Patent Application
20250010292
The present invention claims priority under 35 U.S.C. § 119 to Japanese Patent Application No. 2023-109531 filed on Jul. 3, 2023, the entire contents of which is incorporated herein by reference.
The present disclosure relates to a microfluidic device.
Method for measuring particle size distribution called electrical sensing zone method (Coulter's principle) has been known. In this measurement method, an electrolytic solution that contains a particle is allowed to pass through a pore called nanopore. During passage of the particle, the pore will have therein the electrolytic solution whose amount is reduced by the volume of the particle and will increase the electric resistance. The volume (or, particle size) of the particle can therefore be determined by measuring the electric resistance of the pore.
The inside of the pore device 100R is filled with an electrolytic solution 2 that contains particles 4 to be detected. The inside of the pore device 100R is partitioned with a pore chip 102 into two spaces, in which an electrode 106 and an electrode 108 are individually provided. The pore chip 102 has a pore 104 formed therein. Under potential difference generated between the electrode 106 and the electrode 108, an ion current flows between the electrodes, during which the particles 4 migrate from one space through the pore 104 into the other space while driven by electrophoresis.
The measuring instrument 200R generates a potential difference between a pair of electrodes 106, 108, and acquires information correlated with the resistivity Rp between the electrode pair. The measuring instrument 200R has a transimpedance amplifier 210, a voltage source 220, and a digitizer 230. The voltage source 220 is structured to generate a potential difference Vb between the pair of electrodes 106, 108. The potential difference Vb provides a driving force of electrophoresis, and gives a bias signal for measuring the resistivity Rp.
Between the pair of electrodes 106, 108, there flows microcurrent Is which is inversely proportional to the resistivity of the pore 104.
The transimpedance amplifier 210 converts the microcurrent Is into voltage signal Vs. With the conversion gain denoted as r, the equation below holds.
Substitution of equation (1) into the equation (2) gives equation (3) below.
The digitizer 230 converts the voltage signal Vs into digital data Ds. As can be seen, the voltage signal Vs inversely proportional to the resistivity Rp of the pore 104 is obtainable, with use of the measuring instrument 200R.
For a short period of passage of the particles, the resistivity Rp of the pore 104 increases. The current Is therefore decreases like in a pulsated manner, every time one particle passes. The amplitude of each pulse current correlates with the particle size. The data processor 300 processes the digital data Ds, and typically analyzes the count or particle size of the particles 4 contained in the electrolytic solution 2. A part of the data processor 300 may be placed in a server or a cloud.
The prior pore chip 102 is structured to have an opening (pore) formed in a membrane, with the thickness t considerably smaller than the diameter (aperture) d of the pore (t<d). The present disclosers have studied such low-aspect-ratio pore device, and have recognized problems below.
In the low-aspect-ratio pore device, electric field intensity in the pore demonstrates a large positional dependence in the radial direction. Different signals will therefore be observable between the cases whether the particle passes the center of the pore, or the outer periphery of the pore, thereby degrading measurement accuracy.
The present disclosure has been arrived at considering such circumstances, so that one exemplary embodiment thereof is to provide a device whose measurement accuracy may be improved.
A microfluidic device in one embodiment of the present disclosure has a microfluidic chip. The microfluidic chip has a channel formed in an in-plane direction thereof. The channel has a gate with a narrowed width, and a first part and a second part separated by the gate. With the length of the gate denoted as L, and with the width of the gate denoted as W, a relational expression 1≤L/W<2 is satisfied.
Note that also free combinations of these constituents, and also any of the constituents and expressions exchanged among the method, apparatus, and system, are valid as the present disclosure or modes of the present disclosure. Also note that the description of this section (SUMMARY OF THE INVENTION) does not describe all essential features of the present disclosure, and thus also subcombinations of these features described herein may constitute the present disclosure.
