MICROFLUIDIC SORTING USING HIGH GRADIENT MAGNETIC FIELDS

• US 20160244714A1
• Filed: 10/20/2014
• Published: 08/25/2016
• Est. Priority Date: 10/18/2013
• Status: Active Grant

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: General Hospital Corporation
• Inventors: Spuhler, Philipp S., Pai, Vincent, Karabacak, Murat N., Smith, Kyle C., Fachin, Fabio, Barber, Thomas Alan, Kapur, Ravi, Toner, Mehmet
• Granted Patent: US 10,202,577 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: B01L 2200/0652 Sorting or classification of particles or molecules
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0864 comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
• CPC Class Codes: B01L 2400/043 magnetic forces
• CPC Class Codes: B01L 2400/0487 fluid pressure, pneumatics
• CPC Class Codes: B01L 2400/086 using baffles or other fixed flow obstructions
• CPC Class Codes: B01L 3/00 Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
• CPC Class Codes: B01L 3/502753 characterised by bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation separation in general B01D; microapparatus for analysis using electrophoresis G01N27/44791; sample preparation G01N1/28
• CPC Class Codes: B01L 3/502761 specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules investigating characteristics of particles G01N15/00
• CPC Class Codes: B03C 1/01 by addition of magnetic adjuvants
• CPC Class Codes: B03C 1/0332 using permanent magnets
• CPC Class Codes: B03C 1/0335 using coils
• CPC Class Codes: B03C 1/288 disposed at the outer circumference of a recipient
• CPC Class Codes: B03C 2201/18 Magnetic separation whereby the particles are suspended in a liquid
• CPC Class Codes: B03C 2201/22 characterised by the magnetical field, special shape or generation
• CPC Class Codes: B03C 2201/26 for use in medical applications
• CPC Class Codes: C12M 23/16 Microfluidic devices; Capillary tubes integrated microfluidic structures B01L3/5027; microreactors B01J19/0093
• CPC Class Codes: C12M 35/06 Magnetic means C12M35/02 takes precedence
• CPC Class Codes: C12M 47/04 Cell isolation or sorting purging biological preparations of unwanted cells C12N5/0081, determining the presence or kind of microorganism C12Q1/04
• CPC Class Codes: G01N 1/00 Sampling; Preparing specimens for investigation
• CPC Class Codes: G01N 15/1433 : using image recognition
• CPC Class Codes: G01N 15/1484 : microstructural devices
• CPC Class Codes: G01N 15/149 : specially adapted for sorting particles, e.g. by their size or optical properties
• CPC Class Codes: G01N 2015/1006 : for cytology
• CPC Class Codes: G01N 2035/00237 : Handling microquantities of analyte, e.g. microvalves, capillary networks
• CPC Class Codes: G01N 2035/1034 : Transferring microquantities of liquid
• CPC Class Codes: G01N 35/0098 : involving analyte bound to insoluble magnetic carrier, e.g. using magnetic separation magnetic particles used in immunoassays G01N33/54326; magnetic separation in general B03C

Abstract

Microfluidic devices are described that include a microfluidic channel, a first array of one or more magnets above the microfluidic channel, each magnet in the first array having a magnetic pole orientation opposite to a magnetic pole orientation of an adjacent magnet in the first array, and a second array of one or more magnets beneath the microfluidic channel, each magnet in the second array having a magnetic pole orientation opposite to a magnetic pole orientation of an adjacent magnet in the second array. The first array is aligned with respect to the second array such that magnetic fields emitted by the first array and second array generate a magnetic flux gradient profile extending through the channel. An absolute value of the profile includes a first maximum and a second maximum that bound a local minimum. The local minimum is located within the microfluidic channel or less than 5 mm away from a wall of the microfluidic channel. Methods of using the new devices are also described.

Claims

1. A microfluidic device comprising:

a microfluidic channel;

a first array of two or more magnets arranged above the microfluidic channel,

wherein each magnet in the first array has a magnetic pole orientation that is opposite to a magnetic pole orientation of an adjacent magnet in the first array; and

a second array of two or more magnets arranged beneath the microfluidic channel;

wherein each magnet in the second array has a magnetic pole orientation that is opposite to a magnetic pole orientation of an adjacent magnet in the second array,

wherein the first array is aligned with respect to the second array such that magnetic fields emitted by the first array and the second array generate a magnetic flux gradient profile that extends through the microfluidic channel, and

wherein an absolute value of the magnetic flux gradient profile comprises a first peak and a second peak that bound a local minimum in the magnetic flux gradient profile, and wherein the local minimum is located within the microfluidic channel or less than 5 mm away from a wall of the microfluidic channel.

3. The microfluidic device of claim 1, wherein the magnetic flux gradient profile extends transverse to a central longitudinal axis of the microfluidic channel.

8. The microfluidic device of claim 1, wherein a first interface between two magnets in the first array is substantially aligned with a second interface between two magnets in the second array.

16. The microfluidic device of claim 1, wherein each magnet in the first array has a magnetic pole orientation that is opposite to a magnetic pole orientation of a corresponding magnet in the second array.

17. The microfluidic device of claim 1, wherein at least one of the first peak in the magnetic flux gradient and the second peak in the magnetic flux gradient occurs within the microfluidic channel.

19. The microfluidic device of claim 1, wherein

the first array comprises more than two magnets;

the second array comprises more than two magnets; and

the absolute value of the magnetic flux gradient profile comprises at least two local minima, wherein at least one of the local minima is located within the microfluidic channel.

20. The microfluidic device of claim 1, wherein the microfluidic channel is a first microfluidic channel, wherein the device further comprises a second microfluidic channel arranged adjacent to the first microfluidic channel, and wherein the magnetic flux gradient profile extends through both the first microfluidic channel and the second microfluidic channel.

