EP3743507A1 - Dispositif et procédé pour la désagrégation de tissus - Google Patents

Dispositif et procédé pour la désagrégation de tissus

Info

Publication number
EP3743507A1
EP3743507A1 EP18704159.5A EP18704159A EP3743507A1 EP 3743507 A1 EP3743507 A1 EP 3743507A1 EP 18704159 A EP18704159 A EP 18704159A EP 3743507 A1 EP3743507 A1 EP 3743507A1
Authority
EP
European Patent Office
Prior art keywords
teeth
vessel
rows
dissociation
row
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
EP18704159.5A
Other languages
German (de)
English (en)
Inventor
Christian Reis
Stefan Scheuermann
Armin Schäfer
Daniel EDINGER
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 EP3743507A1 publication Critical patent/EP3743507A1/fr
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C12M45/00—Means for pre-treatment of biological substances
    • C12M45/02—Means for pre-treatment of biological substances by mechanical forces; Stirring; Trituration; Comminuting
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/286—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q involving mechanical work, e.g. chopping, disintegrating, compacting, homogenising
    • 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
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5082—Test tubes per se
    • 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
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
    • B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
    • B02C18/00—Disintegrating by knives or other cutting or tearing members which chop material into fragments
    • B02C18/06—Disintegrating by knives or other cutting or tearing members which chop material into fragments with rotating knives
    • B02C18/062—Disintegrating by knives or other cutting or tearing members which chop material into fragments with rotating knives with rotor elements extending axially in close radial proximity of a concentrically arranged slotted or perforated ring
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
    • B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
    • B02C18/00—Disintegrating by knives or other cutting or tearing members which chop material into fragments
    • B02C18/06—Disintegrating by knives or other cutting or tearing members which chop material into fragments with rotating knives
    • B02C18/08—Disintegrating by knives or other cutting or tearing members which chop material into fragments with rotating knives within vertical containers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
    • B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
    • B02C18/00—Disintegrating by knives or other cutting or tearing members which chop material into fragments
    • B02C18/06—Disintegrating by knives or other cutting or tearing members which chop material into fragments with rotating knives
    • B02C18/08—Disintegrating by knives or other cutting or tearing members which chop material into fragments with rotating knives within vertical containers
    • B02C18/10—Disintegrating by knives or other cutting or tearing members which chop material into fragments with rotating knives within vertical containers with drive arranged above container
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
    • B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
    • B02C19/00—Other disintegrating devices or methods
    • B02C19/0056—Other disintegrating devices or methods specially adapted for specific materials not otherwise provided for
    • 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
    • C12M3/00—Tissue, human, animal or plant cell, or virus culture apparatus
    • C12M3/08—Apparatus for tissue disaggregation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/40—Concentrating samples
    • G01N1/4077—Concentrating samples by other techniques involving separation of suspended solids
    • 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
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • 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
    • B01L2300/04—Closures and closing means
    • B01L2300/046—Function or devices integrated in the closure
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/286—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q involving mechanical work, e.g. chopping, disintegrating, compacting, homogenising
    • G01N2001/2866—Grinding or homogeneising
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/40—Concentrating samples
    • G01N1/4077—Concentrating samples by other techniques involving separation of suspended solids
    • G01N2001/4088—Concentrating samples by other techniques involving separation of suspended solids filtration

Definitions

  • the invention relates to an apparatus and a method for the dissociation of tissue.
  • the device has at least one dissociation mechanism for receiving a tissue sample, which is arranged at least partially in a pot-shaped cell sieve.
  • the invention also relates, in one embodiment, to an apparatus and method for tissue disassembly wherein the tissue is dissociated by a grinder with mutually movable rows of teeth which, when moving in one direction, cut the tissue and move it in the opposite direction to rub the cloth.
  • tissue of different origins differing in their consistency, but one and the same tissue sample can also be very heterogeneous. Therefore, it is not yet succeeded in developing a method with which any kind of tissue can be dissociated.
  • Object of the present invention is to provide an apparatus and a method for the dissociation of tissue, with which any type of tissue can be dissociated and preferably to a single cell suspension ver works.
  • tissue dissociation devices of claim 1 and claim 6 and by the tissue dissociation method of claim 24.
  • tissue dissociation devices of claim 1 and claim 6 and by the tissue dissociation method of claim 24.
  • an apparatus for the dissociation of tissue which has at least one dissociation unit for receiving a tissue sample and at least one pot-shaped cell sieve. At least one dissociation unit is at least partially arranged in the pot-shaped cell strainer.
  • a dissociation plant is understood to mean a device to which the tissue can be dissociated.
  • the dissociation may include cell disruption and / or tissue dissociation.
  • the process of dissociation of tissue may advantageously comprise attrition of tissue and / or production of single-cell suspension and / or isolation of molecules.
  • the device for dissociating tissue in this embodiment has a cup-shaped cell strainer.
  • a cup shape in the most general sense, a concave shape into which the dissociation is at least partially introduced.
  • a pot shape advantageously a cylindrical shape with one side open End face or front side are understood.
  • the term "cylindrical shape” may be understood in the mathematical most general sense and may include cylinders with any base surface, wherein the cylindrical shape preferably has a straight cylinder axis, but advantageously the cylindrical shape has a circular base surface, so that under a cylindrical shape in the context of the invention
  • a circular cylindrical shape can be understood with unilaterally open end face or end face.
  • the dissociation plant also has a circular cross-section. It can then be arranged at least partially in the cell strainer with a coaxial to a cylindrical axis of the nikzylin derförmigen cell strainer with a circular cross-section in its center axis.
