Microfluidic device for obtaining a plasma-reagent mixture and method of implementation

Abstract

The invention relates to a microfluidic device for obtaining a homogeneous plasma-reagent mixture (100). Such a device comprises:- a collection module (110) for blood plasma (102);- a capillary channel (120) in fluid connection with said module (110);- a storage reservoir (130) for a reagent (103) in fluid connection with said channel (120). Said device (100) also comprises: - a means (140) for preventing any fluid return to said module (110); - a mixing chamber (150) in fluid connection with said channel (120), said chamber (150) having a flow outlet (152); - said channel (120) having determined dimensions (L) making it possible to determine a quantity of plasma (102) when said channel (120) is saturated with plasma (102); - the volume of said reservoir (130) being greater than the sum of the volumes of said channel (120) and of said mixing chamber (150). Figure to be published with the abstract: Fig. 1

Description

Title of the invention: Microfluidic device for obtaining a plasma-reagent mixture and method of implementation Technical field

[0001] The present invention relates, in general, to the field of blood testing devices. The invention relates more particularly to a microfluidic device for obtaining a plasma-reagent mixture and a method for implementing such a device in order to ultimately enable the quantification of a blood biomarker of interest. Prior art

[0002] In 2019, according to the World Health Organization, seven of the ten leading causes of death worldwide were chronic diseases, and the percentage of deaths related to such diseases is constantly increasing. Chronic diseases are defined as progressive diseases that have existed for several months. However, many studies have shown that early detection of such diseases increases a patient's chances of survival. For example, in the case of several types of cancer, survival can be more than three times higher when the cancer is diagnosed early (stage one or two).Similarly, early detection of markers linked to acute diseases or symptoms as well as pathogenic agents, such as, for example, the Covid 19 virus, the pathogen associated with Lyme disease or that linked to septicemia or even the Human Immunodeficiency Virus (known by the acronym HIV), makes it possible to assess the risk of a serious pathological form and to quickly direct treatment, which may need to be immediate and vital in certain cases, in order to promote a cure.

[0003] For this reason, blood biomarkers, biological characteristics, are attracting increasing interest as an indicator of a normal or pathological biological process. As such, each biomarker has its own characteristics that allow it to provide information related to an underlying physiopathological process and / or data on the progression of a disease. By analogy, biomarkers are to doctors what fingerprints are to police officers: true signatures that allow the identification not of an individual but of a disease. Biomarkers consist of molecules (proteins, hormones, etc.) and cells whose presence or abnormal concentration in the blood, more particularly in blood plasma, attests to the existence of a pathology. Blood plasma is the liquid component of blood devoid of red blood cells, white blood cells, platelets and other contaminants, constituting about fifty-five percent of the total blood volume and is said to contain at least three hundred proteins.

[0004] A biomarker may be present in patients with a specific disease and absent in healthy individuals or those affected by other diseases. However, precise quantification of a biomarker makes it possible to reflect the evolution of a pathology. For example, the quantity of a biomarker may increase or decrease depending on whether the disease worsens or improves, and vice versa. Thus, such quantitative indicators allow; - to refine a prognosis by providing complete information to characterize a disease (or the presence of a pathogenic agent) in an individual and optimize its management; - to adapt the treatment that best suits a patient. As such, depending on their metabolism, some people assimilate a medication particularly quickly. In this case, the latter can pass more quickly into the blood, its effects are increased and it is therefore necessary to reduce the doses usually prescribed; - to monitor the effects of a therapy. For example, in the case of cancer, cancer cells release various molecules into the bloodstream. If their concentration increases over time, this could mean that the cancer is recurring. Quantifying blood biomarkers therefore appears to be an essential tool for personalized medicine.

[0005] Traditionally, such quantification is possible by using the conventional and proven process of taking blood. However, such a process requires a significant amount of blood, the intervention of qualified personnel and the use of specialized equipment, which provides an expensive and time-consuming technique. Indeed, it requires having a prescription from a doctor to request a blood test, making an appointment with a nurse or a laboratory assuming common availability of health personnel and the patient, waiting for the blood tests to be carried out in the laboratory and the transmission of the results to the doctor followed by their interpretation.

