Microfluidic device and method for monitoring or measuring one or more parameters of fluid

Abstract

The present invention provides a microfluidic device, the microfluidic device comprising: a fluid control module configured to be removably coupled to an external tube; and a replaceable cartridge, the replaceable cartridge being detachably coupled to the fluid control module. The replaceable cartridge may include: a first port arranged in fluid communication with the fluid control module; a micro-channel in fluid communication with the first port, where the fluid control module is configured to manipulate fluid received from the external tube and / or one or more reagent solutions from the micro-channel, and to subsequently dispose the fluid and / or the one or more reagent solutions as waste fluid; a second port arranged in fluid communication with the fluid control module to flow the waste liquid into the microchannel; and a pressure relief valve in fluid communication with the microchannel, where the pressure relief valve is configured to regulate an air gap within the microchannel, the fluid control module is coupled to the microchannel to maintain each of the pre-loaded one or more reagent solutions in the microchannel spaced apart from the waste fluid received from the fluid control module. A method for monitoring or measuring one or more parameters of the fluid is also provided.

Description

[0001] Cross Reference to Related Applications This application claims priority to Singapore Patent Application No. 10202300536X, filed February 28, 2023, the contents of which are hereby incorporated by reference in their entirety for all purposes.

[0002] TECHNICAL FIELD Various embodiments relate to a microfluidic device and method for monitoring or measuring one or more parameters of a fluid received through an external tube, in particular one or more biomarkers of a subject’s blood received through a cannula. BACKGROUND

[0003] Biomarkers such as blood glucose and blood gases of hospitalized patients can fluctuate significantly. Good regulation of such biomarkers is critical to the morbidity and mortality of patients. To achieve optimal regulation of fluctuating biomarkers, frequent monitoring is required.

[0004] For example, in a medical facility, existing clinically validated blood glucose monitoring methods involve finger pricking and hand-held analyzers. For example, existing frequent blood glucose monitoring can involve about 48 finger pricks per 2 days, while more frequent blood glucose monitoring can require about 96 finger pricks per 2 days. This is to provide frequent blood glucose monitoring to achieve optimal blood glucose regulation. This cumbersome and frequent peripheral pricking of patients results in pain, bruising, and skin changes, increasing the suffering of patients. Blood glucose monitoring can be delayed due to the cumbersome process of caring for hospitalized patients and other tasks, affecting timely treatment, blood glucose regulation, and patient outcomes.

[0005] At the same time, other existing options like continuous glucose monitoring (CGM) and optical monitoring that measure interstitial fluid glucose can not be reliable for acutely ill patients and can require calibration devices. CGM can also not be accurate, and optical monitoring can produce results that vary with skin color. Most of these existing methods do not provide immediate results.

[0006] More than 60% of hospitalized patients require intravenous (IV) cannulation during their hospital stay. Intravenous cannulation can be used for hydration, medication, and various blood tests. To obtain accurate results for blood tests through intravenous cannulation, the intravenous cannula needs to be flushed first with saline to avoid any interference. After that, a portion of blood (pre-ambulatory blood: 2-3 mL) is drawn from the intravenous cannula and discarded as it can be diluted by the saline. Blood drawing (mid-stream blood) and analysis are then performed using a different syringe.

[0007] Such methods consume large amounts of blood per test and are labor intensive. Manual replacement of the syringe can contaminate the blood sample and the patient.

[0008] Therefore, there is a need for miniaturized devices to provide a convenient, fast, painless, and accurate method to support frequent biomarker (e.g., blood glucose) monitoring of patients, especially of critically ill patients, thereby addressing at least the above-mentioned problems. SUMMARY

[0009] According to an embodiment, a microfluidic device is provided. The microfluidic device can include a fluid control module configured to be detachably coupled to an external tube, and a replaceable cartridge configured to be detachably coupled to the fluid control module. The replaceable cartridge can include a first port arranged in fluid communication with the fluid control module to flow one or more reagent solutions between the fluid control module and the replaceable cartridge, a microchannel in fluid communication with the first port, the one or more reagent solutions initially preloaded in at least one or more portions of the microchannel, wherein the fluid control module can be further configured to manipulate a fluid received from the external tube and / or the one or more reagent solutions received from the replaceable cartridge, and subsequently dispose the manipulated fluid and / or the manipulated one or more reagent solutions as a waste fluid, a second port arranged in fluid communication with the fluid control module to flow the waste fluid into the microchannel, the second port being different from the first port, and a pressure relief valve in fluid communication with the microchannel. The pressure relief valve can be configured to regulate an air gap within the microchannel to keep each of the preloaded one or more reagent solutions in the microchannel spaced apart from the waste fluid received from the fluid control module.

[0010] According to an embodiment, a method for monitoring or measuring one or more parameters of a fluid received through an external tube is provided. The method can include providing a microfluidic device according to an embodiment and as described herein, the microfluidic device detachably coupled to the external tube, regulating one or more reagent solutions between a fluid control module of the microfluidic device and a replaceable cartridge detachably coupled to the fluid control module, manipulating the one or more reagent solutions received from the replaceable cartridge, obtaining a fluid from the external tube and manipulating the fluid, and sampling the fluid to monitor or measure the one or more parameters of the fluid. The one or more reagent solutions can be initially preloaded in at least one or more portions of a microchannel of the replaceable cartridge. BRIEF DESCRIPTION OF DRAWINGS

[0011] In the drawings, like reference numerals in all different views generally refer to like parts. The drawings are not necessarily to scale, emphasis instead being placed on illustrating the principles of the application. In the following description, various embodiments of the application are described with reference to the following drawings, in which: FIG. 1 A schematic cross-sectional view of a microfluidic device is shown, in accordance with various embodiments.

