured to automatically adjust the flow rate of the waste pump and / or adjust the configuration of one or more of the waste valves to remove waste from the container in the plurality of containers in some amount when a liquid is supplied to the container in the plurality of containers. The amount may be a predetermined about or may be determined by the controller. This may advantageously prevent the container from overflowing and / or protect the structural integrity of the substrate.

[0270] EXAMPLE 1This Example describes an exemplary device comprising an apparatus, a substrate, a plurality of containers, and a liquid reservoir. FIG. 4 shows an angled side-view schematic view of the exemplary system. FIG. 5 shows a top-view schematic view of the exemplary system. FIG. 6 shows an angled side-view schematic view of the exemplary system wherein the substrate is formed from an opaque material. FIG. 7 shows an angled side-view schematic view of the exemplary system wherein the substrate is formed from an optically transparent material. FIG. 8 shows a top-view schematic view of the exemplary system. FIG. 9 shows a top-view schematic view detailing the fluidic connections within the system.

[0271] While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the teachings of the present invention is / are used. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, device, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, devices, articles, materials, kits, and / or methods, if such features, devices, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the scope of the present invention.

[0272] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0273] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.” The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that areconjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0274] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0275] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one,optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0276] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0277] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

Claims

CLAIMSWhat is claimed is:

1. A device, comprising:an apparatus configured to supply liquid to a plurality of containers, the apparatus comprising:an inlet port downstream from and in fluidic communication with a location configured to supply the liquid to the inlet port;a plurality of liquid supply channels downstream from the inlet port, wherein each liquid supply channel in the plurality of liquid supply channels comprises an upstream end and a downstream end, and wherein each upstream end is configured to receive the liquid from the inlet port;a plurality of liquid valves, wherein each liquid valve in the plurality of liquid valves is positioned fluidically between an upstream end of a liquid supply channel in the plurality of liquid supply channels and the inlet port;a plurality of liquid supply ports, wherein each liquid supply port is downstream from and in fluidic communication with a downstream end of a liquid supply channel in the plurality of liquid supply channels, and where each liquid supply port is configured to supply a container in the plurality of containers with the liquid;a liquid pump configured to pump the liquid from the inlet port, through the liquid valves, through the liquid supply channels, and to the liquid supply ports;a plurality of waste removal channels, wherein each waste removal channel in the plurality of waste removal channels comprises an upstream end and a downstream end; and a plurality of waste removal ports, wherein each waste removal port is upstream from and in fluidic communication with an upstream end of a waste removal channel in the plurality of waste removal channels, and wherein each waste removal port is configured to receive waste from a container in the plurality of containers.

2. The device of claim 1, further comprising a waste port upstream from and in fluidic communication with a waste receiving location.

3. The device of claim 2, further comprising a plurality of waste valves, wherein each waste valve in the plurality of waste valves is positioned fluidically between a downstream end of a waste removal channel in the plurality of waste removal channels and the waste port.

4. The device of claim 3, further comprising a waste pump configured to pump waste from the waste removal ports, through the waste removal channel, and to the waste port.

5. The device of claim 3, further comprising a vacuum line configured to transport waste from the waste removal ports, through the waste removal channel, and to the waste port.

6. A method for supplying a container in a plurality of containers with a liquid, comprising:in the device of claim 1 :flowing the liquid from a liquid supply source to and through the inlet port; flowing the liquid from the inlet port to and through a liquid valve in the plurality of liquid valves;flowing the liquid from the liquid valve to and through a liquid supply channel in the plurality of liquid supply channels;flowing the liquid from the liquid supply channel to and through a liquid supply port in the plurality of liquid supply ports; andflowing the liquid from the liquid supply port into the container.

7. A method for removing waste from a container in a plurality of containers, comprising:in the device of claim 3:flowing the waste from the container to and through a waste removal port in the plurality of waste removal ports;flowing the waste from the waste removal port to and through a waste removal channel in the plurality of waste removal channels;flowing the waste from the waste removal channel to and through a waste valve in the plurality of waste valves;flowing the waste from the waste valve to and through the waste port; and flowing the waste from the waste port to a waste receiving location.

