A plasma separation and metering unit

Abstract

A plasma separation and metering unit (110) is disclosed. The plasma separation and metering unit (110) comprises: • at least one housing (112), wherein the housing (112) comprises at least one receptacle (114) forming at least one sample port (116) for receiving at least one biological sample (168) comprising plasma (174); • at least one plasma separation element (118), wherein the plasma separation element (118) is received in the receptacle (114) of the housing (112), wherein the plasma separation element (118) comprises a sample application side (120) facing the sample port (116) and a plasma side (122) opposing the sample application side (120); and • at least one plasma metering capillary (124) extending from the housing (112), wherein an application end (126) of the plasma metering capillary (124) is fluidically connected to the plasma side (122) of the plasma separation element (118) and is configured for receiving the plasma separated from the biological sample (168) by the plasma separation element (118), wherein an outlet end (128) opposing the application end (126) of the plasma metering capillary (124) comprises an outlet opening (130), and wherein the plasma metering capillary (124) further comprises at least one lateral opening (148) in a capillary wall (132), the lateral opening (148) being located adjacent to the outlet end (128).

Description

[0001] A plasma separation and metering unit

[0002] Technical Field

[0003] The invention relates to a plasma separation and metering unit, a plasma separation and metering system and a method for plasma separation and metering. This invention generally relates to in-vitro diagnostics and, in particular, to devices and a method for preparing a biological sample, specifically a clinical sample, for detecting, specifically for quantifying, at least one analyte. The devices and method may be applied for separating plasma from a biological sample, specifically blood. Further the devices and method may provide a metering and elution mechanism for detecting the at least one analyte from the biological sample, specifically from blood. The devices and method may be applied for point-of-care testing. Other applications, however, are also feasible.

[0004] Background art

[0005] Separation of the cellular contents such as erythrocytes from blood such as arterial, venous or capillary blood in order to derive plasma or serum is generally an important step for various in-vitro diagnostic systems for a detection of at least one analyte and, optionally, also of a concentration of the at least one analyte. In common laboratory practices plasma or serum is commonly derived from whole blood by means of centrifugation and subsequent aspiration, via pipetting, of the generated plasma fraction to a container, specifically for subsequent reaction and measurement steps performed in this container

[0006] In the area of point-of-care diagnostics, especially for clinical chemistry, common technical solutions such as centrifugation are cumbersome as well as cost-intensive to realize from the instrument side. Furthermore, sample transfer via pipetting typically requires an automatized liquid handling system with level or volume detection, which further adds costs and leads to an increased complexity to the overall instrumental setup. Thus, separa- tion of plasma or serum is often neglected in many point-of-care applications and said blood sample is used directly for the detection. However, variation of a ratio between cellular components and plasma or serum (known as hemotacrit dependency) can principally lead to imprecisions in the detection. Hence, various approaches such as optical or soft- ware-based approaches are principally necessary to correct for these imprecisions during testing which are prone to errors.

[0007] So far, various methods have been described in the field of point-of-care solutions, especially in the area of miniaturized in-vitro-diagnostics such as microfluidic lab-on-a-chip devices to address challenges in plasma separation & metering.

[0008] WO 2017 / 015243 Al describes a method for extracting plasma from whole blood and metering the amount of plasma to an exact volume for dispensing into a diagnostic test in a fully automatic and selfcontained device. The device can be used in resource limited settings by unskilled users to facilitate sophisticated medical diagnostic testing outside of a hospital, clinic or laboratory.

[0009] Despite the advantages achieved by the above-mentioned devices and methods, several technical challenges remain. Commonly, such devices and methods may be limited with respect to their separation performance as well as with respect to their metering of plasma performance. Further, such may be limited with respect to the volume of plasma that can be generated and the kind of blood sample and anticoagulant that can be used together.

[0010] Problem to be solved

[0011] It is therefore desirable to provide a plasma separation and metering unit, a plasma separation and metering system and a method for plasma separation and metering which at least partially address the above-mentioned technical challenges. Specifically, a metered plasma sample shall be elutable precisely.

[0012] Summary

[0013] This problem is addressed by a plasma separation and metering unit, a plasma separation and metering system and a method for plasma separation and metering with the features of the independent claims. Advantageous embodiments which might be realized in an isolated fashion or in any arbitrary combinations are listed in the dependent claims as well as throughout the specification. As used in the following, the terms “have”, “comprise” or “include” or any arbitrary grammatical variations thereof are used in a non-exclusive way. Thus, these terms may both refer to a situation in which, besides the feature introduced by these terms, no further features are present in the entity described in this context and to a situation in which one or more further features are present. As an example, the expressions “A has B”, “A comprises B” and “A includes B” may both refer to a situation in which, besides B, no other element is present in A (i.e. a situation in which A solely and exclusively consists of B) and to a situation in which, besides B, one or more further elements are present in entity A, such as element C, elements C and D or even further elements.

[0014] Further, it shall be noted that the terms “at least one”, “one or more” or similar expressions indicating that a feature or element may be present once or more than once typically will be used only once when introducing the respective feature or element. In the following, in most cases, when referring to the respective feature or element, the expressions “at least one” or “one or more” will not be repeated, non-withstanding the fact that the respective feature or element may be present once or more than once.

[0015] Further, as used in the following, the terms "preferably", "more preferably", "particularly", "more particularly", "specifically", "more specifically" or similar terms are used in conjunction with optional features, without restricting alternative possibilities. Thus, features introduced by these terms are optional features and are not intended to restrict the scope of the claims in any way. The invention may, as the skilled person will recognize, be performed by using alternative features. Similarly, features introduced by "in an embodiment of the invention" or similar expressions are intended to be optional features, without any restriction regarding alternative embodiments of the invention, without any restrictions regarding the scope of the invention and without any restriction regarding the possibility of combining the features introduced in such a way with other optional or non-optional features of the invention.

[0016] In a first aspect of the present invention a plasma separation and metering unit is disclosed. The plasma separation and metering unit comprises at least one housing. The housing comprises at least one receptacle forming at least one sample port for receiving at least one biological sample comprising plasma, specifically at least one blood sample. Further, the plasma separation and metering unit comprises at least one plasma separation element. The plasma separation element is fluidically connected to the receptacle of the housing. Specifically, the plasma separation element may be received in the receptacle of the housing. Further, there may be intermediate structure between the plasma separation element and the receptacle of the housing such as a transport channel. The plasma separation element comprises a sample application side facing the sample port and a plasma side opposing the sample application side. Further, the plasma separation and metering unit comprises at least one plasma metering capillary extending from the housing. An application end of the plasma metering capillary is fluidically connected to the plasma side of the plasma separation element and is configured for receiving the plasma separated from the biological sample by the plasma separation element. An outlet end opposing the application end of the plasma metering capillary comprises an outlet opening. The plasma metering capillary further comprises a lateral opening in a capillary wall, the lateral opening being located adjacent to the outlet end.

[0017] The term “sample” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary material or combination of materials taken for an analysis, testing or investigation. The sample may be a limited quantity of something which is intended to be similar to and represent a larger amount. However, the sample may also comprise a full specimen. The sample may specifically be a fluid sample, i.e. a sample which fully or partially is in a liquid state. A quantity of the sample may be describable in terms of its volume, mass or size. However, other dimensions are feasible. Specifically, the sample may comprise several materials or compounds. As outlined above, the sample is a biological sample. The term “biological sample” may refer to a clinical specimen, e.g. materials taken from humans or animals. The biological sample may specifically be selected from the group consisting of: blood, specifically venous blood, specifically capillary blood. The term “blood” may refer to body fluid in humans or animals that delivers necessary substances such as nutrients and oxygen to cells and transports metabolic waste products away from the cells. The blood may comprise blood cells and plasma, also referred to as blood plasma. The blood cells may be suspended in the plasma. The term “plasma” may refer to a component of blood which is freed from blood cells. The plasma may comprise water and constituents such as proteins, glucose, clotting factors electrolytes, hormones, carbon dioxide and oxygen. Examples for proteins may be serum albumin, globulin and fibrinogen.

[0018] The plasma may comprise at least one analyte of interest. The term “analyte” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary element, component or com- pound which may be present in the sample and the presence and / or the concentration of which may be of interest. Specifically, the at least one analyte may be one constituent of the plasma such as a protein, glucose, a clotting factor, an electrolyte, a hormone, carbon dioxide or oxygen. Additionally or alternatively, however, other types of analytes may be used and / or any combination of the analytes may be determined.