[0006] To overcome some of the aforementioned time-consuming steps, self-blood collection kits are also known on the market that can be carried out at home by any individual, using a smaller volume of blood, as disclosed in patent application US 2019 / 0111421 by proposing a device for collecting and storing a bodily fluid. However, as in the case of blood sampling, such devices require the services of a laboratory to carry out the tests with specialized equipment and to analyze the results by qualified personnel.

[0007] Patent application US 2017 / 0001192 attempts to partially address these drawbacks by proposing a test device allowing the evaluation of biomarkers in a bodily fluid without resorting to one or more external resources (laboratory, qualified personnel, etc.). However, such a device makes it possible to obtain a qualitative result of a biomarker (presence or absence of the biomarker) but not a quantitative result of any biomarker. Such a solution thus requires laboratory analysis to quantify the biomarker of interest and does not make it possible to identify proteins in low abundance (of the order of microgram-nanogram / milliliter and less) which may be essential markers. Statement of the invention

[0008] Only a quantitative result of biomarkers allows, as previously indicated, enhanced monitoring of a patient's health. Thus, the present invention aims to overcome the aforementioned drawbacks, in particular to propose a microfluidic device for obtaining a homogeneous plasma-reagent mixture and its simplified implementation method in order to ultimately have direct and rapid quantification of a blood biomarker, at home, usable from a single drop of blood and able to be implemented by any user while ensuring reliability and reproducibility of the results due to precise dosage / volume control, at all stages of the method, of the blood plasma and the reagent used.

[0009] In this respect, a first object of the invention discloses a microfluidic device for obtaining a homogeneous plasma-reagent mixture comprising: - a blood plasma collection module; - a first capillary channel having a first end in fluid connection with said collection module; - a storage reservoir for a reagent in fluid connection with said first capillary channel. Said device further comprises: - a means of preventing any fluid return to the collection module, positioned upstream of the fluid connection of said reagent storage tank with said first capillary channel; - a plasma-reagent mixing chamber in fluid connection with a second end of the first capillary channel, said mixing chamber having a flow outlet for a homogeneous plasma-reagent mixture. The first capillary channel has determined dimensions between the fluid connection of said storage tank with the first capillary channel and said second end of said first capillary channel. Such dimensions make it possible to determine a quantity of blood plasma when the first capillary channel is saturated with blood plasma. Furthermore, the volume of said storage tank is greater than the sum of the volumes of the first capillary channel and of said mixing chamber.

[0010] In one embodiment, the storage tank may comprise an actuator designed to cause a forced flow of a reactant, when it is contained in said storage tank, into the first capillary channel and then into said mixing chamber until said mixing chamber is saturated, and a fluid flow through said outlet after saturation of said mixing chamber.

[0011] In a preferred embodiment, the plasma collection module may be composed of: - a semi-permeable membrane intended to receive a quantity of blood and designed to separate the plasma from the other constituents of the blood by gravity; - a membrane holder arranged to concentrate the blood on said membrane; - a specific surface positioned upstream of the fluidic connection with the first capillary channel. In such a mode, said specific surface and said first capillary channel are mutually arranged to extract blood plasma from said membrane and to circulate said blood plasma in said first capillary channel.

[0012] In order to optimize the capillarity phenomenon, the first end of the first capillary channel may preferably be positioned substantially in the center of said plasma collection module.

[0013] In order to promote passive homogeneous mixing of plasma-reagent, said mixing chamber may comprise a network of channels respectively arranged to cause said homogeneous mixing of plasma-reagent.

[0014] A second object of the invention consists of a method for implementing a microfluidic device for obtaining a homogeneous plasma-reagent mixture. Such a method comprises the following steps; - a step of depositing blood plasma in the plasma collection module; - a stage of saturation of the first capillary channel with blood plasma; - a step of triggering the actuator causing the forced flow of the reagent in the first capillary channel beyond saturation of the mixing chamber; - a step of collecting a homogeneous plasma-reagent mixture.