[0012] FIG. 2 shows an enlarged schematic cross-sectional view of a pressure relief valve of the microfluidic device of FIG. 1 at low pressure, in accordance with various embodiments. FIG. 1

[0013] FIG. 3 shows an enlarged schematic cross-sectional view of the pressure relief valve of FIG. 2 at high pressure, in accordance with various embodiments.

[0014] FIG. 4 shows a flowchart illustrating a method for monitoring or measuring one or more parameters of a fluid received through an external tube, in accordance with various embodiments.

[0015] FIG. 5 shows a schematic illustration of a miniaturized intravenous cannula integrated blood sensing system, in accordance with one example.

[0016] FIG. 6 shows a schematic cross-sectional view of another exemplary device.

[0017] FIG. 7 shows a schematic cross-sectional view of the device of FIG. 6 while a sensor flush is being performed.

[0018] FIG. 8 shows a schematic cross-sectional view of the device of FIG. 6 while blood pumping is being performed.

[0019] FIG. 9 shows a schematic cross-sectional view of the device of FIG. 6 while blood sampling is being performed.

[0020] FIG. 10 shows a schematic cross-sectional view of the device of FIG. 6 while a cannula flush is being performed.

[0021] FIG. 11 shows a schematic cross-sectional view of the device of FIG. 6 after multiple repetitions of the workup procedure.

[0022] FIG. 12 shows an exploded schematic view of a wearable microfluidic device, in accordance with one example. DETAILED DESCRIPTION

[0023] ​The following detailed description references the drawings, which illustrate specific embodiments of the application. These embodiments are described in sufficient detail to enable those skilled in the art to practice the application. Other embodiments can be utilized and structural, logical, and electrical changes can be made without departing from the scope of the present application. The various embodiments are not necessarily mutually exclusive, as some embodiments can be combined with one or more other embodiments to form new embodiments.

[0024] Embodiments described in the context of one of the methods or apparatuses are equally applicable to the other method or apparatus. Similarly, embodiments described in the context of a method are equally applicable to the apparatus, and vice versa.

[0025] Features described in the context of an embodiment can correspondingly be applied to the same or similar features in other embodiments. Features described in the context of an embodiment can correspondingly be applied to other embodiments, even if not explicitly described in those other embodiments. Furthermore, additions and / or combinations and / or alternatives can be applied to features described in the context of an embodiment, corresponding to the same or similar features in other embodiments.

[0026] In the context of the various embodiments, the articles "a", "an", and "the" as used in reference to a feature or element are intended to include one or more of the features or elements.

[0027] In the context of the various embodiments, the term "about" applied to a value of an item includes the exact value and reasonable variations.

[0028] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0029] As used herein, a phrase of the form "at least one of A or B" can include A or B or both A and B. Correspondingly, a phrase of the form "at least one of A or B or C", or any further listing, can include any and all combinations of one or more of the associated listed items.

[0030] As used herein, the expression "configured to" can mean "constructed to" or "arranged to".

[0031] Various implementations can provide automated microfluidic devices for in-line blood analysis, more specifically for blood monitoring via intravenous cannulation. Microfluidic devices eliminate the need for repeated finger punctures, which are painful for blood collection. In other words, microfluidic devices can include miniaturized devices for frequent and painless blood monitoring of hospitalized patients with minimal blood consumption. For example, one application could be frequent monitoring of glucose levels in critically ill patients. The device can include a microfluidic module integrated with sensors and a replaceable solution cartridge pre-loaded with reagents for both blood flushing and waste collection.

[0032] FIG. 1 A schematic cross-sectional view of a microfluidic device 100 according to various embodiments is shown. The microfluidic device 100 may include: a fluid control module 102 configured to be detachably coupled to an external tube (a portion of which is indicated as by double-headed arrow 106); and a replaceable cartridge 104 configured to be detachably coupled to the fluid control module 102. The replaceable cartridge 104 may include: a first port 108 arranged in fluid communication with the fluid control module 102 to allow one or more reagent solutions 110 to flow between the fluid control module 102 and the replaceable cartridge 104; a microchannel 112 in fluid communication with the first port 108, wherein the one or more reagent solutions 110 are initially pre-loaded in at least one or more portions of the microchannel 112; a second port 114 arranged in fluid communication with the fluid control module 102; and a pressure relief valve 116 in fluid communication with the microchannel 112. The fluid control module 102 can be further configured to manipulate fluid 117 received from external tube 106 and / or one or more reagent solutions 110 received from replaceable cartridge 104, and subsequently dispose of the manipulated fluid and / or the manipulated one or more reagent solutions as waste liquid 118. A second port 114, different from the first port 108, can be used to allow waste liquid 118 to flow into microchannel 112. A pressure relief valve 116 can be configured to adjust an air gap 120 within the microchannel 112 to maintain each of the pre-loaded one or more reagent solutions 110 in the microchannel 112 spaced from the waste liquid 118 received from the fluid control module 102. By adjusting the air gap 120, the pressure relief valve 116 can also be configured to adjust each of the pre-loaded one or more reagent solutions 110 and waste liquid 118 in the microchannel 112.

[0033] In the context of the various embodiments, the term "manipulation" associated with fluid 117 may mean directing or regulating the flow of the fluid, or measuring or monitoring the fluid. The term "manipulation" associated with the one or more reagent solutions 110 may mean directing or regulating the flow of more reagent solutions, or allowing the one or more reagent solutions to mix and react with the fluid and / or another one or more reagent solutions.

