# US 11,896,974 B2 · Microfluidic device for size and deformability measurements and applications thereof

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- Number: US 11,896,974 B2
- Document ID: US11896974B2
- Status: Granted
- Kind: B2
- Application number: 17/859,400
- Filed: 2022-07-07
- Published: 2022-11-03
- Granted: 2024-02-13
- Earliest claimed: 2019-01-17
- Assignees: The Regents of the University of Michigan
- Applicants: Regents of the University of Michigan
- Inventors: Mark A. Burns; Alyse D. Krausz; Sarah Elizabeth Mena; Martin Patrick De Beer; Kevin R. Ward; Frederick Korley
- Web page: https://patentgrep.com/patent/US11896974B2

## CPC

- B01L 3/502761: {specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads or physically stretching molecules}
- B01L 3/502707: {characterised by the manufacture of the container or its components}
- B01L 3/502715: {characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces}
- G01N 1/28: Preparing specimens for investigation {including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q}(mounting specimens on microscopic slides G02B21/34; means for supporting the objects or the materials to be analysed in electron microscopes H01J37/20 {; laboratory gas handling apparatus B01L5/00})
- G01N 15/1433: using image recognition
- G01N 21/6428: {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)}
- G01N 33/54366: {Apparatus specially adapted for solid-phase testing}
- G01N 33/54393: {Improving reaction conditions or stability, e.g. by coating or irradiation of surface, by reduction of non-specific binding, by promotion of specific binding}
- G01N 33/6803: {General methods of protein analysis not limited to specific proteins or families of proteins}
- B01L 2200/0668: Trapping microscopic beads
- B01L 2200/12: Specific details about manufacturing devices
- B01L 2300/0627: Sensor or part of a sensor is integrated
- G01N 2015/1006: {for cytology}
- G01N 2015/1493: {Particle size}
- G01N 2015/1495: {Deformation of particles}
- G01N 2021/6439: {with indicators, stains, dyes, tags, labels, marks}
- B01L: CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

A microfluidic device system includes a channel having an entrance and an exit, a height at the entrance being greater than a height at the exit. The height of the channel may decrease continuously from the height at the entrance to the height at the exit. Cells or particles or beads traveling through the channel become trapped based on their size and/or deformability. A visual sensor captures images of the trapped cells or particles or beads, and image software analyzes the captured images to provide size and/or deformability and/or fluorescence information. A method of fabricating such a microfluidic device includes introducing a glass wafer to an etching solution at a specific rate such that a first end of the glass wafer is etched longer than other portions of the glass wafer.

## Claims

### Claim 1

A microfluidic device system (2) comprising:
a data collection and readout device (4) connected to a visual sensor (8), the visual sensor (8) operatively connected to a microfluidic device (10) for detection within the microfluidic device (10);
an inlet (132) by which a solution enters the microfluidic device (10), wherein the inlet (132) is connected to a supply line (14) that is connected to a container (12);
wherein the microfluidic device (10) further comprises a channel (126) having an entrance (128) and an exit (130), a height (H1) at the entrance (128) being greater than a height (H2) at the exit (130), and a height of the channel between the entrance and the exit has multiple decreases in height along a length of the channel between the entrance and the exit,
wherein:
the channel comprises at least a first length region having a continuously decreasing height, a second length region having a continuously decreasing height, and a step-wise decrease in height as a transition between the first length region and the second length region,
the height of the channel continuously decreases from a first height to a second height along an entire length of the first length region,
the height of the channel continuously decreases from a third height to a fourth height along an entire length of the second length region, and
the step-wise decrease comprises a decrease in the height of the channel from the second height to the third height, wherein the step-wise decrease in height occurs over a length of the channel that is less than one or both of the lengths of the first and second length regions.

### Claim 2 (depends on 1)

The microfluidic device system (2) of claim 1, wherein the channel (126) has a width equal to or greater than 1000 μm.

### Claim 3 (depends on 1)

The microfluidic device system of claim 1, wherein one or both of the first length region and the second length region has a decreasing height profile that is linear.

### Claim 4 (depends on 1)

The microfluidic device of claim 1, wherein one or both of the first length region and the second length region has a quadratic decreasing height profile.

### Claim 5 (depends on 1)

A method of using the microfluidic device system of claim 1, comprising:
introducing an anti-interaction agent to the channel of the microfluidic device (204);
introducing a solution to the channel of the microfluidic device, wherein the solution comprises cells or particles;
flowing the solution through the channel;
trapping the cells or particles within the channel;
stopping the flow of the solution through the channel;
capturing an image of the trapped cells or particles;
sending the image to a data collection/readout device;
analyzing the image using image software to determine size or deformability information about the trapped cells or particles.