[0015] According to a preferred embodiment, the step of saturating the first capillary channel with blood plasma may consist of waiting for a predetermined duration, depending on the sizing of the first capillary channel, for it to reach saturation with blood plasma.

[0016] The step of collecting the homogeneous plasma-reagent mixture, for its part, may consist of positioning a reactive strip downstream of the outlet of the mixing chamber of such that said strip collects all or part of said homogeneous plasma-reagent mixture. Brief description of the drawings

[0017] The description of the invention will now be continued by the detailed description of an exemplary embodiment, given below for illustrative but non-limiting purposes, with reference to the appended drawings, in which:

[0018] [Fig-1] shows a preferred example of implementation of a microfluidic device obtaining a plasma-reactive mixture according to the invention;

[0019] [Fig.2] shows a representative flowchart of steps in the implementation process of a device in accordance with the invention;

[0020] [Fig.3], [Fig.4], [Fig.5], [Fig.6] and [Fig.7] are schematic views of the device according to the invention illustrating different stages of implementation of said device according to the invention. Description of the embodiments

[0021] In order to simplify the description, the same reference is used in different figures to designate the same object or element. Thus, when the description cites a referenced object, this object may be identified in several figures. In addition, the figures as well as the description are given as non-limiting examples of embodiment.

[0022] As a preamble, it is important to recall the definition of the following terms: - hydrophilicity is a term used to characterize a molecular property resulting from the existence of strong attractions or affinities between certain molecular groups and water. In other words, it is the affinity of a substance for water or the ability to be wetted by water without being dissolved; - hydrophobicity is a term used to describe and characterize surfaces that appear to "repel water" or that water appears to have difficulty wetting, particularly because water molecules are polar and have a preferential attraction to other polar molecules; - surface tension / surface energy and contact angle: an interface separating two different media is associated with an energy per unit area, the origin of which is the cohesive force between identical molecules. A representative example of such a quantity is that of a drop of liquid placed on a support / solid: such a drop forming an angle, called the contact angle, which varies according to the surface tension of the support / solid. Thus, if there is repulsion between the liquid and the solid, the drop placed on the solid will tend to "group together" and take on a spherical shape, thus presenting a "high" contact angle. Conversely, if there is attraction between the liquid and the solid, the drop placed on the solid will tend to spread out, thus presenting a "low" contact angle. In the case of a liquid such than water, if the contact angle is greater than zero degrees and less than ninety degrees, the water tends to spread and wet the support / solid: we then speak of a wetting or hydrophilic surface. In the case where the contact angle is substantially equal to zero degrees, the wetting is total. Thus, the higher the contact angle, the less the support / solid is wettable by water; - capillarity is a property of fluids dependent on the surface tension of such fluids, giving them the ability to move up or down through a capillary tube / channel. The distance traveled by a liquid in the tube is greater the thinner the tube is; - Blood plasma is the liquid part of blood composed of more than ninety percent water. Thus, blood plasma is considered to be primarily hydrophilic.

[0023] A preferred example of a microfluidic device 100 for obtaining a homogeneous plasma-reagent mixture, in accordance with the invention, is shown in [Fig. 1]. Said device 100 is composed of at least one blood plasma collection module 110 in fluid connection with a first end 120a of a capillary channel 120, itself in fluid connection with a storage reservoir 130 of a reagent 103. Said device 100 further comprises a means 140 for preventing any fluid return to said collection module 110, positioned upstream of the fluid connection of said storage reservoir 130 with said capillary channel 120. The device 100 also comprises a mixing chamber 150 in fluid connection with a second end 120b of the capillary channel 120. Said device 100 is implemented by said method 200, illustrated in the flowchart in [Fig.2], in order to obtain a homogeneous mixture 104 of reactive plasma from a minimum quantity of blood 101, more particularly blood plasma, of the order of ten to one hundred microliters, such a mixture 104 allowing, ultimately, the quantification of a blood biomarker of interest.

