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WO2025172533A1 - Unité de séparation et de dosage de plasma - Google Patents

Unité de séparation et de dosage de plasma

Info

Publication number
WO2025172533A1
WO2025172533A1 PCT/EP2025/054030 EP2025054030W WO2025172533A1 WO 2025172533 A1 WO2025172533 A1 WO 2025172533A1 EP 2025054030 W EP2025054030 W EP 2025054030W WO 2025172533 A1 WO2025172533 A1 WO 2025172533A1
Authority
WO
WIPO (PCT)
Prior art keywords
plasma
metering
plasma separation
capillary
sample
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/054030
Other languages
English (en)
Inventor
Gernot Hochmuth
Eloisa Lopez-Calle
Ludwig POLLICH
Christopher Probst
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Roche Diagnostics Operations Inc
Original Assignee
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Roche Diagnostics Operations Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG, Roche Diagnostics GmbH, Roche Diagnostics Operations Inc filed Critical F Hoffmann La Roche AG
Publication of WO2025172533A1 publication Critical patent/WO2025172533A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0605—Metering of fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0681—Filter
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces

Definitions

  • 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.
  • 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.
  • 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
  • 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.
  • a metered plasma sample shall be elutable precisely.
  • 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.
  • 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.
  • 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.
  • a 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the sample may comprise several materials or compounds.
  • the sample is a biological sample.
  • 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.
  • 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.
  • 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.
  • the plasma may comprise at least one analyte of interest.
  • 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.
  • 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.
  • 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.
  • the plasma separation and metering unit may be configured for separating plasma from the biological sample which may specifically be blood.
  • the plasma separation and metering unit comprises the plasma separation element which will further be described below in more detail.
  • 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.
  • 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.
  • the plasma separation and metering unit comprises the at least one housing.
  • 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.
  • 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.
  • sample port for receiving the biological sample.
  • sample port 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.
  • the housing may be manufactured by injection molding.
  • 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).
  • PC polycarbonate
  • PMMA polymethyl methacrylate
  • COC/COP cyclic olefin copolymer
  • the plasma separation and metering unit comprises the at least one plasma separation element.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the biological sample 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.
  • the biological sample may cover a surface of the sample application side of the plasma separation element at least partially.
  • the plasma separation element may be a semi-permeable membrane which is permeable for plasma.
  • the plasma may be transferred from the sample application side to the opposing plasma side. Underneath the plasma side, the plasma may be collected.
  • 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.
  • 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.
  • the plasma separation element is fluidically connected to the receptacle of the housing.
  • 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.
  • 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.
  • 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.
  • the plasma separation and metering unit comprises the plasma metering capillary.
  • 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.
  • the capillary may comprise dimensions in the millimeter or sub-millimeter range.
  • 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 specifically may refer, without limitation, to a capillary which is configured for providing a metered amount of plasma.
  • 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.
  • the sample processing unit may specifically be attachable to the vessel such that the sample processing unit opening faces a vessel opening.
  • the vessel may be fluidically connected to the sample processing unit via the sample processing unit opening and the vessel opening.
  • 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.
  • another one of the two directions may refer to a counterclockwise motion.
  • the anticlockwise motion may correspond to an opposite sense of rotation.
  • the biological sample may be blood, specifically venous blood, specifically capillary blood.
  • a volume of the biological sample may be of 10 pl to 200 pl, preferably of 20 pl to 100 pl.
  • 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.
  • the enhancing of the plasma separation and metering may be a passive enhancing.
  • 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.
  • Embodiment 1 A plasma separation and metering unit, wherein the plasma separation and metering unit comprises:
  • 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;
  • 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;
  • the plasma metering capillary • 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.
  • 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.
  • 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.
  • 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°.
  • 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°.
  • 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.
  • 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.
  • 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.
  • Embodiment 13 The plasma separation and metering unit according to any one of the preceding embodiments, wherein the housing is manufactured by injection molding.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Embodiment 30 The plasma separation and metering unit according to the preceding embodiment, wherein the surface profiling comprises a plurality of microstructures.
  • 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.
  • 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.
  • Embodiment 33 A plasma separation and metering system, wherein the plasma separation and metering system comprises:
  • At least one vessel wherein the vessel is configured for receiving at least one washing solution, specifically at least one washing buffer solution;
  • sample processing unit is attachable to the vessel
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Embodiment 38 The method according to any one of the three preceding embodiments, wherein an overpressure is applied on the sample port.
  • Embodiment 39 The method according to the preceding embodiment, wherein the overpressure is in the range of 10 mbar to 1000 mbar.
  • 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
  • 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);
  • 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;
  • Figure 9 shows several pictures depicting a plasma separation and metering in a plasma metering capillary over time
  • 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.
  • Figure 1 shows an exemplary embodiment of a plasma separation and metering unit 110 in a cross-sectional view according to the present invention.
  • 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.
  • 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.
  • 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.
  • the plasma separation element 118 may exemplarily be made of asymmetric polysulfone.
  • 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.
  • 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.
  • 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.
  • 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 d o of 1 mm to 3 mm and an inner diameter d, of 0.5 mm to 1.3 mm.
  • a length /, specifically an overall length, of the plasma metering capillary 124 may be in the range between 1 mm to 10 mm.
  • 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.
  • 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.
  • FIGS 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.
  • Figure 1 reference is made to the description of Figure 1 above.
  • 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.
  • the plasma metering capillary 124 as illustrated in Figures 2A to 2C may comprise one single lateral opening 148.
  • 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.
  • the slot 150 may be formed by a groove 154 within the at least one capillary wall 132 of the plasma metering capillary 124.
  • 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.
  • the longitudinal side walls 158 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 l c of 1 mm to 10 mm, as illustrated in Figure 2C.
  • 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.
  • the plasma metering capillary 124 may correspond, at least partially, to the plasma metering capillary 124 according to Figures 2A to 2C.
  • Figures 2A to 2C 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
  • the longitudinal side walls 158 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 l c of 1 mm to 10 mm.
  • 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.
  • the plasma metering capillary 124 may correspond, at least partially, to the plasma metering capillary 124 according to Figures 2A to 2C.
  • Figures 2A to 2C Figures 2A to 2C
  • 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.
  • the at least two lateral openings 148 may be orientated 90 ° and 270 ° from the longitudinal axis 152 of the plasma metering capillary 124.
  • the at least two lateral openings 148 may have an identical opening angle.
  • the lateral opening 148 may respectively have a length l c of 1 mm to 10 mm.
  • the at least two lateral openings 148 may have an identical length l c .
  • 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.
  • Figure 1 See Figure 1 above.
  • 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.
  • the surface 162 may be a surface of the funnel compartment 144.
  • 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.
  • the microstructures 164 may be pillars with a diameter d p of 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.
  • 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.
  • Figures 6A to 6D demonstrate an operation of the plasma separation and metering unit 10.
  • 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.
  • FIGS 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.
  • the method may correspond, at least partially, to the method as illustrated in Figures 6A to 6B.
  • Figures 6A to 6B above.
  • 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.
  • FIGS 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.
  • the method may correspond, at least partially, to the method as illustrated in Figures 6A to 6B.
  • Figures 6A to 6B above.
  • 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.
  • 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.
  • 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.
  • 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.
  • the method may correspond, at least partially, to the method as illustrated in Figures 6A to 6B.
  • Figures 6 A to 6B reference is made to the description of Figures 6 A to 6B above.
  • the plasma separation and metering in the plasma metering capillary 124 is exemplary shown over a time period of 75 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.
  • 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.
  • the plasma separation efficiency is defined as the duration needed to generate plasma and to entirely fill the plasma metering capillary 124.
  • the method for plasma separation and metering was performed 60 times.
  • 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.
  • Figures 11 A to 1 ID show an elution of a plasma sample from the plasma metering capillary 124.
  • 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.
  • 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.
  • 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.
  • Figures 8A and 8B For further details, reference is made to the description of Figures 8A and 8B above.
  • 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.
  • the washing solution 190 may be displaced.
  • the washing solution 190 may be displaced from the vessel 186 towards the plasma separation and metering unit 110.
  • 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.
  • the washing solution 190 in the plasma separation and metering system 184 as illustrated in Figure 11D may comprise the plasma 174.
  • separated and metered plasma 174 may be eluted from the plasma metering capillary 124 by an additional washing step.
  • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

