Source: https://patents.google.com/patent/US9260693B2/en
Timestamp: 2018-12-19 09:57:34
Document Index: 202711796

Matched Legal Cases: ['Application No. 200580046282', 'Application No. 2007', 'Application No. 200780019958', 'Application No. 05853002', 'Application No. 2093', 'Application No. 2', 'Application No. 2', 'Application No. 2', 'Application No. 2007']

US9260693B2 - Actuation of parallel microfluidic arrays - Google Patents
Actuation of parallel microfluidic arrays Download PDF
US9260693B2
US9260693B2 US14517396 US201414517396A US9260693B2 US 9260693 B2 US9260693 B2 US 9260693B2 US 14517396 US14517396 US 14517396 US 201414517396 A US201414517396 A US 201414517396A US 9260693 B2 US9260693 B2 US 9260693B2
US14517396
US20150140545A1 (en )
This application is a continuation-in-part of U.S. Ser. No. 13/371,277, filed Feb. 10, 2012, which is a continuation of U.S. Ser. No. 11/800,469, filed May 4, 2007, which claims priority to U.S. Provisional Ser. No. 60/798,154, filed May 5, 2006, and entitled “Actuation of Parallel Microfluidic Arrays” and this application is a continuation-in-part of U.S. Ser. No. 14/179,760, filed Feb. 13, 2014, which is a continuation of U.S. Ser. No. 13/240,521, filed Sep. 22, 2011, which is a continuation of U.S. Ser. No. 11/295,183, filed Dec. 5, 2005, which claims priority to U.S. Provisional Ser. No. 60/633,396, filed Dec. 3, 2004, and entitled “Unitary Cartridge For Particle Processing”. The contents of each application is herein incorporated by reference in its entirety.
FIG. 12 illustrates a unitary cartridge for particle processing according to an illustrative embodiment, of the invention.
FIG. 13 illustrates a unitary cartridge for particle sorting according to an illustrative embodiment of the invention.
FIG. 14 illustrates a unitary particle sorting cartridge of embodiment of the invention including an aggregation filter.
FIG. 15 illustrates a unitary particle sorting cartridge of another embodiment of the invention including pumps and filters for controlling liquid level and/or the concentration of sheath fluid, as well as providing sheath recycling.
A suitable switching mechanism is described in U.S. Pat. Nos. 6,877,528, 6,808,075, 6,976,590 and 7,157,274 and U.S. patent application Ser. No. 11/295,183, now U.S. Pat. No. 8,277,764, the contents of which are herein incorporated by reference.
FIG. 12 illustrates a particle processing cartridge 100 for performing a process on a sample, having many, and preferably all, fluid contact surfaces encapsulated according to an illustrative embodiment of the invention. The illustrative unitary particle processing cartridge 100 can be designed to perform any suitable process or multiple processes on a sample. Preferably, the unitary particle processing cartridge performs a microfluidic process on a sample. The cartridge may contain one or more particle processing subsystems 110 enabling one or more unit processes to be applied to a sample, such as a suspension, loaded into the cartridge 100. The particle processing subsystem 110 may be separately inserted into and removable from the cartridge 100, or may be integrally formed on the cartridge substrate. For example, the cartridge substrate may have formed therein a recess or chamber for receiving the particle processing subsystem 110. Some examples of unit processes that may be incorporated into a unitary cartridge 100 include, but are not limited to, incubation or staining of particles, washing of particles, including variants where supernatant is purified. heating or cooling of particles in a suspension, mixing cells or other particles with chemicals or beads, size-based filtering of particles, depletion or enhancement of a subset of particles in the suspension, sorting of particles, and other suitable processes known in the art.
Ideally, in order to prepare particles, such as cells for research or clinical applications, using a unitary cartridge 100 of the illustrative embodiment of the invention, a user loads the “source”, such as a cell suspension, into the cartridge via a sample input port 102, operates the cartridge using the processing subsystem 110 and extracts the final product in as finished a condition as possible via a processed sample output port 106. If a processing means, such as a sheath fluid, solution, mixing suspension, magnetic beads and so on, is necessary, the processing means may be loaded into the cartridge 100 via a processor input port 104 and stored in a processing means source 114. Alternatively, a single port can serve as both the sample input port and the processor input port. An extraction port 108 may be used to access byproducts of the processing subsystem 110.