  • the dissociation plant is protected in the cell sieve against rotation relative to the cell sieve.
  • the cell strainer advantageously has at least one surface which acts as a sieve for the tissue constituents produced by the dissociation plant.
  • a mesh size of the screen depending on the tissue by the dissociation he testified tissue components may be suitably chosen.
  • a cell strainer which has a circular cylindrical cup shape with an open and a closed end face or end face, wherein the closed end face or end face and the lateral surface are formed by respective sieves.
  • the sieves can be advantageously carried by a frame.
  • the frame can specify the outer shape of the cell siebes.
  • the frame advantageously runs along edges of the cylindrical shape, whereby the sections of the frame extending along the edges of the cylindrical shape can be connected to one another by struts, which can preferably run parallel to the cylinder axis.
  • This shape of the frame is advantageous for both circular cylindrical screens, as well as cylindrical screens with other bases.
  • the frame can be advantageously made of plastic.
  • the device for Dissociation of tissue at least one vessel for receiving a tissue sample have.
  • the vessel may be part of the dissociation plant.
  • a grinder is arranged in the vessel, with which the tissue sample can be dissociated.
  • the feature may advantageously comprise at least two mutually movable rows of teeth, each having a plurality of teeth.
  • the grinder can thus have at least a first row of teeth with a plurality of teeth and at least one second row of teeth with a plurality of teeth.
  • surgeonwei se are then adjacent to the rows of teeth at such a distance zueinan arranged that cause the teeth of each adjacent rows of teeth in a distance range around their minimum distance from each other a dissociation of a portion of the tissue sample.
  • the at least one first row of teeth can be movable relative to the at least one second row of teeth, so that the teeth of the respective first row of teeth move past the teeth of the respective second row of teeth.
  • One of the at least one first rows of teeth and one of the at least one second rows of teeth can then be arranged adjacent to each other at such a distance that the teeth of these adjacent rows of teeth, when moved past each other, into a distance range about their minimum distance from one another Dissociation of a part of the tissue sample cause.
  • the vessel may have a bottom and a lid.
  • the bottom and the cover can be designed so that they together form the vessel or put together. But it is also possible that the bottom and lid cover opposite sides of a cylindrical shell, so that soil, cover and shell together form the vessel.
  • the vessel may be cylindrical, particularly preferably circular cylindrical. Particularly preferred then the rows of teeth are arranged concentrically around a cylinder axis of the vessel.
  • the teeth of the tooth-rich can be designed so that when they move in a direction past each other, cut the part of the tissue sample and if they move past each other in a direction opposite to this direction, rubbing the part of the tissue sample.
  • grinder may include both cutting and trimming devices, so the term “crusher” may be used as an alternative to the term “grinder”.
  • the grinder may have at least two mutually BE wegbare rows of teeth. Each of the rows of teeth then has a more number of teeth.
  • the term "row of teeth” should in this case generally describe a set of teeth that move together in the comminution process.
  • the teeth of a row of teeth may advantageously be arranged along a line which may have different shapes be arranged a circular closed line.
  • adjacent rows of teeth are arranged at such a distance from one another that the teeth of these adjacent rows of teeth cause a dissociation of a portion of the tissue sample in a distance range about their minimum distance from each other.
  • the distance between two rows of teeth can be defined here either as the distance of the lines along which the teeth of a row of teeth are arranged or as the distance of the teeth at the point of their respective closest approach.
  • the distance between the rows of teeth is advantageously dimensioned so that the teeth cause a dissociation of a part of the tissue sample when they are moved past each other.
  • the respectively dissociated part of the tissue sample is that part on which the two teeth, which move past each other, act in a crushing manner.
  • the dissociation takes place in a Abstandsbe the teeth from each other by the minimum distance of the teeth vonei nander instead.
  • teeth of the adjacent rows of teeth do not have to be assigned to one another in pairs.
  • the teeth of the adjacent rows of teeth pass one another after each other.
  • the teeth are configured to cut the tissue as they move in a direction past one another and grind the tissue as they move past each other in opposite directions.
  • the teeth can have a variety of different shapes.
  • the teeth may have a cutting edge on one side in the direction of movement and have on their opposite side a part of a milling or tearing device in their direction of motion, so that two teeth of adjacent rows of teeth meeting with this side will cause the tissue to break down ken.
  • the teeth may also have other cross-sections ha ben, such as cylindrical or have a karoförmige, parallelogram or diamond-shaped base.
  • the rows of teeth are circular and con centric to each other configured. That is, the teeth of a row of teeth are each lined up along a circle and these circles are con centric to each other. The cutting direction described and the trimming described are then advantageously tangential or parallel to the ent speaking circular lines.
  • the device for the dissociation of tissue may further comprise a reagent vessel, in the opening of the dissociation plant and / or the vessel for receiving the Gewe can be arranged sample.
  • the reagent vessel z. B. be a glass jar or a plastic container or be made of other suitable Materi alien.
  • the reagent vessel may have a cylindrical portion, the length of which in the direction of its cylinder axis is longer than a diameter of the reagent vessel.
  • the cylindrical shape can have on one side the opening in which the dissociation unit and / or the vessel can be arranged.
  • rows of teeth relative to the reagent vessel can be movable and arranged in the bottom of the vessel rows of numbers can be ge compared to the reagent vessel fixed.
  • the vessel will be used in the Publ tion of the reagent vessel and there, for example, be screwed. Therefore, in this embodiment, the rows of teeth fixed relative to the reagent vessel should be fixed in the state in which the vessel is arranged for intended use in the reagent vessel. The mobility of the teeth arranged in the cover can then be effected by suitable design of the vessel.