21. The microfluidic device of claim 20, wherein the second microfluidic channel is in fluid communication with the first microfluidic channel.

24. The microfluidic device of any one of claim 1, further comprising:

a first channel fluidly coupled to an output of the microfluidic channel; and

a second channel fluidly coupled to the output of the microfluidic channel, wherein the local minimum is aligned with a longitudinal axis of the first or second channel.

28. A method of sorting a target analyte using the microfluidic device of claim 1, the method comprising:

flowing a fluid sample through the microfluidic channel, the fluid sample comprising a target analyte and one or more magnetic particles; and

exposing, during operation of the microfluidic device, the fluid sample to the magnetic flux gradient profile, wherein the magnetic flux gradient deflects the one or more bound magnetic particles toward the local minimum.

29. The method of claim 28, wherein the fluid sample comprises one or more second particles in addition to the target analyte, and wherein the one or more magnetic particles are bound to the one or more second particles such that the magnetic flux gradient deflects the second particles with the one or more magnetic particles away from an initial fluid flow trajectory of the fluid sample without deflecting the target analyte, and wherein the method further comprises collecting the target analyte from the fluid flow trajectory at an output of the microfluidic channel subsequent to the deflection of the one or more second particles.

30. The method of claim 28, wherein the one or more magnetic particles are bound to the target analyte such that the magnetic flux gradient deflects the target analyte with the one or more magnetic particles away from an initial fluid flow trajectory of the fluid sample, and wherein the method further comprises collecting the target analyte at an output of the microfluidic channel.

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34. A method of sorting analytes in a microfluidic device, wherein the microfluidic device comprises a magnetophoresis region, the method comprising:

flowing a fluid sample containing a mixture of a plurality of first analytes and a plurality of second analytes into the magnetophoresis region,

wherein the plurality of second analytes are bound to magnetic particles,

wherein a magnetic flux gradient profile within the magnetophoresis region deflects the plurality of second analytes from the fluid sample,

wherein an absolute value of the magnetic flux gradient profile comprises a first peak and a second peak that bound a local minimum in the magnetic flux gradient profile, and

wherein the local minimum is located within the microfluidic channel in the magnetophoresis region or less than 5 mm from a microfluidic channel wall in the magnetophoresis region.

35. The method of claim 34, wherein the microfluidic device further comprises a hydrodynamic particle sorting region arranged upstream from and in fluid communication with the magnetophoresis region and an inertial focusing region arranged upstream from and in fluid communication with the magnetophoresis region, the method further comprising:

prior to flowing the fluid sample into the magnetophoresis region, introducing the fluid sample into the hydrodynamic particle sorting region to separate a first portion of the first analytes from the fluid sample, wherein the remaining fluid sample from the hydrodynamic sorting region comprises the plurality of second analytes and a second portion of the first analytes and is passed to the magnetophoresis region; and

prior to flowing the remaining fluid sample into the magnetophoresis region, flowing the remaining fluid sample from the hydrodynamic region into the inertial focusing region, wherein the inertial focusing region focuses analytes in the remaining fluid sample into one or more common streamlines, wherein the magnetic flux gradient profile within the magnetophoresis region deflects the second plurality of analytes from the one or more common streamlines.

40. The method of claim 34, wherein the first plurality of analytes is not bound to magnetic particles.

43. The method of claim 34, wherein the microfluidic device further comprises a first inertial focusing region and a second inertial focusing region, wherein each inertial focusing region is fluidly coupled to a common input port of the magnetophoresis region, the method further comprising:

flowing a first fluid sample portion into the first inertial focusing region, wherein the first inertial focusing region focuses analytes in the first fluid sample portion into a first streamline; and

flowing a second fluid sample portion into the second inertial focusing region, wherein the second inertial focusing region focuses analytes in the second fluid sample portion into a second streamline,

wherein both the first and second streamlines enter the common input port of the magnetophoresis region.

44. The method of claim 43, wherein the magnetic flux gradient profile within the magnetophoresis region deflects the second plurality of analytes from the first and second fluid streamlines into a separate third fluid streamline.

45. The method of claim 44, further comprising, subsequent to deflecting the second plurality of analytes:

directing the first, second, and third fluid streamlines to first, second, and third output channels, respectively;

collecting, at the first and second output channels, the first plurality of analytes; and

collecting, at the third output channel, the second plurality of analytes.

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46. A method of sorting analytes in a microfluidic device comprising a first microfluidic channel arranged in fluid communication with a second microfluidic channel, wherein a magnetic flux gradient extends through both the first and second microfluidic channels, the method comprising:

introducing a fluid sample containing a first plurality of analytes into the first microfluidic channel,

wherein the first plurality of analytes are bound to magnetic particles, and wherein the magnetic flux gradient profile within the first microfluidic channel deflects a first portion of the first plurality of analytes from the fluid sample; and

flowing a remaining fluid sample from the first microfluidic channel into the second microfluidic channel, wherein the magnetic gradient profile deflects a second portion of the first plurality of analytes from the remaining fluid sample, and

wherein the absolute value of the magnetic flux gradient profile comprises a first peak and a second peak that bound a local minimum in the magnetic flux gradient profile, the local minimum being located within one of the first microfluidic channel or the second microfluidic channel, and wherein either the first peak or the second peak is located within the other one of the first microfluidic channel or the second microfluidic channel.

48. The method of claim 46, wherein the remaining fluid sample comprises a second plurality of analytes that are not bound to magnetic particles, the method further comprising:

collecting the second plurality of analytes at a first output of the second microfluidic channel; and

collecting the second portion of the first plurality of analytes at a second output of the second microfluidic channel.

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