MICROFLUIDIC CHIP AND DEVICE

A microfluidic device and a microfluidic chip are provided. The microfluidic device includes the microfluidic chip, a pouring element, a flow adjustment element and a processor. The microfluidic chip includes a sorting assembly, a sample outlet channel, a pouring channel, a collection channel and a waste channel. The sorting assembly includes a sample inlet channel and a sorting chamber. The pouring element is connected to the pouring channel. The flow adjustment element is connected to a distal end of the sample outlet channel. The processor is configured to control the pouring element to pour a guiding fluid into the pouring channel entering the sample outlet channel and control the flow adjustment element to adjust a flow resistance of a drain section of the sample outlet channel.

BACKGROUND

Technical Field

The present disclosure is related to chips and devices for collecting target particles/cells in a fluidic sample, and more particularly related to microfluidic chips and devices.

Description of Related Art

Microfluidic chips and devices have been widely applied in various fields, particularly in the bio-related fields, such as the biomedical field, the biochemical field and so on. In the application of the bio-related field, a blood sample containing various cells is loaded in a microfluidic chip for collecting at least one target cell among the various cells. The ability to collect the target cells via the microfluidic chip or device represents significant advance in disease screening and monitoring.

SUMMARY

The present application provides a microfluidic chip and device for accurately sorting and collecting at least one target cell in a fluidic sample.

In accordance with some embodiments of the present application, a microfluidic device and a microfluidic chip are provided, wherein the microfluidic device includes the microfluidic chip, and further includes a pouring element, a flow adjustment element and a processor. The microfluidic chip includes a first sorting assembly, a first sample outlet channel, a pouring channel, a collection channel and a first waste channel. The first sorting assembly includes a first sorting chamber, a first sample inlet channel, and two guiding channels, wherein the first sample inlet channel and the two guiding channels are converged at the first side of the first sorting chamber. The first sample inlet channel is positioned between the two guiding channels. The first sample inlet channel extends to reach a first side of the first sorting chamber and is configured to allow a fluidic sample entering the first sorting chamber. The first sample outlet channel extends to reach a second side of the first sorting chamber at an inlet end of the first sample outlet channel. The pouring channel is branched from the first sample outlet channel at a first joint of the first sample outlet channel. The collection channel is branched from the first sample outlet channel at a second joint of the first sample outlet channel and includes an ejection hole connected to a droplet ejection device to dispense a single droplet. The first sorting chamber bifurcates into the first waste channel and the first sample outlet channel at the second side. The first sample outlet channel consists of an entrance section positioned between the inlet end of the first sample outlet and the first joint, a buffer section positioned between the first joint and the second joint, and a drain section positioned between the second joint and the distal end of the first sample outlet. The pouring element is connected to the pouring channel. The flow adjustment element is connected to a distal end of the first sample outlet channel. When the flow adjustment element is actuated, a flow resistance to the fluid flow in the drain section is lower than a flow resistance to the fluid flow in the collection channel. The processor is configured to control the pouring element to pour a guiding fluid into the pouring channel entering the buffer section of the first sample outlet channel and control the flow adjustment element to adjust a flow resistance of the drain section of the first sample outlet channel.

DESCRIPTION OF THE EMBODIMENTS

Refer toFIG. 1, which depicts a microfluidic device for sorting and collecting at least one target cell in a fluidic sample according to an embodiment of the present application. The microfluidic device10includes the microfluidic chip100. The microfluidic chip100includes a first sorting assembly120, a first sample outlet channel150, a pouring channel160, a collection channel170and a first waste channel140. The first sorting assembly120includes a first sample inlet channel110. Specifically, a fluidic sample to-be processed may be injected into the microfluidic chip100through the first sample inlet channel110and later sorted by the first sorting assembly120. When no target cell is detected in the fluidic sample, the fluidic sample is drained out through the first waste channel140. Alternately, when at least one target cell is detected in the fluidic sample, the fluidic sample with the target cell is sorted by the sorting operation of the first sorting assembly120and pushed to enter the first sample outlet channel150. The target cell entering the first sample outlet channel150may be ejected from the collection channel170by pouring a fluid flow from the pouring channel160into the first sample outlet channel150to push the target cell to travel towards the collection channel170.

The first sorting assembly120further includes two first guiding channels122and124and a first sorting chamber130. The first sample inlet channel110extends to reach a first side131of the first sorting chamber130and includes a fluidic sample inlet hole112. In other words, the first sample inlet channel110extends between the first side131of the first sorting chamber130and the fluidic sample inlet hole112. The first sample inlet channel110and the fluidic sample inlet hole112are configured to allow a fluidic sample entering the first sorting chamber130. The first sample inlet channel110and the two first guiding channels122and124are converged at the first side131of the first sorting chamber130. The joint of the first sample inlet channel110connecting to the first side131of the first sorting chamber130is positioned between joints of the two first guiding channels122and124connecting to the first side131of the first sorting chamber130, as shown inFIG. 1.