[0019] The term “plasma separation and metering unit” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary unit which is configured for separating a component of the biological sample from other components of the biological sample. Specifically, the plasma separation and metering unit may be configured for separating plasma from the biological sample which may specifically be blood. For this purpose, the plasma separation and metering unit comprises the plasma separation element which will further be described below in more detail. Further, the term “plasma separation and metering unit” may refer to an arbitrary unit which is configured for providing a metered volume of the biological sample, specifically of a component of the biological sample, specifically of plasma. For this purpose, the plasma separation and metering unit comprises the plasma metering capillary which will further be described below in more detail. The plasma separation and metering unit may comprise the plasma separation element and the plasma metering capillary and these may interact with each other in order to fulfill at least one common function as will further be described below in more detail.

[0020] As outlined above, the plasma separation and metering unit comprises the at least one housing. The term “housing” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an element or component having at least one interior space and at least one wall fully or partially surrounding the at least one interior space and providing protection to the interior space, such as one or more of a mechanical protection or a protection against environmental influences such as one or more of moisture, oxygen or microbial contaminations. The housing may generally be adapted to fully or partially surround and / or receive one or more elements in order to provide one or more of a mechanical protection, a mechanical stability, an environmental protection against moisture and / or ambient atmosphere, a shielding against electromagnetic influences or the like. The housing may also provide a basis for attachment and / or holding one or more further components or elements. As outlined above, the housing comprises the at least one receptacle. The receptacle may specifically be an open receptacle having at least one opening. The biological sample may be applied via the opening of the receptacle. The receptacle may have an arbitrary shape. Specifically, the receptacle may have a cross-section having a shape which corresponds to a shape of the plasma separating membrane. As outlined above, the receptacle forms the sample port for receiving the biological sample. The term “sample port” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary unit or subunit of the plasma separation and metering unit configured for receiving, accepting or making contact to the biological sample to be separated into different components by the plasma separating membrane. The sample port may specifically be a cavity within the housing of the plasma separation and metering unit.

[0021] Specifically, the housing may be manufactured by injection molding. Specifically, the housing may be made of at least one material selected from the group consisting of polycarbonate (PC), polymethyl methacrylate (PMMA), cyclic olefin copolymer (COC / COP). However, also other materials may be possible.

[0022] As outlined above, the plasma separation and metering unit comprises the at least one plasma separation element. The term “membrane” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary element which may have an essentially flat shape and which may be configured for separating one component of a sample, specifically of a fluid sample, from other components of the sample. The term “separation” may generally refer to an arbitrary process of eliminating specific components of a sample or may as well refer to an arbitrary process of removing at least one part of the sample from an original residence. Thus, the removed part of the sample and the residual part of the sample may have a different chemical composition, respectively. The term “plasma separation element” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary element, specifically to an arbitrary membrane, which is configured for eliminating plasma, for removing plasma from the biological sample which may specifically be blood or for separating plasma from the cellular constituents of the biological sample. Thus, the plasma separation element may specifically be a semi-permeable membrane which is permeable for plasma but which may be non-permeable for the cellular constituents of the biological sample. The plasma separation element may specifically have at least one microporous structure. The plasma separation element may also be referred to as plasma separation membrane.

[0023] The terms “sample application side” and “plasma side” as used herein are broad terms and are to be given its ordinary and customary meaning to a person of ordinary skill in the art and are not to be limited to a special or customized meaning. The terms specifically may refer, without limitation, to opposing sides of the plasma separation element, specifically to two opposing longitudinal sides of the plasma separation element. The sample application side may face an outer environment of the plasma separation and metering unit. When the biological sample is applied to the plasma separation and metering unit, the biological sample may get into contact with the sample application side of the plasma separation element. Thus, the biological sample may cover a surface of the sample application side of the plasma separation element at least partially. As described above, the plasma separation element may be a semi-permeable membrane which is permeable for plasma. Thus, the plasma may be transferred from the sample application side to the opposing plasma side. Underneath the plasma side, the plasma may be collected.

[0024] Specifically, the plasma separation element may have a thickness of 50 pm to 1000 pm, preferably of 75 pm to 750pm, most preferably of 100 pm to 500 pm. However, also other thicknesses may be feasible. The plasma separation element may have an arbitrary shape. However, preferably, the plasma separation element may have a round shape. Specifically, the plasma separation element may have a diameter of 1 mm to 50 mm, preferably of 5 mm to 20 mm, most preferably of 6 mm to 10 mm. However, also other dimensions may be feasible.

[0025] Specifically, the plasma separation element may be at least partially made of asymmetric polysulfone. Further, additionally or alternatively, the plasma separation element may be made at least partially of fibers selected from the group consisting of natural fibers; synthetic fibers, specifically glass fibers; or mixtures thereof. However, also other materials may be feasible.

[0026] As outlined above, the plasma separation element is fluidically connected to the receptacle of the housing. Specifically, the plasma separation element may be attached to at least one surface of the receptacle by at least one adhesive, specifically by at least one double-sided adhesive. Specifically, the adhesive may be a circumferential adhesive element. The circumferential adhesive element may be configured for adhering an outer rim of the plasma separation element to the surface of the receptacle. Further, the plasma separation element may be irreversibly attached to the at least one surface of the receptacle by at least one method selected from the group consisting of thermobonding; ultrasonic welder; laser welding; adhesive bonding. Also other embodiments for attaching the plasma separation membrance to the surface of the receptacle may be feasible.

[0027] As outlined above, the plasma separation and metering unit comprises the plasma metering capillary. The term “capillary” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary small, elongate void volume such as a small tube. Generally, the capillary may comprise dimensions in the millimeter or sub-millimeter range. Commonly, a fluidic medium may migrate through the capillary by capillary action wherein the fluidic medium may flow in narrow spaces of the capillary without an assistance of external forces like gravity due to intermolecular forces between the fluidic medium and a surface of the capillary facing the fluidic medium. The term “plasma metering capillary” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a capillary which is configured for providing a metered amount of plasma. Thus, the plasma metering capillary may be configured for metering the amount of plasma to an exact volume. The void volume may specifically have a precise geometry of a known volume. The plasma metering capillary may be configured for being filled accurately and repeatably with the known volume leading to the plasma being metered to the known volume prior to eluting the plasma from the plasma metering capillary.

[0028] The capillary may specifically have at least one channel. The void volume as described above may be formed by the channel. The term “channel” may generally refer to an arbitrary element which may have an elongated shape and which may provide a free volume or lumen and which enables a flow of a fluid medium there through. Consequently, the channel may be configured to receive a fluid medium and / or to provide a transfer of the fluid medium from one end of the channel to the other end of the channel. The term “lumen” generally refers to an interior volume of an arbitrary element. The interior volume may specifically be an open interior volume. Thus, the interior volume may not be fully enclosed or surrounded by a wall of the element. Instead, a flow of a fluid medium or an insertion of another object from one end of the element to a further end through the lumen may be feasible. The channel may specifically be a straight channel. As further used herein, the term “straight” may refer to a continuous extension of the channel in one direction without a bend, angle or curve. Consequently, the channel may essentially extend in one dimension. However, small aberrations of the channel from the extension in one dimension may be existent specifically due to slight inaccuracies during manufacturing of the plasma metering capillary.

[0029] The plasma metering capillary may specifically be a micro capillary. As further used herein, the term “micro capillary” may refer to a capillary having a channel with dimensions at a small, typically sub-millimeter scale. Specifically, the plasma metering capillary may have an inner diameter of 0.1 mm to 3 mm, preferably of 0.25 mm to 2 mm, most preferably of 0.5 mm to 1.3 mm. The inner diameter of the plasma metering capillary may refer to a diameter of the channel. The channel may specifically at least partially have a round cross-section. Still, other shapes are also possible. Further, the plasma metering capillary may have an outer diameter of 0.5 mm to 5 mm, preferably of 0.75 mm to 4 mm, most preferably of 1 mm to 3 mm. Further, the plasma metering capillary may have a of 0.5 mm to 20 mm, preferably of 0.75 mm to 15 mm, most preferably of 1 mm to 10 mm. Also other dimensions may be feasible.