8. A substrate, comprising:a plurality of containers;a plurality of substrate liquid supply ports, wherein each container in the plurality of containers comprises a substrate liquid supply port;a plurality of substrate waste disposal ports, wherein each container in the plurality of containers comprises a substrate waste disposal port;a liquid supply port connecting region located upstream from and in fluidic communication with a substrate liquid supply port in the plurality of substrate liquid supply ports, wherein the liquid supply port connecting region is configured to connect to a substrate liquid supply port;a waste removal port connecting region located downstream from and in fluidic communication with a substrate waste disposal port in the plurality of substrate waste disposal ports, wherein the waste removal port connecting region is configured to connect to a waste removal port;a plurality of substrate liquid supply channels, wherein each substrate liquid supply channel within the plurality of substrate liquid supply channels is located fluidically between a substrate liquid supply port in the plurality of substrate liquid supply ports and the liquid supply port connecting region, and configured to flow a liquid from the liquid supply port connecting region to the substrate liquid supply port; anda plurality of substrate waste removal channels, wherein each waste removal channel in the plurality of substrate waste removal channels is located fluidically between a substrate waste disposal port in the plurality of substrate waste disposal ports and the waste removal port connecting region, and configured to flow waste from the substrate waste disposal port to the waste removal port connecting region.

9. A device as in claim 1, wherein the plurality of containers is disposed on a substrate.

10. A device as in claim 1, wherein each container in the plurality of containers is a well in a multi- well plate.

11. A device as in claim 9, wherein the device is configured to receive the substrate.

12. A device as in claim 9, wherein at least a portion of a surface of the substrate is transparent to at least one wavelength of light.

13. A device as in claim 12, wherein the wavelength of light is greater than or equal to 400 nm and less than or equal to 700 nm.

14. A device as in claim 4, wherein the liquid pump and / or waste pump is disposed in and / or on the apparatus.

15. A device as in claim 1, wherein the device comprises a microfluidic chip.

16. A device as in claim 1, wherein each container in the plurality of containers is a cell culture chamber.

17. A device as in claim 1, further comprising a controller configured to direct the flow of the liquid.

18. A device as in claim 17, wherein the controller is configured to control the plurality of liquid valves.

19. A device as in claim 17, wherein the device comprises a waste pump, and wherein the controller is configured to control the liquid pump and / or the waste pump.

20. A device as in claim 1, wherein the device comprises one or more gaskets.

21. A device as in claim 1, wherein the liquid pump is a rotary membrane pump, a peristaltic pump, a rotary pump, a piston pump, or a diaphragm pump.

22. A device as in claim 1, wherein the liquid valves are pneumatic valves, turning valves, or rotary membrane valves.

23. A device as in claim 3, wherein the waste valves are pneumatic valves, turning valves, or rotary membrane valves.

24. A method as in claim 6, wherein the liquid comprises a pH-adjusting liquid.

25. A method as in claim 6, wherein the liquid comprises a cell-culture medium.

26. A method as in claim 24, wherein the pH-adjusting liquid comprises a buffer.

27. A method as in claim 6, wherein the liquid comprises waste.

28. A method as in claim 6, wherein the liquid has a temperature of greater than or equal to 2 °C and less than or equal to 37 °C.

29. A method as in claim 6, wherein liquid supply source is a liquid reservoir.

30. A device as in claim 2, wherein the inlet port and / or waste port is in fluidic communication with a reservoir.

31. A device as in claim 2, wherein the inlet port and / or waste port comprises a septum.

32. A device as in claim 2, wherein the inlet port and / or waste port comprises a foil configured to be punctured when the port is fluidically connected to a reservoir.

33. A device as in claim 1, wherein the inlet port is configured to form a seal with a reagent reservoir.

34. A device as in claim 2, wherein the waste port is configured to form a seal with a waste reservoir.

35. A device as in claim 1, wherein the inlet port is in fluidic communication with a reagent reservoir.

36. A device as in claim 1, wherein each liquid supply port is configured to form a seal with a container in the plurality of containers.

37. A device as in claim 1, wherein each waste removal port is configured to form a seal with a container in the plurality of containers.

38. A device as in claim 1, further comprising at least one sensor.

39. A method as in claim 6 or 7, further comprising performing a measurement using a sensor.

40. A method as in claim 39, further comprising flowing the liquid into the container in an amount determined based on the sensor measurement.

41. A method as in claim 39, further comprising flowing the liquid into the plurality of containers in an amount determined based on the sensor measurement.

42. A method as in claim 39, further comprising flowing the liquid out of the container in an amount determined based on the sensor measurement.

43. A method as in claim 39, further comprising flowing the liquid out of the plurality of containers in an amount determined based on the sensor measurement.

44. A device as in claim 38, wherein the sensor is a pH sensor.

45. A method as in claim 39, further comprising measuring a pH of a liquid contained by the container.

46. A method as in claim 45, further comprising flowing a pH-adjusting liquid into the plurality of containers in an amount and / or at a pH determined based on the measurement of the pH.

