EP3975840A2 - Système microfluidique et procédé pour le réglage ciblé des propriétés de perméation d'une membrane semi-perméable - Google Patents

Système microfluidique et procédé pour le réglage ciblé des propriétés de perméation d'une membrane semi-perméable

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Publication number
EP3975840A2
EP3975840A2 EP20729677.3A EP20729677A EP3975840A2 EP 3975840 A2 EP3975840 A2 EP 3975840A2 EP 20729677 A EP20729677 A EP 20729677A EP 3975840 A2 EP3975840 A2 EP 3975840A2
Authority
EP
European Patent Office
Prior art keywords
microchannel
microfluidic system
pressure
membrane
semipermeable membrane
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
EP20729677.3A
Other languages
German (de)
English (en)
Inventor
Florian Schmieder
Frank Sonntag
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.)
Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
Original Assignee
Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
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 Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV filed Critical Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
Publication of EP3975840A2 publication Critical patent/EP3975840A2/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1678—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes intracorporal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/6866—Extracorporeal blood circuits, e.g. dialysis circuits
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1621—Constructional aspects thereof
    • A61M1/1631—Constructional aspects thereof having non-tubular membranes, e.g. sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1621—Constructional aspects thereof
    • A61M1/1633—Constructional aspects thereof with more than one dialyser unit
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
    • B01D63/08—Flat membrane modules
    • B01D63/088—Microfluidic devices comprising semi-permeable flat membranes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/14—Dynamic membranes
    • B01D69/141—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes
    • B01D69/142—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes with "carriers"
    • B01D69/144—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes with "carriers" containing embedded or bound biomolecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3621—Extra-corporeal blood circuits
    • A61M1/3639—Blood pressure control, pressure transducers specially adapted therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0244—Micromachined materials, e.g. made from silicon wafers, microelectromechanical systems [MEMS] or comprising nanotechnology
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2311/00—Details relating to membrane separation process operations and control
    • B01D2311/14—Pressure control
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2313/00—Details relating to membrane modules or apparatus
    • B01D2313/24—Specific pressurizing or depressurizing means
    • B01D2313/243—Pumps
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/02—Form or structure of the vessel
    • C12M23/16—Microfluidic devices; Capillary tubes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/02—Membranes; Filters
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N13/00—Investigating surface or boundary effects, e.g. wetting power; Investigating diffusion effects; Analysing materials by determining surface, boundary, or diffusion effects
    • G01N13/04—Investigating osmotic effects
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types

Definitions

  • a microfluidic system and a method for the targeted setting of the permeation properties of a semipermeable membrane are provided.
  • the system according to the invention and the method according to the invention it is possible to adjust the permeation properties of the semipermeable membrane of the system at any time during a measurement by means of a feedback mechanism so that the membrane keeps the desired permeation properties constant or changes them in a targeted manner.
  • the semipermeable membrane is populated with kidney cells, for example, a more realistic measurement of a kidney function (e.g. depending on a drug and / or cosmetic) can be carried out with the system and method according to the invention than with known ones
  • WO 2011/059786 A1 describes a microfluidic device which has a first and a second microchannel, with both microchannels being separated by a semipermeable filtration membrane and on a Liquid within the first microchannel can be pressurized by a pump in order to analyze a pressure-intensified transport of an analyte through the semipermeable membrane.
  • a pump in order to analyze a pressure-intensified transport of an analyte through the semipermeable membrane.
  • the object of the present invention was to provide a microfluidic system and a method with which it is possible, please include to set the permeation properties of a semipermeable membrane in a microfluidic system in a targeted manner and thus ensure that physiologically relevant membranes are measured during a measurement of biological semipermeable membranes Permeation properties are present.
  • physiological filtration properties in an artificial membrane in a microfluidic system which artificially imitates the biological barrier between the “blood side” and the “urine side” in a kidney in a living organism.
  • a microfluidic system comprising a) a first microchannel
  • At least one semipermeable membrane at least one semipermeable membrane, the at least one semipermeable membrane spatially separating the first microchannel from the second microchannel and being permeable to at least one test substance; and d) at least one means for regulating a pressure in the first and / or second microchannel;
  • the microfluidic system also contains at least one detection unit,
  • the microfluidic system furthermore contains a control unit which is configured for this purpose via a communicative connection to the at least one Detek
  • test substance and / or the pressure To obtain test substance and / or the pressure and to control the at least one means for regulating a pressure in the first and / or second microchannel as a function of the information obtained about the concentration of the min least one test substance and / or the pressure.