Embodiments will now be described, by way of example only, with reference to the accompanying drawings which are meant to be exemplary, not limiting, and wherein like elements are numbered alike in several Figures, in which:
Some exemplary embodiments of the present disclosure will be outlined. This outline is intended for briefing some concepts of one or more embodiments, for the purpose of basic understanding of the embodiments, as an introduction before detailed description that follows, without limiting the scope of the invention or disclosure. This outline is not an extensive overview of all possible embodiments and is therefore intended neither to specify key elements of all embodiments, nor to delineate the scope of some or all of the embodiments. For convenience, the term “one embodiment” may be used to designate a single embodiment (example or modified example), or a plurality of embodiments (Examples or Modified Examples) disclosed in the present specification.
The microfluidic device according to one embodiment has a microfluidic chip. The microfluidic chip has a channel formed in an in-plane direction thereof. The channel has a gate with a narrowed width, and a first part and a second part separated by the gate. With the length of the gate denoted as L, and with the width of the gate denoted as W, a relational expression 1≤L/W<2 is satisfied.
This structure can generate, in the gate, an electric field which is substantially uniform in the width and height directions. The structure can generate electric signals at the same intensity upon passage of every particle thorough the gate, regardless of the route of passage, and can therefore improve the measurement accuracy.
In one embodiment, a cross-sectional shape of the gate may be rectangular.
In one embodiment, the cross-section of the gate may have the width and the length which are substantially equal.
In one embodiment, the microfluidic chip may be formed of polydimethylsiloxane. The polydimethylsiloxane has an advantage over other materials, in terms of workability and cost. The microfluidic chip may alternatively be formed of a cyclic olefin-based resin such as COP (cyclic olefin polymer) or COC (cyclic olefin copolymer).
In one embodiment, the microfluidic chip may have an inflow port (inlet) structured to communicate the outside of the microfluidic chip with the first part; and an outflow port (outlet) structured to communicate the outside of the microfluidic chip with the second part.
In one embodiment, the microfluidic chip may have a first inflow port structured to communicate the outside of the microfluidic chip with the first part; a second inflow port structured to communicate the outside of the microfluidic chip with the second part; a first outflow port structured to communicate the outside of the microfluidic chip with the first part; and a second outflow port structured to communicate the outside of the microfluidic chip with the second part.
The microfluidic chip may further have a first electrode opening structured to communicate a bottom face of the microfluidic chip with the first part; and
A microparticle measurement system according to one embodiment may have any one of the aforementioned microfluidic devices; and a measuring instrument connected to the microfluidic device and structured to measure an electric signal.
Preferred embodiments will be explained below, referring to the attached drawings. All similar or equivalent constituents, members and processes illustrated in the individual drawings will be given same reference signs, so as to properly avoid redundant explanations. The embodiments are merely illustrative and are not restrictive about the disclosure or the invention. All features and combinations thereof described in the embodiments are not always necessarily essential to the disclosure or the invention.
Dimensions (thickness, length, width, etc.) of the individual members illustrated in the drawings may be appropriately enlarged or shrunk for easy understanding. Furthermore, the dimensions of the plurality of members do not necessarily indicate the dimensional relationship among them, so that a certain member A, if depicted thicker than another member B in a drawing, may even be thinner than the member B.
In the present specification, a “state in which a member A is coupled to a member B” includes a case where the member A and the member B are physically and directly coupled, and a case where the member A and the member B are indirectly coupled while placing in between some other member that does not substantially affect the electrically coupled state, or does not degrade the function or effect demonstrated by the coupling thereof.
Similarly, a “state in which a member C is provided between the member A and the member B” includes a case where the member A and the member C, or the member B and the member C are directly coupled, and a case where they are indirectly coupled, while placing in between some other member that does not substantially affect the electrically coupled state among the members, or does not degrade the function or effect demonstrated by the members.
In the present specification, reference signs attached to electric signals such as voltage signal and current signal, or circuit elements such as resistor, capacitor, and inductor represent voltage value, current value, or circuit constants (resistivity, capacitance, and inductance) of the individual components as necessary.
Prior to describing a microfluidic device 400 according to an embodiment, a prior pore chip and relevant problems thereof will be described.
With use of such membrane 810 having a thickness t of several tens nanometers, a relational expression between the diameter d of the pore 812 (referred to as pore diameter) and the thickness t of the membrane 810 will be given by:
d>t. Defining now the aspect ratio of the pore as t/d, the prior pore chip 800 is understood to have a low aspect ratio.
