Methods and Apparatus for the Manipulation of Particle Suspensions and Testing Thereof
First Claim
Patent Images
1. A microfluidic device for analysis of individual particles in a suspension comprising:
- a substrate with one or more microfluidic channels adapted for individual addressability of particles, said substrate coupled to a plate with an array of apertures.
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Abstract
Apparatus and methods are provided for analysis of individual particles in a microfluidic device. The methods involve the immobilization of an array of particles in suspension and the application of experimental compounds. Such methods can also include electrophysiology studies including patch clamp recording, electroporation, or both in the same microfluidic device. The apparatus provided includes a microfluidic device coupled to a multi-well structure and an interface for controlling the flow of media within the microchannel device.
229 Citations
181 Claims
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1. A microfluidic device for analysis of individual particles in a suspension comprising:
a substrate with one or more microfluidic channels adapted for individual addressability of particles, said substrate coupled to a plate with an array of apertures. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
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10. A microfluidic system for the analysis of particle suspensions comprising:
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a microfluidic layer comprising at least one microscale flow channel adapted to contain particle suspensions, and an observation area for imaging the particle suspensions;
a structure comprising one or more reservoirs in fluid communication with the microfluidic layer, wherein the reservoirs of the structure are in fluid communication with the microflow and main flow channels of the microfluidic layer;
an interface detachably connectable to the microfluidic layer, wherein the interface controls fluid flow and pressure to one or more reservoir, thereby controlling pressure delivery to each microscale flow channel. - View Dependent Claims (11, 12, 13, 14, 16, 17, 18, 19, 20, 21)
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15. (canceled)
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22. A method for analyzing a plurality of individual particles in suspension comprising:
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repeatedly introducing pluralities of particles into a microfluidic chamber via flow;
repeatedly acquiring images of said particles; and
analyzing said images to characterize the particle population. - View Dependent Claims (23, 24, 25, 26, 27, 28, 29, 30, 31)
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32. A system for performing particle imaging, counting, characterization, and classification comprising:
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a microfluidic device containing a chamber adapted and arranged for simultaneous imaging of a plurality of particles;
a flow actuation system in fluid communication with the microfluidic device that can introduce a population of particles into the chamber;
an image acquisition system positionable for imaging the chamber; and
an image analysis system in communication with the image acquisition system. - View Dependent Claims (33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50)
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51. A microfluidic system for sorting individual particles based on optical observation comprising:
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a microfluidic layer with at least two microscale channels intersecting with a main flow channel;
a multi-well structure in fluid communication with the microfluidic layer, with the wells of said multi-well structure in fluid communication with the channels of the microfluidic layer;
an interface which is removably coupled to the microfluidic device which controls the flow of fluid in the microfluidic channels and can apply a positive or negative pressure to each of the wells of the multi-well plate, thereby applying positive or negative pressure to the microscale channels in the microfluidic layer; and
a control system in optical and fluid communication with the microfluidic layer, and adapted for particle identification and selective pressure application depending on observed particle position. - View Dependent Claims (52)
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53. A microfluidic system comprising:
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a structure comprising a plurality of open reservoirs; and
a substrate comprising microfluidic channels on one side, said substrate coupled to the structure with the channel side facing the substrate, wherein the microfluidic channels are in alignment with the open reservoirs of the structure such that the reservoirs of the structure are in fluidic communication with the microfluidic channels. - View Dependent Claims (54)
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55. A microfluidic system for trapping individual particles in an array for analysis comprising:
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a microfluidic layer comprising an array, at least two microscale channels and a main flow channel wherein the microscale channels intersect with the main flow channel and wherein the array is adapted to trap individual particles;
a structure comprising a plurality of reservoirs coupled to the microfluidic layer, wherein the reservoirs of the structure are in fluid communication with the microscale and main flow channels of the microfluidic layer; and
an interface detachably connectable to the microfluidic layer, wherein the interface controls fluid flow, and pressure to one or more reservoir, thereby controlling pressure delivery to each microscale channel. - View Dependent Claims (56, 57, 58, 59, 60)
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61. A method for analyzing a plurality of individual particles comprising:
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disposing a suspension of particles into one or more reservoir of a microfluidic device comprising one or more reservoir and a plurality of intersecting channels in fluid communication with the one or more reservoir;
immobilizing a plurality of individual particles at one or more junction of the plurality of intersecting channels;
perfusing one or more compounds across the particles; and
analyzing the plurality of individual particles. - View Dependent Claims (62, 63, 64, 65, 66, 67, 68, 69)
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70. A system for single particle analysis the system comprising:
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a microfluidic device comprising one or more reservoirs and adapted for holding and manipulating particles and compounds; and
an interface adapted to provide pressure to the one or more reservoirs, wherein the interface is detachably coupled to the microfluidic device. - View Dependent Claims (71)
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- 72. A system for conducting patch clamp measurements on an array of immobilized particles, wherein the distance between immobilized particles is substantially below 0.1 mm.