  • the semipermeable membrane can be an artificially produced (artificial) and / or a naturally occurring semipermeable membrane.
  • An artificial membrane can be understood as a membrane that is constructed from a polymer material (preferably a plastic) or an amorphous material.
  • the membrane can preferably be produced by bombarding a plastic film with electrons or particles (nuclear track membrane) or by electrospinning thin fibers (“electrospinning”)
  • the membrane can be made by molding microstructures in a polymer.
  • a naturally occurring semipermeable membrane can be understood as a biological basement membrane, i.e. an extracellular membrane
  • BO Matrix of a biological barrier such as the glomerular blood-urine barrier or the blood-brain barrier. If this basement membrane is formed in an organoid, it can be both, namely on the one hand manufactured artificially (artificial) and occurring in nature (e.g. in a certain organ of a naturally occurring organism).
  • organoid is understood to mean, in particular, an organ-like microstructure a few millimeters in size, which can be produced artificially using cell culture methods. Under suitable culture conditions, an organoid can be made up of one or a few tissue cells, embryonic stem cells
  • Organoid usually has only rudimentary preliminary stages of vascularization (i.e. vessels) and almost no stroma, but shows physiologically relevant, organ-like properties.
  • Control unit is configured to have at least one means for regulating a pressure in the first and / or second microchannel (optionally all such means in the system) as a function of information about the concentration of the test substance in the second microchannel (i.e. a concentration of the test sub
  • tracer feedback can be referred to as “tracer feedback”. This results in the essential advantage that the permeation properties of the semi-permeable membrane can be controlled in a targeted manner at any point in time during a measurement with the system according to the invention
  • Time windows are kept constant or can be changed selectively.
  • the permeation properties can be targeted in a specific way
  • BO th physiological range can be kept and thus prevented that the cellular homeostasis changes in an undesirable way compared to the "real" situation in vivo. It can thus be excluded that an effect of a certain substance (eg a toxic effect of a drug or of a cosmetic) on the filtration properties of the
  • the microfluidic system according to the invention can also be easily integrated into known body-on-a-chip models (e.g. via a fluidic connection of the first microchannel to such models).
  • the reason for this is that the system according to the invention is suitable for adapting a certain pressure, which is applied via the connected body-on-a-chip model in the first microchannel, by means of the feedback mechanism so that the desired permeation properties of the membrane are achieved.
  • the microfluidic system can be characterized in that the first microchannel has a fluid inlet and / or has a fluid outlet.
  • the first microchannel can be designed as a (closed) fluid circuit, i.e. a fluid (i.e. a liquid) can circulate in the first microchannel (e.g. via the action of a pump).
  • the first microchannel can be sterile and / or implantable. The advantage here is that the microfluidic system can be used as an artificial kidney for a patient.
  • the first microchannel can form a fluid circuit.
  • the at least one means for regulating a pressure of a liquid in the first and / or second microchannel is / are preferably arranged downstream of the fluid inlet and upstream of the semipermeable membrane.
  • the second microchannel of the microfluidic system can have a reservoir that is preferably fluidically connected to the second microchannel and is particularly preferably arranged downstream of the at least one detection unit.
  • the reservoir has the advantage that the second microchannel (apart from the fluidic connection to the first microchannel) can be closed in a fluid-tight manner and nevertheless over the reservoir for a long time. filtered liquid can be collected. Long-term measurements are thus also possible in the case of a "closed" second microchannel.
  • the second microchannel can have a fluid outlet.
  • the second microchannel can be sterile and / or implantable. This embodiment is advantageous if the second microchannel of the microfluidic system, or the entire microfluidic system, is also implanted in a living body.
  • the second microchannel can form a fluid circuit.
  • the at least one detection unit is preferably arranged downstream of the se mipermeable membrane and / or upstream of a reservoir (if the system has a reservoir at this point).
  • the at least one semipermeable membrane is a glomerular semipermeable membrane.
  • the at least one semipermeable membrane can be arranged in a side wall of the first microchannel, preferably arranged downstream of the at least one means for regulating a pressure of a liquid in the first and / or second microchannel, and optionally arranged upstream of a fluid outlet.
  • the at least one semipermeable membrane can be arranged in a side wall of the second microchannel, preferably arranged upstream of the at least one detection unit, and optionally arranged upstream of a reservoir and a fluid outlet.