[0034] In various embodiments, the fluid control module 102 may include: a first microvalve 122 configured to regulate fluid 117 between the microfluidic device 100 and the external tube 106; a second microvalve 124 in fluid communication with the first microvalve 122; and a pump module 126 in fluid communication with the first microvalve 122 and the second microvalve 124, the pump module 126 being configured to direct the one or more reagent solutions 110 toward or away from the first microvalve 122 and the second microvalve 124. The second microvalve 124 may be disposed between the first microvalve 122 and the pump module 126.

[0035] For example, the first micro-valve 122 may include a bidirectional micro-valve or a multi-way micro-valve, and the second micro-valve 124 may include a unidirectional micro-valve. For example, each of the first micro-valve 122 or the second micro-valve 124 may be passive or active, normally closed or normally open, mechanical or non-mechanical. Preferably, each of the first micro-valve 122 or the second micro-valve 124 may be a normally closed micro-valve based on one of the following types: bistable, electrically controlled, piezoelectric, or thermally controlled.

[0036] In various embodiments, pump module 126 may include: a first pump 128 configured to cooperate with pressure relief valve 116 to draw one or more reagent solutions 110 from replaceable cartridge 104 and direct the drawn reagent solutions 110 to a first microvalve 122 and a second microvalve 124; and a second pump 130 arranged in fluid parallel with the first pump 128, configured to cooperate with pressure relief valve 116 to draw one or more reagent solutions 110 away from the first microvalve 122 and the second microvalve 124 and direct the drawn reagent solutions 110 to replaceable cartridge 104, thereby allowing fluid 117 from external tube 106 to follow the drawn reagent solutions 110 in a direction toward a first port 108 of replaceable cartridge 104. In practice, pump module 126 may provide bidirectional pumping. For example, each of the first pump 128 or the second pump 130 can be passive (e.g., air-driven, capillary, magnetically driven, chemically driven, gravity-driven, surface tension driven) or active, or mechanical (e.g., piezoelectric, electromagnetic, electrostatic, shape memory alloy (SMA), thermo-pneumatic, phase change, ionically conductive polymer film (ICPF), dielectric elastomer film (DEF), diaphragm). Preferably, each of the first pump 128 or the second pump 130 can be an active micropump, or a diaphragm micropump, or a piezoelectric micropump.

[0037] The fluid control module 102 may further include a tortuous channel arranged between the pump module 126 and the first microvalve 122 and the second microvalve 124. The tortuous channel can accommodate a sufficiently long conduit filling a small space or region within the fluid control module 102 to draw one or more reagent solutions 110 from the first microvalve 122 and the second microvalve 124 by cooperating with the pressure relief valve 116 to operate the second pump 130, thereby allowing a sufficient amount of fluid 117 to be drawn from the external tube 106 into the tortuous channel. With a sufficient amount of fluid 117 placed within the tortuous channel, midstream flow of fluid 117 can be sampled via the second microvalve 124. In other words, such a tortuous channel design can advantageously maximize the channel length within the space of the fluid control module 102, thereby increasing the volume of fluid drawn to achieve the extraction of midstream fluid 117. In blood monitoring, the tortuous channel can help avoid contamination of upstream blood with saline solution.

[0038] In various embodiments, the fluid control module 102 may further include a check valve arranged in fluid communication with the second port 114 to prevent backflow of waste liquid 118.

[0039] In various embodiments, the microfluidic device 100 may further include a sensing module 132 configured to receive fluid 117 via a second microvalve 124 and monitor or measure one or more parameters of the fluid 117. In one example, the sensing module 132 may be integrated into the fluid control module 102. Such integration can provide form factor and user experience advantages because the microfluidic device 100 can be compact and a single component / unit for easy user operation. In another example (not shown in the figures), the sensing module 132 may be externally coupled to the fluid control module 102.

[0040] Sensing module 132 may include one or more biomarker sensors. For example, the one or more biomarker sensors may include, but are not limited to, at least one of the following: blood gas sensor, blood glucose sensor, blood pressure sensor, temperature sensor, lactate sensor, ammonia sensor, or protein-based detection sensor. The one or more biomarker sensors may be based on one or more of the following operating principles: electrochemical, thermal, impedance, biomolecular, or colorimetric. Some biomarker sensors may be self-powered or passive, while others may require a power source such as a battery to operate. Information acquired by the one or more biomarker sensors may be processed and presented, for example, using indicators mounted on microfluidic device 100. For example, fluid control module 102 may include an integrated processor (circuit system board) to control microvalves (e.g., 122, 124), pumps (e.g., 126), readout of information from sensing module 132, process data, and display the processed data in a meaningful manner (e.g., in the form of an alarm system via audio, visual, and display panels). Alternatively or additionally, information may be transmitted to a remote processor for processing and subsequent display. This allows for alerts to relevant individuals (such as nurses or doctors) to be sent via a software application on a tablet or mobile device. Electronic and electrical components for the sensing module 132, miniature valves (e.g., 122, 124), and pumps (e.g., 126) can be mounted on a printed circuit board. The printed circuit board can be arranged or stacked above or below the fluid control module 102.

[0041] In various embodiments, the replaceable cartridge 104 may include a third port arranged in fluid communication with the sensing module 132. The fluid control module 102 may further include a micropump configured to cooperate with a pressure relief valve 116 to draw out one or more pre-loaded reagent solutions 110 from the replaceable cartridge 104 and direct the drawn-out reagent solutions 110 to the sensing module 132 through the third port, which is different from the first port 108 and the second port 114. In other words, the micropump can provide directed pumping for fluid flow from the replaceable cartridge 104 to the fluid control module 102 through the third port.