  • the components of the grinder so the rows of teeth, be designed as interchangeable inserts. These inserts can be inserted into the vessel.
  • the rows of teeth Kings nen be arranged on two plates, so that the teeth are arranged between the plates in a common plane.
  • the idea according to the invention is also realized by a device which has at least one vessel for receiving a tissue sample, and a grinder arranged in the vessel, wherein the grinder has at least two mutually movable rows of teeth.
  • the grinder and the rows of teeth advantageously the above can also be true true.
  • each of the rows of teeth may have a plurality of teeth, wherein adjacent rows of teeth are arranged in a sol chen distance from each other, that the teeth of each of these adjacent rows of teeth in a distance range to their minimum from each other was a dissociation of a part effecting the tissue sample, wherein the teeth are configured to intersect the portion of the tissue sample as they move past each other in one direction and, as they move past each other in that direction, to grind the portion of the tissue sample.
  • the cup-shaped cell strainer is not essential.
  • the ge called Dissoziationswerk may advantageously be the grinder in this Ausgestal device.
  • the device can alswei sen a reagent vessel, in whose opening said vessel and the grinder can be arranged. It can also be here arrange the arrange in the lid of the vessel ten rows of teeth relative to the reagent vessel and be arranged in the Bo arranged in the vessel rows of teeth relative to the reagent vessel. What has been said above about the reagent vessel can apply here accordingly.
  • the cell strainer and / or the dissociation unit and / or the vessel and / or the grinding mechanism can be arranged at least partially within a closure cap of the reagent vessel.
  • the cap can embrace the Publ tion of the reagent vessel.
  • the cell sieve, the dissociation mechanism, the vessel and / or the grinding mechanism can be as described above be arranged the opening of the reagent vessel.
  • the closure cap engages around the opening of the reagent vessel the corresponding elements can at the same time be arranged at least partially within the closure cap.
  • the fact that the closure cap encompasses the opening of the reagent vessel may mean, in particular, that the closure cap encloses or comprises the opening.
  • the cell strainer, the Dissozia tionswerk, the vessel and / or the grinder be fastened to the cap or be clamped or clamped by means of the cap between an edge of the reagent and the cap.
  • the corresponding element may, for example, have an edge which runs along an outer circumference of the corresponding element and, when the closure cap is screwed onto the reagent vessel, rests on the edge of the reagent vessel and is pressed against this edge by the closure cap.
  • the rows of teeth nikför mig and concentric with each other.
  • the rows of teeth can run in a common plane and ge in this plane against each other to be movable.
  • the rows of teeth extend in a common plane and are movable in this plane against each other.
  • this plane is parallel to a bottom surface of the vessel and / or to a lid surface of the vessel.
  • the teeth arranged on the bottom protrude from the Bo into the vessel and the teeth arranged on the lid protrude from the lid into the vessel.
  • the teeth can each have a general cylindrical shape, ie a shape which is defined by suitably shaped side surfaces which extend parallel to a straight line which is perpendicular to the tooth row. In a cross-section perpendicular to this line, the teeth can each have the shape described, with which they cut in one direction and grind in the opposite direction.
  • the teeth each have a cross section in a plane perpendicular right to its cylinder axis or in a plane parallel to the common Plane in which the rows of teeth extend, which have a sharp corner and a spit zen corner opposite rounded side.
  • the pointed corner and the rounded side are preferably opposite to each other in the direction of movement of the rows of teeth.
  • the teeth thus have preference, in their cross section, a teardrop shape.
  • the spit zen corners of teeth adjacent rows of teeth are opposite and thus the round corners.
  • the corresponding sides are curved in the same direction as the line along which the row of teeth runs.
  • the radius of curvature of one of these two sides can be substantially equal to the radius of curvature of the line along which the row of teeth runs ver.
  • the drop shape can be advantageously understood as a parallelogram in which one of the two ge separated by a short diagonal of the parallelogram triangles is replaced by a circular arc adjacent to the obtuse angles of the parallelogram to the other of the two triangles.
  • the circular arc here forms the rounded side and the remaining tip angle forms the sharp corner.
  • the drop shape is then mirror-symmetrical around the long diagonal of the original parallelogram, ie the axis of the tip to the farthest point on the round corner.
  • the radius of the circular arc can lie on the short diagonal of the original triangle.
  • the arc may be just a half-circle so that the center of the arc lies on the short diagonal of the original triangle.
  • the circular arc can also adjoin the straight sides in such a way that the straight sides lie tangentially on the circular arc. In this case, the midpoint is a bit farther from the top.
  • the drop shape described above may also be bent along the long diagonal of the parallelogram.
  • the mirror symmetry works then lost and the shape is more like a fin.
  • the vessel can close a circular cylindrical volume.
  • the rows of teeth can then rotate the cylinder axis coaxially.
  • the cylindrical volume limiting Be tenwand of the vessel have one or more projections in the direction of the tooth rows, wherein the side wall of the adjacent teeth row of this side wall has such a distance that the teeth of this to nearest row of teeth in cooperation with the projections a dissociation cause a portion of the tissue sample.
  • the projections may, for example, have a triangular shape in a sectional plane perpendicular to the cylindrical axis of the vessel.
  • the vessel and / or the lid may have a base, which is circulated by the rows of teeth.
  • the base may have one or more projections in the direction of the rows of teeth, wherein the basis of the base next row of teeth from this base has a sol chen distance that the teeth of this first row of teeth in egg nem distance range at its minimum distance to the projections, a dissociation of a part effect the tissue sample.