  • a side wall of the (first and / or second) microchannel means in particular a wall of the (first and / or second) microchannel which is arranged essentially perpendicular to a flow direction of a liquid in the (first and / or second) microchannel.
  • the at least one semipermeable membrane contains or consists of a plastic, preferably a plastic selected from the group consisting of elastomer, thermoplastic and combinations thereof, particularly preferably a plastic selected from the group consisting of PES, PET, PC , PMMA, COC, TPE, TPU, silicone, and combinations thereof.
  • the at least one semipermeable membrane contains or consists of a natural substance, preferably a natural substance selected from the group consisting of substance of an extracellular matrix from an organism, particularly preferably a natural substance selected from the group consisting of collagen (preferably collagen IV), gelatine, matrigel, self-assembling nanofibrillar peptides, heparin-based hydrogels, alginate, nanofibrillary cellulose, xanthan, fibrinogen and combinations thereof.
  • this natural substance can be mixed with a factor selected from the group consisting of growth factors, coupling factors (e.g.
  • laminins glycosaminoglycans, especially heparan sulfate), integrins, and glomerulus-specific coupling proteins (e.g. nidogen, agrin, protocadherins (FAT1 or FAT2) and CD2- associated protein (CD2AP)
  • nidogen e.g. nidogen, agrin, protocadherins (FAT1 or FAT2) and CD2- associated protein (CD2AP)
  • CD2-associated protein ie the natural product membrane can be bound to these factors (molecules).
  • the binding of the factors to the membrane can take place covalently or non-covalently.
  • the at least one semipermeable membrane can also contain or consist of a mixture or combination of plastic and natural material.
  • the membrane is the basement membrane of a kidney organoid, which was preferably produced by differentiating stem cells, preferably induced, pluripotent stem cells (iPSCs).
  • the basement membrane produced in this way is synthesized by the cells of the organoid and thus has almost completely the in vivo composition of the basement membrane.
  • the at least one semipermeable membrane has an upper side in the direction of the first microchannel the biological cells, preferably kidney cells, particularly preferably human kidney cells, are arranged, the biological cells being selected very particularly preferably from the group consisting of endothelial cells, the endothelial cells in particular being fenestrated and / or arranged confluently on the top.
  • the at least one semipermeable membrane in the direction of the second microchannel has an underside on which biological cells, preferably kidney cells, particularly preferably human kidney cells, are arranged, the biological cells being very particularly preferably selected from Group consisting of podocytes, the podocytes in particular being differentiated and / or being arranged confluently on the underside.
  • biological cells preferably kidney cells, particularly preferably human kidney cells
  • the membrane is part of an, ideally vascularly polarized, organoid, the first channel being arranged in particular as a vascular pole to the organoid and thus flowing through the blood side of the vascularized organoid.
  • the microfluidic system can have at least one second semipermeable membrane that spatially separates the first microchannel from the second microchannel and is permeable to a test substance (e.g. certain ions).
  • a test substance e.g. certain ions
  • the at least one second semipermeable membrane is a tubular semipermeable membrane.
  • the at least one second semipermeable membrane can have at least one of the abovementioned properties of the at least one (first) semipermeable membrane.
  • the at least one second semipermeable membrane can (also) be arranged in a side wall of the first microchannel.
  • the at least one second semipermeable membrane is preferably arranged downstream of the at least one (first) semipermeable membrane, optionally arranged upstream of a fluid outlet.
  • the at least one second semipermeable membrane can be arranged in a side wall of the second microchannel, preferably arranged downstream of the at least one (first) semipermeable membrane and upstream of the at least one detection unit. It is optionally arranged upstream of a reservoir and a fluid outlet.
  • the at least one second semipermeable membrane can contain or consist of a plastic, preferably a plastic selected from the group consisting of elastomer, thermoplastic and combinations thereof, particularly preferably a plastic selected from the group consisting of PES, PET, PC, PMMA , COC, TPE, TPU, silicone and combinations thereof.
  • the at least one second semipermeable membrane contains or consists of a natural substance, preferably a natural substance selected from the group consisting of the substance of an extracellular matrix of an organism, particularly preferably a natural substance selected from the group consisting of collagen (preferably Collagen IV), gelatin, matrigel, self-assembling nanofibrillar peptides, alginate, nanofibrillary cellulose, xanthan gum, fibrinogen and combinations thereof.
  • this natural product membrane can be loaded with a factor selected from the group consisting of growth factors, coupling factors (e.g.
  • laminins and / or glycosaminoglycans especially heparan sulfate), integrins, nidogen, fibronectin and combinations thereof.