A plurality of chambers disposed between the ports and the subsystem 110 may also be provided. Preferably, at least some of the chambers are rigidly connected to each other to form the unitary cartridge 100. As shown, the illustrative cartridge 110 includes a sample input chamber 112 for storing a sample to be processed, which may be provided by the sample input port 102. The sample input chamber 112 is in fluid communication with the processing subsystem 110 via a fluid path 116. A processing means input chamber 114 may store a processing means provided via processor input port 104. A fluid path 118 fluidly connects the processing means input chamber 112 to the particle processing component 110. A processed sample chamber, illustrated as “keep” chamber 124 a, stores a sample processed by the processing subsystem 110, and may be fluidly connected to the particle processing component 110 via a fluid path 126. A sample output port, such as extraction port 106 may be used to retrieve the sample from the processed sample chamber. A byproduct output chamber, illustrated as a “keep” chamber 124 b, may store a byproduct of the process performed using the subsystem, such as unselected particles in a sorting system, or a byproduct solution for another process, which may be provided to the byproduct output chamber 124 b from the particle processing component 110 using another fluid path 128. A plurality of pneumatic ports 101, 103, 105 and 107 in communication with the fluid paths applies pressure to facilitate fluid flow through the cartridge. In addition, a plurality of additional ports, chambers and fluid paths may be provided in the cartridge, depending on the type of process performed.
The unitary particle processing cartridge 100 may include a plurality of sample processing subsystems 110 in the cartridge. For example, two or more sample processing subsystems 110 may be disposed in series on the cartridge to allow sequential processing of a sample. An enrichment region between the serial processing subsystems may allow for resetting of sample parameters between processes. An example of a suitable enrichment region between two sample processing stages 110 is found in U.S. application Ser. No. 10/329,008. For example, the enrichment region may be formed by a filter disposed between the sample processing subsystems on the cartridge.
According to another embodiment, a unitary particle processing cartridge may be used for particle sorting. The illustrative cartridge 200 performs cell sorting, though one skilled in the art will recognize that the cartridge 200 may perform sorting on any type of particle. FIG. 13 illustrates a unitary particle sorting cartridge 200 including a microfluidic based sorting component 120 for sorting particles without an aerosol phase according to an illustrative embodiment of the invention. Upstream of the sorting component 120, the cartridge 200 includes a cell source 112 for storing particles to be sorted, a sheath fluid source 114 storing a sheath fluid for facilitating a sorting process, a sterile filtered pneumatic port 101 for the cell source, a sample loading port 102 for the cell source, a sterile filtered pneumatic port 103 for the sheath fluid and a fluid loading port 104 for the sheath fluid reservoir 114. The pneumatic ports 101, 103 apply pressure to induce or facilitate fluid flow through the cartridge. Channels, illustrated as tubes 116 and 118, connect the cell source 112 and sheath fluid reservoir 114, respectively, to inlets of the sorting component 120. Downstream of the sorting component 120, the cartridge includes keep chambers 124 a, 124 for collecting sorted particles, tubes 126, 128 connecting the outlets of the sorting component 120 to the keep chambers 124 a, 124 b. The cartridge also includes an extraction port 106, 108 for each keep chamber 124 a, 124 b, respectively, for extracting collected fluid from each keep chamber, and sterile fluid pneumatic ports 105, 107, respectively. The cartridge processes relatively large volumes (0.1 ml to 5000 ml of suspension) and equal or larger volumes of sheath fluid through the system and out into output chambers 124 a, 124 b.
The sorting component 120 may be separately manufactured, stored, and/or shipped, and subsequently inserted into the cartridge substrate 200, creating a flexible connection. Alternatively, the sorting component 120 may be integrally and rigidly formed on the cartridge substrate 200.
As shown, fluidic connections from the cell source 112 or sheath reservoir 114 to the sorting component 120 and from the sorting component to the keep chambers 124 a, 124 b, can be made with single tubes or arrays of tubes. The tubes creating the fluid paths can be of any appropriate diameter.