[0042] Figure 2 shows an enlarged schematic cross-sectional view of the pressure relief valve 116 under low pressure according to various embodiments, while Figure 3 shows an enlarged schematic cross-sectional view of the pressure relief valve 116 under high pressure according to various embodiments. The pressure relief valve 116 may include: a bidirectional pressure relief valve comprising a body 240 having an internal deformable interface 242 forming a passage 244 within the body 240; and a movable ball 246 configured to move along the passage 244 against the internal deformable interface 242 of the body 240, such that the internal deformable interface 242 is deformable in shape to provide pressure balance within the microfluidic device 100. A vent 248 may be provided at one end of the passage 244, while an orifice 250 may be in fluid communication with a microchannel 112 at the opposite end of the passage 244. As shown in Figure 2, when fluid 117 is not flowing into the microfluidic device 100, for example, when fluid 117 flows out into the external tube 106, low pressure may occur in the sealed replaceable cartridge 104. In such cases, the movable ball 246 moves toward the orifice 250 to prevent air from entering the microchannel 112 under low pressure, thereby maintaining pressure balance. On the other hand, as shown in Figure 3, when fluid 117 flows into the microfluidic device 100, more specifically into the fluid control module 102, the movable ball 246 moves toward the vent 248 under high pressure, and the pressure relief valve 116 attempts to release the pressure in the replaceable cartridge 104 to maintain pressure balance. The different pressures controlled by the pressure relief valve 116, combined with the activation of the first pump 128 or the second pump 130, allow the controlled movement of fluid 117, the one or more reagent solutions 110, and / or waste liquid 118.

[0043] It should be understood that FIG. 1 The schematic views of the microfluidic device 100 in Figures 2 and 3 and the pressure relief valve 116 in Figures 2 and 3 are not limiting and are for illustrative purposes only. For example, variations in layout, shape, size, and arrangement are possible without departing from the intended function of the microfluidic device 100 and the pressure relief valve 116, respectively.

[0044] In the case where two or more reagent solutions are pre-loaded in the replaceable cartridge 104, each of these reagent solutions can be arranged as different sections within the microchannel 112, wherein air gaps separate adjacent reagent solutions. The air gaps can be adjusted by a pressure relief valve 116. In another example, each of these reagent solutions can be housed in an independent chamber within the replaceable cartridge 104, and each of these independent chambers can have at least one port (which can be described in a similar context to the first port 108 and / or the second port 114), said at least one port being configured to be removably coupled to the fluid control module 102. In other words, different reagent solutions can enter the fluid control module 102 through different ports, and the number of such ports is not limited to just two ports (e.g., as shown in the image). FIG. 1 108, 114 shown).

[0045] The microfluidic device 100, according to various embodiments, can be configured in shape and size as a wearable or portable microfluidic device. For example, the microfluidic device 100 may include a device for blood monitoring via intravenous cannulation. In other words, the device can be used to pump / sample a test solution (blood) from an intravenous cannula for automated on-site analysis. More specifically, the device may include a microfluidic control module (e.g., FIG. 1 The device includes a fluid control module 102 and a replaceable cartridge (e.g., 104) with a reagent solution (e.g., 110) and a bidirectional pressure relief valve (e.g., 116), wherein the reagent solution and waste liquid (e.g., 118) are separated by an air gap (e.g., 120). The microfluidic control module can be electronically controlled or programmed to provide an automated microfluidic module by using at least two pumps or micropumps (e.g., 128, 130) for bidirectional pumping and flushing of multiple test and reagent solutions, and at least two valves or microvalves (e.g., 122, 124) for guiding the flow of blood (e.g., fluid 117) and reagent solutions. The device may further include at least one sensor (e.g., sensing module 132) for detection and measurement purposes. The replaceable cartridge (or interchangeably referred to as a replaceable microfluidic cartridge) can include pre-loaded reagents such that waste liquid can be collected in the same sealed chamber (i.e., the replaceable cartridge) to occupy the space of the consumed reagent solution, thereby minimizing the total volume of the chamber. Waste liquid and multiple reagent solutions can be separated by air gaps in the device to avoid potential contamination. A bidirectional pressure relief valve can be integrated to enable repeatable bidirectional blood or reagent solution extraction and flushing by repeatedly pumping in and out of the sealed chamber with various test and reagent solutions. Waste liquid can be collected and transferred to the same chamber as the reagent solution, achieving volume and weight savings. Advantageously, the sealed chamber facilitates pressure regulation and allows fluid movement with the device.

[0046] Figure 12 shows an exploded schematic view of a wearable microfluidic device 1201 according to one example. As shown in Figure 12, the wearable microfluidic device may be provided with a wristband 1203 coupled to housings 1270, 1272, which house a stacked arrangement of a fluid control module 102, a battery 1280, and a printed circuit board 1278, which houses electronic and electrical components for a sensing module 132, microvalves (e.g., 122, 124), and a pump (e.g., 126). The top portion of housing 1270 may include a display panel 1274 and a visual and / or auditory indicator 1276. Housings 1270, 1272 may be suitably designed to: easily receive a replaceable cartridge 104 for coupling with the fluid control module 102; remove the replaceable cartridge 104 from housings 1270, 1272; and provide access between a venous cannula 1206 and the fluid control module 102. Various modules and components can be arranged as depicted in Figure 12 to minimize the fluid path length and sample volume requirements for each test. Such arrangements or components allow for compact and user-friendly designs.