The first sorting chamber130bifurcates into the first waste channel140and the first sample outlet channel150at a second side132of the first sorting chamber130. The first waste channel140extends between the second side132of the first sorting chamber130and a waste outlet hole142passing through the outer surface of the microfluidic chip100and forming a fluidic communication with the first waste channel140. The first sample outlet channel150may have an inlet end152reaching a second side132of the first sorting chamber130and a distal end154distant from the inlet end152. The pouring channel160is branched from the first sample outlet channel150at a first joint JA of the first sample outlet channel150. The collection channel170is branched from the first sample outlet channel150at a second joint JB of the first sample outlet channel150and includes an ejection hole171, wherein the first joint JA is positioned between the inlet end152and the second joint JB of the first sample outlet channel150. In the embodiment, the first sample outlet channel150may be divided into an entrance section150A extending from the inlet end152to the first joint JA, a buffer section150B extending from the first joint JA to the second joint JB and a drain section150C extending from the second joint JB to the distal end154. In some embodiments, a channel diameter of the buffer section150B may be gradually reduced from the first joint JA to the second joint JB.

The microfluidic device10further includes a processor PR and a guiding fluid source BS. The guiding fluid source BS is configured to provide a guiding fluid to the two first guiding channels122and124via respective guiding fluid inlet holes128. The processor PR may control the guiding fluid source BS to determine the flow flux of the guiding fluid injected to the two first guiding channels122and124. According to the present embodiment, an adjustment hole126passing through the outer surface of the microfluidic chip100may be further formed in the path of the first guiding channel122, and an adjustment tube BAT connected to the guiding fluid source BS may be inserted into the adjustment hole126. In this way, the processor PR may also control the guiding fluid source BS to additionally provide the guiding fluid through the adjustment tube BAT. In addition, a switch SW1is attached to the adjustment tube BAT to control the fluid flow in the adjustment tube BAT. According to the present embodiment, each of the first sample inlet channel110and the two first guiding channels122and124allows a fluid from the exterior to enter the microfluidic chip100and may further include a filter section FS. The filter sections FS may each include a plurality of filtering slits for filtering unwanted particles, bubbles, or impurities in the entering fluid. Some exemplary embodiments of the structure of the filter sections FS have been disclosed in U.S. Patent Publication No. US20180326419A1, and the entire disclosure thereof is herein incorporated by reference.

The microfluidic device10further includes a pouring element PE connecting to an end of the pouring channel160. In some embodiments, the pouring element PE may include a pouring tube PT connected to a guiding fluid source/tank (not shown) and a valve161attached to the pouring tube PT, wherein the pouring tube PT may be inserted to the hole formed at the end of the pouring channel160. The processor PR may control the pouring element PE to pour guiding fluid into the pouring channel160by controlling the valve161to open. Specifically, when the valve161is opened, the guiding fluid is allowed to enter the pouring channel160from the guiding fluid source/tank through the pouring tube PT. In some embodiments, the pouring element PE may further include a pump capable of pushing the guiding fluid entering the pouring channel160to increase the flow rate of the guiding fluid in the pouring channel160. In some embodiments, the pouring element PE and the first sorting assembly120may share the same guiding fluid source BS, but in alternative embodiments, the pouring element PE and the first sorting assembly120may connect to different guiding fluid sources.

The microfluidic device10also includes a flow adjustment element such as a valve151connected to the distal end154of the first sample outlet channel150. The processor PR may control the valve151to open or close. According to the present embodiment, an intrinsic flow resistance to the fluid flow in the drain section150C of the first sample outlet channel150is lower than an intrinsic flow resistance to the fluid flow in the collection channel170. Once the processor PR controls the valve151to open, the drain section150C of the first sample outlet channel150is a free channel without being clogged, thus the fluid flow arriving the second joint JB tends to enter the drain section150C rather than the collection channel170due to the greater intrinsic flow resistance in the collection channel170. To the contrary, when the processor PR controls the valve151to close, the flow resistance to the fluid flow in the drain section150C increases and the fluid flow arriving the second joint JB tends to enter the collection channel170. In some embodiments, the collection channel170may have a smaller channel diameter than the drain section150C to increase the intrinsic flow resistance.

In general, the internal volume of the first sample outlet channel150between the first joint JA and the second joint JB (i.e. the buffer section150B) is 0.01 μL-1000 μL. The internal volume of the first sample outlet channel150between the second joint JB and the distal end154(i.e. the drain section150C) is 0.01 μL-1000 μL. The internal volume of the collection channel170is 0.01 μL-1000 μL. However, the disclosure is not limited thereto.