  • the vessel is designed here so that it encloses a cylindrical inner space.
  • the base can also be configured cylindrically with a cylinder axis coaxial with the cylinder axis of the vessel. The rows of teeth can then circulate the base circularly with the cylinder axis as center point.
  • a diameter of the vessel in the plane in which the rows of teeth extend greater than or equal to 0.5 cm, preferably greater than or equal to 1 cm, preferably greater than or equal to 2 cm and / or less than or equal to 4 cm , preferably less than or equal to 3 cm.
  • a minimum distance of teeth of adjacent teeth hen in the state of greatest approximation each greater than or equal to 50 miti, preferably greater than or equal to 100 miti, preferably greater than or equal to 200 miti and / or less than or equal to 500 miti, preferably less than or equal to 400 miti, preferably less than or equal to 300 miti.
  • the minimum distance to be described here is to be understood to mean that, when the teeth of adjacent and interacting rows of teeth move together, the teeth move towards each other, then reach the minimum distance and then move away from each other.
  • the minimum distance should be the distance between two points of the profiles of the teeth moving past each other, which has the lowest value.
  • the housing may have a bottom and a lid, wherein one half of the rows of teeth on the Bo can be arranged and the other half of the rows of teeth can be arranged on the lid.
  • advantageously arranged on the cover rows of teeth can each be adjacent to the floor arranged rows of teeth in a plane in which the rows of teeth, adjacent.
  • a row of teeth arranged on the cover cooperates with a row of teeth arranged on the bottom for tissue dissociation.
  • adjacent rows of teeth can be moved relative to one another.
  • one half of the rows of teeth relative to the housing can be fixedly arranged and the other half of the rows of teeth, which in each case interact with the fixed rows of teeth for dissociation, can be movable relative to the housing.
  • the movable rows of teeth can be arranged on the lid.
  • the lid can advantageously be movable.
  • the cover may be fixed relative to the housing, and the rows of teeth may be designed to be movable relative to the cover and thus also relative to the housing.
  • a suitable mechanism can be integrated in the cover, which FITS preferred from outside the housing when it is closed by the lid, can be driven.
  • said Ver closing cap of the reagent vessel in its center an opening aufwei sen. It can also advantageously the lid of the vessel an opening tion, which is coaxial with the opening in the closure cap, so that the opening of the closure cap and the vessel are continuous. It Kings then nen the openings in the cap and in the lid be designed so that a drive shaft the lid of the dissociation or the vessel for moving the teeth of the at least one second row of teeth or arranged on the lid at least one row of teeth relative to the teeth of at least a first row of teeth or the at least one row of teeth arranged on the floor can drive.
  • the drive shaft can intervene through the opening in the cap into the opening in the lid of the vessel.
  • the cover of the Ge housing or dissociation work also a magnetic element aufwei sen, by means of which the at least one row of teeth is driven by a magnet.
  • an opening in the cap is not required, but may still be provided, for example, to bring substances into the housing can.
  • the opening in the cap and / or the opening in the lid of the vessel may have a septum, through which liquid keit in the dissociation, the vessel and / or the reagent vessel can be introduced.
  • a septum can be accommodated at an end of the opening facing the reagent vessel in the lid of the vessel, so that a drive shaft can engage through the closure cap and the opening of the lid into the opening in the lid without being prevented by the septum.
  • the closure cap and the cover each have an opening, so it is particularly advantageous if the opening in the closure cap is sealed against the opening in the lid.
  • the cell strainer and / or the bottom of the vessel may comprise elements by means of which a relative movement of the soil relative to the cell strainer, for. B. when driving the lid with means of a motor can be prevented.
  • the vessel is liquid-tight can be.
  • the vessel for liquids such as the cell suspension is permeable.
  • the device according to the invention has a reagent vessel and / or a cell sieve as described above. It is then possible first to make a tissue dissociation by means of the dissociation unit or the grinder and then to further process the same in the reagent vessel and / or in the cell sieve, for example to centrifuge or to clean. After the digestion process has ended, the cell suspension can be separated from tissue residues, for example by centrifugation become. It can then be collected in the reagent vessel, which may for example be a centrifuge tube, the cell suspension. It is advantageous here that from the introduction of the tissue sample on the digestion to further processing and examinations, the system can remain closed, whereby the risk of contamination can be significantly reduced while user friendliness is increased.
  • the said rows of teeth can be firmly integrated in the lid and in the floor. But it is also possible to design the rows of teeth in the lid and / or in the bottom of the vessel as exchangeable inserts. In particular, such a replaceable insert in the lid relative to the lid can be movably ge outsourced so that it is driven to move the teeth.
  • the grinder can thus have, for example, two inserts with one or more rows of teeth, which mesh and rotate in opposite directions.
  • the dissociation can also be formed onswerk that an insert with at least one row of teeth on the cap of the reagent vessel is arranged and an insert is inserted with at least one row of teeth in the cell sieve or is firmly integrated into this.
  • the two inserts can be seen together as a housing in the sense described above or form such a housing.
  • one of the inserts may have a concentric with the rows of teeth surrounding the rows of sheath, which can act as the outer wall of the housing Ge. It can then be placed with the arranged on the bottom of the housing rows of teeth on the lid of the other insert. The floor can then rest on an edge of said lateral surface and advantageously be slidably mounted with respect to this.
  • the vessel for receiving the tissue sample on the one hand have the lid with the at least one second row of teeth and on the other hand the floor with the at least one first row of teeth.
  • the at least one second row of teeth can thus be arranged on an end face of the lid and a lateral surface can rotate around the end face at its edge.