[0024] A first step 210 of said method 200 consists in supplying said plasma collection module 110 with blood plasma 102. For this, the blood plasma 102, isolated from the blood prior to said method 200 according to the invention, can be deposited or contained directly in the collection module 110 which is in fluid connection with the first end 120a of said capillary channel 120, considered as the upper part of said capillary channel 120, the second end 120b being considered as the lower part of said capillary channel 120 when said capillary channel 120 is oriented in space as indicated in [Fig.l]. Thus, as illustrated in [Fig.3], said blood plasma 102 can move automatically in the capillary channel 120 by capillarity, a phenomenon defined previously in the present description and thus flow vertically (from top to bottom according to [Fig.l]) along said channel 120.In a preferred but non-limiting embodiment, in order to optimize such a phenomenon. of capillarity and to maximize the associated effect, it is preferable that the first end 120a of the capillary channel 120 is positioned substantially in the center of the lower surface of the collection module 110. Alternatively, said first end 120a of the capillary channel 120 may be positioned between the outer edge and the center of the lower surface of the collection module 110.

[0025] Alternatively, it is conceivable that the blood plasma 102 is isolated, using said device 100 according to the invention, from a drop of blood 101, or even two, taken by the user himself. Such a drop 101 can be collected for example using a lancet device that the user applies to the tip of his finger or any other suitable device. As soon as the tip of the user's finger is pierced / pricked by the lancet, the user can thus move his finger to the blood plasma collection module 110 to deposit the drop of blood 101 there, as illustrated in [Fig. 1]. In this respect, as illustrated in [Fig. 3], in a preferred example, said module 110 may comprise a semi-permeable membrane 111 through which the collected blood 101 can pass.Such a semi-permeable membrane 111, for example of the Pall Vivid® brand known and available on the market, thus makes it possible to separate the constituents of the blood according to their size. For this purpose, the white blood cells, the red blood cells and other large diameter constituents are trapped in said membrane 111 so as to “filter” the blood plasma 102; a filtering efficiency percentage of the order of sixty percent or more is considered. Thus, by gravity, when said membrane 111 is substantially horizontal, the blood plasma 102 is collected below said membrane 111.

[0026] Furthermore, in order to concentrate the blood 101 on said membrane 111 and to prevent the blood 101 from spreading outside the separation / filtration surface, delimited by the edges of said membrane 111, the collection module 110 may comprise a membrane holder 112 positioned so as to press and hold the edges of said membrane 111. However, those skilled in the art cannot be limited to such a membrane holder device 112 and may envisage any other type of device making it possible to fulfill this function.

[0027] Once the blood plasma 102 has been separated from the other constituents of the blood, it must be possible to recover it to allow the continuity of said plasma 102 in said device 100. As such, said blood plasma 102 must be removed from the semi-permeable membrane 111 but also conveyed to the capillary channel 120. To do this, as illustrated in [Fig. 1], the collection module 110 may comprise a specific surface 113, positioned upstream of the fluid connection of said plasma collection module 110 and the first end 120a of the capillary channel 120. Such a specific surface 113 makes it possible, by gravity, to extract the plasma 102 from said membrane 111 and to circulate / progress it by capillarity within the device 100 into the capillary channel 120.

[0028] However, to allow the continuity of the blood plasma 102 in the device 100 and not only the retention of said plasma 102, in other words to absorb the blood plasma 102 from said specific surface 113, the latter must have an optimized balance between hydrophobic and hydrophilic properties, properties specified previously in the present description. Indeed, because the blood plasma 102 is mainly hydrophilic (formed of approximately ninety percent water) but also contains hydrophobic material, said specific surface 113 must have a suitable surface tension and be made of a hydrophilic material without being soluble in water.In this respect, said specific surface 113 may preferably be made of polymethyl methacrylate, a thermoplastic polymer known by the acronym PMMA, having a mainly hydrophilic character (the contact angle with water is of the order of sixty-eight degrees) and having a good balance between the hydrophobic groups (methylene) and the hydrophilic groups (carbonyl). However, the person skilled in the art cannot be limited to such a material and may envisage any other type of material making it possible to obtain such properties or the equivalent, such as, for example, derivatives of polyacrylamide, polyurethane, poly(hydroxyethyl methacrylamide) or poly(ethylene glycol).