[0047] Figure 4 illustrates a flowchart of a method 400 for monitoring or measuring one or more parameters of fluid received through an external tube, according to various embodiments. As shown in Figure 4, at step 402, a microfluidic device 100, detachably coupled to an external tube 106 according to various embodiments, can be provided. (See also: Regarding...) FIG. 1 The features of the described microfluidic device 100 can be similarly applied to method 400. At step 404, one or more reagent solutions 110 can be adjusted between the fluid control module 102 of the microfluidic device 100 and a replaceable cartridge 104 detachably coupled to the fluid control module 102. The one or more reagent solutions 110 may initially be pre-loaded in at least one or more portions of the microchannels 112 of the replaceable cartridge 104. At step 406, the one or more reagent solutions 110 received from the replaceable cartridge 104 can be manipulated. At step 408, fluid 117 can be obtained from the external tube 106 and manipulated. More specifically, the flow of fluid 117 can be manipulated or controlled. At step 410, fluid 117 can be sampled to monitor or measure the one or more parameters of fluid 117.

[0048] In various embodiments, adjusting the one or more reagent solutions 110 between the fluid control module 102 and the replaceable cartridge 104 at step 404 may include: opening a first microvalve 122 of the fluid control module 102; closing a second microvalve 124 of the fluid control module 102; activating a first pump 128 of the pump module 126 of the fluid control module 102 to guide the one or more reagent solutions 110 through a first port 108 of the replaceable cartridge 104 and the fluid control module 102 to an external tube 106; and activating a pressure relief valve 116 of the replaceable cartridge 104 to a low-pressure mode to maintain pressure balance within the replaceable cartridge 104. The low-pressure mode may be as shown in FIG2, and pressure balance can be maintained in the low-pressure mode because the one or more reagent solutions 110 flow out to the external tube 106.

[0049] Manipulating the receipt of the one or more reagent solutions 110 from the replaceable cartridge 104 at step 406 may include: closing the first microvalve 122; opening the second microvalve 124 to guide the one or more reagent solutions 110 received from the replaceable cartridge 104 to the sensing module 132 of the fluid control module 102; and subsequently disposing of the one or more reagent solutions 110 as waste liquid 118 through the second port 114 of the replaceable cartridge 104 from the sensing module 132 to the microchannel 112, while maintaining an air gap 120 between the waste liquid 118 and the one or more reagent solutions 110 pre-loaded in the replaceable cartridge 104. At step 406, the pressure relief valve 116 may be in a low-pressure mode.

[0050] Obtaining and manipulating fluid 117 from external pipe 106 at step 408 may include: opening a first microvalve 122; closing a second microvalve 124; deactivating a first pump 128; activating a second pump 130 of pump module 126 to direct fluid 117 from external pipe 106 to pump module 126; and activating pressure relief valve 116 to a high-pressure mode to maintain pressure balance within replaceable cartridge 104. In other words, fluid 117 may be directed into a portion of the tortuous channel of fluid control module 102. The high-pressure mode may be as shown in FIG3, and pressure balance can be maintained in the high-pressure mode as fluid 117 flows into microfluidic device 100.

[0051] Sampling the fluid 117 at step 410 may include: closing the first microvalve 122; opening the second microvalve 124; deactivating the second pump 130; and activating the first pump 128 to guide a midstream sample of the fluid 117 to the sensing module 132 for monitoring and measurement; and subsequently disposing of the midstream sample of the fluid 117 as waste liquid 118 through the second port 114 from the sensing module 132 into the microchannel 112, while maintaining an air gap 120 between the waste liquid 118 and the one or more reagent solutions 110 pre-loaded in the replaceable cartridge 104. At step 410, the pressure relief valve 116 may be in a high-pressure mode.

[0052] In various embodiments, in addition to activating the first pump 128 to direct the midstream sample of fluid 117 to the sensing module 132 for monitoring and measurement, method 400 may further include activating a micropump of the fluid control module 102 to extract one or more reagent solutions 110 pre-loaded in a replaceable cartridge 104, and directing the extracted one or more reagent solutions 110 to the sensing module 132 through a third port of the replaceable cartridge 104 to allow the extracted one or more reagent solutions 110 to react or mix with the midstream sample of fluid 117 for monitoring and measurement.

[0053] Method 400 may further include repeating steps 404 to 410 to repeatedly monitor or measure one or more parameters of fluid 117.

[0054] In various embodiments, the external tube 106 may include a cannula comprising one end inserted into the subject and an opposite end detachably coupled to the microfluidic device 100. The fluid 117 may include extracted blood from the subject, and the one or more parameters of the fluid 117 may include or represent one or more biomarkers of the subject. The one or more reagent solutions 110 may include saline solutions, optionally one or more enzymatic solutions, optionally one or more drugs, optionally one or more nutrient solutions, and optionally a calibration solution for the sensing module 132.

[0055] While the methods described above are shown and described as a series of steps or events, it should be understood that any order of such steps or events should not be construed as limiting. For example, some steps may occur in a different order and / or concurrently with other steps or events besides those shown and / or described herein. Furthermore, not all of the shown steps may be required to implement one or more aspects or implementations described herein. Additionally, one or more of the steps described herein may be performed in one or more separate actions and / or phases.

[0056] The following describes a microfluidic device 100 in the form of an automated intravenous cannulation integrated microfluidic blood testing device. FIG. 1 For example, the device is actually a device for midstream blood sampling and testing; and the operating procedure of the device corresponding to method 400 of Figure 4.

[0057] The automated, miniaturized device enables painless blood analysis via intravenous cannulation, facilitating frequent monitoring of patient conditions (e.g., each test lasting less than 1 hour) and is user-friendly with minimal blood consumption. The device can be used for critically ill patients with hypoglycemia, diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), and / or other serious conditions. It can also be used to monitor other biomarkers, such as cortisol levels for mental health monitoring.