  • the man tel dye a cylindrical surface which is concentric with an axis about which extend the teeth of at least one second row of teeth.
  • the floor may then have a plate, which may also have openings on which the at least one first row of teeth is arranged. In assembled to stand the plate of the bottom can rest on that edge of the lateral surface of the lid, which is opposite to the end face of the lid.
  • the vessel thus formed may advantageously be arranged at least partially in the closure cap of the reagent vessel and more preferably be screwed with the cap in the opening of the reagent vessel.
  • a method for the dissociation of tissue is also described which can be carried out with a device as described above.
  • a tissue sample is introduced into the corresponding device and then the dissociation unit or the grinder is driven.
  • the dissociation unit or the grinder is driven.
  • the at least two mutually movable against each other rows of teeth are moved against each other.
  • the device is designed so that the tissue sample is cut in one direction and grated in the other
  • the inventions to the invention method advantageously the rows of teeth are moved against each other both in the cutting direction and in the rubbing direction.
  • the rows of teeth with a rotational speed of greater than or equal to 60 U / min, preferably greater than or equal to 200 U / min, preferably greater than or equal to 300 U / min and / or less than or equal to 700 U / min, preferably less than or equal to 500 U / min, more preferred less than or equal 400 rev / min are moved against each other.
  • the rows of teeth while they are moved against each other, are moved periodically in the direction of this movement perpendicular direction.
  • the periodic movement can thus take place in the direction of the cylinder axis of the vessel or the axis of rotation of the rows of teeth.
  • the tissue is provided with a liquid such as a medium or enzyme solution.
  • a liquid such as a medium or enzyme solution.
  • the grinder can also be decoupled from the lid or housing be driven, for example by a magnetic drive.
  • the plate carrying a part of the teeth can be moved with an external magnet.
  • the corresponding plate can for this purpose have magnetic material.
  • the comminution process can advantageously be carried out between 30 seconds and 10 minutes with one or more direction changes.
  • the rotation time > 1 min, more preferably> 4 min and / or ⁇ 10 min, preferably ⁇ 7 min betra conditions.
  • the vessel may be cavities of a microtiter plate.
  • tissue dissociation can be parallelized.
  • the cavities in the microtiter plate individually, partially or in parallel.
  • disposable cavity strips are suitable, where the base plate serves only as a frame.
  • the lid can be used, for example, as a carrier for a grinding cylinder or as a carrier for several grinding cylinders, e.g. also in the form of stripes, serve.
  • the method can by driving the dissociation plant or the grinder generated cell suspension after driving the dissociation unit or the grinder be cleaned and / or centrifuged.
  • the device may first be placed on a drive device through which the dissociation unit or grinder is driven for tissue dissociation, and then the device may be placed in a centrifuge to centrifuge the dissociated cell suspension in the reagent vessel.
  • the industrial sample before, during and / or after driving the dissociation unit or the grinder at least one medi um added. This can be done, for example, by a described as described before ben ausgestaltetes septum in an opening of the lid and / or the United closure cap.
  • a rotation Rich tion and / or a rotational speed of driving the Dissoziati onstechnikes or the grinder based on stored during the driving he parameters are stored. These parameters may include, for example, one or more selected from a torque, a rheological parameter and / or an optical density.
  • the progress of the dissociation can be detected during the course of the execution of the method, so that the tissue digestion can be executed up to a predetermined point, and when predetermined target values of the parameters considered can be ended.
  • a transmitted to the dissociation plant or the grinder by a drive force or zizerstechnik on the dissociation transmitted by a drive torque can be measured by means of one or more sensors. From the force thus measured or the torque thus measured, a degree of dissociation of the fabric can be determined.
  • a degree of dissociation of the fabric can be determined.
  • FIG. 1 shows an example of a device according to the invention for the dissociation of tissue
  • FIG. 2 shows a further example of a device according to the invention for the dissociation of tissue
  • FIG. 3 shows a multiplicity of devices according to the invention for dissociating tissue arranged in a microtiter plate
  • FIG. 4 shows a device according to the invention for the dissociation of tissue with a dissociation plant and a pot-shaped cell sieve
  • Figure 5 is a device shown in Figure 4 with a reagent vessel
  • Figure 6 shows the device shown in Figure 5 mounted on a device Antriebsvorrich for driving the Dissoziationswerks.
  • FIG. 1 shows an example of a device according to the invention for the dissociation of tissue.
  • the device 1 for the dissociation of tissue is circular.
  • the device has a base 2, of which in the plan view of Figure 1, a circular side wall 2a can be seen.
  • the bottom 2 is closed by a cover 3, of which in the sectional view of Figure 1, a cylindrical side wall 3 can be seen.
  • the elements 2 and 3 together form a vessel 4 for receiving a tissue sample.
  • the vessel 4 is limited here by the side wall 3 of the lid.
  • the bottom 2 has around a center of the housing 2, a base member 2b, which has an opening in its interior. In this opening can be a centra engage the element of the lid 3.
  • the device has a grinder with two mutually movable rows of teeth 5a-5f and 6a-6f.
  • Each of the rows of teeth has a plurality of teeth 5a - 5f and 6a - 6f.
  • the Zahnrei hen are arranged at such a distance from each other that the teeth 5a
  • FIG. 1 The partial images of Figure 1 show the grinder in a state in which the teeth 5a and 6a to 5f and 6f each have a mini malen distance to each other.
  • the teeth have a teardrop shape in a cross section perpendicular to the axis of rotation about which the rows of teeth revolve.
