Microfluidic devices for isolating particles

Patent metadata

Field	Value
Publication number	US-10151753-B2
Application number	US-201415104775-A
Country	US
Kind code	B2
Filing date	Dec 17, 2014
Priority date	Dec 17, 2013
Publication date	Dec 11, 2018
Grant date	Dec 11, 2018

Abstract

In one aspect, a system for isolating particles includes a first array of magnets, a second array of magnets arranged generally in parallel with and spaced apart from the first array of magnets, and a micro fluidic device. The micro fluidic device includes a substrate, an inlet arranged on the substrate and configured to receive a fluid sample, an outlet arranged on the substrate, a first region of the substrate including a channel connected to the inlet, where the first region of the substrate is arranged to sandwich the channel between the first and second arrays of magnets.

First claim

What is claimed is:

1. A system for isolating particles comprising:
a first array of magnets arranged in a two-dimensional checkerboard pattern of magnets with directly adjacent magnets in the array having dipole moments aligned in opposite directions;
a second array of magnets arranged in a two-dimensional checkerboard pattern of magnets with directly adjacent magnets in the array having dipole moments aligned in opposite directions, wherein the second array of magnets is arranged generally in parallel with and spaced apart from the first array of magnets; and
a microfluidic device comprising:
a substrate;
an inlet arranged on the substrate and configured to receive a fluid sample;
an outlet arranged on the substrate;
a first region of the substrate comprising a channel connected to the inlet, wherein the first region of the substrate is arranged to sandwich the channel between the first and second arrays of magnets; and
a second region of the substrate in fluid communication with the channel and comprising a particle capture zone containing a plurality of particle capture sites, wherein each particle capture site comprises a receptacle sized to confine a first type of particle and an opening in fluid communication with the outlet, wherein a size of the receptacle is larger than a diameter of the first type of particle, and a size of the opening is smaller than the diameter of the first type of particle to trap the first type of particle in the receptacle, but allow passage of articles smaller than the opening.

2. The system of claim 1 , wherein each of the magnets in the first array of magnets and the second array of magnets comprises NdFeB, SmCo, Fe, Ni, Co, FePt, MnFe2O4, CoFe2O4, NiFe2O4, ZnMnFe2O4, or iron oxide.

3. The system of claim 1 , wherein a peak magnitude value of a magnetic field strength at a point between the first array of magnets and the second array of magnets is about 0.45 T or more.

4. The system of claim 1 , wherein a magnitude of an average magnetic field strength along a line extending from the first array of magnets to the second array of magnets is about 0.35 T or more.

5. The system of claim 1 , further comprising:
a tweezer device configured to displace the particle captured in one of the particle capture sites; and
a receiver device configured to receive the displaced particle,
wherein the tweezer device is an optical tweezer device, and wherein the optical tweezer device comprises an optical source for generating an optical beam, and a lens for focusing the optical beam into one of the particle capture sites.

6. The system of claim 1 , wherein, for at least one particle capture site, the receptacle is sized to receive and confine a single first type of particle, and
wherein, for the at least one particle capture site, the opening is small enough to prohibit passage of the first type of particle and large enough to allow passage of a second type of particle.

7. The system of claim 1 , wherein at least one particle capture site comprises a first wall and a corresponding second wall,
wherein the receptacle is bounded by the first wall and the second wall, and
wherein the opening is defined between an end of the first wall and an end of the second wall.

8. The system of claim 1 , wherein at least one of the particle capture sites comprises a wall, wherein the receptacle is defined by a recess in the wall, and wherein the opening extends from the receptacle on a first side of the wall to a second opposite side of the wall.

9. The system of claim 1 , further comprising a fluid manifold arranged on the substrate between the particle capture zone and the outlet.

10. A method for isolating particles, the method comprising:
providing a first and a second array of magnets, wherein the first and second arrays of magnets are positioned to sandwich a region including a channel of a microfluidic device, and wherein the magnets in the first and second arrays are arranged in a two-dimensional checkerboard pattern of magnets with directly adjacent magnets in each array having dipole moments aligned in opposite directions;
providing a sample fluid comprising a plurality of particles into the channel, wherein at least one first type of particle is bound to a magnetic bead, and wherein a magnetic field extending between the first and second magnet arrays within the channel causes the at least one first type of particle to separate from remaining particles in the fluid sample;
providing the fluid sample containing the remaining particles to a particle capture zone of the microfluidic device, wherein the particle capture zone comprises a plurality of particle capture sites each comprising a receptacle that is larger than a diameter of a second type of particle in the remaining particles and that has an opening that is smaller than the diameter of the second type of particle to trap the second type of particle in the receptacle, but allow passage out of the receptacle of other remaining particles smaller than the opening; and
capturing one or more of the second type of particles in the receptacles of the particle capture sites of the microfluidic device, wherein the one or more second type of particles are not bound to a magnetic bead.

11. The method of claim 10 , wherein capturing the second type of particle comprises receiving a single second type of particle in a receptacle of one of the particle capture sites.

12. The method of claim 10 , further comprising displacing the one or more second type of particles from the particle capture sites using an optical tweezer, wherein displacing the one or more second type of particles from the particle capture sites comprises displacing a single one of the second type of particles from a single one of the particle capture sites, and wherein the optical tweezer is configured to provide a plurality of optical traps.

13. The method of claim 10 , further comprising flowing a first additional fluid through at least the particle capture zone, wherein the first additional fluid comprises a plurality of first fluorescent markers, and the method further comprises allowing the plurality of the first fluorescent markers to bind to one or more of the second type of particle.

14. The method of claim 13 , further comprising:
optically exciting the first fluorescent markers bound to the one or more second type of particle;
obtaining an image of the one or more second type of particle; and
determining a characteristic of the second type of particle based on the obtained image.

15. The method of claim 14 , wherein determining the characteristic of the second type of particle based on the obtained image comprises determining an intensity of fluorescence associated with the second type of particle based on the obtained image.

16. The method of claim 14 , further comprising:
flowing an elutant through at least the particle capture zone, wherein flowing the elutant causes the fluorescently labeled particles to release from second type of particle;
flowing a second additional fluid sample through at least the particle capture zone, wherein the second additional fluid comprises a plurality of a second type of fluorescent marker, and wherein one of more of the second type of fluorescent markers bind to one or more of the second type of particle.

17. The method of claim 16 , further comprising:
optically exciting one or more of the second fluorescent markers bound to second type of particle;
obtaining a second image of the second type of particle; and
determining a characteristic of the second type of particle based on th

Assignees

• Massachusetts Gen Hospital

Inventors

• Lee Hakho
• Weissleder Ralph
• Lee Kyungheon
• Song Jun

Classifications

• G01N33/575 Primary

  for cancer · CPC title

• B01L2200/0647

  Handling flowable solids, e.g. microscopic beads, cells, particles · CPC title

• B03C2201/18

  Magnetic separation whereby the particles are suspended in a liquid · CPC title

• B01L2300/0654

  Lenses; Optical fibres · CPC title

• G01N21/6428

  Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" (in vivo A61B5/00; immunoassay G01N33/53) · CPC title