[0030] The channel of the plasma metering capillary may be at least partially enclosed by a capillary wall of the plasma metering capillary. As further used herein, the term “wall” may generally refer to an arbitrary structure, specifically a structural material, which is configured to at least partially surround another object or volume thereby defining physical limits of an object. Further, the wall may be configured to protect the volume or the other object at least partially enclosed by the wall. The capillary wall may circumferentially enclose the channel of the plasma metering capillary. The term “circumferentially enclosing” may generally refer to a property of an arbitrary object or volume of being fully enclosed by another object in at least two dimensions. Specifically, the channel of the plasma metering capillary may be at least partially enclosed by the capillary wall in directions perpendicular to a longitudinal axis of the plasma metering capillary.

[0031] As outlined above, the plasma metering capillary extends from the housing. Specifically, the plasma metering capillary may be arranged such that the longitudinal axis of the plasma metering capillary is oriented transverse, specifically perpendicular, to a longitudinal axis of the plasma separation element. The terms “application end” and “outlet end” as used herein are broad terms and are to be given its ordinary and customary meaning to a person of ordinary skill in the art and are not to be limited to a special or customized meaning. The terms specifically may refer, without limitation, to opposing ends of the plasma metering capillary. The application end may face the plasma separation element, specifically the plasma side of the plasma separation element. The application end of the plasma metering capillary may be at least partially received within the housing of the plasma separation and metering unit. The plasma may migrate through the channel from the application end to the outlet end by capillary action. The outlet end may be configured for eluting the plasma from the plasma metering capillary, specifically from the channel of the plasma metering capillary as will further be described below in more detail.

[0032] As outlined above, the application end is fluidically connected to the plasma side of the plasma metering membrane. The term “fluidically” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to property of two or more elements, wherein the two or more elements are connected such that a transfer of an arbitrary fluid medium from one of the two elements to the other one of the two elements or vice versa is provided.

[0033] The plasma metering capillary may be arranged directly underneath the plasma separation element. The plasma separation element and the plasma metering capillary may be spaced apart from each other, e.g. in a distance to each other. Thus, at least one void volume may be formed between the plasma separation element and the plasma metering capillary. Specifically, the receptacle may comprise at least one funnel compartment arranged adjacent to the application end of the plasma metering capillary, specifically above the application end of the plasma metering capillary. The funnel compartment may specifically refer to a conically tapered compartment. A diameter of the funnel compartment may gradually decrease, specifically along a direction perpendicular to a direction of extension of the plasma separation element. The plasma separation element may be fluidically connected to the receptacle of the housing such that the funnel compartment is covered at least partially, preferably fully, by the plasma separation element. The funnel compartment may be configured for collecting the plasma, specifically after the plasma has passed through the plasma separation element. The funnel compartment may open into the plasma metering capillary, specifically into the application end of the plasma metering capillary. The funnel compartment may be configured for guiding the plasma into the application end. At least one surface of the housing, specifically at least one surface of the receptacle of the housing may comprise at least one surface profiling. Specifically, the surface may be a surface of the funnel compartment. The surface profiling may comprise a plurality of microstructures. Thus, the surface profiling may be a micro-profiling. The term “microprofiling” may generally refer to an arbitrary surface profiling in which elevations and / or depressions of the surface have dimensions in the range of 1 or more micrometers, i.e. of 1 pm to 1000 pm, preferably of 10 pm to 500 pm. The dimensions may specifically refer to a height, a width and / or a depth of the elevations or the depressions.

[0034] Specifically, the surface profiling may comprise an at least partially periodical arrangement of at least one element selected from the group consisting of: a rectangle, a square, a pillar. Exemplarily, the surface profiling may comprise a plurality of pillars having a diameter of 10 pm to 500 pm, a height of 10 pm to 500 pm and a distance between individual pillars (edge-to-edge) of 10 pm to 1000 pm. However, also other types of elements may be feasible.

[0035] The surface profiling may specifically have a large number of the elements. The elements may be designed as an elevation on the surface. Specifically, the elements may be isolated elements which are arranged at a distance from adjacent elements. The elements may be designed to be free of contact with one another. Alternatively, the elements may at least partially touch each other. The elements may extend from the surface of the housing, in particular the elements may extend transversely, preferably perpendicularly, to the surface of the housing.

[0036] Thus, the surface profiling may be a periodic surface profiling. The term "periodic surface profiling" may generally refer to a profiling of any surface, which occurs repetitively in a recurring sequence. In particular, as already stated above, the surface profiling may comprise the arrangement of elevations and depressions which occur repeatedly in a recurring sequence on the surface. The arrangement of elevations and depressions may form a unit and several of the units may be arranged on the surface.

[0037] Further, additionally or alternatively, the plasma separation and metering unit may further comprise at least one further membrane arranged between the plasma separation element and the plasma metering capillary. At least one surface of the further membrane may comprise at least one surface profiling. With regard to further details concerning the design of the surface profiling, reference may be made to the description of the surface profiling of the at least one surface of the receptacle of the housing above. As outlined above, the plasma metering capillary comprises the outlet opening. The term “outlet opening” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an opening located at the outlet end of the plasma metering capillary. Specifically, the outlet opening may be located at a front side of the plasma metering capillary. The channel may open into the outlet opening.

[0038] Further, as outlined above, the plasma metering capillary comprises the lateral opening in the capillary wall. The term “lateral opening” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an opening located at the outlet end of the plasma metering capillary. Specifically, the lateral opening may be located at a longitudinal side of the plasma metering capillary. Specifically, the lateral opening may be an opening within the capillary wall. The lateral opening may be located on a shell surface of the capillary wall.

[0039] Thus, the lateral opening may refer to an opening which is different from the outlet opening. The lateral opening and the outlet opening may refer to two different openings of the plasma metering capillary. Exemplarily, the lateral opening may be a through hole within the capillary wall. However, preferably, the lateral opening may comprise at least one slot extending along a longitudinal axis of the plasma metering capillary. The term “slot” may generally refer to an opening, specifically a passage opening, a slit or to a notch in the capillary wall of the plasma metering capillary. Specifically, the slot may extend from the outlet end of the plasma metering capillary.

[0040] As outlined above, the lateral opening is located adjacent to the outlet opening. The term “adjacent” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a property of an arbitrary element of being in proximity of another element. The term “adjacent” may also be referred to as “contiguous”, “adjoint”, “besides” or further related terms. Consequently, the element and the other element may be arranged in a neighboring fashion with respect to each other. Specifically, as outlined above, the outlet opening may be located at the front side of the plasma metering capillary and the lateral opening may be located on the longitudinal side of the plasma metering capillary. Thereby, the outlet opening and the lateral opening may be arranged in a distance to each other. Thus, the lateral opening may be a through hole within the capillary wall and the outlet opening and the lateral opening may be separated from each other by at least one section of the capillary wall. Further, alternatively, the outlet opening may be located at the front side of the plasma metering capillary and the lateral opening may be located on the longitudinal side of the plasma metering capillary and, thereby, the outlet opening and the lateral opening may be in direct contact with each other. Thus, the lateral opening may extend from the outlet end of the plasma metering capillary. The lateral opening may be a slot extending from the outlet end and may form a recess within the outlet opening.

[0041] The lateral opening may have a length of 0.5 mm to 20 mm, preferably of 0.75 mm to 15 mm, most preferably of 1 mm to 10 mm. However, also other lengths may be feasible. The term “length” as further used herein may be viewed in a direction along the longitudinal axis of the plasma metering capillary.

[0042] The lateral opening may specifically be the slot and the slot may comprise longitudinal side walls being formed in the capillary wall. The longitudinal side walls may extend along the longitudinal axis of the plasma metering capillary. In a top view of the outlet end of the plasma metering capillary, the side walls, with respect to the longitudinal axis as vertex, may be arranged at an angle of 5° to 90°, preferably of 10° to 80°, most preferably of 15° to 65°. The top view of the outlet end of the plasma metering capillary may correspond to a view on the front side of the plasma metering capillary.

[0043] Further, alternatively, in the top view of the outlet end of the plasma metering capillary the longitudinal side walls, with respect to the longitudinal axis as vertex, may be arranged at an angle of essentially 180°. In this context, the term “essentially” is to be understood as meaning that deviations from the angle of 180° may be present. For example, in the top view of the outlet end of the plasma metering capillary the longitudinal side walls, with respect to the longitudinal axis as vertex, may be arranged at an angle which is 0.01% to 0.5% larger or smaller than the angle of 180°. Specifically, the plasma metering capillary may comprise one single slot wherein the in the top view of the outlet end of the plasma metering capillary the longitudinal side walls, with respect to the longitudinal axis as vertex, may be arranged at an angle of essentially 180°.