47. A device as in claim 1, wherein the device comprises two or more sensors.

48. A device as in claim 1, wherein the device further comprises a sensor for carbon dioxide, cell concentration, cell viability, nutrients, metabolites (such as lactate, glucose), temperature, pressure, humidity, and / or viscosity.

49. A device as in claim 1, wherein the device comprises an optical sensor, an electrochemical sensor, and / or an acoustic sensor.

50. A device as in claim 1, wherein the apparatus is positioned inside an instrument.

51. A device as in claim 50, wherein the instrument comprises an optical detector.

52. A device as in claim 51, wherein the optical detector comprises a microscope.

53. A device as in claim 50, wherein the instrument further comprises a light source.

54. A method as in claim 6 or 7, further comprising performing an optical measurement.

55. A method as in claim 54, wherein the optical measurement is performed on a liquid contained by the container.

56. A method as in claim 54, further comprising flowing the liquid into the container in an amount determined based on the optical measurement.

57. A method as in claim 54, further comprising flowing the liquid into the plurality of containers in an amount determined based on the optical measurement.

58. A device as in claim 1, wherein one or more substrates is disposed on the device.

59. A device as in claim 1, further comprising a second inlet port downstream from and in fluidic communication with a second location configured to supply a second liquid to the second inlet port, wherein the second inlet port upstream from and in fluidic communication with the plurality of liquid valves.

60. A method as in claim 6, further comprising supplying a first liquid to a first plurality of containers and a second liquid to a second plurality of containers.

61. A method as in claim 6, further comprising supplying a first liquid to a first plurality of containers in an amount determined based on a first sensor measurement and supplying a second liquid to a second plurality of containers based on a second sensor measurement.

62. A method as in claim 6, further comprising supplying a first liquid to a first container in the plurality containers in an amount determined based on a first sensor measurement and supplying a second liquid to a second container in the plurality of containers based on a second sensor measurement.

63. A method as in claim 7, further comprising flowing waste out of a first plurality of containers in a first amount and removing waste from a second plurality of containers in a second amount.

64. A method as in claim 7, further comprising flowing waste out of a first container in the plurality of containers in a first amount and removing waste from a second container in the plurality of containers in a second amount.

65. A method as in claim 6, wherein the liquid comprises a therapeutic agent.

66. A method as in claim 65, wherein the therapeutic agent comprises a small molecule drug, a biologic, an antibody, an antibody fragment, a nucleic acid-based therapeutic, and / or a cell-based therapeutic.

67. A method as in claim 7, further comprising performing one or more measurements on the waste.

68. A method as in claim 6, wherein the container in the plurality of containers contains a starting liquid, further comprising, prior to flowing the liquid to the container:flowing the starting liquid from the container to and through a waste removal port in the plurality of waste removal ports;flowing the starting liquid from the waste removal port to and through a waste removal channel in the plurality of waste removal channels;flowing the starting liquid from the waste removal channel to and through a waste valve in a plurality of waste valves;flowing the starting liquid from the waste valve to and through a waste port; andflowing the starting liquid from the waste port to a waste receiving location.

69. The method of claim 68, wherein the liquid comprises cell-culture media and a therapeutic agent.

70. The method of claim 69, further comprising incubating the liquid in the container.

71. The method of claim 70, further comprising sensing a property of the liquid in the container during the incubation.

72. The method of claim 71, wherein the property is cell viability, cell morphology, impedance, or fluorescence.

73. The method of claim 71, further comprising:flowing the liquid from the container to and through the waste removal port in the plurality of waste removal ports;flowing the liquid from the waste removal port to and through the waste removal channel in the plurality of waste removal channels;flowing the liquid from the waste removal channel to and through the waste valve in the plurality of waste valves;flowing the liquid from the waste valve to and through the waste port; and flowing the liquid from the waste port to a waste receiving location.

74. The method of claim 73, further comprising performing one or more measurements on the liquid after the liquid has been flowed to the waste receiving location.

75. The method of claim 73, further comprising:flowing a second liquid to and through the inlet port;flowing the second liquid from the inlet port to and through the liquid valve in the plurality of liquid valves;flowing the second liquid from the liquid valve to and through the liquid supply channel in the plurality of liquid supply channels;flowing the second liquid from the liquid supply channel to and through the liquid supply port in the plurality of liquid supply ports; andflowing the second liquid from the liquid supply port into the container.

76. The method of claim 75, wherein flowing the second liquid to the inlet port comprises flowing the second liquid from the liquid supply source to and through the inlet port.

77. The method of claim 75, wherein flowing the second liquid to the inlet port comprises flowing the second liquid from a second liquid supply source to and through the inlet port.

Images