[0058] Figure 5 illustrates a schematic diagram of a miniaturized intravenous cannula integrated blood sensing system according to one example. As shown in Figure 5, the exemplary device 500 is worn by a subject 501 using a wristband 503, with the illustration in Figure 5 indicated by a rectangular dashed box 507, which shows the interior of the device 500 coupled to an intravenous cannula 506. One port 509 of the intravenous cannula 506 is coupled to the device 500, another port 511 can be coupled to a needle that can be inserted into a vein of the subject, and yet another port 513 can be retained for drug delivery.

[0059] Device 500 includes a miniaturized replaceable cartridge 504 pre-loaded with various reagents 510 and a microfluidic control module 502, which includes multiple pumps 528, 530, valves 522, 524, and sensors 532. In this example, a micropump 515 and a check valve 517 may be incorporated into the microfluidic control module 502. The replaceable cartridge 504 can also serve as a waste collection chamber by using an air gap to separate different reagents and waste liquids. A pressure valve (not shown in Figure 5) is integrated into the replaceable cartridge 504 to ensure repeatable bidirectional aspiration and flushing of blood / solution. The miniaturized replaceable cartridge 504 and the microfluidic control module 502 work together to control the repeated aspiration and flushing of blood cannulas with minimized size and weight. The characteristics of device 500 can be summarized in Table 1 below.

[0060] Table 1 Device 500 may include and FIG. 1 The same or similar elements or components in the microfluidic device 100 are therefore designated with reference numerals ending in the same number, and similar elements may be referred to as such. FIG. 1As described in the relevant context of the microfluidic device 100, its corresponding description can therefore be omitted here. Essentially, the miniaturized replaceable cartridge 504, reagent 510, microfluidic control module 502, multiple pumps 528 and 530, valves 522 and 524, and sensor 532 can be respectively integrated with… FIG. 1 The replaceable cartridge 104, the one or more reagent solutions 110, the fluid control module 102, the first pump 128 and the second pump 130, the first microvalve 122 and the second microvalve 124, and the sensing module 132 are described in a similar context.

[0061] Figure 6 shows a schematic cross-sectional view of another exemplary device 600. As shown in Figure 6, reagent 610 is pre-loaded into the microchannel 612 of the replaceable cartridge 604 and can be used to flush the cannula 606 (partially shown) or the sensor 632 integrated in the fluid control module 602. Waste liquid 618 is separated by an air gap 620. If desired, other reagents (not shown in Figure 6), such as calibration solutions for the sensor 632, can be integrated into the replaceable cartridge 604.

[0062] The pressure relief valve 616 works in conjunction with the micropumps 628 and 630 of the bidirectional pump module 626 to allow blood 617 (see Figures 8-10) to be drawn into a replaceable cartridge 604 and reagent 610 to be flushed from the replaceable cartridge 604 into the cannula 606. The replaceable cartridge 604 may be a sealed chamber. The device 600 includes a check valve 615 to prevent backflow of waste fluid 618. The sensor 632, micropumps 628 and 630, and microvalves 622 and 624 may be electrically controlled and programmed to function.

[0063] Device 600 may include and FIG. 1 The same or similar elements or components in the microfluidic device 100 are therefore designated with reference numerals ending in the same number, and similar elements may be referred to as such. FIG. 1 As described in the relevant context of the microfluidic device 100, its corresponding description can be omitted here. Essentially, reagent 610, microchannel 612, replaceable cartridge 604, cannula 606, sensor 632, fluid control module 602, waste liquid 618, air gap 620, pressure relief valve 616, micropump 628, 630, bidirectional pump module 626, blood 617, and microvalves 622, 624 can be respectively connected to… ​ The one or more reagent solutions 110, microchannels 112, replaceable cartridges 104, external tubes 106, sensing modules 132, fluid control modules 102, waste liquid 118, air gaps 120, pressure relief valves 116, first pumps 128 and second pumps 130, pump modules 126, fluid 117, first microvalve 122 and second microvalve 124 are described in a similar context.

[0064] Figures 6 to 10 illustrate the operating procedure of device 600 according to one example. Figures 6 to 10 can be viewed in sequence.

[0065] In Figure 6, initial flushing can be performed. Device 600 can be connected to cannula 606. Pump 628 is started (as indicated by the white arrow) and valve 622 is opened. As indicated by directional arrow 660, reagent 610 as flushing saline is pumped to cannula 606 with the aid of pressure relief valve 616; wherein, given the low pressure formed in replaceable cartridge 604, movable ball 646 is moved to a position within pressure relief valve 616 to maintain pressure balance.

[0066] Figure 7 shows a schematic cross-sectional view of the device 600 during sensor flushing. As shown in Figure 7, valve 622 is closed, valve 624 is opened, and flushing brine 610 is pumped to sensor 632, as indicated by directional arrow 760. This time, waste liquid 618 is pushed back into replaceable cartridge 604 through waste liquid port 614. The sealed cartridge design allows air gaps (e.g., air gap 620) to migrate. Because pressure balance can be maintained under the low pressure formed within replaceable cartridge 604, pressure relief valve 616 is not activated or affected.

[0067] Figure 8 shows a schematic cross-sectional view of the device 600 during blood pumping. As shown in Figure 8, valve 622 is opened, valve 624 is closed, and pump 630 is turned on or activated (as indicated by the white arrow) to draw blood 617 (forward flow) into a fluid passage (e.g., a tortuous passage), as indicated by the directional arrow 860. Pressure relief valve 616 is activated, in which movable ball 646 is moved to another position within pressure relief valve 616 to release the high pressure formed within cartridge 604 (sealed chamber). By releasing the high pressure generated due to the drawn blood 617 entering the fluid control module 602, pressure balance can be maintained within the replaceable cartridge 604.