[0044] Further, specifically, the plasma metering capillary may comprise at least two of the lateral openings, specifically of the slots. The longitudinal side walls of at least two of the lateral openings may, in the top view of the outlet end of the plasma metering capillary, with re- spect to the longitudinal axis as vertex, be arranged at an angle of 15° to 45°. Specifically, the angle of the at least two lateral openings may be identical. The lateral openings may be, in the top view of the outlet end of the plasma metering capillary, arranged opposite to each other.

[0045] Specifically, the plasma metering capillary and the housing may form an integral unit. Thus, the plasma metering capillary and the housing may be designed integrally. The term “integrally” may refer to a state wherein two or more components may be permanently built into at least another one of the two or more components. Exemplarily, the plasma metering capillary may be fixedly attached to the housing. Further, exemplarily, the plasma metering capillary and the housing may form a single piece.

[0046] In a further aspect of the present invention, a plasma separation and metering system is disclosed. The plasma separation and metering system comprises at least one vessel. The vessel is configured for receiving at least one washing solution, specifically at least one washing buffer solution. Specifically, the washing solution may be received in the vessel, specifically in at least one receptacle of the vessel. Further, the plasma separation and metering system comprises at least one sample processing unit. The sample processing unit is attachable to the vessel. The sample processing unit comprises the plasma separation and metering unit as described above or as will further be described below in more detail. The plasma separation and metering system is configured to be rotatable around a rotation axis of the plasma separation and metering system whereby the washing solution is transported to the plasma separation and metering unit.

[0047] The term “system” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a group of at least two elements which may interact with each other in order to fulfill at least one common function. The at least two components may be handled independently or may be coupled, connectable or integratable in order to form a common component. The term “plasma separation and metering system” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a group of at least two elements or components which comprises the plasma separation and metering unit as described above and which additionally provides means for eluting the plasma from the plasma separation and metering unit. Further details may be given below in more detail. The term “vessel” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary element creating a partially enclosed space that may be usable to contain, store and / or to transport objects or materials. The enclosed space may also be referred to as interior space. Thus, the vessel may particularly be made of a durable and / or of an at least partly rigid material such as thermoformed plastic. Specifically, the cup may be manufactured by injection molding. However, other embodiments are feasible. The cup may also be referred to as container, reaction chamber, detection chamber or cup.

[0048] The vessel may specifically be a reaction and measurement vessel. The term “reaction and measurement vessel” may refer to an arbitrary vessel which is configured for receiving and holding at least one substance, specifically at least one liquid substance, and for enabling a reaction within the vessel, such as within at least one interior space of the vessel. Further, the term specifically may refer, without limitation, to an arbitrary vessel being configured for conducting at least one measurement, specifically at least one analytical measurement, specifically at least one optical measurement of one or more analytes of interest. Thereby, the one or more analytes of interest may be received in the reaction and measurement vessel. Specifically, the one or more analytes of interest may be dissolved in at least one fluid medium which is received in the reaction and measurement vessel. Specifically, the reaction and measurement vessel may comprise at least one optical window which is received in at least one wall of the reaction and measurement vessel.

[0049] The term ’’washing solution” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary solution which is configured for washing or eluting the sample or constituents of the sample from the capillary of the sample application area. Specifically, the washing solution may be a washing buffer solution.

[0050] The term “sample processing unit” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary unit which is configured for receiving at least one sample and for transferring the sample from one component of the sample processing unit to another component of the sample processing unit. Specifically, the sample processing unit may be config- ured for performing at least one sample preparation procedure. Specifically, the sample preparation procedure may include separating constituents of the sample from other constituents of the sample. Further, the sample processing unit may be configured for providing a metered volume of the biological sample, specifically of a component of the biological sample.

[0051] The sample processing unit may specifically comprise at least one sample processing unit housing having at least one sample processing unit opening. The term “sample processing unit housing” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an element or component of the sample processing unit having at least one interior space and at least one wall partially surrounding the at least one interior space and providing protection to the interior space, such as one or more of a mechanical protection or a protection against environmental influences such as one or more of moisture, oxygen or microbial contaminations. Thus, the term “interior space” may refer to a space which is partially enclosed by the walls of the sample processing unit housing. The interior space of the sample processing unit, specifically of the sample processing unit housing, may be accessible via the sample processing unit opening. The plasma separation and metering unit may integrated in the wall of the sample processing unit. Specifically, the sample processing unit opening may form the sample port of the plasma separation and metering unit and the plasma metering capillary may extend into the interior space of the sample processing unit. Specifically, the housing of the plasma separation and metering unit and the wall of the sample processing unit may be formed integrally, specifically as one single piece.

[0052] As outlined above, the sample processing unit is attachable to the vessel. The attachment of the sample processing unit to the vessel may specifically be a reversible attachment. However, an irreversible attachment may also be feasible. The sample processing unit may specifically be attachable to the vessel such that a leakage of fluids such as the washing solution and / or the chemical reagent and / or the sample is prevented. The sample processing unit may be attachable to the vessel via at least one mechanism selected from the group consisting of a turning mechanism, gasket, tight fit between the respective surfaces of the sample processing unit and the vessel.

[0053] The sample processing unit may specifically be attachable to the vessel such that the sample processing unit opening faces a vessel opening. Thus, after attachment of the sample processing unit to the vessel, the vessel may be fluidically connected to the sample processing unit via the sample processing unit opening and the vessel opening.

[0054] The plasma separation and metering system is configured to be rotatable around the rotation axis of the plasma separation and metering system whereby the washing solution is transported to the plasma separation and metering unit. The term “rotation axis” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a straight line that describes a rotation of an arbitrary object. The term “transporting” may generally refer to an active transfer of an arbitrary material from one location to another location. By rotating the plasma separation and metering system around the rotation axis, the vessel may be tilted such that the washing solution may leave the vessel and may be transferred into the interior volume of the sample processing unit. The rotation of the plasma separation and metering system may specifically refer to a two-dimensional rotation. The plasma separation and metering system may be configured to be rotatable around the rotation axis in at least two possible directions. One of the two directions may refer to a clockwise motion. The clockwise motion may correspond to a direction of hands of an arbitrary clock, specifically from the top to the right, then down and then to the left, and back up to the top. Further, another one of the two directions may refer to a counterclockwise motion. The anticlockwise motion may correspond to an opposite sense of rotation.

[0055] In a further aspect of the present invention, a method for plasma separation and metering is disclosed. The method comprises using the plasma separation and metering unit as described above or as will further be described below in more detail. The method comprises applying at least one biological sample comprising plasma to the sample port of the plasma separation and metering unit, wherein the plasma is generated and drawn from the sample port into the plasma metering capillary. The generation of the plasma may specifically refer to a separation of the plasma from the biological sample.

[0056] The biological sample may be blood, specifically venous blood, specifically capillary blood. For further details on the biological sample, reference may be made to the description above. Specifically, a volume of the biological sample may be of 10 pl to 200 pl, preferably of 20 pl to 100 pl.

[0057] Specifically, an overpressure may be applied on the sample port, specifically on an opening of the sample port. The overpressure may be configured for enhancing the plasma sep- aration and metering. Specifically, the overpressure may be generated by at least one device selected from the group consisting of a syringe piston, a pneumatic system. Thus, the enhancing of the plasma separation and metering may be an active enhancing. The overpressure may be in the range of 10 mbar to 1000 mbar. The overpressure may be kept constant during performance of the method for plasma separation and metering or may be varied over time, specifically at distinct points of time during performance of the method for plasma separation and metering.

[0058] Further, the overpressure may be applied on the sample port through sealing the sample port with at least one sealing cap, specifically with at least one flexible sealing cap. Thus, the enhancing of the plasma separation and metering may be a passive enhancing. During sealing of the sample port with the sealing cap, e.g. during insertion of the sealing cap into the opening of the receptacle, an air displacement may be generated which may generate, in turn, a non-constant and / or a non-linear overpressure onto the biological sample, which may decay over the process period. The sealing cap may be placed on the sample port manually such as by a user or a patient. Further, alternatively, the sealing cap may be placed on the sample port automatically, specifically by an automatized process. The automatized process may apply a constant displacement of an outer surface of the flexible sealing cap thus resulting in a controlled generation of overpressure onto the biological sample.