Although the histogram should ideally be unimodal since the standard particle has a uniform diameter, the measured results demonstrated two split peaks, indicating strong bimodality. The bimodality of the histogram makes estimation of the particle size difficult and degrades the measurement accuracy.
The present disclosers has focused on the electric field strength in the pore 812, as a possible reason for the bimodality found with use of the prior pore chip 800.
The problem in the prior art has been described. Paragraphs below will explain a microfluidic device 400 according to embodiments capable of solving the problem.
The microfluidic device 400 has stacked therein a microfluidic chip 410, an electrode sheet 440, and a support substrate 460. The microfluidic chip 410 has a microchannel 412 formed in-plane (in the x-y plane). Although the microchannel 412 possibly has a so-called micrometer order size (a channel width of several to several hundreds micrometers), the width at the gate thereof may locally have a submicron or nanometer order size, since the width is designed in consideration of the particles to be measured, as described later.
The microfluidic chip 410 may be formed of polydimethylsiloxane. The microfluidic chip 410 may alternatively be formed of a cyclic olefin-based resin such as COP (cyclic olefin polymer) or COC (cyclic olefin copolymer). Method for forming the microchannel 412 may rely upon any technique having been known or would be available for the future, without special limitation.
The microchannel 412 extends in the x-direction, with one end connected to an inlet 424, and with the other end connected to an outlet 426. One of the inlet 424 and the outlet 426 may be used as an inflow port of the electrolytic solution that contains the microparticles, and the other may be used as an air vent.
The inlet 424 communicates the first space 420 with the upper face of the microfluidic chip 410, meanwhile the outlet 426 communicates the second space 422 with the upper face of the microfluidic chip 410.
The first electrode opening 428 communicates the first space 420 with the bottom face of the microfluidic chip 410. The second electrode opening 430 communicates the second space 422 with the bottom face of the microfluidic chip 410.
The electrode sheet 440 has a first electrode E1 and a second electrode E2 formed thereon. The first electrode E1 is drawn out through the first electrode opening 428 outwards, meanwhile the second electrode E2 is drawn out through the second electrode opening 430 outwards.
The first electrode E1 has a first channel-side electrode 442, a first interconnect 444, and a first measuring instrument-side electrode 446. The first measuring instrument-side electrode 446 is formed at a position that does not overlap the microfluidic chip 410. Meanwhile the first channel-side electrode 442 is formed at a position that overlaps the first electrode opening 428 and exposes in the first space 420. The first interconnect 444 connects the first channel-side electrode 442, and the first measuring instrument-side electrode 446.
Similarly, the second electrode E2 has a second channel-side electrode 448, a second interconnect 450, and a second measuring instrument-side electrode 452. The second measuring instrument-side electrode 452 is formed at a position that does not overlap the microfluidic chip 410. Meanwhile the second channel-side electrode 448 is formed at a position that overlaps the second electrode opening 430 and exposes in the second space 422. The second interconnect 450 connects the second channel-side electrode 448, and the second measuring instrument-side electrode 452.
The first electrode E1 and the second electrode E2 are electrically connectable, respectively at their first measuring instrument-side electrode 446 and the second measuring instrument-side electrode 452, to an unillustrated measuring instrument.
With the length of the gate 414 denoted as L, a relational expression 1≤L/W<2 is satisfied. Similarly, a relationship of 1≤L/H<2 is satisfied. The width W and the height H may be substantially equal or different. The L/W is referred to as aspect ratio.
The structure of the microfluidic device 400 has been explained. Next, microparticle measurement with use the microfluidic device 400 will be described.
The measuring instrument 200 is structured similarly to the measuring instrument 200R in
The current Is that flows from the first electrode E1 to the second electrode E2 is inversely proportional to impedance Z between the first electrode E1 and the second electrode E2. The microparticles 2 are positively or negatively charged and migrate while driven by an electric field (electrophoresis) generated between the first electrode E1 and the second electrode E2. Upon passage of the microparticles 2 through the gate 414, the impedance Z between the first electrode E1 and the second electrode E2 increases, and the current Is decreases. That is, in the microfluidic device 400, the gate 414 acts as the pore 104 in the prior pore device 100R.