[0029] Alternatively or in addition, it is possible to optimize or even improve the hydrophilic characteristics of the chosen material(s) with the use of treatments making it possible to functionalize the surfaces of said materials, in particular to modify their surface tension, such as, for example, plasma gas treatments (argon, oxygen, etc.), Corona treatments or even chemical treatments (with sodium hydroxide, polyvinyl alcohol, or hydroxypropylmethylcellulose, etc.).

[0030] Once the step 210 of depositing blood plasma 102 in the plasma collection module 110 has been completed and the continuity of said plasma 102 has been achieved into the capillary channel 120 by capillarity, a step 220 of saturating the capillary channel 120 with blood plasma 102 is carried out, as illustrated in [Fig. 2]. This step 220 thus makes it possible to have a constant and controlled volume of blood plasma 102 within the capillary channel 120. To do this, the capillary channel 120 has determined dimensions including a predefined length L, as illustrated in [Fig. 4]. Said length L corresponds to the length defined between the fluid connection of said storage reservoir 130 with the capillary channel 120 and said second end of said channel 120. Said length L thus makes it possible, for a given section diameter of said channel 120, to determine and control a quantity of blood plasma 102 when the capillary channel 120 is saturated with plasma 102. For example, for volumes of blood plasma of the order of ten to one hundred microliters, the capillary channel 120 may have an internal diameter substantially between zero point three and one point five millimeters and a length L between fifteen and eighty millimeters. Such a capillary channel 120 may be made of glass, plastic or made of any other material having suitable characteristics (hydrophilic properties, properties promoting capillarity, electrostatic properties and even mechanical properties such as elasticity). However, preferably, plastic materials will be favored because the functionalization of their surface (making it possible in particular to increase the hydrophilic properties and / or to improve capillarity) is easier than for other materials.Furthermore, such a capillary channel 120 may be integrated into said device 100 in the form of a separate element. However, as a variant, in the case where the device 100 comprises a flexible or rigid body, not shown in the figures for the sake of simplification, housing the constituents of said device 100, such as the collection module 110, the capillary channel 120, the storage tank 130, the mixing chamber 140, such constituents could be created directly by molding or additive manufacturing of said body or by removing material from the latter using laser or machining technology.

[0031] Furthermore, in order to promote the saturation of the capillary channel 120 with blood plasma 102, the volume of the capillary channel 120 may be sized to be less than the volume of the blood plasma 102 contained in the collection module 110. Alternatively, the step 220 of saturating the capillary channel 120 with blood plasma 102 may consist of waiting, once the blood plasma 102 flows along the capillary channel 120, for a predetermined duration, defined according to the sizing of said capillary channel 120. However, a person skilled in the art would not be able to limit the invention to such a step and could envisage any other manner of implementing the saturation step 220, such as, for example, the appearance of a colored indicator when the capillary channel 120 is saturated with blood plasma 102 or the use of information delivered by a sensor, for example an optical sensor, positioned in the immediate vicinity of the second end. 120b of said channel 120.

[0032] In order to prevent any backflow or overflow, according to a first embodiment, the means 140 for preventing any fluid return to the collection module 110 may consist of a non-return valve. Thus, the latter authorizes the passage of said blood plasma 102 into the capillary channel 120 from the collection module 110 and prohibits any return flow of said plasma 102 from the capillary channel 120 to the collection module 110.

[0033] In another preferred embodiment illustrated in [Fig.5], such a means 140 for preventing any fluid return may consist of a screw whose stroke causes a “pinching” of said capillary channel 120. Such a screw can thus be actuated, once the saturation of the capillary channel 120 with blood plasma 102 has been obtained, in order to put pressure on the capillary channel 120, pinch it and / or close it, thus making it possible to stop any flow of blood plasma 102 towards the collection module 110. The manual or motorized actuation of such a screw allows said screw to press against the capillary channel 120 when it is desired to “close” said channel 120 at its first end 120a.