[0059] The term “sealing cap” may generally refer to an arbitrary element which is configured to seal off one or more elements from external influences, such as from one or more of humidity or moisture, ambient air or other detrimental media, specifically fluid media. Specifically, the sealing cap may be configured to surround the at least one element to be sealed off from the environmental influences in at least two dimensions. The sealing cap specifically may be made of at least one compressible material such as at least one flexible and / or inelastic material. As an example, the sealing cap may fully or partially be made of a plastic material which is flexible and / or deformable, such as at least one elastomeric material. As an example, the sealing cap may be made of at least one material selected from the group consisting of a thermoplastic polymer, specifically polyethylene (PE), specifically polypropylene (PP); a silicone-based material. Also other materials may be feasible.

[0060] The methods and devices according to the present invention provide a large number of advantages over known methods and devices. Specifically, a fully integrated plasma separation and metering unit, specifically for application in point-of-care test systems may be provided. The plasma separation and metering unit may have a simple design. The plasma may be metered to a known volume. Further, for eluting the plasma from the plasma metering capillary, the plasma metering capillary does not need to be disassembled from the plasma separation and metering unit. The plasma separation and metering system may have the capability to precisely elute the metered plasma sample by bringing the outlet end of the plasma metering capillary into contact with the washing solution.

[0061] Summarizing and without excluding further possible embodiments, the following embodiments may be envisaged:

[0062] Embodiment 1 : A plasma separation and metering unit, wherein the plasma separation and metering unit comprises:

[0063] • at least one housing, wherein the housing comprises at least one receptacle forming at least one sample port for receiving at least one biological sample comprising plasma, specifically a blood sample, wherein the receptacle is an open receptacle having at least one opening, wherein the biological sample may be applied via the opening of the receptacle, wherein the opening is configured to allow insertion of a sealing cap into the opening of the receptacle;

[0064] • at least one plasma separation element, wherein the plasma separation element is fluidically connected to the receptacle of the housing, wherein the plasma separation element comprises a sample application side facing the sample port and a plasma side opposing the sample application side;

[0065] • at least one plasma metering capillary extending from the housing, wherein an application end of the plasma metering capillary is fluidically connected to the plasma side of the plasma separation element and is configured for receiving the plasma separated from the biological sample by the plasma separation element, wherein an outlet end opposing the application end of the plasma metering capillary comprises an outlet opening, and wherein the plasma metering capillary further comprises a lateral opening in a capillary wall, the lateral opening being located adjacent to the outlet end.

[0066] Embodiment 2: The plasma separation and metering unit according to the preceding embodiment, wherein the lateral opening comprises at least one slot extending along a longitudinal axis of the plasma metering capillary. Embodiment 3 : The plasma separation and metering unit according to the preceding embodiment, wherein the slot extends from the outlet end of the plasma metering capillary.

[0067] Embodiment 4: The plasma separation and metering unit according to any one of the two preceding embodiments, wherein the slot is formed by a groove within the at least one capillary wall of the plasma metering capillary.

[0068] Embodiment 5: The plasma separation and metering unit according to any one of the three preceding embodiments, wherein the slot comprises longitudinal side walls being formed in the capillary wall, wherein the longitudinal side walls extend along the longitudinal axis of the plasma metering capillary.

[0069] Embodiment 6: The plasma separation and metering unit according to the preceding embodiment, wherein, in a top view of the outlet end of the plasma metering capillary, the longitudinal side walls, with respect to the longitudinal axis as vertex, are arranged at an angle of 5° to 90°, preferably of 10° to 80°, most preferably of 15° to 65°.

[0070] Embodiment 7: The plasma separation and metering unit according to embodiment 5, wherein in a top view of the outlet end of the plasma metering capillary the longitudinal side walls, with respect to the longitudinal axis as vertex, are arranged at an angle of essentially 180°.

[0071] Embodiment 8: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma metering capillary comprises at least two of the lateral openings.

[0072] Embodiment 9: The plasma separation and metering unit according to the preceding embodiment, wherein the lateral openings are, in a top view of the outlet end of the plasma metering capillary, arranged opposite to each other.

[0073] Embodiment 10: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the lateral opening has a length of 0.5 mm to 20 mm, preferably of 0.75 mm to 15 mm, most preferably of 1 mm to 10 mm.

[0074] Embodiment 11 : The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma metering capillary is fixedly attached to the housing. Embodiment 12: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma metering capillary and the housing form an integral unit.

[0075] Embodiment 13: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the housing is manufactured by injection molding.

[0076] Embodiment 14: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma separation element and the plasma metering capillary are spaced apart from each other.

[0077] Embodiment 15: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the receptacle comprises at least one funnel compartment arranged adjacent to the application end of the plasma metering capillary configured for guiding the plasma into the application end.

[0078] Embodiment 16: The plasma separation and metering unit according to the preceding embodiment, wherein the plasma separation element is fluidically connected to the receptacle of the housing such that the funnel compartment is covered at least partially, preferably fully, by the plasma separation element.

[0079] Embodiment 17: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma separation element is attached to at least one surface of the receptacle by at least one adhesive, specifically by at least one double-sided adhesive.

[0080] Embodiment 18: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma separation element is irreversibly attached to at least one surface of the receptacle by at least one method selected from the group consisting of: thermobonding; ultrasonic welder; laser welding; adhesive bonding:

[0081] Embodiment 19: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma separation element has a of 50 pm to 1000 pm, preferably of 75 pm to 750 pm, most preferably of 100 pm to 500 pm. Embodiment 20: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma separation element has a diameter of 1 mm to 50 mm, preferably of 5 mm to 20 mm, most preferably of 6 mm to 10 mm.

[0082] Embodiment 21 : The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma separation element is at least partially made of asymmetric polysulfone.

[0083] Embodiment 22: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma separation element is made at least partially of fibers selected from the group consisting of: natural fibers; synthetic fibers, specifically glass fibers.

[0084] Embodiment 23 : The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma separation element has at least one microporous structure.

[0085] Embodiment 24: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma metering capillary is a micro capillary.

[0086] Embodiment 25: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma metering capillary is arranged directly underneath the plasma separation element.

[0087] Embodiment 26: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma metering capillary has an outer diameter of 0.5 mm to 5 mm, preferably of 0.75 mm to 4 mm, most preferably of 1 mm to 3 mm.

[0088] Embodiment 27: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma metering capillary has an inner diameter of 0.1 mm to 3 mm, preferably of 0.25 mm to 2 mm, most preferably of 0.5 mm to 1.3 mm.

[0089] Embodiment 28: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma metering capillary has a length of 0.5 mm to 20 mm, preferably of 0.75 mm to 15 mm, most preferably of 1 mm to 10 mm. Embodiment 29: The plasma separation and metering unit according to any one of the preceding embodiments, wherein at least one surface of the housing, specifically at least one surface of the receptacle of the housing, comprises at least one surface profiling.

[0090] Embodiment 30: The plasma separation and metering unit according to the preceding embodiment, wherein the surface profiling comprises a plurality of microstructures.

[0091] Embodiment 31 : The plasma separation and metering unit according to any one of the two preceding embodiments, wherein the surface profiling comprises an at least partially periodical arrangement of at least one element selected from the group consisting of: a rectangle, a square, a pillar.

[0092] Embodiment 32: The plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma separation and metering unit further comprises at least one further membrane arranged between the plasma separation element and the plasma metering capillary, wherein at least one surface of the further membrane comprises at least one surface profiling.

[0093] Embodiment 33: A plasma separation and metering system, wherein the plasma separation and metering system comprises:

[0094] • at least one vessel, wherein the vessel is configured for receiving at least one washing solution, specifically at least one washing buffer solution; and

[0095] • at least one sample processing unit, wherein the sample processing unit is attachable to the vessel, wherein the sample processing unit comprises the plasma separation and metering unit according to any one of the preceding embodiments, wherein the plasma separation and metering system is configured to be rotatable around a rotation axis of the plasma separation and metering system whereby the washing solution is transported to the plasma separation and metering unit.

[0096] Embodiment 34: The plasma separation and metering system according to the preceding embodiment, wherein the vessel comprises at least one optical window which is received in at least one wall of the vessel.