In some embodiments, the fluidic sample to be processed by the microfluidic device10may be a whole blood sample. The whole blood sample is injected into the first sample inlet channel110via the fluidic sample inlet hole112. In some embodiments, the whole blood sample may be treated by mixing with a known reagent so as to dye target cells (particles) in the whole blood sample to be fluorescent. Thereafter, the treated whole blood sample is injected into the first sample inlet channel110. Therefore, the fluorescent dyed target cells in the whole blood sample can be detected by an optical determination technique. For example, a linear light beam may be used to irradiate the whole blood sample travelling in the first sample inlet channel110. Once the fluorescent dyed target cells in the whole blood sample pass through the linear light beam, the linear light beam may be absorbed or transferred to another wavelength, which allows the detection of the fluorescent dyed target cells. In the embodiment, the detection of the fluorescent dyed target cells may be performed at a section of the first sample inlet channel110adjacent to the first sorting chamber130. However, the disclosure is not limited thereto.

Please refer toFIG. 1. When no fluorescent dyed target cell is detected in the fluidic sample travelling in the first sample inlet channel110, the processor PR may control the flow flux of the guiding fluid in the first guiding channel124to be higher than the flow flux of the guiding fluid in the first guiding channel122. In this way, the fluidic sample is guided into the first waste channel140and then drained from the waste outlet hole142. In general, the valve151remains open and the valve161remains close. Some of the fluidic sample and the guiding fluid might stream into the first sample outlet channel150and be drained away from the distal end154of the first sample outlet channel150. Namely, the distal end154of the first sample outlet channel150may not be clogged when no fluorescent dyed target cell is detected in the fluidic sample.

When at least one fluorescent dyed target cell is detected in the fluidic sample streaming in the first sample inlet channel110, the processor PR may control the flow flux of the guiding fluid in the first guiding channel124to be lower than the flow flux of the guiding fluid in the first guiding channel122. In one embodiment, the processor PR directly controls the guiding fluid source BS to provide guiding fluid with a higher flow flux to the first guiding channel122and provide guiding fluid with a lower flow flux to the first guiding channel124.

In another embodiment, the processor PR controls the switch SW1to open so as to provide additional guiding fluid to the first guiding channel122such that the flow flux of the guiding fluid in the first guiding channel124can be lower than the flow flux of the guiding fluid in the first guiding channel122. Therefore, the fluidic sample having the detected fluorescent dyed target cell TC is guided into the first sample outlet channel150.

FIGS. 2A-2Cshows how the dispensation of a detected fluorescent dyed target cell TC is achieved. In the present embodiment, as shown inFIG. 2A, when the switch SW1is opened, the valve151is opened and the valve161is closed under the control of the processor PR, the fluidic sample having the detected fluorescent dyed target cell TC is allowed to move forward along the entrance section150A, and then enter the buffer section150B. In some embodiments, the position of the detected fluorescent dyed target cell TC in the fluidic sample may be determined based on the flow rate of the fluidic sample. Once the fluorescent dyed target cell TC enters the buffer section150B as shown inFIG. 2B, the processor PR closes the valve151to increase the flow resistance in the drain section150C and opens the valve161to pour guiding fluid into the pouring channel160as shown inFIG. 2C. Since the valve151is closed and the flow resistance in the drain section150C is increased, the poured guiding fluid tends to stream towards the ejection hole171rather than the distal end154and hence pushes the detected fluorescent dyed target cell TC into the collection channel170. In other words, the detected fluorescent dyed target cell TC eventually enters the collection channel170from the buffer section150B and streams towards the ejection hole171under the push of the poured guiding fluid as shown inFIG. 2C. The fluorescent dyed target cell TC is then ejected from the ejection hole171. Meanwhile, the valve151may be reopened, and the valve161may be closed again.

In some embodiments, a detection of the present of the fluorescent dyed target cell TC may be performed at a first predetermined location between the inlet end152and the first joint JA (i.e. the entrance section150A) in the first sample outlet channel150. According to one embodiment of the present invention, if a fluorescent dyed target cell TC is detected in the sorting chamber, the switch SW1may be opened for a very short time (i.e. 7 ms) to prevent another fluorescent dyed target cell TC from entering the first sample outlet channel150. Once the fluorescent dyed target cell TC reaches the first predetermined location, the switch SW1may be closed. Thus, it ensures that only a single fluorescent dyed target cell TC exists in the first sample outlet channel150.