### Claim 6 (depends on 5)

The method of using the microfluidic device system of claim 5, wherein more than one image is captured, each image corresponding with a separate portion of the channel.

### Claim 7 (depends on 5)

The method of using the microfluidic device system of claim 5, wherein the size or deformability information identifies a number of subsets having certain sizes or deformability characteristics.

### Claim 8 (depends on 7)

The method of using the microfluidic device system of claim 7, wherein the size or deformability information further identifies the relative size of each of the number of subsets.

### Claim 9 (depends on 1)

A method of fabricating the microfluidic device system of claim 1, comprising:
fabricating the microfluidic device, comprising:
preparing a glass wafer for etching;
etching the glass wafer by introducing the glass wafer into an etching solution at a specific rate with a first end of the glass wafer being etched longer than subsequent portions of the glass wafer;
performing additional etching on the glass wafer by submerging the entire glass wafer, including a previously un-etched portion of the glass wafer, in an etching solution; and
measuring the etched profile of the glass wafer to thereby fabricate the microfluidic device; and
operatively coupling the microfluidic device to the visual sensor.

### Claim 10 (depends on 9)

The method of claim 9, further comprising:
drilling the inlet and an outlet to the microfluidic device (10) on a separate glass wafer;
bonding the separate glass wafer to the etched glass wafer (416).

### Claim 11 (depends on 9)

The method of claim 9, wherein the etched profile has a target slope, and wherein the specific rate is determined based on the target slope.

### Claim 12 (depends on 1)

A method for using the microfluidic device system of claim 1, comprising:
flowing an analysis solution through the channel, the analysis solution comprising a plurality of beads, each bead having a multiplex formed on a surface thereof, the multiplex being formed by association of first and second molecules with a target protein,
trapping each bead of the plurality of beads along the channel based on the diameter of the bead;
detecting the trapped plurality of beads with the visual sensor.

### Claim 13 (depends on 12)

The method of claim 12, further comprising forming the analysis solution by combining a first solution with the target protein and a second solution, wherein
the first solution comprises the plurality of beads, each bead having a diameter and a surface substantially coated with the first molecule, and, the second solution comprises the second molecule associated with a quantum dot,
wherein the first molecule and the second molecule associate with the target protein to form the multiplex on the surface of each bead of the plurality of beads.

### Claim 14 (depends on 13)

The method of claim 13, wherein the first solution, the target protein, and the second solution are combined prior to introduction into the microfluidic device.

### Claim 15 (depends on 14)

The method of claim 14, wherein the first solution, the target protein, and the second solution are combined within the microfluidic device.

### Claim 16 (depends on 12)

The method of claim 12, further comprising forming the analysis solution by introducing the target protein into the microfluidic device, the microfluidic device being preloaded with a solution comprising the plurality of beads, each bead having a diameter and a surface substantially coated with the first molecule, and the second molecule associated with a quantum dot.

### Claim 17 (depends on 12)

The method of claim 12, wherein detecting the trapped plurality of beads comprises detecting a fluorescence of the multiplex on the surface of at least one of the trapped beads.

### Claim 18 (depends on 12)

The method of claim 12, wherein detecting the trapped plurality of beads with the visual sensor comprises:
capturing an image of the trapped plurality of beads,
sending the image to the data collection/readout device; and
analyzing the image using image software to measure a fluorescence of the multiplex on the surface of at least one of the trapped beads located at one or more locations along the channel.

### Claim 19

A microfluidic device system (2) comprising:
a data collection and readout device (4) connected to a visual sensor (8), the visual sensor (8) operatively connected to a microfluidic device (10) for detection within the microfluidic device (10);
an inlet (132) by which a solution enters the microfluidic device (10), wherein the inlet (132) is connected to a supply line (14) that is connected to a container (12);
wherein the microfluidic device (10) further comprises a channel (126) having an entrance (128) and an exit (130), a height (H1) at the entrance (128) being greater than a height (H2) at the exit (130), and a height of the channel between the entrance and the exit has multiple decreases in height along a length of the channel between the entrance and the exit,
wherein:
the channel comprises at least one region in which the height of the channel continuously decrease and at least one step-wise decrease in height, and
the height of the channel has continuously decreasing slope between the entrance and the exit.