[0034] However, other types of means 140 for preventing any fluid return to the collection module 110 could consist, for example, of a valve designed for on-off applications for which said valve opens or closes depending on the pressure of the fluid passing through it. We can cite valves known on the market by the name guillotine valve or direct passage valve. Such a valve can also be actuated manually by the user himself once the saturation step 220 has been carried out but it can also be envisaged to automate such an actuation. In the latter case, such a device comprises a processing unit, such as a microprocessor, arranged to exploit the information emanating from a sensor designed or positioned to detect the saturation of the capillary channel 120 and produce a closing signal intended for an electrically controlled valve.Alternatively, instead of using a sensor, it is possible to imagine the use of a clock, otherwise known as a "timer" in Anglo-Saxon terminology. Thus, in such a case, the closing signal to the electrically controlled valve could be made on the basis of a predetermined elapsed time.

[0035] It should be noted that, because such a means 140 for preventing any fluid return is positioned upstream of the fluid connection of said storage reservoir 130 with said capillary channel 120 (i.e. substantially at the level of the first end 120a of the capillary channel 120), this also makes it possible to further guarantee the constancy of the volume of blood plasma 102 contained in the part of said capillary channel 120 defined by the length L.

[0036] As illustrated in [Fig.2] and in [Fig.5], there follows (parallel to or after the actuation of the means 140 for preventing any fluid return when this requires such actuation) a step 230 to cause the forced flow of a reagent 103, previously contained in the storage reservoir 130 of a reagent 103, into the capillary channel 120. As such, such a storage reservoir 130 may be in the form of a flexible pouch, commonly called a “blister pouch”, fluidically connected to the capillary channel 120 by means, for example, of a capillary tube forming a T-junction 120c with the capillary channel 120. Thus, in such an embodiment, the reagent 103 is contained in said pouch flexible and the forced flow of said reagent 103 in said channel 120 can be caused by mechanical compression carried out by the user of said device 100. In other words, the user himself presses on the flexible bag to release its contents (the reagent 103) into the capillary channel 120. However, the person skilled in the art cannot be limited to the shape / design of such a storage reservoir 130. Any other type of storage reservoir, such as for example a syringe actuated by the user, could be used instead of the flexible bag. Alternatively, such storage reservoirs 130 (flexible bag, syringe or any other type) may comprise an actuator 131, causing a displacement of a piston or a compression thus causing the forced flow of the reagent 103 in the capillary channel 120.Step 230 would therefore consist of controlling such an actuator 131 either manually (by the user) or automatically like the electrically controlled valve mentioned previously to prevent any fluid return to the collection module 110. The processing unit possibly producing a signal for closing said valve would also produce a signal for controlling such an actuator 131.

[0037] Thus, as illustrated in [Fig.5] and in [Fig.6], due to the saturation of the capillary channel 120 with blood plasma 120, the forced flow of the reagent 103 within said channel 120 causes the flow of said blood plasma 102 and of the reagent 103 contained in said capillary channel 120, into said mixing chamber 150 which is in fluidic connection with the second end 120b of said channel 120 (i.e. the lower part of said channel 120 in the illustrated embodiment). In other words, such a forced flow of the reagent 130 acts as a “fluidic piston” to set in motion blood plasma 102 contained in the saturated capillary channel 120, up to said mixing chamber 150, within which a homogeneous mixture 104 of plasma-reagent will be obtained.To promote or even facilitate the homogenization of the plasma-reagent mixture 104 passively, said mixing chamber 150 may comprise a network of channels 151 arranged for example in a zigzag, serpentine, or herringbone pattern. A person skilled in the art cannot be limited as to the design of the mixing chamber 150 allowing a homogeneous plasma-reagent mixture 104 because any other type of design or structure could be envisaged, such as for example, a so-called micropillar structure. In addition, such a mixing chamber 150 comprises an outlet 152 through which said homogeneous and constant plasma-reagent mixture 104 can flow. Such an outlet 152 thus corresponds to an ejection / evacuation outlet of said plasma-reagent mixture 104 to the outside of said device 100.