[0068] Figure 9 shows a schematic cross-sectional view of device 600 during blood sampling. As shown in Figure 9, valve 622 is closed, valve 624 is opened, and an active pump 628 (as indicated by the white arrow) can pump a small amount of blood 617 (e.g., 50 µL) to sensor 632 for testing, as indicated by directional arrow 960. This allows for mid-flow sampling of low-volume blood. Waste liquid 618 is pushed into replaceable cartridge 604, and air gap 620 remains in place. Pressure relief valve 616 is not activated because pressure balance can be maintained under the high pressure formed within replaceable cartridge 604.

[0069] Figure 10 shows a schematic cross-sectional view of the device 600 during cannula flushing. As shown in Figure 10, valve 622 is opened and valve 624 is closed. With the activation of pump 628, blood 617 is flushed back into cannula 606 with the aid of pressure relief valve 616; wherein, based on the low pressure formed within replaceable cartridge 604, movable ball 646 is moved back to its position within pressure relief valve 616 to maintain pressure balance. In other words, unused blood 617 can be flushed back into the body of the subject through cannula 606.

[0070] For blood analysis, the steps described in Figures 6 to 10 can be repeated programmatically. Figure 11 shows a schematic cross-sectional view of the device 600 after multiple repetitions. As more waste liquid 618 is pumped into the replaceable cartridge 604 and more rinsing solution 610 is pumped out, the air gap 620 migrates from the waste liquid port 614 to the reagent port 608. In effect, no contamination occurs, and the overall size of the replaceable cartridge 604 can be minimized.

[0071] The advantage of a replaceable cartridge with a fluid control module suitable for online blood (glucose) testing and waste collection is that waste can be collected together with reagent solutions (such as rinse or calibration solutions) into the same single chamber of the cartridge, and small-volume blood collection, more specifically, small-volume midflow blood sampling, is possible for repeated testing. This capability is made possible considering the presence of large volumes of waste, and minimizing the overall size of the portable microfluidic device is crucial. A pressure relief valve plays a vital role in the sealed chamber, enabling repeated bidirectional pumping of multiple reagents / solutions / waste (e.g., repeated blood extraction and rinsing), within which an air gap serves to separate multiple reagents and waste to prevent contamination.

[0072] While the invention has been specifically shown and described with reference to particular embodiments, those skilled in the art will understand that various changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the scope of the invention is indicated by the appended claims, and all variations falling within the meaning and equivalence of the claims are contemplated and included.

Claims

1. A microfluidic device, characterized in that, The microfluidic device comprises: a fluid control module configured to be detachably coupled to an external tube; and a replaceable cartridge configured to be detachably coupled to the fluid control module, wherein the replaceable cartridge comprises: a first port arranged in fluid communication with the fluid control module to flow one or more reagent solutions between the fluid control module and the replaceable cartridge; a microchannel in fluid communication with the first port, the one or more reagent solutions initially pre-loaded in at least one or more portions of the microchannel, wherein the fluid control module is further configured to manipulate a fluid received from the external tube and / or the one or more reagent solutions received from the replaceable cartridge, and subsequently dispose the manipulated fluid and / or the manipulated one or more reagent solutions as a waste fluid; a second port arranged in fluid communication with the fluid control module to flow the waste fluid into the microchannel, the second port being different from the first port; and a pressure relief valve in fluid communication with the microchannel, wherein the pressure relief valve is configured to regulate an air gap within the microchannel to maintain each of the pre-loaded one or more reagent solutions in the microchannel spaced apart from the waste fluid received from the fluid control module.

2. The microfluidic device of claim 1, wherein, The fluid control module comprises: a first microvalve configured to regulate the fluid between the microfluidic device and the external tube; a second microvalve in fluid communication with the first microvalve; and a pump module in fluid communication with the first microvalve and the second microvalve, the pump module configured to direct the one or more reagent solutions towards or away from the first microvalve and the second microvalve.

3. The microfluidic device of claim 2, wherein, The first microvalve comprises a bidirectional microvalve or a multi-way microvalve, and the second microvalve comprises a unidirectional microvalve.

4. The microfluidic device of claim 2 or 3, wherein, The pump module comprises: a first pump configured to work in cooperation with the pressure relief valve to draw the one or more reagent solutions from the replaceable cartridge and direct the drawn one or more reagent solutions towards the first microvalve and the second microvalve; and a second pump arranged in fluid parallel with the first pump, the second pump configured to work in cooperation with the pressure relief valve to draw the one or more reagent solutions away from the first microvalve and the second microvalve and direct the drawn one or more reagent solutions towards the replaceable cartridge.

5. The microfluidic device of any one of claims 2 to 4, wherein, The fluid control module further comprises a meandering channel arranged between the pump module and the first microvalve and the second microvalve.

6. The microfluidic device of any one of claims 1 to 5, wherein, The microfluidic device further comprises a sensing module configured to receive the fluid and monitor or measure one or more parameters of the fluid.

7. The microfluidic device of claim 6, wherein, The sensing module is integrated in the fluid control module.

8. The microfluidic device of claim 6 or 7, wherein, The sensing module comprises one or more biomarker sensors.

9. The microfluidic device of any one of claims 6 to 8, wherein, the replaceable cartridge includes a third port arranged in fluid communication with the sensing module; and wherein the fluid control module includes a micropump configured to work in cooperation with the pressure relief valve to draw another one or more reagent solutions pre-loaded in the replaceable cartridge and direct the drawn another one or more reagent solutions to the sensing module through the third port, the third port being different from the first port and the second port.