[0097] Embodiment 35: A method for plasma separation and metering, wherein the method comprises using the plasma separation and metering unit according to any one of the preceding embodiments referring to a plasma separation and metering unit, wherein the method com- prises applying at least one biological sample comprising plasma to the sample port of the plasma separation and metering unit, wherein the plasma is generated and drawn from the sample port into the plasma metering capillary.

[0098] Embodiment 36: The method according to the preceding embodiments, wherein a volume of the biological sample is the range of 10 pl to 200pl, preferably in the range of 20 pl to lOOpl.

[0099] Embodiment 37: The method according to any one of the two preceding embodiments, wherein the biological sample is blood, specifically venous blood, specifically capillary blood.

[0100] Embodiment 38: The method according to any one of the three preceding embodiments, wherein an overpressure is applied on the sample port.

[0101] Embodiment 39: The method according to the preceding embodiment, wherein the overpressure is in the range of 10 mbar to 1000 mbar.

[0102] Embodiment 40: The method according to any one of the two preceding embodiments, wherein the overpressure is generated by at least one device selected from the group consisting of: a syringe piston, a pneumatic system

[0103] Embodiment 41 : The method according to any one of the three preceding embodiments, wherein the overpressure is applied on the sample port through sealing the sample port with at least one sealing cap, specifically with at least one flexible sealing cap.

[0104] Embodiment 42: The method according to the preceding embodiment, wherein the sealing cap is made of at least one material selected from the group consisting of: a thermoplastic polymer, specifically polyethylene, specifically polypropylene; a silicone-based material.

[0105] Embodiment 43 : The method according to any one of the two preceding embodiments, wherein the sealing cap is placed on the sample port manually.

[0106] Embodiment 44: The method according to any one of the three preceding embodiments, wherein the sealing cap is placed on the sample port automatically.

[0107] Short description of the Figures Further optional features and embodiments will be disclosed in more detail in the subsequent description of embodiments, preferably in conjunction with the dependent claims. Therein, the respective optional features may be realized in an isolated fashion as well as in any arbitrary feasible combination, as the skilled person will realize. The scope of the invention is not restricted by the preferred embodiments. The embodiments are schematically depicted in the Figures. Therein, identical reference numbers in these Figures refer to identical or functionally comparable elements.

[0108] In the Figures:

[0109] Figure 1 shows an exemplary embodiment of a plasma separation and metering unit in a cross-sectional view according to the present invention; show an exemplary embodiment of a plasma metering capillary of a plasma separation and metering unit according to the present invention in a perspective view (Figure 2A), in a top view (Figure 2B) and in a side view (Figure 2C);

[0110] Figures 3 A to 3 C show a further exemplary embodiment of a plasma metering capillary of a plasma separation and metering unit according to the present invention in a perspective view (Figure 3A), in a top view (Figure 3B) and in a side view (Figure 3C);

[0111] Figures 4A to 4C show a further exemplary embodiment of a plasma metering capillary of a plasma separation and metering unit according to the present invention in a perspective view (Figure 4A), in a top view (Figure 4B) and in a side view (Figure 4C);

[0112] Figure 5 shows an exemplary surface profiling of a housing of a plasma sepa- ration and metering unit according to the present invention in a top vi ew;

[0113] Figures 6A to 6D show an exemplary method for plasma separation and metering, wherein a plasma separation and metering unit is depicted in a cross- sectional view, respectively; Figures 7A to 7B show details of an exemplary method for plasma separation and metering, wherein a plasma separation and metering unit is depicted in a cross-sectional view, respectively;

[0114] Figures 8A to 8B show details of an exemplary method for plasma separation and metering, wherein a plasma separation and metering unit is depicted in a cross-sectional view, respectively;

[0115] Figure 9 shows several pictures depicting a plasma separation and metering in a plasma metering capillary over time;

[0116] Figure 10 shows experimental data showing a plasma separation efficiency over time until a plasma metering capillary of a plasma separation and metering unit according to the present invention is fully filled; and

[0117] Figures HA to 11D show a method for plasma separation and metering with a plasma separation and metering system according to the present invention, wherein the plasma separation and metering system is illustrated in a cross-sectional view, respectively.

[0118] Detailed description of the embodiments

[0119] Figure 1 shows an exemplary embodiment of a plasma separation and metering unit 110 in a cross-sectional view according to the present invention.

[0120] The plasma separation and metering unit 110 comprises at least one housing 112. The housing 112 comprises at least one receptacle 114 forming at least one sample port 116 for receiving a biological sample, specifically a blood sample.

[0121] Further, the plasma separation and metering 110 unit comprises at least one plasma separation element 118. The plasma separation element 118 is fluidically connected to the receptacle 114 of the housing 112. Specifically, the housing 112 may be configured for holding the plasma separation element 118. The plasma separation element 118 comprises a sample application side 120 facing the sample port 116 and a plasma side 122 opposing the sample application side 120. The plasma separation element 118 may be attached to at least one surface 134 of the receptacle 114 by at least one adhesive 136, specifically by at least one double-sided adhesive 138. The plasma separation element 118 may have at least one mi- croporous structure. Further, the plasma separation element 118 may exemplarily be made of asymmetric polysulfone. Further, the plasma separation element 118 may have a thickness t of 100 pm to 500 pm and may have a diameter d, specifically an outer diameter, of 6 mm - 10 mm.

[0122] Further, the plasma separation and metering unit 110 comprises at least one plasma metering capillary 124 extending from the housing 112. The plasma metering capillary 124 may comprise at least one capillary channel 140. An application end 126 of the plasma metering capillary 124 is fluidically connected to the plasma side 122 of the one plasma separation element 118 and is configured for receiving plasma separated from the biological sample by the plasma separation element 118. An outlet end 128 opposing the application end 126 of the plasma metering capillary 124 comprises an outlet opening 130. The plasma metering capillary 124 further comprises at least one lateral opening in a capillary wall 132, the lateral opening being located adjacent to the outlet end 128. The lateral opening is not illustrated in Figure 1.

[0123] The plasma metering capillary 124 may specifically be a micro-capillary 142. The plasma metering capillary 124 may be located underneath the plasma separation element 118. The plasma metering capillary 124 may be configured for collecting and metering a separated plasma sample. Specifically, the plasma metering capillary 124 may be placed directly underneath the plasma separation element 118. The plasma metering capillary 124 may have an outer diameter doof 1 mm to 3 mm and an inner diameter d, of 0.5 mm to 1.3 mm. Further, a length / , specifically an overall length, of the plasma metering capillary 124 may be in the range between 1 mm to 10 mm.

[0124] The receptacle 114 may comprise at least one funnel compartment 144 arranged adjacent to the application end 126 of the plasma metering capillary 124, specifically at least one conically tapered compartment 146, configured for guiding the plasma into the application end 126. Specifically, the plasma separation element 118 may be fluidically connected to the receptacle 114 of the housing 112 such that the funnel compartment 144 is covered at least partially, preferably fully, by the plasma separation element 118.

[0125] Figures 2A to 2C show an exemplary embodiment of a plasma metering capillary 124 of a plasma separation and metering unit 110 according to the present invention in a perspective view (Figure 2A), in a top view (Figure 2B) and in a side view (Figure 2C). The plasma metering capillary 124 may correspond, at least partially, to the plasma metering capil- lary 124 of the plasma separation and metering unit 110 according to Figure 1. Thus, reference is made to the description of Figure 1 above.

[0126] The plasma metering capillary 124 comprises the outlet opening 130. The plasma metering capillary 124 further comprises at least one lateral opening 148 in the capillary wall 132, the lateral opening 148 being located adjacent to the outlet end 128, specifically adjacent to the outlet opening 130.

[0127] The plasma metering capillary 124 as illustrated in Figures 2A to 2C may comprise one single lateral opening 148. Specifically, the lateral opening 148 may comprise at least one slot 150 extending along a longitudinal axis 152 of the plasma metering capillary 124. The slot 150 may extend from the outlet end 128 of the plasma metering capillary 124. Specifically, the slot 150 may be formed by a groove 154 within the at least one capillary wall 132 of the plasma metering capillary 124. Further, the slot 150 may comprise longitudinal side walls 158 being formed in the capillary wall 132, wherein the longitudinal side walls 158 extend along the longitudinal axis 152 of the plasma metering capillary 124. The lateral opening 148 may be oriented essentially 90° from the longitudinal axis 152. The longitudinal axis 152 may also be referred to as horizontal axis. In a top view of the outlet end 128 of the plasma metering capillary 124, as illustrated in Figure 2B, the longitudinal side walls 158, with respect to the longitudinal axis 152 as vertex, may be arranged at an angle a of 15° to 65°. The lateral opening 148 may have a length lcof 1 mm to 10 mm, as illustrated in Figure 2C.