[0038] Furthermore, said microfluidic device 100 for obtaining a plasma-reagent mixture in accordance with the invention is sized so that the volume of said storage reservoir 130 is greater than the sum of the volumes of said capillary channel 120 and said mixing chamber 150. By way of illustration but not limitation, such a mixing chamber 150 could have a volume of sixty microliters (which could correspond to dimensions of four millimeters in diameter by five millimeters in length) to two hundred and fifty microliters (which could correspond to dimensions of five millimeters in diameter by thirteen millimeters in length) and the storage reservoir 130 could have a volume of one hundred to three hundred microliters. Thus, the flow of the blood plasma 102 and the reagent 103 contained in said capillary channel 120 will take place until said chamber 150 is saturated with plasma-reagent mixture 104, thus allowing the flow of a constant plasma-reagent mixture 104 via the outlet 152 of the mixing chamber 150.

[0039] Thus, once the homogeneous and constant plasma-reagent mixture 104 flows from the outlet 152 of the mixing chamber 150, said method 200 for implementing a microfluidic device 100 for obtaining a homogeneous plasma-reagent mixture in accordance with the invention comprises a final step 240 of collecting said mixture 104. In a preferred embodiment of the invention, as illustrated in [Fig. 7], such a step 240 may consist of positioning a reactive strip 160 such as, for example, a lateral flow immunoassay strip, also known by the acronym “LFI” meaning “Lateral Flow Immunoassay”, downstream of the outlet 152 of said mixing chamber 150. Said mixture 104 can thus be deposited on said reactive strip 160.

[0040] Such a reactive strip 160 can be used directly by the user to obtain a quantification of the blood biomarker of interest by positioning said strip 160 in an optical reader allowing immediate reading / display by the user of the quantified result. Thus, an individual wishing for enhanced monitoring of his health can use, from his place of residence or while on the move, a system for quantifying a blood biomarker comprising a microfluidic device 100 for obtaining a homogeneous plasma-reagent mixture in accordance with the invention, a reactive strip 160 and an optical reader. Such a system could include wired or wireless communication means with a remote computer entity for transmitting quantification results.Such a computer entity may consist of a mobile electronic object (laptop, touchscreen tablet or smart mobile phone) hosting a suitable software application or computer program allowing, for example, the recording of results and / or the creation of a medical dashboard or a history of analyses carried out.

[0041] It will be appreciated by those skilled in the art that the present disclosure is not limited to what is particularly shown and described above. Other modifications may be envisaged without departing from the scope of the present invention defined by the appended claims. In particular, in the preferred example described above, the device 100 comprises a capillary channel. However, to increase the capillary force exerted on the plasma present in the collection module 110, a device 100 may comprise several capillary channels (two, three or even more) opening on the one hand into the collection module 110 and, on the other hand, into the mixing chamber 150, possibly via a “mother” collector channel. Furthermore, mention has been made herein of a capillary channel favoring industrial use because it is not deformable. However, a capillary tube could, as a variant, be used.