  • the factor or factors can be bound to the membrane covalently or non-covalently.
  • the at least one second semipermeable membrane can also contain or consist of a mixture or combination of plastic and natural material.
  • the at least one second semipermeable membrane has an upper side in the direction of the first microchannel on which biological cells, preferably kidney cells, particularly preferably human kidney cells, are arranged.
  • biological cells are preferably selected from the group consisting of endothelial cells, the endothelial cells particularly preferably being fenestrated, in particular being arranged confluently on the upper side.
  • the at least one second semipermeable membrane has an underside in the direction of the second microchannel on which biological cells, preferably kidney cells, particularly preferably human kidney cells, are arranged.
  • the biological cells are preferably selected from the group consisting of podocytes, the podocytes being particularly preferably differentiated, in particular with the formation of foot processes and / or slit membranes.
  • the microfluidic system can contain at least one in vitro-generated artificial organoid, the first microchannel being arranged as a “vascular pole” to the organoid (and thus flowing through the “blood side” of the vascularized organoid), and the second microchannel as a “urinary pole” to the organoid is arranged (and thus forms the "urine side” of the organoid).
  • the at least one means for regulating a pressure in the first and / or second microchannel can contain or consist of a pump, the pump preferably being arranged in the first microchannel.
  • Pressure regulation in the first and / or second microchannel via a pump has the advantage that pressure and flow rate are regulated together, i.e. the flow velocity is increased with the pressure and vice versa. In this respect, pressure control via a pump comes very close to pressure control via a heart of a living organism.
  • the microfluidic system has a valve for regulating the volume flow before and after the semipermeable membrane.
  • This valve can simulate the naturally occurring narrowing or widening of the diameter of the inlet and outlet arteriole in order to control the flow and pressure. This allows the pressures and volume flows of a medium flowing past to be regulated in a simple manner.
  • the associated principle is called "tubuloglomerular feedback"("TGF").
  • the at least one means for regulating a pressure in the first microchannel can contain or consist of a deflectable, preferably liquid-impermeable, membrane which is preferably arranged on a side wall of the first microchannel.
  • the at least one means for regulating a pressure in the first microchannel can contain or consist of a reservoir with liquid, which is preferably fluidically connected to the first microchannel.
  • the at least one means for regulating a pressure in the first and / or second microchannel can contain or consist of a gas reservoir with gas, which is preferably fluidly connected to the first microchannel and is particularly preferably arranged above a reservoir with liquid, the Gas storage is particularly preferably suitable for regulating a gas pressure delivered to a reservoir with liquid, in particular controlled via the at least one means for regulating a pressure in the first and / or second microchannel.
  • the gas reservoir can be present above the reservoir.
  • the at least one means for regulating a pressure in the second microchannel can contain or consist of a deflectable, preferably liquid-impermeable, membrane, which is preferably arranged on a side wall of the second microchannel.
  • the at least one means for regulating a pressure in the second microchannel can contain or consist of a reservoir with liquid, which is preferably fluidically connected to the second microchannel.
  • the at least one means for regulating a pressure in the second microchannel can contain or consist of a gas reservoir with gas, which is preferably fluidly connected to the second microchannel and is particularly preferably arranged above a reservoir with liquid, the gas reservoir being particularly is preferably suitable for regulating a gas pressure delivered to a reservoir with liquid, in particular controlled by the at least one means for regulating a pressure in the first and / or second microchannel.
  • a reservoir with liquid and / or via a gas reservoir preferably via a liquid reservoir with a fluidically connected gas reservoir
  • the pressure in the first and / or second microchannel is regulated independently of the flow rate (and thus different from pressure regulation via a pump) can be. Consequently, it becomes possible to identify a situation in the
  • the pressure in the first and / or second microchannel can be dynamically adjusted via these various regulators, without, for example, the flow rate on the (or the) semipermeable membrane (s) or to influence the shear stress (pump speed
  • the at least one detection unit of the microfluidic system can contain or consist of a detector (i.e. a sensor), which is selected from the group consisting of optical detection unit, electrical
  • cellular detection unit preferably a cellular detection unit which contains or consists of human cells, in particular human kidney cells
  • function of the cellular detection unit is based on the fact that certain never
  • BOR cells are suitable for measuring a salt concentration and have a
  • Signal cascade regulate the flow through a membrane (e.g. a glomerular membrane).
  • a membrane e.g. a glomerular membrane.
