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EP2696962A1 - Ensemble et procédé de filtration - Google Patents

Ensemble et procédé de filtration

Info

Publication number
EP2696962A1
EP2696962A1 EP12714699.1A EP12714699A EP2696962A1 EP 2696962 A1 EP2696962 A1 EP 2696962A1 EP 12714699 A EP12714699 A EP 12714699A EP 2696962 A1 EP2696962 A1 EP 2696962A1
Authority
EP
European Patent Office
Prior art keywords
filter
pressure
pressure difference
permeate
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.)
Withdrawn
Application number
EP12714699.1A
Other languages
German (de)
English (en)
Inventor
Katja Friedrich
Joachim Bangert
Walter Gumbrecht
Karsten Hiltawsky
Peter Paulicka
Manfred Stanzel
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.)
Siemens AG
Siemens Corp
Original Assignee
Siemens AG
Siemens Corp
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 Siemens AG, Siemens Corp filed Critical Siemens AG
Publication of EP2696962A1 publication Critical patent/EP2696962A1/fr
Withdrawn legal-status Critical Current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
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • 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
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3403—Regulation parameters
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/14—Ultrafiltration; Microfiltration
    • B01D61/18—Apparatus therefor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/14—Ultrafiltration; Microfiltration
    • B01D61/22—Controlling or regulating
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0002—Organic membrane manufacture
    • B01D67/0023—Organic membrane manufacture by inducing porosity into non porous precursor membranes
    • B01D67/0032—Organic membrane manufacture by inducing porosity into non porous precursor membranes by elimination of segments of the precursor, e.g. nucleation-track membranes, lithography or laser methods
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/50—Polycarbonates
    • 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
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G01N33/491—Blood by separating the blood components
    • 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
    • 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 arrangement and a method of filtration, which in particular for the filtration of cells, e.g. Tumor cells, from a sample, e.g. a blood sample, are suitable.
  • a pressure difference of the pressure upstream and downstream of a filter is determined; and adjusting the pressure difference upstream of downstream of the filter so that the pressure difference does not exceed a predetermined value.
  • CTC circulating tumor cells
  • a method of detecting CTC involves filtering blood samples, wherein size selection of the cells takes place by means of appropriate pore sizes and allows isolation of the tumor cells.
  • a disadvantage of this method is that the cells are often damaged by the filtration process itself and then can be used only limited for further investigations.
  • the driving force is a pressure gradient.
  • An inflow (feed) is filtered through the membrane, whereby the liquid can penetrate the membrane (permeate) and larger particles accumulate on the membrane as a filter cake (retentate).
  • the dead-end filtration is different
  • Concentration gradient / concentration polarization from the retentates on the membrane.
  • the filter cake increases the filtration resistance and thus the pressure loss across the membrane.
  • Backwashing creates a discontinuous feed stream, which can cause production slumps, consumption of cleaning media, and additional technical effort.
  • the invention relates to a method according to claim 1 and a device according to claim 15.
  • Pressure difference or the feed stream can be controlled to a constant value.
  • the behavior of the filtering remains predictable.
  • a suspension is passed through a filter, e.g. a filter membrane,
  • permeate is forced through the filter and retained retentate on the filter surface (or in the pores and voids of the filter).
  • the direction of flow is also reversed, eg during a backwash of the filter.
  • the term push-through also defines the predominant direction of the pressure difference: positive pressure difference from upstream to downstream. In the exceptional case mentioned would be the
  • a pressure difference of zero can be set. This is independent of the orientation of the filter in the room. For the special case that the flow direction on the filter is vertical or a vertical component (asc in the direction of or against the gravitational force), it should also be taken into account that the water column on the filter contributes to the pressure difference.
  • the direction of flow of the filtration at the filter is substantially in the direction of gravitational force. This retains retained retentate on the surface of the filter, which z.b. a simple further processing of the Retenats allows.
  • the invention relates to a method for filtering a suspension, comprising the following steps:
  • a suspension is a liquid which is in it
  • the pressure difference does not exceed a value of 50 mbar, preferably 10 mbar. In some cases, an upper value of the pressure difference of 5 mbar, 1 mbar or less may be preferred.
  • the pressure through the water column is taken into account, and where 1 cm water column corresponds to approximately 1 mbar.
  • the water column corresponds to the level of the suspension above the filter in a substantially horizontal arrangement of the filter, being filtered from top to bottom.
  • the height of the water column over the filter is monitored and limited to a predetermined fraction, eg 1/2, 1/4, or preferably 1/10 of the pressure difference.
  • a fraction of 1/10 would correspond eg to a contribution through the water column of 1 mbar at a pressure difference of 10 mbar, which corresponds to a level height of 1 cm above the filter, and a contribution eg by a negative pressure downstream of the filter of 9 mbar.
  • an overpressure is applied upstream of the filter.
  • a negative pressure is applied downstream of the filter.
  • the adjustment of the pressure difference during the permeation of permeate through the filter by regulating to a constant value or to a value which is within a predetermined range, takes place.
  • This can be a printing plate
  • the printing plate may e.g. be designed as a valve that can selectively open and close a connection to an overpressure reservoir or a vacuum reservoir.
  • the volume of permeate passed through the filter be determined.
  • the feed it is possible to measure the feed, to measure the fill level above the filter, to measure a fill level or a gas volume displaced by permeate downstream of the filter in a catch tank.