10. The microfluidic device of any one of claims 1 to 9, wherein, the pressure relief valve includes a bidirectional pressure relief valve, the bidirectional pressure relief valve includes: a body having an inner deformable interface forming a passageway within the body; and a movable ball configured to move along the passageway against the inner deformable interface of the body such that the inner deformable interface is able to deform in shape to provide pressure balance within the microfluidic device.

11. The microfluidic device of any one of claims 1 to 10, wherein, the fluid control module further includes a check valve arranged in fluid communication with the second port to prevent backflow of the waste liquid.

12. A method for monitoring or measuring one or more parameters of a fluid received through an external tube, characterized in that, the method includes: (i) providing the microfluidic device according to any one of claims 1 to 11, the microfluidic device being detachably coupled to the external tube; (ii) regulating one or more reagent solutions between a fluid control module of the microfluidic device and a replaceable cartridge detachably coupled to the fluid control module, wherein the one or more reagent solutions are initially pre-loaded in at least one or more portions of microchannels of the replaceable cartridge; (iii) manipulating the one or more reagent solutions received from the replaceable cartridge; (iv) obtaining a fluid from the external tube and manipulating the fluid; and (v) sampling the fluid to monitor or measure the one or more parameters of the fluid.

13. The method of claim 12, wherein, regulating the one or more reagent solutions between the fluid control module and the replaceable cartridge includes: opening a first micropump of the fluid control module; closing a second micropump of the fluid control module; activating a first pump of a pump module of the fluid control module to direct the one or more reagent solutions through a first port of the replaceable cartridge and the fluid control module to the external tube; and activating a pressure relief valve of the replaceable cartridge to a low pressure mode to maintain pressure balance within the replaceable cartridge.

14. The method of claim 13, wherein, manipulating the one or more reagent solutions received from the replaceable cartridge includes: closing the first micropump; opening the second micropump to direct the one or more reagent solutions received from the replaceable cartridge to a sensing module of the fluid control module; and subsequently disposing the one or more reagent solutions as waste liquid from the sensing module through a second port of the replaceable cartridge to the microchannels while maintaining an air gap between the waste liquid and the one or more reagent solutions pre-loaded in the replaceable cartridge.

15. The method of claim 14, wherein, obtaining a fluid from the external tube and manipulating the fluid includes: opening the first micropump; closing the second micropump; deactivating the first pump; activating a second pump of the pump module to direct the fluid from the external tube towards the pump module; and activating the pressure release valve to a high pressure mode to maintain the pressure balance within the replaceable cartridge.

16. The method of claim 15, wherein, sampling the fluid includes: closing the first micro valve; opening the second micro valve; deactivating the second pump; and activating the first pump to direct the midstream sample of the fluid to the sensing module for monitoring and measurement; and subsequently disposing the midstream sample of the fluid as waste fluid from the sensing module through the second port while maintaining the air gap between the waste fluid and the one or more reagent solutions pre-loaded in the replaceable cartridge.

17. The method of claim 16, wherein, In addition to activating the first pump to direct the midstream sample of the fluid to the sensing module for monitoring and measurement, the method further includes activating a micro pump of the fluid control module to draw additional one or more reagent solutions pre-loaded in the replaceable cartridge and direct the drawn additional one or more reagent solutions to the sensing module through a third port of the replaceable cartridge to allow the drawn additional one or more reagent solutions to react with the midstream sample of the fluid for monitoring and measurement.

18. The method according to any one of claims 12 to 17, characterized in that, The method further includes: repeating (ii) to (v) to repeatedly monitor or measure the one or more parameters of the fluid.

19. The method according to any one of claims 12 to 18, characterized in that, The external tube includes a cannula including one end inserted into a subject and an opposite end detachably coupled to the microfluidic device, the fluid includes extracted blood of the subject, and the one or more parameters of the fluid include one or more biomarkers of the subject.

20. The method of any one of claims 12-19, wherein, The one or more reagent solutions include a saline solution, optionally one or more enzymatic solutions, optionally one or more pharmaceuticals, optionally one or more nutritional fluids, and optionally a calibration solution. activating a second pump of the pump module to direct the fluid from the external tube towards the pump module; and activating the pressure release valve to a high pressure mode to maintain the pressure balance within the replaceable cartridge. sampling the fluid includes: closing the first micro valve; opening the second micro valve; deactivating the second pump; and activating the first pump to direct the midstream sample of the fluid to the sensing module for monitoring and measurement; and subsequently disposing the midstream sample of the fluid as waste fluid from the sensing module through the second port while maintaining the air gap between the waste fluid and the one or more reagent solutions pre-loaded in the replaceable cartridge. In addition to activating the first pump to direct the midstream sample of the fluid to the sensing module for monitoring and measurement, the method further includes activating a micro pump of the fluid control module to draw additional one or more reagent solutions pre-loaded in the replaceable cartridge and direct the drawn additional one or more reagent solutions to the sensing module through a third port of the replaceable cartridge to allow the drawn additional one or more reagent solutions to react with the midstream sample of the fluid for monitoring and measurement. The method further includes: repeating (ii) to (v) to repeatedly monitor or measure the one or more parameters of the fluid. The external tube includes a cannula including one end inserted into a subject and an opposite end detachably coupled to the microfluidic device, the fluid includes extracted blood of the subject, and the one or more parameters of the fluid include one or more biomarkers of the subject. The one or more reagent solutions include a saline solution, optionally one or more enzymatic solutions, optionally one or more pharmaceuticals, optionally one or more nutritional fluids, and optionally a calibration solution.

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