  • the at least one detection unit contains or consists of an optical detection unit which is configured to acquire information about a concentration of a fluorescence-labeled test substance.
  • the test substance is preferably selected from the group consisting of inulin, sinistrine, creatinine, glucose, urea, paraaminohippuric acid, albumin, beta-2-microglobulin, zinc-alpha-2-glycoprotein, particles in the nanometer range (1 nm to ⁇ 1 pm) to the small micrometer range (1 pm to 10 pm) and combinations thereof.
  • the advantage of an optical detection unit is that a concentration of a fluorescence-marked test substance can be measured in a quick, simple and reliable manner.
  • an optical detection unit also takes into account resorption properties of the at least one (first) and / or at least one second semipermeable membrane in the concentration measurement of the test substance (here: an absorbent and / or fluorescent substance) in the second microchannel can.
  • the concentration measurement of the test substance here: an absorbent and / or fluorescent substance
  • above all reabsorption on the at least one second (tubular) semipermeable membrane can be detected and contribute to controlling the means for regulating a pressure in the first and / or second microchannel.
  • the at least one detection unit contains or consists of an electrical detection unit which is suitable for detecting information about a concentration of an ion.
  • the ion is preferably selected from the group consisting of sodium ion, calcium ion, chloride ion, potassium ion, carbonate ion, hydrogen carbonate ion, magnesium ion, citrate ion, phosphate ion, sulphate ion, (heavy) metal ion and combinations thereof.
  • the advantage of an electrical detection unit is that it can also be used to take into account resorption properties of the at least one (first) and / or at least one second semipermeable membrane in the concentration measurement of the test substance (here: ions) in the second microchannel.
  • the control unit of the microfluidic system can be configured to give the at least one means for regulating the pressure in the first and / or second microchannel (preferably all means for regulating the pressure) a signal, the pressure in the first microchannel, especially that at the ( first) semipermeable membrane applied pressure, to increase and / or to lower the pressure in the second microchannel, especially on an underside of the at least one semipermeable membrane, if the concentration of the test substance (or the information about it) is below a certain threshold , wherein the signal is preferably selected from the group consisting of increasing the flow rate of a pump, reducing the channel cross-section of the first microchannel downstream of the membrane, deflecting a liquid-tight membrane in the direction of an interior of the first microchannel, increasing a liquid column in a reservoir, Increase in gas
  • control unit of the microfluidic system can be configured to give a signal to the at least one means for regulating the pressure in the first and / or second microchannel (preferably all means for regulating the pressure), the pressure in the first microchannel, especially at the ( first) semipermeable membrane, to lower and / or to increase the pressure in the second microchannel, especially on an underside of the at least one semipermeable membrane, if the concentration of the test substance is above a certain threshold value, the signal preferably being selected the group consisting of lowering the flow rate of a pump, reducing the channel cross section of the first microchannel upstream of the membrane, deflecting a liquid-tight membrane in the direction of an outer space of the first microchannel, lowering a liquid column in a reservoir, lowering the gas pressure above the liquid column in a reservoir and combinations of this.
  • the signal is preferably a reduction in the channel cross section of the first microchannel upstream of the membrane, since this enables the TGF to be mapped very realistically.
  • the microfluidic system can be sterile and / or implantable, preferably is suitable to be implanted in a human or an animal. For this suitability, certain dimensions of the microfluidic system are necessary, which not every conceivable microfluidic system has.
  • implantability is that the entire system can be used, for example, as an artificial kidney in a living patient.
  • a method for the targeted adjustment of the permeation properties of a semipermeable membrane in a microfluidic system comprises the steps
  • microfluidic system according to the invention in vitro (ie ex vivo) to investigate the influence of a medicament and / or cosmetic on the function of kidney cells, preferably on the function of human kidney cells, particularly preferably on the filtration properties and / or absorption properties of human kidney cells. It is also proposed that the microfluidic system according to the invention be used in vitro (ie ex vivo) or in vivo as an artificial kidney of a living being, preferably as an artificial kidney of a human.
  • the subject according to the invention is intended to be explained in more detail using the following figures, without wishing to restrict it to the specific embodiments shown here.
  • FIG. 1 shows schematically a microfluidic system according to the invention.
  • the microfluidic system contains a first microchannel 1 and a second microchannel 2, which are spatially separated from one another by a semipermeable membrane S.
  • the semipermeable membrane S is permeable to at least one test substance (e.g. fluorescence-labeled inulin and / or sodium ions).