In order to verify superiority of the microfluidic device 400, results of an electromagnetic field simulation will be described.
In the device with the aspect ratio given by L/W=1, electric field vectors inside the gate 414 are found to appear in parallel without component in the direction of y-axis, demonstrating a uniform electric field distribution.
For comparison, the same simulation was conducted while setting the length L of the gate 414 to 50 nm.
With the aspect ratio L/W controlled to 1 or larger, this embodiment can obtain a uniform electric field distribution at the gate 414. The same level of intensity of the signals will be obtainable, regardless of the route of passage of the particles. A highly unimodal histogram is therefore obtainable, while preventing the histogram from splitting. This successfully improves detection accuracy of the particle size or particle type.
With the aspect ratio L/W increased, or with the length L of the gate 414 elongated, the gate 414 will become more likely to cause clogging, and more likely to have a plurality of particles concurrently reside therein, thus degrading the measurement accuracy of the particle size distribution. Denoting now φ as the diameter of the particle, and if L<2×φ holds, then the count of the particle that can concurrently reside in the gate 414 is regarded as 1. Now the diameter φ of the particle that can pass through the gate 414 is limited by the width W of the gate 414, where a relationship of φ<W holds. Therefore, if L<2×W, that is L/W<2, then the probability that a plurality of particles can concurrently reside in the gate 414 may be reduced, whereby the measurement accuracy may be improved. Similarly, since φ<H holds, a probability that a plurality of particles can concurrently reside in the gate 414 may be reduced if a relation L<2×H, that is L/H<2 holds, whereby the measurement accuracy may be improved.
Next, a modification of the microfluidic device 400 of First Embodiment will be explained.
The height of the first space 420 and the second space 422 decreases continuously and gradually towards the gate 414.
In the microfluidic device 400 described in First Embodiment, the first space 420, the gate 414, and the second space 422 can be filled with the liquid by injection through the inlet 424, if the width W (and/or height H) of the gate 414 is up to several micrometers (3 μm, for example). The liquid injected through the inlet 424 will, however, be less likely to enter the gate 414 having a width W narrower than 3 μm.
The paragraphs below will describe Second Embodiment, regarding a microfluidic device with a small cross-sectional area of the gate 414, suited to detection of further smaller microparticles.
On the side of the first space 420E, there are provided a first inlet 431 and a first outlet 432. The first inlet 431 communicates one end of the first space 420E with the upper face of the microfluidic chip 410E. The first outlet 432 communicates the other end of the first space 420E with the upper face of the microfluidic chip 410E.
Similarly, on the side of the second space 422E, there are provided a second inlet 433 and a second outlet 434. The second inlet 433 communicates one end of the second space 422E with the upper face of the microfluidic chip 410E. The second outlet 434 communicates the other end of the second space 422E with the upper face of the microfluidic chip 410E.
The first space 420E and the second space 422E are connected while placing a gate 414E in between.
Prior to the measurement, the liquid is injected through the first inlet 431 into the first space 420E, so as to fill the inside thereof from the first inlet 431 towards the first outlet 432. Similarly, the liquid is injected through the second inlet 433 into the second space 422E, so as to fill the inside thereof from the second inlet 433 towards the second outlet 434. Upon arrival of the liquid in the first space 420E and the second space 422E at the gate 414E, also the gate 414E is filled with the liquid by capillarity.
Also in Second Embodiment, the internal heights of the first space 420E and the second space 422E may be gradated stepwise.
The modification described in First Embodiment can also be applied to Second Embodiment. For example, Second Embodiment may lack the first electrode opening 428 and the second electrode opening 430 and may instead have the rod-shaped first electrode E1 and second electrode E2 inserted into the first inlet 431 and the second inlet 433, respectively.
Having described the present disclosure with use of specific terms referring to the embodiments, the embodiments merely illustrate the principle and applications of the present disclosure, allowing a variety of modifications and layout change without departing from the spirit of the present disclosure specified by the claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2023-109531 | Jul 2023 | JP | national |