[0128] Figures 3 A to 3C show a further exemplary embodiment of a plasma metering capillary 124 of a plasma separation and metering unit 110 according to the present invention in a perspective view (Figure 3A), in a top view (Figure 3B) and in a side view (Figure 3C). The plasma metering capillary 124 may correspond, at least partially, to the plasma metering capillary 124 of the plasma separation and metering unit 110 according to Figure 1. Thus, reference is made to the description of Figure 1 above. Further, the plasma metering capillary 124 may correspond, at least partially, to the plasma metering capillary 124 according to Figures 2A to 2C. Thus, reference is made to the description of Figures 2A to 2C above.

[0129] In the embodiment according to Figures 3A to 3C, in a top view of the outlet end 128 of the plasma metering capillary 124 the longitudinal side walls 158, with respect to the longitudinal axis 152 as vertex, may be arranged at an angle a of essentially 180°. Further, as specifically illustrated in Figure 3C, the lateral opening 148 may have a length lcof 1 mm to 10 mm.

[0130] Figures 4A to 4C show a further exemplary embodiment of a plasma metering capillary 124 of a plasma separation and metering unit 110 according to the present invention in a perspective view (Figure 4A), in a top view (Figure 4B) and in a side view (Figure 4C). The plasma metering capillary 124 may correspond, at least partially, to the plasma metering capillary 124 of the plasma separation and metering unit 110 according to Figure 1. Thus, reference is made to the description of Figure 1 above. Further, the plasma metering capillary 124 may correspond, at least partially, to the plasma metering capillary 124 according to Figures 2A to 2C. Thus, reference is made to the description of Figures 2A to 2C above.

[0131] In the embodiment according to Figures 4A to 4C, the plasma separation and metering capillaryl24 may comprise at least two of the lateral openings 148. The lateral openings 148 may be, in a top view of the outlet end 128 of the plasma metering capillary 124, arranged opposite to each other. Specifically, the at least two lateral openings 148 may be orientated 90 ° and 270 ° from the longitudinal axis 152 of the plasma metering capillary 124. Specifically, the at least two lateral openings 148 may have an identical opening angle. Further, the lateral opening 148 may respectively have a length lcof 1 mm to 10 mm. Specifically, the at least two lateral openings 148 may have an identical length lc.

[0132] Figure 5 shows an exemplary surface profiling 160 of the housing 112 of the plasma separation and metering unit 110 according to the present invention in a top view. The housing 112 may correspond, at least partially, to the housing 112 of the plasma separation and metering unit 110 according to Figure 1. Thus, reference is made to the description of Figure 1 above.

[0133] Specifically, at least one surface 162 of the housing 112, specifically at least one surface 162 of the receptacle 114 of the housing 112, may comprise the at least one surface profiling 160. Specifically, the surface 162 may be a surface of the funnel compartment 144. Thus, the surface profiling 160. may be arranged underneath the plasma separation element 118. The surface profiling 162 may comprise a plurality of microstructures 164. The surface profiling 162 may be configured for enhancing the separation of plasma and a subsequent filling of the plasma metering capillary 124 with the plasma. In the embodiment as illustrated in Figure 5, the microstructures 164 may be pillars with a diameter dpof 10 pm to 500 pm, a height of 10 gm to 500 gm and a distance between individual pillars (edge-to- edge) of 10 gm to 1000 gm.

[0134] Figures 6A to 6D show an exemplary method for plasma separation and metering, wherein a plasma separation and metering unit 110 is depicted in a cross-sectional view, respectively. The plasma separation and metering unit may correspond, at least partially, to the plasma separation and metering unit 110 according to Figure 1. Thus, reference is made to the description of Figure 1 above. Specifically, Figures 6A to 6D demonstrate an operation of the plasma separation and metering unit 10.

[0135] The method as illustrated in Figures 6A to 6D comprises using the plasma separation and metering unit 110. Further, the method comprises applying at least one biological sample 168 comprising blood plasma, specifically at least one clinical sample 170, to the sample port 116 of the plasma separation and metering unit 110, wherein plasma is generated and drawn from the sample port 116 into the plasma metering capillary 124.

[0136] As illustrated in Figure 6A, the clinical sample 170 which may be whole blood such as venous or capillary blood and which may be provided with or without an anticoagulant such as EDTA, lithium heparin or others may be applied to the sample port 116 of the plasma separation and metering unit 110. Specially, a volume of clinical sample 170 may range between 20 pl to 100 pl.

[0137] As illustrated in Figure 6B, after the application of the clinical sample 170 onto a surface 172 of the plasma separation element 118 which may specifically face away from the application end 126 of the plasma metering capillary 124, plasma 174 may be generated by passive separation of cellular contents and plasma, specifically due to the microporous structure of the plasma separation element 118 and thus generated capillary forces.

[0138] Subsequently, as illustrated in Figure 6C, the plasma 174 may be transferred, specifically exited on another side of the plasma separation element 118 facing towards the application end 126 of the plasma metering capillary 124. Specifically, the other side may correspond to the plasma side 122.

[0139] Subsequently, as illustrated in Figure 6D, the plasma 174 may be drawn into the plasma metering capillary 124 which may gradually fill over time. After the plasma 174 has reached the outlet end 128 of the plasma metering capillary 124, a flow of plasma 174 may come to an automatic halt. Figures 7A to 7B show details of an exemplary method for plasma separation and metering, wherein a plasma separation and metering unit 110 is depicted in a cross-sectional view, respectively. The plasma separation and metering 110 unit may correspond, at least partially, to the plasma separation and metering unit 110 according to Figure 1. Thus, reference is made to the description of Figure 1 above. Further, the method may correspond, at least partially, to the method as illustrated in Figures 6A to 6B. Thus, reference is made to the description of Figures 6A to 6B above.

[0140] As illustrated in Figures 7A and 7B, the process of plasma separation and metering may be actively enhanced by applying an overpressure, specifically a defined overpressure, on the sample port 116, specifically on an opening of the sample port 116. The defined overpressure may be generated via a syringe piston or by a pneumatic system as illustrated schematically in Figure 7B with arrows 176. The overpressure may range between 10 mbar and 1000 mbar and may be kept either constant during over an entire separation and metering time or may be varied at distinct time points of the process.

[0141] Figures 8A to 8B show details of an exemplary method for plasma separation and metering, wherein a plasma separation and metering unit 110 is depicted in a cross-sectional view, respectively. The plasma separation and metering unit 110 may correspond, at least partially, to the plasma separation and metering unit 110 according to Figure 1. Thus, reference is made to the description of Figure 1 above. Further, the method may correspond, at least partially, to the method as illustrated in Figures 6A to 6B. Thus, reference is made to the description of Figures 6A to 6B above.

[0142] As illustrated in Figures 8A and 8B, the process may be passively enhanced by applying a constant overpressure on the opening of the sample port 116 via the means of a sealing cap 178, specifically a flexible sealing cap 180. Specifically, the flexible sealing cap 180 may be placed into the sample port 116 after the application of the clinical sample 170. An air displacement generated during an insertion of the flexible sealing cap 180 into the sample port 116 may generate a non-constant and / or a non-linear overpressure onto the clinical sample 170, which may decay over the process period. The flexible sealing cap 180 may be made from materials such PE, PP and other thermoplastic polymers, silicone-based materials or others. For separation, an operator may insert the flexible sealing cap 180 manually into the sample port 116 or the flexible sealing cap 180 may be inserted into the sample port 116 by an automatized process which is applying a constant displacement of an outer surface 182 of the flexible sealing cap 180 thus resulting in a controlled generation of overpressure onto the clinical sample 170.

[0143] Figure 9 shows several pictures depicting a plasma separation and metering in a plasma metering capillary 124 of a plasma separation and metering unit 110 over time. The plasma separation and metering unit 110 may correspond, at least partially, to the plasma separation and metering unit 110 according to Figure 1. Thus, reference is made to the description of Figure 1 above. Further, the method may correspond, at least partially, to the method as illustrated in Figures 6A to 6B. Thus, reference is made to the description of Figures 6 A to 6B above.