Est divulguée une unité de séparation et de dosage de plasma (110). L'unité de séparation et de dosage de plasma (110) comprend : • au moins un logement (112), le logement (112) comprenant au moins un réceptacle (114) formant au moins un orifice pour échantillon (116) destiné à recevoir au moins un échantillon biologique (168) comprenant du plasma (174) ; • au moins un élément de séparation de plasma (118), l'élément de séparation de plasma (118) étant reçu dans le réceptacle (114) du logement (112), l'élément de séparation de plasma (118) comprenant un côté d'application d'échantillon (120) faisant face à l'orifice pour échantillon (116) et un côté plasma (122) opposé au côté d'application d'échantillon (120) ; et • au moins un capillaire de dosage de plasma (124) s'étendant à partir du logement (112), une extrémité d'application (126) du capillaire de dosage de plasma (124) étant en communication fluidique avec le côté plasma (122) de l'élément de séparation de plasma (118) et étant conçue pour recevoir le plasma séparé de l'échantillon biologique (168) par l'élément de séparation de plasma (118), une extrémité de sortie (128) opposée à l'extrémité d'application (126) du capillaire de dosage de plasma (124) comprenant une ouverture de sortie (130), et le capillaire de dosage de plasma (124) comprenant en outre au moins une ouverture latérale (148) dans une paroi capillaire (132), l'ouverture latérale (148) étant située adjacente à l'extrémité de sortie (128).
PCT/EP2025/054030 2024-02-16 2025-02-14 Unité de séparation et de dosage de plasma Pending WO2025172533A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017015243A1 (fr) 2015-07-21 2017-01-26 Mcneely Michael Ryan Séparation et dosage automatiques du plasma
US20220323954A1 (en) * 2019-06-07 2022-10-13 Thinxxs Microtechnology Ag Transfer system for samples, more particularly samples to be analyzed

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017015243A1 (fr) 2015-07-21 2017-01-26 Mcneely Michael Ryan Séparation et dosage automatiques du plasma
US20180207638A1 (en) * 2015-07-21 2018-07-26 Michael Ryan McNeely Automatic plasma separation and metering
US20220323954A1 (en) * 2019-06-07 2022-10-13 Thinxxs Microtechnology Ag Transfer system for samples, more particularly samples to be analyzed

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