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77. A system for conducting patch clamp experiments comprising:
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a microfluidic device with at least two intersecting channels and a detection zone;
an interface detachably coupled to the microfluidic device, wherein the interface is adapted for moving material within the microfluidic device; and
an electrode array electrically in communication with the microfluidic device. - View Dependent Claims (78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92)
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93. A system for intracellular delivery comprising:
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a microfluidic device with a plurality of intersecting channels and a detection zone;
an interface detachably coupled to the microfluidic device, wherein the interface is adapted for moving material within the device, and an electrode array;
a patch clamp amplifier in electrical communication with the electrode array;
a logic device in communication with the interface and patch clamp amplifier; and
a software control system in communication with the logic device and adapted to control the system for intracellular delivery. - View Dependent Claims (94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113)
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114. A system for performing electroporation and electrophysiology measurements of cells on the same platform comprising:
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a microfluidic device adapted to perform electroporation and electrophysiology measurements;
a patch clamp amplifier in electrical communication with the microfluidic device; and
a current measurement system in electrical communication with the microfluidic device. - View Dependent Claims (115)
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116. A method of performing electroporation and electrophysiology measurements of cells on the same platform comprising:
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providing a combined electroporation and electrophysiology measurement platform comprising a microfluidic device, a patch clamp amplifier and a current measurement system;
electroporating cells disposed within the microfluidic device;
interrogating the cells disposed within the microfluidic device, wherein interrogating the cells comprises performing patch clamp measurements on the cells using the patch clamp amplifier and the current measurement system. - View Dependent Claims (117, 118)
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119. A single cell electrophysiology and electroporation array system for intracellular compound delivery and analysis comprising:
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a substrate;
a main flow channel in said substrate adapted to hold cells in a fluidic medium;
at least one lateral opening in a side of said main flow channel;
at least one trapping channel operatively connected to said lateral opening;
at least two electrical connections, one connected to said main flow channel and one connected to said trapping channel, such that an electric field can be focused where a cell contacts said lateral opening, and such that one or more characteristics of said cell can be detected; and
wherein a cell in the main flow channel can be selectively immobilized at said lateral opening by negative pressure in the trapping channel. - View Dependent Claims (120, 121, 122, 123, 124)
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125. A method for measuring the characteristics of particles in the presence of shear forces comprising:
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dispensing a particle suspension into the wells of a microfluidic device;
introducing said suspension into one or more microfluidic channels of the device;
providing flow within one or more of the microfluidic channels; and
measuring a characteristic of the particle suspension. - View Dependent Claims (126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 139)
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137. (canceled)
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140. A device for performing shear force experiments at multiple shear rates comprising:
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a microfluidic layer wherein the microfluidic layer is irreversibly bonded to a plate comprising reservoirs;
a plurality of microfluidic channels disposed within the microfluidic layer and comprising at least two different fluidic resistances; and
an observation area comprising an optically viewable portion of the device in which the plurality of microfluidic channels exhibit different shear forces simultaneously.
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141. A method for performing multiple shear force experiments comprising:
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introducing a particle suspension comprising particles into a number of branches of a branched microfluidic channel;
applying a shear force to said particles by providing flow in the channel branches; and
measuring one or more characteristic of said particles in response to the applied shear forces. - View Dependent Claims (142, 143, 144, 145, 147)
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146. A device for measuring the effects of shear forces on a plurality of different specimens comprising:
a plurality of microfluidic channels in fluidic communication with a one or more wells in a perforated plate, wherein the microfluidic channel is configured to provide substantially the same shear force in a section of each microfluidic channel.
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158. A method for measuring the effects of compounds on particles under shear stress, comprising:
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dispensing a suspension of particles comprising particles into one or more wells of a microfluidic device comprising a plurality of wells;
dispensing one or more compounds into one or more wells of the microfluidic device;
introducing the particles into microfluidic channels of the microfluidic device;
applying shear forces to the particles by providing flow through the microfluidic channels;
exposing the particles to compounds at a time selected from at least one of before, during or after the application of shear stress; and
measuring a characteristic of the particles at a time selected from at least one of the group consisting of before, during or after the application of shear stress and compounds. - View Dependent Claims (159, 160, 161, 162, 163, 164, 165, 166, 167)
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168. A system for performing shear force experiments on particles, comprising:
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a microfluidic device comprising one or more microfluidic channel irreversibly attached to a plate comprising reservoirs;
a flow actuation system in fluid communication with the microfluidic device and configured to introduce a population of particles into at least one of the microfluidic channels and apply shear stress to the particles; and
a measurement system in optical communication with the microfluidic device for determining one or more characteristics of the population of particles. - View Dependent Claims (169, 170, 171, 172, 173, 174, 175, 176, 179, 180, 181)
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177. (canceled)
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Specification