  • the drop shape In the direction of a line along which the teeth 5a - 5f and 6a - 6f are arranged in the ent speaking row of teeth, the drop shape has on the one hand a tip and on the other hand opposite a rounding.
  • the tips of the teeth 5a - 5f of one row of teeth are opposite to the tips of the teeth 6a - 6f of the other row of teeth.
  • the curves of these teeth are opposed to each other.
  • the teeth 5a-5f, together with the teeth 6a-6f cut the tissue as they move in the direction of the tips and tear the tissue as they move in the direction of the curves.
  • the wall of the lid 3 has triangular projections 7a-7d projecting from the wall in the direction of the teeth 5a
  • the base member 2b has triangular teeth 8a-8c projecting from the base 2b in the direction of the teeth 5a-5f and 6a-6f.
  • the teeth 5a-5f of the inner row of teeth move past these projections 8a-8c, between the teeth 5a-5f and the projections 8a
  • the teeth 6a-6f of the inner row of teeth can be arranged on the lid 3 and moved with it.
  • the teeth 5a-5f of the outer row of teeth are advantageously arranged on the bottom 2 of the vessel 4 and fixed with respect to this.
  • the base element 2b with the projections 8a-8c is advantageously arranged on the underside of the vessel 4 and fixed against it. If now the cover 3 or an element arranged on the cover 3 and carrying the teeth 6a-6f are rotated, the teeth 6a-6f move in a circle past the teeth 5a-5f and the projections 8a-8c and cause a dissociation of the teeth tissue. At the same time, the projections 7a-7d on the cover move past the teeth 5a-5f, causing dissociation of the tissue there.
  • FIG. 2 shows a further embodiment of a device according to the invention for the dissociation of tissue.
  • the construction of the device shown in Figure 2 corresponds to that shown in Figure 1, so that reference should be made to the description of Figure 1. In the following, only the differences from FIG. 1 are executed.
  • the teeth 5a-5f and 6a-6f likewise have a teardrop shape which, however, is bent in the direction of the center point and the axis of rotation with respect to the teardrop shape shown in FIG.
  • these teeth 5a-5f and 6a-6f likewise have a pointed side and a round side, which, however, in FIG. 2, unlike in FIG. 1, are connected by curved sides.
  • the inside of the outer teeth 5a-5f is optionally parallel to the course of this row of teeth curved, that is, has substantially the same radius of curvature.
  • the outer sides of the teeth 5a - 5f and 6a - 6f are optionally curved with a smaller radius of curvature than the toothed row.
  • FIG. 3 shows a multiplicity of devices according to the invention, which are arranged in 4x6 cavities 10 of a microtiter plate 9.
  • a cover 3 is provided which carries the teeth 6a, 6b of one of the rows of teeth.
  • Above each cavity 10 forms a vessel 2, in which teeth 5a, 5b, 5c of a white direct row of teeth are arranged.
  • the arrangement of the teeth and Ausgestal direction of the teeth can be realized as shown in Figures 1 and 2.
  • the Teeth 5a, 5b, 5c can also be designed as inserts for the cavities 10, so that they can be used in commercially available microtiter plates 9.
  • Tissue processing can be done in the examples of Figures 1 to 3 in example as follows.
  • An inner diameter of the cavities can be, for example, 2 cm.
  • the teeth 5a-5f can be rotated with respect to the teeth 6a-6f, for example at a rotational speed of 60-700 rpm.
  • the rotation speed can be adjusted accordingly.
  • the duration of the dissociation can be chosen, for example, between 1 and 10 min.
  • One or more changes of direction can be made during this time. In this way, for example, pieces of tissue can be dissociated from a mass of 50 mg to 3 g.
  • a minimum distance of the teeth of adjacent rows of teeth for example betra between 50 and 500 pm.
  • FIG. 4 shows an exploded view of an apparatus according to the invention for the dissociation of tissue with a dissociation unit 1, which is configured here with a lid 1a and a bottom 1b.
  • the dissociation plant is in Figure 4 at least partially inside a cap 41 of a Rea genzgefäßes, which is shown in Fig. 5, arranged.
  • the device also has a pot-shaped cell sieve 42, in which the dissociation unit 1 is arranged.
  • the cap 41, the lid la, the bottom lb and the cell strainer 42 are cylindrical in Figure 4 and arranged with coaxial cylinder axes.
  • the components are shown exploded in the direction of the cylinder axis, in the assembled state, however, they are all in one another.
  • the cell strainer 42 is cup-shaped in the example shown, in the form of a closed on one side circular cylinder.
  • the cell screen 42 has four cell screen surfaces 44 in the cylinder surface.
  • the dissociation plant 1 facing away from the end face 43 of the cell strainer 45 is closed by a cell. Those of the cell screen surface 45 opposite end face of the cup-shaped cell strainer is open.
  • the dissociation plant has on the one hand the lid la and on the other the bottom lb.
  • the lid 1a has an end face, which is not visible in the figure, on which a plurality of teeth 5a, 5b are arranged so that they are parallel to the cylinder axis of the lid.
  • the teeth of the cover la are surrounded by a lateral surface lc, which runs along an edge of the front side of the lid, on which the teeth 5a, 5b are arranged.
  • the lateral surface lc here is a cylindrical surface whose cylinder axis coincides with the Zy cylinder axis of the dissociation unit 1 as well as the cell strainer 42.
  • the bottom 1b of the dissociation plant 1 has teeth 6a which cooperate with the teeth of the cover for dissociation.
  • the cover la also has a central through-opening ld, which extends in the middle of the unrecognizable Stirnflä surface and is surrounded by the teeth 5a, 5b.