An embodiment of a unitary particle processing cartridge of the present invention, such as the unitary particle processing cartridge 100 shown in FIG. 12 or the unitary particle sorting cartridge 200 of FIG. 13 has several properties that are improvements in operation of a cell or particle sorting system. For example, most, and preferably all, of the fluid contact surfaces are built into one object (“the cartridge”). The unitary cartridge including all the fluid contact surfaces can be inserted into a processing instrument (the platform containing sorting optics, electronics, control software and other subsystems the suspension never contacts) with a single operation. The unitary cartridge can also be disposed of in a single operation after use. The cartridge can be sterilized after assembly all at once. The cartridge can be shipped to the user in a sterile, ready to use form. Each cartridge (and therefore all fluid contact surfaces needed for a single processing run) can be given a barcode or other unique identification, making all of the parts that represent possible sources of product contamination fully traceable. In addition, no fluid waste needs to be removed from the cartridge in operation. Rather, fluid waste can be disposed of with the disposal of the cartridge, without requiring separate handling of the fluid waste.
Use of a unitary particle processing cartridge of the present invention can enhance operator and product isolation. To use the cartridge to perform a particle processing operation, such as particle sorting, a user can receive the cartridge sealed and sterile from the manufacturer. The user may then take a cartridge to a biosafety hood, such as a sterile laminar flow hood, and perform a sterile operation (in the manner of conventional tissue culture for that type of sample) to load cell sample and sheath reservoirs. The cartridge is preferably sealed before and after this operation. The user places the cartridge in the sorting to instrument platform. The system sorts the cells or particles in the sample into one or more of the keep chambers in the cartridge. The user removes the cartridge from the system and takes the cartridge back to the biosafety hood to remove the processed samples through their extraction ports. The user may then dispose of the used cartridge and unneeded fluids in a safe manner. Similar steps may be taken to perform other processes on a sample using a unitary particle processing cartridge.
As shown in FIG. 14, a unitary particle processing cartridge 100′ of an embodiment of the invention may include also an aggregation filter 180 to help remove clumps of cells and prevent clogging of the sorting component. As shown, the aggregation filter 180 can be added to the fluid line(s) 116 connecting the cell source 112 to the processing component 110. The aggregation filter 180 may comprise any suitable material suitable for filtering a sample and may be disposed in any location along a fluid flow path in the cartridge 100′.
As shown in FIG. 15, a unitary particle processing cartridge 100″ of another embodiment of the invention may include a component for liquid level/concentration control and sheath recycling after performing particle processing using the processing component 110. The illustrative cartridge 100″ includes a pump 192, 194 and a filter 182, 184 downstream of each processed particle chamber 124 a, 124 b, respectively, that receives processed particles from the processing component. The pumps 192 and 194 and filters 182, 184 facilitate liquid level/concentration control and recycling of a processing means, such as sheath fluid, used to process the particles. The filters 182, 184 maybe three-port flow filters, for example, hollow fiber filters, for removing fluid, such as sheath fluid, from a fluid path (i.e., the corresponding processed particle chamber 124). The system thus removes sheath fluid from the processed particle chambers to raise the concentration of collected particles in the processed particle chambers and to control the level of liquid in each processed particle chamber 124 a, 124 b.
The illustrative unitary particle processing cartridge 100″ also includes a recycling component for recycling fluid collected by the filters 182, 184. As shown, the excess fluid may be recovered (recycled) and returned into the processing medium reservoir 114, for example, a sheath fluid reservoir, using a recycling path 1121, recycling reservoir 191 and a pump 190. The recycling reservoir 191 receives the removed fluid from the filters 182 and 184, and the pump 190 returns the extracted fluid from the filters 182 and 184 to the chamber to 114 via fluid path 1121 for reuse during subsequent particle processing procedures.
In general, a unitary particle processing cartridge of an illustrative embodiment of the invention is a single object sealed against liquid transfer either in or out of the cartridge, except at specific ports that are only used in a specific standard operating procedure (SOP) that guarantees that their use does not violate the isolation of the interior of the cartridge or leak interior samples into the exterior.