Claims

1. Claims Microfluidic device for obtaining a homogeneous plasma-reagent mixture (100) comprising: - a blood (101) collection module (110); - a first capillary channel (120) having a first end (120a) in fluid connection with said collection module (110); - a storage reservoir (130) for a fluid, said storage reservoir (130) being in fluid connection with said first capillary channel (120); - a mixing chamber (150) in fluid connection with a second end (120b) of the first capillary channel (120) arranged to passively cause a homogeneous mixture (104) of fluids from said first capillary and having an outlet (152) for flow of said homogeneous mixture; - a means (140) for preventing any fluid return to the collection module (110), positioned upstream of the fluid connection (120c) of said storage tank (130) of a reagent (103) with said first capillary channel (120); characterized in that: - the collection module (110) comprises: i) a semi-permeable membrane (111) arranged to receive a quantity of blood (101) and designed to separate, by gravity when said semi-permeable membrane (111) is substantially horizontal, the constituents of the blood according to their sizes and thus trap said constituents other than the blood plasma (102); ii) a specific surface (113) arranged between said semi-permeable membrane (111) and the first end (120a) of the first capillary channel (120) and having hydrophobic, hydrophilic and surface tension properties for extracting blood plasma (102) from the semi-permeable membrane (111) and circulating said blood plasma (102) in said first capillary channel (120); - the first capillary channel (120) has determined dimensions (L) between the fluid connection of said storage reservoir (130) with the first capillary channel (120) and said second end (120b) of said first capillary channel (120), to control the quantity of blood plasma (102) when the first capillary channel (120) is saturated with blood plasma (102); - the fluid contained in the storage tank is a reagent (103) intended to be mixed with blood plasma; - said storage tank (130) is arranged to: i) contain a volume of reagent (130) greater than the sum of the volumes of fluids that the first capillary channel (120) and the mixing chamber (150) can contain; ii) have an actuator (131) designed to cause a forced flow of said reagent (103) in the first capillary channel (120) resulting in a flow of a homogeneous plasma-reagent mixture (104) through said flow outlet (152) of the mixing chamber (150) when said actuator is controlled after saturation of the first capillary channel with blood plasma (102).

2. Microfluidic device for obtaining a homogeneous plasma-reagent mixture (100) according to one of the preceding claims, for which the first end (120a) of the first capillary channel (120) is positioned substantially in the center of said plasma collection module (110).

3. Microfluidic device for obtaining a homogeneous plasma-reagent mixture (100) according to any one of the preceding claims, for which the collection module (110) comprises a membrane holder (112) arranged to concentrate the blood (101) on said semi-permeable membrane (111).

4. Microfluidic device for obtaining a homogeneous plasma-reactive mixture (100) according to any one of the preceding claims, for which the specific surface (113) is made of polymethyl methacrylate, thermoplastic polymer, polyacrylamide derivatives, polyurethane, poly[hydroxyethyl methacrylamide] or poly[ethylene glycol].

5. Microfluidic device for obtaining a homogeneous plasma-reagent mixture (100) according to any one of the preceding claims, for which said mixing chamber (150) comprises a network of channels (151) respectively arranged in zigzags, serpentines or herringbone patterns to passively cause said homogeneous plasma-reagent mixture (104).

6. Method for implementing (200) a microfluidic device for obtaining a homogeneous plasma-reactive mixture (100) arranged according to any one of the preceding claims, said method comprising:

7. - a step of depositing blood or blood plasma (102) on the semi-permeable membrane (111) of the plasma collection module (110), when said device is positioned so that the semi-permeable membrane (111) is horizontal; - a step (220) of saturating the first capillary channel (120) with blood plasma (102); - a step (230), subsequent to said step of saturating the first capillary channel (120) with blood plasma (102), of controlling the actuator (131) of the storage tank (130) causing the forced flow of a reagent (103) previously contained in said storage tank (130) into the first capillary channel (120) beyond saturation of the mixing chamber (150); - a step (240) of collecting a homogeneous plasma-reactive mixture (104) from the flow outlet (152) of the latter (150). Method of implementing (200) a microfluidic device for obtaining a homogeneous plasma-reactive mixture (100) according to the preceding claim, for which the step of saturating (220) the first capillary channel (120) with blood plasma (102) consists of waiting, as soon as the blood plasma (102) flows in the first capillary channel (120), a predetermined duration, depending on the sizing of the first capillary channel (120). Method for implementing (200) a microfluidic device for obtaining a homogeneous plasma-reactive mixture (100) according to one of claims 6 and 7, for which the step (240) of collecting the homogeneous plasma-reactive mixture (104) consists of positioning a reactive strip (160) downstream of the outlet (152) of the mixing chamber (150) so that said strip (160) collects all or part of said homogeneous plasma-reactive mixture (104).

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