Microfluidic sorting using high gradient magnetic fields

Patent metadata

Field	Value
Publication number	US-11725180-B2
Application number	US-202117502869-A
Country	US
Kind code	B2
Filing date	Oct 15, 2021
Priority date	Oct 18, 2013
Publication date	Aug 15, 2023
Grant date	Aug 15, 2023

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.

First claim

What is claimed is:

1. A method of sorting particles in a microfluidic device, wherein the microfluidic device comprises a particle sorting region, an inertial focusing region, and a magnetophoresis region, the method comprising:
flowing a fluid sample comprising blood through the particle sorting region, wherein the fluid sample comprises:
a plurality of first particles,
a plurality of second particles, and
a plurality of third particles bound to magnetic particles, and
wherein upon flowing through the particle sorting region, the plurality of first particles are removed from the fluid sample based on a size of the first particles;

flowing the fluid sample from the particle sorting region into a first microfluidic channel located within the inertial focusing region, wherein, upon entering the first microfluidic channel, the plurality of second particles and the plurality of third particles are inertially focused along a common streamline within the fluid sample; and
flowing the fluid sample comprising the plurality of second particles and the plurality of third particles focused along the common streamline from the first microfluidic channel into a second microfluidic channel located within the magnetophoresis region,
wherein the magnetophoresis region comprises a first array of magnets arranged above the second microfluidic channel and a second array of magnets arranged beneath the second microfluidic channel of the magnetophoresis region such that each magnet in the first array faces a corresponding magnet in the second array,
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, 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 an interface between two magnets in the first array is aligned with an interface between two magnets in the second array,
wherein the first array and the second array produce a magnetic flux gradient profile that extends transverse to a central longitudinal axis of the second microfluidic channel, wherein the magnetic flux gradient profile comprises a local minimum positioned within the second microfluidic channel due to the alignment of the first array and the second array with respect to one another,
wherein the common streamline within the fluid sample, as the fluid sample enters the second microfluidic channel, is aligned so as to be laterally offset from the local minimum of the magnetic flux gradient profile, and
wherein the magnetic flux gradient profile within the magnetophoresis region deflects the plurality of third particles from the one or more common streamlines in the fluid sample without deflecting the plurality of second particles from the one or more common streamlines.

2. The method of claim 1 , wherein the plurality of first particles comprises at least one of:
one or more red blood cells, or
one or more platelets.

3. The method of claim 2 ,
wherein the plurality of second particles comprises one or more white blood cells, and
wherein the plurality of third particles comprises one or more target cells different from the white blood cells.

4. The method of claim 3 , wherein each of the magnetic particles comprises a magnetic bead configured to specifically bind to the one or more target cells.

5. The method of claim 3 , wherein the one or more target cells comprises:
one or more circulating endothelial cells.

6. The method of claim 3 , wherein the one or more target cells comprises:
one or more circulating tumor cells.

7. The method of claim 2 ,
wherein the plurality of third particles comprises one or more white blood cells, and
wherein the plurality of second particles comprises one or more target cells different from the white blood cells.

8. The method of claim 7 , wherein each of the magnetic particles comprises a magnetic bead configured to specifically bind to the one or more white blood cells.

9. The method of claim 7 , wherein the one or more target cells comprises:
one or more circulating endothelial cells.

10. The method of claim 7 , wherein the one or more target cells comprises:
one or more circulating tumor cells.

11. The method of claim 1 , wherein the fluid sample is whole blood.

12. The method of claim 1 , wherein the fluid sample is diluted blood.

13. A system for sorting particles, the system comprising:
a microfluidic device comprising:
a particle sorting region,
an inertial focusing region comprising a first microfluidic channel, and
a magnetophoresis region comprising:
a second microfluidic channel,
a first array of magnets arranged above the second microfluidic channel, and
a second array of magnets arranged beneath the second microfluidic channel,
wherein each magnet in the first array faces a corresponding magnet in the second array,
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,
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 an interface between two magnets in the first array is aligned with an interface between two magnets in the second array,
wherein the first array and the second array produce a magnetic flux gradient profile that extends transverse to a central longitudinal axis of the second microfluidic channel, and
wherein the magnetic flux gradient profile comprises a local minimum positioned within the second microfluidic channel due to the alignment of the first array and the second array with respect to one another,

wherein the microfluidic device is configured to:
receive a fluid sample comprising blood, the fluid sample comprising a plurality of first particles, a plurality of second particles, and a plurality of third particles bound to magnetic particles,
flow the fluid sample through the particle sorting region, wherein upon flowing through the particle sorting region, the plurality of first particles are removed from the fluid sample based on a size of the first particles,
flow the fluid sample from the particle sorting region into the first microfluidic channel of the inertial focusing region, wherein, upon entering the first microfluidic channel, the plurality of second particles and the plurality of third particles are inertially focused along a common streamline within the fluid sample, and
flow the fluid sample comprising the plurality of second particles and the plurality of third particles focused along the common streamline from the first microfluidic channel into the second microfluidic channel of the magnetophoresis region,
wherein during operation of the microfluidic device:
the common streamline within the fluid sample, as the fluid sample enters the second microfluidic channel, is aligned so as to be laterally offset from the local minimum of the magnetic flux gradient profile, and
the magnetic flux gradient profile within the magnetophoresis region deflects the plurality of third particles from the one or more common streamlines in the fluid sample without deflecting the plurality of second particles from the one or more common streamlines.

14. The system of claim 13 , wherein the microfluidic device is configured to flow the fluid sample through the particle sorting region, such that at least one of (i) one or more red blood cells or (ii) one or more platelets, are removed from the fluid sample based on a size

Assignees

• Massachusetts Gen Hospital

Inventors

• Spuhler Philipp S
• Smith Kyle C
• Fachin Fabio
• Barber Thomas Alan
• Kapur Ravi
• Toner Mehmet
• Pai Vincent
• Karabacak Nezihi Murat

Classifications

• G01N15/1433

  using image recognition · CPC title

• G01N15/149

  specially adapted for sorting particles, e.g. by their size or optical properties · CPC title

• C12M47/04 Primary

  Cell isolation or sorting (purging biological preparations of unwanted cells C12N5/0081, determining the presence or kind of microorganism C12Q1/04) · CPC title

• B01L3/00

  Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers · CPC title

• B01L3/502753

  characterised by bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation · CPC title