In one embodiment, the unitary particle processing cartridge is operated by being placed in a machine or system (the “Operating Machine”) which may apply means of to actuation and sensing to the cartridge to perform one or more “unit process operations” on a suspension that has been loaded into the cartridge. The unit process operations performed using the cartridge may change the state of the suspension, measure some properties of the suspension, both change the state and measures selected properties of a suspension, or other perform another suitable process on a suspension loaded in the cartridge. Examples of unit processes suitable for use with the unitary cartridge of an illustrative embodiment of the invention include, but are not limited to, measuring the number of cells in a suspension, measuring the amount of liquid in a suspension, measuring the type of cells in a suspension, which may be a cytometry operation, sorting cells in the suspension, collecting a subset of the cells in a suspension, heating the cells in a suspension, filtering a suspension to increase the concentration of cells therein, and changing the liquid or its chemical components in a suspension.
The operating machine that operates on the unitary particle processing cartridge may use electrical, mechanical, pneumatic, optical, magnetic or other suitable actuation or sensing means known in the art to perform unit process operations on a suspension in the cartridge. Examples of actuation or sensing means suitable for use in an operating machine that employs the unitary cartridge of the illustrative embodiment of the invention include, but are not limited to, pneumatic means, mechanical means, optical means, magnetic means and electrical means. To actuate or sense using a pneumatic means, a gas may be injected through a sterile filter to drive a liquid suspension from one chamber to another or from a chamber through a component such as a size filter and into a second chamber. To actuate or sense using a mechanical means, a peristaltic pump head may be built into the cartridge so that an external rotor may fit into that head and by rotating it pump liquid or gas from one chamber to another. To actuate or sense using an optical means, a light beam may be disposed relative to the cartridge to pass through a microchannel in the cartridge in order to count cells or particles that pass through that microchannel and transiently block or scatter the light on its way to a photodetector. To actuate or sense using a magnetic means, a rotating magnet may be brought close to a chamber containing a conventional magnetic stir bar, causing that stir bar to rotate and stir or mix the suspension in that chamber. To actuate or sense using an electrical means, conventional silicon pressure or temperature sensors may be built into the cartridge and their electrical leads may be connected to through the means of external contact pins. The operating machine may then apply and read voltages to or from these contact pins to operate the sensors. Alternatively, using an electrical means, a data storage means, which may be part of a microcontroller or CPU, digital or analog, may be built into the cartridge if it is advisable for the cartridge itself to be given a logging function or intelligence function to support its use or standard operating procedures for handling the cartridge. Power for these devices may come from the operating machine or be derived from batteries or electrical power storage means located within the unitary cartridge. In another embodiment of a mechanical means for performing a process in a suspension loaded in a cartridge, two chambers may be connected by a tube with a region containing a soft wall to form a valve. Then, the operating machine may press on this region with a mechanical plate or other suitable means to temporarily or permanently crimp that region and selectively block liquid or gas flow from one chamber to another.
The use of the cartridge allows the operating machine to be isolated from and external to the processing subsystem and fluid contact surface. In this manner, the operating machine can be used repeatedly, while the fluid contact surfaces can be disposable.
1. A particle processing cartridge assembly for sorting individual particles on a particle-by-particle basis from a stream of particles, the particle processing cartridge assembly comprising:
a microfluidic chip having:
at least one microsorter having fluid contact surfaces including a microfluidic channel having a sample input, a switching region, a keep output and a waste output; and
at least one switch element operatively interfaced with the switching region and configured to selectively sort individual particles on a particle-by-particle basis from the stream of particles flowing within the microfluidic channel; and
2. The cartridge assembly of claim 1, wherein the cartridge includes a sorted sample extraction port in fluid communication with the keep chamber and configured to be unsealed after the sorting operation has ended to provide access to fluid within the keep chamber.
3. The cartridge assembly of claim 1, further comprising a plurality of microsorters.
4. The cartridge assembly of claim 1, wherein all the fluid contact surfaces needed for the sorting operation are enclosed within the particle processing cartridge assembly.
5. The cartridge assembly of claim 1, wherein the microfluidic channel includes a detection region wherein particle characteristics of individual particles of a sample are detected on a particle-by-particle basis during the sorting operation.
6. The cartridge assembly of claim 1, wherein the microfluidic chip and the cartridge are provided as a unitary particle processing cartridge assembly.
7. The cartridge assembly of claim 6, wherein the unitary particle processing cartridge assembly is a rigid and integral assembly.
8. The cartridge assembly of claim 1, wherein the particle processing cartridge assembly is configured to allow pressurized air to drive the stream of particles through the microfluidic channel.
