System and method for isolating and analyzing cells
First Claim
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1. A system for isolating and analyzing single cells, comprising:
- a substrate having a broad surface;
a set of wells defined at the broad surface of the substrate, each well of the set of wells comprising;
a base surface defined within the substrate,an open surface directly opposing the base surface and coplanar with the broad surface,a wall, extending between the base surface and the open surface in a direction substantially perpendicular to the broad surface of the substrate, the wall, base surface, and open surface cooperatively defining an open volume, anda set of channels, defined by the wall, that fluidly couple each well to at least one adjacent well in the set of wells;
a fluid delivery module defining an inlet and comprising a plate, the plate defining a recessed region fluidly connected to the inlet and facing the broad surface of the substrate, the fluid delivery module comprising a cell capture mode operable to provide a fluid layer between the recessed region and the broad surface of the substrate, through which a sample containing a set of single cells flows in a direction perpendicular to the broad surface, the cell capture mode further operable to deliver at least one of the set of single cells into the open volume of at least one of the set of wells from the direction substantially perpendicular to the broad surface, wherein the fluid delivery module is further operable in a reagent delivery mode operable to deliver reagent fluid, through the inlet, and laterally in a second direction parallel to the broad surface, to the set of wells; and
a heating plate coupled to the plate of the fluid delivery module within the recessed region, the heating plate at least partially defining the fluid layer through which a convective flow provided by the heating plate can flow in the second direction parallel to the broad surface, wherein, with the heating plate, the system is operable in a diffusion mode that provides diffusion transport between the convective flow and the set of wells.
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Abstract
A system and method for isolating and analyzing single cells, comprising: a substrate having a broad surface; a set of wells defined at the broad surface of the substrate, and a set of channels, defined by the wall, that fluidly couple each well to at least one adjacent well in the set of wells; and fluid delivery module defining an inlet and comprising a plate, removably coupled to the substrate, the plate defining a recessed region fluidly connected to the inlet and facing the broad surface of the substrate, the fluid delivery module comprising a cell capture mode.
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Citations
20 Claims
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1. A system for isolating and analyzing single cells, comprising:
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a substrate having a broad surface; a set of wells defined at the broad surface of the substrate, each well of the set of wells comprising; a base surface defined within the substrate, an open surface directly opposing the base surface and coplanar with the broad surface, a wall, extending between the base surface and the open surface in a direction substantially perpendicular to the broad surface of the substrate, the wall, base surface, and open surface cooperatively defining an open volume, and a set of channels, defined by the wall, that fluidly couple each well to at least one adjacent well in the set of wells; a fluid delivery module defining an inlet and comprising a plate, the plate defining a recessed region fluidly connected to the inlet and facing the broad surface of the substrate, the fluid delivery module comprising a cell capture mode operable to provide a fluid layer between the recessed region and the broad surface of the substrate, through which a sample containing a set of single cells flows in a direction perpendicular to the broad surface, the cell capture mode further operable to deliver at least one of the set of single cells into the open volume of at least one of the set of wells from the direction substantially perpendicular to the broad surface, wherein the fluid delivery module is further operable in a reagent delivery mode operable to deliver reagent fluid, through the inlet, and laterally in a second direction parallel to the broad surface, to the set of wells; and a heating plate coupled to the plate of the fluid delivery module within the recessed region, the heating plate at least partially defining the fluid layer through which a convective flow provided by the heating plate can flow in the second direction parallel to the broad surface, wherein, with the heating plate, the system is operable in a diffusion mode that provides diffusion transport between the convective flow and the set of wells. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
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10. A system for isolating and analyzing single cells, comprising:
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a chip comprising; a substrate having a broad surface; a set of wells defined at the broad surface of the substrate, each of the set of wells comprising a base surface defined within the substrate, an open surface directly opposing the base surface and coplanar with the broad surface of the substrate, and a wall extending between the base surface and the open surface; and a fluid delivery module defining an inlet and an outlet, and fluidly connecting the inlet and outlet to each well in the set of wells; an imaging subsystem, including an optical assembly positioned at a first side of the chip and oriented in a direction perpendicular to the broad surface; a cell removal subsystem comprising a cell extractor, the cell removal subsystem positioned at a second side of the chip opposing the first side; and a flow control subsystem fluidly coupled to the inlet and outlet of the chip, the flow control subsystem operable in a flow mode that applies one of a positive pressure gradient and a negative pressure gradient between the inlet and outlet of the fluid delivery module, wherein the flow mode further promotes a flow of a sample containing a single cell in a direction substantially parallel to the broad surface of the substrate, and captures the single cell within the wall of a well of the set of wells from a direction normal to the base surface of the well. - View Dependent Claims (11, 12, 13, 14, 15, 16, 17, 18)
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19. A system for isolating and analyzing single cells, comprising:
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a chip comprising; a substrate having a broad surface; a set of wells defined at the broad surface of the substrate, each of the set of wells comprising a base surface defined within the substrate, an open surface directly opposing the base surface and coplanar with the broad surface of the substrate, and a wall extending between the base surface and the open surface, wherein the wall of each of the set of wells reduces a characteristic dimension of each of the set of wells from the open surface to the base surface of each of the set of wells in a series of discrete steps; a fluid delivery module defining an inlet and an outlet, and fluidly connecting the inlet and outlet to each well in the set of wells; an imaging subsystem, including an optical assembly positioned at a first side of the chip and oriented in a direction perpendicular to the broad surface; and a cell removal subsystem comprising a cell extractor, the cell removal subsystem positioned at a second side of the chip opposing the first side.
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20. A system for isolating and analyzing single cells, comprising:
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a chip comprising; a substrate having a broad surface; a set of wells defined at the broad surface of the substrate, each of the set of wells comprising a base surface defined within the substrate, an open surface directly opposing the base surface and coplanar with the broad surface of the substrate, and a wall extending between the base surface and the open surface, wherein the wall of each well of the set of wells defines a set of channels, the set of channels fluidly connecting each well to at least one adjacent well of the set of wells, and wherein the set of wells is divided into subsets of wells, wherein each well of each subset is fluidly connected by its set of channels to each of its surrounding wells of the subset of wells, and wherein the walls of each well of each subset prevent fluid communication between each subset and its surrounding subsets of wells; and a fluid delivery module defining an inlet and an outlet, and fluidly connecting the inlet and outlet to each well in the set of wells; an imaging subsystem, including an optical assembly positioned at a first side of the chip and oriented in a direction perpendicular to the broad surface; and a cell removal subsystem comprising a cell extractor, the cell removal subsystem positioned at a second side of the chip opposing the first side, wherein the cell extractor of the cell removal subsystem comprises a repositionable capillary tube.
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Specification