  • This opening ld he leaves on the one hand, a coupling of a motor for driving the lid la and beyond also the introduction of liquids in the dissociation onstechnik 1.
  • the opening ld can be configured as a tubular channel extending from the end face of the lid la to the end of the lateral surface lc of the lid.
  • closure cap 41 also has an opening which is coaxial with the opening 1d and which is sealed off from the opening 1d.
  • FIG. 5 shows the dissociation plant shown in FIG. 4 as an exploded view with a reagent vessel 51.
  • the dissociation plant 1 is arranged in the closure cap 41 with a lid 1a and a bottom 1b and surrounded by the cell strainer 42.
  • the closure cap 41 with a lid 1a and a bottom 1b and surrounded by the cell strainer 42.
  • the reagent vessel 51 has a circular cylindrical shape with a tapered ver closed end and an opening 52 in that of the tip opposite the end face of the cylindrical shape.
  • the closure cap 41 can be screwed onto the opening 52 and surrounds or surrounds the opening 52.
  • the dissociation unit 1 and the cell sieve 42 are in the screwed state in the closed position. cap 41 and disposed in the opening 52 or just behind the opening 52 in the interior of the reagent vessel 51.
  • FIG. 5A shows the device in a perspective view.
  • Figure 5B shows the device in conjunction with a drive device 53 as a perspective view
  • Figure 5C shows the device shown in Figure 5B assembled in a sectional view.
  • the teeth 5a of the cover la move relative to the teeth 6a of the bottom 1b and thus cause a dissociation of tissue introduced into the dissociation mechanism 1.
  • the lid 1a and the bottom 1b of the dissociation unit 1 form a housing within which the tissue is dissociated.
  • the housing is not fluid-tight so that the cell suspension can flow out of the dissociation apparatus 1 when the apparatus is rotated so that the reagent vessel 51 faces downwards or when the apparatus is placed in a centrifuge in which the centrifugal force is applied in the direction of Rea genzgefäßes 51 acts.
  • the reagent vessel 51 may advantageously be a standard laboratory vessel, and also the lid 41 may be a standard laboratory vessel lid.
  • the lid can also be fixed by means of a circumferential clamping ring.
  • the implementation of the coupling of the drive 53 to the bottom lb of the dis sociators 1 can be fitted with plain bearings to ensure a low-resistance rotation and simultaneous tightness.
  • FIG. 6 shows the device shown in FIG. 5, applied to a tissue grinder device, which acts here as a drive device 53.
  • the tissue grinder Device 53 may in this case again have a shaft 54 which engages in the lid 1a of the dissociation unit 1 and can rotate it.
  • a tissue sample to be examined is introduced into the dissociation unit 1 or the housing of the dissociation unit 1.
  • a liquid for. As medium or enzyme solution, are filled and merged with the Bo lb in the cell strainer 42 via a union nut or cap 41.
  • the cutting unit can also be operated decoupled from the lid la, z. B. by an integrated magnet.
  • the lid 1a and the dissociation unit 1 can be decoupled and the lid 1a can be driven by rotation of a magnet over the lid.
  • the lid la of the cutter is connected to the drive 53 and is driven by it.
  • the bottom 1b of the dissociation unit 1 or the housing 1 is fixed here and can be inserted directly into the cell sieve 42.
  • the bottom 1b of the dissociation unit 1 which may be integrated in the cell strainer 42, is screwed to the lid 1a of the dissociation unit 1 through the cap 41 on the reagent container 51.
  • the cell suspension example by centrifugation of tissue residues is separated. Further washing steps to increase the cell yield can be effected by a septum, which can be integrated into the opening 1 d in the lid lb.
  • the cell suspension can be collected in the reagent vessel 51 and can thus remain in a closed system from the introduction of the tissue sample via digestion to further investigations, which considerably reduces the risk of contamination and at the same time simplifies the user-friendly operation. increased.
  • Tissue processing with the described rows of teeth can be used for centrifugal tubes 51 and cell filters (with, for example, a mesh between 10 and 200 microns) at a Schneidtechnik penmes of for example 2 cm and a rotational speed of for example 10 to 700 U / min. respectively.
  • Other scalings are possible, in which case the rotation speed is preferably adjusted.
  • a rotation time of, for example, 1 to 10 minutes and one or more directional changes of the rotation may be useful.
  • dissociation of tissue pieces from a mass of, for example, 50 mg to 3 g can be achieved.
  • the minimum distance between teeth of adjacent rows of teeth is preferably between 50 and 500 pm.
  • a reagent vessel 51 is suitable for the processing of one or more tissue samples simultaneously.
  • you can lines, z. B. be provided in the form of plain bearings to ensure a resistance poorer rotation and simultaneous tightness.
  • the opening in the closure cap 41 and in the lid la can be sealed against one another.
  • tissue remnants of single cells in the closed system can be separated.
  • the degree of digestion ie the dissociation efficiency
  • the digestion of the tissue sample by means of sensors, for. B. based on a turbidity measurement, via an optical sensor and / or a torque measurement and / or rheological measurements of the digestion tools.
  • the recorded parameters can be analyzed and converted into a generally valid differential equation for the description of the viability and yield of the Zielzel len at different process parameters.
  • an intelligent control of the rotational direction and speed of rotation of the grinder as well as the duration of the tissue dissociation can take place. This allows each tissue sample to be individually sized to ensure optimal cell yield.
  • the method according to the invention can be carried out, for example, by first loading the dissociation unit 1 with a tissue sample and determining the weight of the tissue sample. Medium may also be added.