[0144] Specifically, in Figure 9, the plasma separation and metering in the plasma metering capillary 124 is exemplary shown over a time period of 75 s. Firstly, at 0 s, the plasma 174 may be located at the application end 126. Thereafter, the plasma 174 may gradually travel towards the outlet end 128 and may reach the outlet end 128 at 75 s.

[0145] Figure 10 shows experimental data showing a plasma separation efficiency over time t in min for alanine aminotransferase (ALT), formerly also known as glutamate pyruvate transaminase (GPT) until a plasma metering capillary 124 of a plasma separation and metering unit 100 according to the present invention is fully filled. The plasma separation and metering 110 unit may correspond, at least partially, to the plasma separation and metering unit 110 according to Figure 1. Thus, reference is made to the description of Figure 1 above. The plasma separation efficiency is defined as the duration needed to generate plasma and to entirely fill the plasma metering capillary 124. For preparing Figure 10, the method for plasma separation and metering was performed 60 times.

[0146] Figures 11 A to 1 ID show a method for plasma separation and metering with a plasma separation and metering system 184 according to the present invention, wherein the plasma separation and metering 184 is illustrated in a cross-sectional view, respectively. The plasma separation and metering system 184 may specifically be a point-of-care plasma separation and metering system 198. Specifically, Figures 11 A to 1 ID show an elution of a plasma sample from the plasma metering capillary 124.

[0147] The plasma separation and metering system 184 comprises vessel 186, specifically at least one reaction and measurement vessel 188. The vessel 186 is configured for receiving at least one washing solution 190, specifically at least one washing buffer solution 192. Further, the plasma separation and metering system 184 comprises at least one sample processing unit 194. The sample processing unit 194 is attachable to the vessel 186. The sample processing unit 194 comprises the plasma separation and metering unit 110. The plasma separation and metering 110 unit may correspond, at least partially, to the plasma separation and metering unit 110 according to Figure 1. Thus, reference is made to the description of Figure 1 above. The process of plasma separation and metering may be passively enhanced by applying a constant overpressure on the opening of the sample port 116 via the sealing cap 178. For further details, reference is made to the description of Figures 8A and 8B above.

[0148] The plasma separation and metering system 184 is configured to be rotatable around a rotation axis 196 of the plasma separation and metering system 184 whereby the washing solution 190 is transported to the plasma separation and metering unitlO. Thus, by rotating the plasma separation and metering system 184 around the rotation axis 196, the washing solution 190 may be displaced.

[0149] As illustrated in Figure 11B, by rotating the plasma separation and metering system 184 around the rotation axis 196 as schematically illustrated with arrow 200, the washing solution 190 may be displaced from the vessel 186 towards the plasma separation and metering unit 110. When the washing solution 190 comes in contact with the plasma metering capillary 124, such as illustrated in Figure 11C, plasma may be eluted from the plasma metering capillary 124. Thus, the washing solution 190 in the plasma separation and metering system 184 as illustrated in Figure 11D may comprise the plasma 174. Thus, separated and metered plasma 174 may be eluted from the plasma metering capillary 124 by an additional washing step.

[0150] List of reference numbers plasma separation and metering unit housing receptacle sample port plasma separation element

[0151] Sample application side plasma side plasma metering capillary application end outlet end outlet opening capillary wall surface adhesive double-sided adhesive capillary channel micro-capillary funnel compartment conically tapered compartment lateral opening slot longitudinal axis groove longitudinal side wall surface profiling surface microstructure pillar biological sample clinical sample surface plasma arrow sealing cap flexible sealing cap outer surface test carrier system vessel washing solution washing buffer solution sample processing unit rotation axis point-of-care-test arrow

Claims

Claims1. A plasma separation and metering unit (110), wherein the plasma separation and metering unit (110) comprises:• at least one housing (112), wherein the housing (112) comprises at least one receptacle (114) forming at least one sample port (116) for receiving at least one biological sample (168) comprising plasma (174), wherein the receptacle (114) is an open receptacle having at least one opening, wherein the biological sample may be applied via the opening of the receptacle (114), wherein the opening is configured to allow insertion of a sealing cap (178) into the opening of the receptacle (114);• at least one plasma separation element (118), wherein the plasma separation element (118) is fluidically connected to the receptacle (114) of the housing (112), wherein the plasma separation element (118) comprises a sample application side (120) facing the sample port (116) and a plasma side (122) opposing the sample application side (120); and• at least one plasma metering capillary (124) extending from the housing (112), wherein an application end (126) of the plasma metering capillary (124) is fluidically connected to the plasma side (122) of the plasma separation element (118) and is configured for receiving the plasma separated from the biological sample (168) by the plasma separation element (118), wherein an outlet end (128) opposing the application end (126) of the plasma metering capillary (124) comprises an outlet opening (130), and wherein the plasma metering capillary (124) further comprises at least one lateral opening (148) in a capillary wall (132), the lateral opening (148) being located adjacent to the outlet end (128).

2. The plasma separation and metering unit (110) according to the preceding claim, wherein the lateral opening (148) comprises at least one slot (150) extending along a longitudinal axis (152) of the plasma metering capillary (124).

3. The plasma separation and metering unit (110) according to the preceding claim, wherein the slot (150) extends from the outlet end (128) of the plasma metering capillary (124).

4. The plasma separation and metering unit (110) according to any one of the two preceding claims, wherein the slot (150) comprises longitudinal side walls (158) being formed in the capillary wall (132), wherein the longitudinal side walls (158) extend along the longitudinal axis (152) of the plasma metering capillary (124).

5. The plasma separation and metering unit (110) according to the preceding claim, wherein, in a top view of the outlet end (128) of the plasma metering capillary (124), the longitudinal side walls (158), with respect to the longitudinal axis (152) as vertex, are arranged at an angle of 5° to 90°.

6. The plasma separation and metering unit (110) according to claim 4, wherein in a top view of the outlet end (128) of the plasma metering capillary (124), the longitudinal side walls (158), with respect to the longitudinal axis (152) as vertex, are arranged at an angle of essentially 180°.

7. The plasma separation and metering unit (110) according to any one of the preceding claims, wherein the plasma metering capillary (124) comprises at least two of the lateral openings (148).

8. The plasma separation and metering unit (110) according to any one of the preceding claims, wherein the lateral opening (148) has a length of 0.5 mm to 20 mm.

9. The plasma separation and metering unit (110) according to any one of the preceding claims, wherein the plasma metering capillary (124) and the housing (112) form an integral unit.

10. The plasma separation and metering unit (110) according to any one of the preceding claims, wherein the receptacle (114) comprises at least one funnel compartment (144) arranged adjacent to the application end (126) of the plasma metering capillary (124), wherein the funnel compartment (144) is configured for guiding the plasma (174) from the plasma side (122) of the at least one plasma separation element (118) towards the application end (126) of the plasma metering capillary (124).

11. The plasma separation and metering unit (110) according to any one of the preceding claims, wherein at least one surface (162) of the housing (112) comprises at least one surface profiling (160), wherein the surface profiling (160) comprises a plurality of microstructures (164).

12. A plasma separation and metering system (184), wherein the plasma separation and metering system (184) comprises:• at least one vessel (186), wherein the vessel (186) is configured for receiving at least one washing solution (190); and• at least one sample processing unit (194), wherein the sample processing unit (194) is attachable to the cup (186), wherein the sample processing unit (194) comprises the plasma separation and metering unit (110) according to any one of the preceding claims referring to a plasma separation and metering unit (110), wherein the plasma separation and metering system (184) is configured to be rotatable around a rotation axis (196) of the plasma separation and metering system (184) whereby the washing solution (190) is transported to the plasma separation and metering unit (110).

13. A method for plasma separation and metering, wherein the method comprises using the plasma separation and metering unit (110) according to any one of the preceding claims, wherein the method comprises applying at least one biological sample (168) comprising plasma (174) to the sample port (116) of the plasma separation and metering unit (110), wherein the plasma (174) is generated and drawn from the sample port (116) into the plasma metering capillary (124).

14. The method according to the preceding claim, wherein an overpressure is applied on the sample port (116), wherein the overpressure is in the range of 10 mbar to 1000 mbar.

15. The method according to the preceding claim, wherein the overpressure is applied on the sample port (116) through sealing the sample port (116) with at least one sealing cap (178).

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