9. The cartridge assembly of claim 1, wherein the particle processing cartridge assembly includes a unique identifier.
10. The cartridge assembly of claim 1, wherein the fluid contact surfaces of the cartridge include a sheath chamber configured to supply sheath fluid to the microsorter upstream of the switching region.
11. The cartridge assembly of claim 1, wherein the fluid contact surfaces of the cartridge include at least one recycling channel.
12. The cartridge assembly of claim 1, wherein the fluid contact surfaces of the cartridge include at least one filter element.
13. A system for sorting individual particles on a particle-by-particle basis from a stream of particles, the system comprising:
a particle processing cartridge assembly including a microfluidic chip and a cartridge,
the microfluidic chip having:
the cartridge having fluid contact surfaces including a sample chamber, a keep chamber and a waste chamber, wherein the sample chamber of the cartridge is in fluid communication with the sample input of the microfluidic channel, wherein the keep chamber of the cartridge is in fluid communication with the keep output of the microfluidic channel, wherein the waste chamber of the cartridge is in fluid communication with the waste output of the microfluidic channel; and
14. The system of claim 13, further comprising a plurality of microsorters and a plurality of actuators wherein each actuator is associated with one of the plurality of microsorters.
15. The system of claim 13, wherein the at least one switch element is configured to be actuated by the at least one actuator in response to a desired particle characteristic of an individual particle being detected in a detection region of the microfluidic channel, and wherein the at least one actuator is external to and separately formed from the particle processing cartridge assembly.
16. The system of claim 13, wherein the actuator is configured to supply at least one of a mechanical, electrical, pneumatic or magnetic force to the at least one switch element to cause the switch element to sort the selected particle from the stream.
17. A method for sorting particles comprising:
operating the operating machine to process the sample, including the steps of:
flowing the sample containing particles through the microfluidic particle sorting component;
detecting whether individual particles flowing within the microfluidic particle sorting component have a predetermined characteristic;
causing the switch actuation element provided on the operating machine to actuate the switch element included in the microfluidic particle sorting component in response to the predetermined characteristic of an individual particle being detected;
deflecting the individual particle from the particles flowing within the microfluidic particle sorting component into the selected particle fluid output reservoir, and
18. The method of claim 17, wherein the cartridge remains sealed during the steps of operatively interfacing, operating, and removing, and wherein all fluid contact surfaces required for a microfluidic particle sorting operation are enclosed by the cartridge and are isolated from exposure to an exterior environment during the microfluidic particle sorting operation.
US14517396 2004-12-03 2014-10-17 Actuation of parallel microfluidic arrays Active US9260693B2 (en)
US63339604 true 2004-12-03 2004-12-03
US11295183 US8277764B2 (en) 2004-12-03 2005-12-05 Unitary cartridge for particle processing
US79815406 true 2006-05-05 2006-05-05
US11800469 US8123044B2 (en) 2006-05-05 2007-05-04 Actuation of parallel microfluidic arrays
US13240521 US8679422B2 (en) 2004-12-03 2011-09-22 Unitary cartridge for particle processing
US13371277 US8863962B2 (en) 2006-05-05 2012-02-10 Actuation of parallel microfluidic arrays
US14179760 US9823252B2 (en) 2004-12-03 2014-02-13 Unitary cartridge for particle processing
US14517396 US9260693B2 (en) 2004-12-03 2014-10-17 Actuation of parallel microfluidic arrays
US15042996 US10065188B2 (en) 2004-12-03 2016-02-12 Actuation of parallel microfluidic arrays
US13371277 Continuation-In-Part US8863962B2 (en) 2006-05-05 2012-02-10 Actuation of parallel microfluidic arrays
US14179760 Continuation-In-Part US9823252B2 (en) 2004-12-03 2014-02-13 Unitary cartridge for particle processing
US13240521 Continuation US8679422B2 (en) 2004-12-03 2011-09-22 Unitary cartridge for particle processing
US15042996 Continuation US10065188B2 (en) 2004-12-03 2016-02-12 Actuation of parallel microfluidic arrays
US20150140545A1 true US20150140545A1 (en) 2015-05-21
US9260693B2 true US9260693B2 (en) 2016-02-16
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