The processor PR may close the valve151and open the valve161after a time interval after the switch SW1is opened so as to guide the detected fluorescent dyed target cell TC to travel towards the collection channel170and consequently enable the detected fluorescent dyed target cell TC to be ejected through the ejection hole171. However, the disclosure is not limited thereto. In one embodiment of the present invention, a detection of the present of the fluorescent dyed target cell TC may be performed at a second predetermined location between the first joint JA and the second joint JB (i.e. the buffer section150B). When the fluorescent dyed target cell TC reaches the second predetermined location, the process may close the valve151and open the valve161to flush the fluorescent dyed target cell TC to the collection channel170. The flushing will last until the fluorescent dyed target cell TC ejected by the droplet ejection device172. The time interval can be determined by the distance between the first predetermined location and second predetermined location, and the flow flux of the fluidic sample in the first sample outlet channel.

According to some embodiments, the droplet ejection device172may be a nozzle inserted into the ejection hole171, as shown inFIG. 2C. The nozzle is used to dispense a single droplet containing the fluorescent dyed target cell TC arriving the ejection hole171. However, the disclosure is not limited thereto. For example, in another embodiment, a needle, a tube, or the like may be inserted into the ejection hole171to take out the fluorescent dyed target cell TC arriving the ejection hole171.

Refer toFIG. 3, which depicts a microfluidic chip according to an embodiment of the present application. The microfluidic chip300includes a first sorting system301, a second sorting system303and a connection channel320. The first sorting system301includes a first sorting assembly310, a first sample outlet channel318, a pouring channel360, a collection channel370and a first waste channel316. The first sorting assembly310includes a first sorting chamber310A, a first sample inlet channel312and two first guiding channels314A and314B, wherein the first guiding channel314A may include a first adjustment hole BAH1. The structure of the first sorting system301ofFIG. 3is similar with the structure of the microfluidic chip100ofFIG. 1. The sorting and collecting mechanism of the first sorting system301is similar with the sorting and collecting mechanism of the microfluidic device10. For the convenience of understanding, repeated and redundant description is hence omitted here.

In comparison to the microfluidic chip100, the microfluidic chip300further includes the second sorting system303and the connection channel320. The second sorting system303includes a second sorting assembly330, a second sample outlet channel338, and a second waste channel336. The second sorting assembly330includes a second sorting chamber330A, a second sample inlet channel332and two second guiding channels334A and334B, wherein the second guiding channel334A may include a second adjustment hole BAH2. The connection channel320forms a fluidic communication between the second sample outlet channel338and the first sample inlet channel312, as shown inFIG. 3.

The second sorting system303provides a preliminary sorting mechanism for the first sorting system301. Specifically, a fluidic sample may be loaded into the second sample inlet channel332via the fluidic sample inlet hole332A. A processor (not shown) is disposed to respectively control the flow flux of the guiding fluid in the two second guiding channels334A and334B. The fluidic sample is preliminarily sorted via the second sorting system303. The sorting mechanism of the second sorting system303is similar to the sorting mechanism of the microfluidic device10. For the convenience of understanding, repeated and redundant description is omitted.

After being sorted via the second sorting system303, the fluidic sample sequentially streams in the second sample outlet channel338, the connection channel320and the first sample inlet channel312. Due to the preliminary sorting mechanism of the second sorting system303, the concentration of the target cells in the fluidic sample (i.e. the purity of the fluidic sample) entering the first sample inlet channel312would be increased in comparison with the fluidic sample in the second sample inlet channel332, which benefits the collection of the target cells via the ejection hole371. In some embodiments of the present application, a droplet ejection device (not shown) is connected to the ejection hole371to dispense a single droplet containing one target cell arriving the ejection hole371.

Refer toFIG. 4, which depicts a microfluidic chip according to an embodiment of the present application. In comparison to the microfluidic chip300ofFIG. 3, the connection channel320A of the microfluidic chip300A ofFIG. 4further includes a plurality of longitudinal-particle-separation sections3021serially disposed along the extending direction of the connection channel320A. Each of the longitudinal-particle-separation sections3021includes a winding portion3021A and a shortcut portion3021B, wherein the winding portion3021A and the shortcut portion3021B are connected in parallel between two joints at opposite terminals of each of the longitudinal-particle-separation sections3021, and the path length of the winding portion3021A is greater than the path length of the shortcut portion3021B. In the present embodiment, the fluidic sample streams along the winding portion3021A and the shortcut portion3021B in different velocities, so as to further separate the target cells in the fluidic sample away from each other. In this way, the fluidic sample streaming in the first sample inlet channel312A of the microfluidic chip300A has target cells farther away from each other in comparison to the target cells of the fluidic sample streaming in the first sample inlet channel312of the microfluidic chip300, which helps the operator or the user collect a single target cell among the target cells form the ejection hole371A.