  • the rotational direction, rotational speed and / or duration of the dissociation can be controlled by the on-line acquisition of process parameters such as torque, and rheological parameters and optical density.
  • the recorded parameters can be analyzed and forwarded by means of decay equations to a feedback system of the motor control of the drive 53.
  • the feedback system can allow individual dissociation of each tissue sample to increase efficiency and yield.
  • the reagent vessel 51 can be placed in a centrifuge. After a first centrifugation as many washing steps, for example, by he neute addition of medium via the integrated septum in the engine coupling done. The purified cells then collect at the bottom of the Rea genzgefäßes 51st
  • the device according to the invention and the method according to the invention he allow a very targeted dissociation of tissue, with a desired final state of dissociation can be achieved very precisely.
  • a suitable combination of tooth geometries, cell sieves and dissociation units if required, and intelligent control predetermined dissociation levels can be exactly adjusted.
  • the described combination of tissue dissociation and centrifugation in a closed system allows complete processing of a tissue sample without the risk of contamination.
  • the described drop shapes and curved shapes of the teeth the tissue can be cut very gently and / or ge grind, which can be selected between cutting and grinding as needed. By controlling the direction of rotation, the predominant de force can be determined.
  • tissue samples are not only processed more gently for the cells, but also save time.
  • the tissue no longer needs to be cut into very small pieces with a scalpel, but can be processed in bulk or in a few pieces.
  • the tissue sample can be purified directly without further pipetting steps.
  • the process is semi-automatable, which gives a higher reproducibility and standardization.
  • the technology can be inserted into automated processes.
  • Another advantage of the system is its parallelizability.
  • the possibility of simultaneous use of several centrifugal tubes, the tissue processing can be parallelized so that several samples can be processed simultaneously.
  • the advantage on the one hand saves time and on the other sources of error are minimized.
  • all necessary preparatory work steps for all samples can be carried out simultaneously and do not need to interfere anymore.
  • An improved comparability of the results is given.
  • An example of this is a certain incubation time with an enzyme solution, which can only be maintained if samples are added exactly the same time before the dissociation with the enzyme.
  • the centrifuge tube format allows the system to be integrated into an automated process.
  • An automation prevents differences in the workup as it would be the case in the implementation by different employees. This leads to an improved reproduction and comparability of the results.
  • the device in its centrifuge tube variant is disposable, the probability of contamination and auxiliary resources can be minimized very much.
  • the device is suitable for cell disruption as well as for the generation of single cells from tissue.
  • Cell disruption is e.g. protein isolation or nucleic acid isolation, as well as other processes involving analysis of cell constituents.
  • the gentler dissociation of tissue is advantageous when individual cells are needed. This is the case, for example, in the examination of tumor cells by mass spectrometry, infrared spectroscopy or ELISA. Potentiel les tumor tissue can be dissociated for histological examination.
  • the production of single-cell suspensions is important for the generation of 2D cultures, 3D cultures, single-cell characterization, high-throughput drug screening, and organ-on-chip technology.
  • the system is not limited to application to tumor tissue, but can be theoretically adapted to any type of tissue.

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Abstract

L'invention concerne un dispositif et un procédé pour la désagrégation de tissus. Dans un mode de réalisation, le dispositif présente au moins un mécanisme de désagrégation destiné à recevoir un échantillon tissulaire qui est agencé au moins partiellement dans un tamis cellulaire en forme de cuvette. Dans un mode de réalisation, l'invention concerne en outre un dispositif et un procédé pour la désagrégation de tissus, le tissu étant désagrégé par un mécanisme de broyage, présentant des rangées de dents mobiles les unes contre les autres, qui découpent le tissu lorsqu'elles se déplacent les unes le long des autres dans un sens et qui déchirent le tissu lorsqu'elles se déplacent les unes le long des autres dans la direction opposée.
EP18704159.5A 2018-01-24 2018-01-24 Dispositif et procédé pour la désagrégation de tissus Pending EP3743507A1 (fr)

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US20230167398A1 (en) * 2020-04-22 2023-06-01 Cellunite Gmbh System and method for automated cell processing
US11987787B2 (en) 2020-07-22 2024-05-21 AVITA Medical Americas, LLC Devices, methods, and kits for preparing a cell suspension
WO2023001910A1 (fr) 2021-07-23 2023-01-26 Cellunite Gmbh Système et procédé pour le traitement cellulaire
CN113930321B (zh) * 2021-11-12 2023-12-08 青岛华大智造科技有限责任公司 解离组件、组织解离管、解离装置及组织解离方法

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IT1260682B (it) * 1993-09-28 1996-04-22 Consult T S S N C Di Roggero G Dispositivo trituratore meccanico di materiale biologico
DE19729028C1 (de) * 1997-07-08 1999-05-06 Fraunhofer Ges Forschung Vorrichtung sowie Verfahren zur Isolierung von Zellmaterial aus einem Gewebeverband und/oder einer Flüssigkeit
EP2540394B1 (fr) * 2011-06-27 2016-05-04 Miltenyi Biotec GmbH Dispositif pour fragmenter un tissu
PL2775928T3 (pl) * 2011-11-08 2019-09-30 Auxocell Laboratories Inc. Systemy i metody przetwarzania komórek
SI3233289T1 (sl) * 2014-12-15 2020-07-31 Human Brain Wave S.R.L. Naprava za ločevanje biološkega materiala in pripadajoč postopek izdelave in postopek za pripravo celičnih suspenzij in tkivnih mikrograftov
DE102016216345B3 (de) * 2016-08-30 2018-01-25 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Vorrichtung und Verfahren zur Dissoziation von Gewebe

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