  • a liquid containing the at least one test substance can be introduced into the first microchannel 1 via a fluid inlet 11.
  • the liquid can leave the first microchannel 1 via the fluid outlet 12.
  • a pump 4 causes a certain speed of movement of the liquid along the semipermeable membrane 3 in the first microchannel 1 and a certain pressure of this liquid on the semipermeable membrane 3.
  • the pressure of the liquid on the semipermeable membrane 3 can also be via a reservoir 5 be set with liquid and a steerable membrane 6 from.
  • the pump 4, the reservoir 5 and the deflectable membrane 6 are connected to a control unit 8 via a communicative connection 10.
  • the control unit 8 is also connected via a further communicative connection 9 to a detection unit 7 which is configured to detect information about a concentration of the test substance in a liquid in the second microchannel 2 of the system.
  • the second microchannel 2 here has a reservoir 13 and also a fluid outlet 14.
  • the microfluidic system represents an artificial kidney.
  • the semipermeable membrane 3 is covered on a surface in the direction of the first microchannel 1 with endothelial cells 15 of the kidney, whereby the part of the system on this side of the semipermeable membrane 3 is called the “blood side "A of the microfluidic system.
  • the semipermeable membrane 3 is covered on a surface in the direction of the second microchannel 2 with podocytes 16 of the kidney, whereby the part of the system on this side of the semipermeable membrane 3 as" urine side "B of the microfluidic system is called.
  • FIG. 2 schematically shows a further microfluidic system according to the invention.
  • the description of Figure 1 applies here accordingly, but this has Embodiment a second semipermeable membrane 17, which is in the first microchannel downstream of the (first) semipermeable membrane 3 is arranged.
  • the (first) semipermeable membrane forms a glomerular filtration of a kidney (primarily primary filtration) and the second semipermeable membrane 17 forms a tubular filtration function of the kidney (primarily reabsorption of ions).
  • a detection of the concentration of ions downstream of the second semipermeable membrane can thus provide a control variable for the pump 4, the reservoir 5 and the deflectable membrane 6, which is better matched to the situation in vivo, ie reflects the reality in the living organism more accurately.
  • reservoir of the first microchannel (means for regulating a pressure in the first and / or second microchannel);
  • deflectable membrane (means for regulating a pressure in the first and / or second microchannel);
  • detection unit e.g. optical and electrical detection unit
  • control unit 10 communicative connection (between control unit and at least one means for regulating the pressure in the first and / or second microchannel);
  • biological cells on top of the at least one semipermeable membrane e.g. endothelial cells of the kidney
  • the at least one semi-permeable len membrane e.g. podocytes of the kidney
  • A "blood side", if the system simulates a kidney

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Veterinary Medicine (AREA)
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  • Physics & Mathematics (AREA)
  • Molecular Biology (AREA)
  • Anesthesiology (AREA)
  • Vascular Medicine (AREA)
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  • Surgery (AREA)
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  • Dispersion Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
  • Optics & Photonics (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Separation Using Semi-Permeable Membranes (AREA)

Abstract

L'invention concerne un système microfluidique et un procédé pour le réglage ciblé des propriétés de perméation d'une membrane semi-perméable. Le système selon l'invention et le procédé selon l'invention permettent de régler les propriétés de perméation de la membrane semi-perméable du système à tout moment durant une mesure par un mécanisme de rétroaction de telle façon que la membrane maintient constantes les propriétés de perméation souhaitées ou que celles-ci sont modifiées de manière ciblée.
EP20729677.3A 2019-05-27 2020-05-26 Système microfluidique et procédé pour le réglage ciblé des propriétés de perméation d'une membrane semi-perméable Pending EP3975840A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102019207752.8A DE102019207752B3 (de) 2019-05-27 2019-05-27 Mikrofluidisches System und Verfahren zur gezielten Einstellung der Permeationseigenschaften einer semipermeablen Membran
PCT/EP2020/064592 WO2020239776A2 (fr) 2019-05-27 2020-05-26 Système microfluidique et procédé pour le réglage ciblé des propriétés de perméation d'une membrane semi-perméable

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EP3975840A2 true EP3975840A2 (fr) 2022-04-06

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CN102596373A (zh) 2009-10-29 2012-07-18 查尔斯斯塔克德雷珀实验室公司 用于血液透析的微流体装置
US10478543B2 (en) * 2013-01-11 2019-11-19 The Charles Stark Draper Laboratory, Inc. Systems and methods for increasing convective clearance of undesired particles in a microfluidic device

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