  • the volume of the passed through the filter is preferably, the volume of the passed through the filter
  • the suspension is a suspension of cells in an aqueous solution.
  • the method of the invention is particularly suitable for filtration and examination of circulating tumor cells (CTC) in fluid samples, e.g. Blood samples. It is possible to filter the cells so gently, that at the cells retained at the filter still functional
  • CTC circulating tumor cells
  • the filter has a membrane with pores whose pore direction extends exclusively perpendicular to the surface of the membrane.
  • the membrane is a polycarbonate track etched membrane.
  • Pore direction perpendicular to the surface e.g., by a small membrane thickness relative to the pore size
  • a membrane is a track etch ⁇ membrane made of polycarbonate or from the COC with the
  • this comprises
  • the method comprises the additional step of adjusting a pressure difference for a predetermined period of time chosen so that no permeate is pushed through the membrane during this period of time.
  • this comprises
  • the retentate can be kept permanently liquid-covered.
  • process fluids e.g.
  • washing buffer, fixation buffer, permeabilization buffer, staining solutions, etc. The filter is closed by a corresponding overpressure "from below", as this overpressure counteracts the water column.
  • a regulation includes the determination of a controlled variable (actual value), the comparison with a reference variable (nominal value) and the adaptation of the controlled variable to the reference variable.
  • the invention further relates to a device for
  • the means for determining a pressure difference comprises a
  • Device also means for determining the level height of a liquid above the filter.
  • Pressure difference during the permeation through the filter to a constant value or within a predetermined range of values.
  • the overpressure being at least as high as the pressure of the water column over the filter.
  • Device also means for determining the volume of permeate pressed by the filter.
  • the filter has a membrane with pores whose pore direction is substantially perpendicular to the surface of the membrane
  • the membrane is a polycarbonate track etched membrane.
  • Fig. 1 is a schematic representation of a filtration process
  • Fig. 2 is a schematic representation of a
  • Fig. 3 is a schematic representation of a scheme for
  • Fig. 1 shows a schematic representation of a
  • Filtriervorgangs wherein an influx (feed) is passed through a filter, wherein a permeate passes through the filter and a retentate is retained.
  • a filter device 1 with a funnel or inlet 11 is shown schematically.
  • the feed stream 12 is passed through a filter device with filter membrane 14 and retains a retentate (so-called filter cake) 13.
  • Seals 15 create a tight connection between
  • Collecting vessel may also be arranged in a sealed connection with the membrane 14, so that e.g. a negative pressure can be built up.
  • FIG. 3 schematically shows an exemplary control for carrying out the method according to the invention. Using a differential pressure sensor, a pressure difference between the funnel (inlet) and the receiver (drain) is measured and compared with a setpoint. A regulator regulates accordingly a negative pressure in the collecting container
  • Reservoir in front of the filter can be filled as needed.
  • the working air vacuum is applied in a catch tank downstream of the filter. It creates a suction effect of the air through the membrane on the medium (to
  • the resulting permeate then penetrates through the filter. At suitable drain points, the permeate separates from the filter and runs into the collecting container. The displaced air volume may be evaluated for further information (e.g., feed flow determination).
  • This embodiment offers several advantages: There are no mechanical shearing forces on the permeate. There is a minimal risk of contamination, the pressure stage (for example a pump) does not come into contact with the permeate, the permeate does not come into contact with the pump components. in the
  • Container remains the permeate and can be further processed.
  • the procedure is in principle location-independent.
  • the technical embodiment of this disclosed embodiment comprises in a first arrangement a holding device for the filter, which is geometrically adapted to the membrane, to the flow conditions and to the filling technique.
  • additional microfluidic structure is present to optimize contact surfaces in reactions, evaporation surfaces, etc.
  • the holding device for the filter is easy to clean or as a cheap disposable article, optionally in combination with the filter itself executed.
  • the membrane of the filter is at many, but small support points of the holding device.
  • the permeate can collect in a channel structure of the holding device. In the holding device are
  • Drain holes provided so that the negative air pressure can not escape through the membrane, but only on the
  • Permeate is effective.
  • drainage aids are provided on the drain holes (e.g., as a collection channel or guide tube).
  • preload by tension spring pressure, weight or similar
  • the collecting container requires tightness and sufficient pressure resistance. On it connections for filter / membrane and air pressure can be provided.
  • the collecting container is preferably easy to clean or can be a cheaper
  • the filling height above the filter in such a way
  • a storage container for the suspension to be filtered is provided in front of the filter, which can be placed under a defined (over) pressure, similar to eg a syringe.
  • the container can simply be set to air pressure ("open").
  • the defined pressure can be applied as a combination of volume changes (syringe principle) and applied pressure (gas, liquids).
  • Air flow-protected external space for example by a differential pressure sensor.
  • Source for printing i.A. Positive and negative pressure. This is shown by way of example and schematically in FIG.
  • a measurement of the filtrate flow by permeate volume determination from the control error can be provided.
  • adjustable presets of pressure and feed flow e.g. for acceleration, minimization of strain on membrane and on the filtrate (e.g., cells) is ensured.
  • regulating the pressure difference can be a complete
  • Stopping the feed stream can be achieved, the control influences by capillary effects, gravity and the like.
  • One way to control the pressure difference is to provide an air reservoir of suitable volume and vacuum.
  • the pressure difference is set by calculating the air volume to set the desired pressure difference, from valve opening time,
  • Valve resistance and pressure difference target pressure minus
  • Adjustment of the working pressure is the provision of sufficiently reliable overpressure and vacuum supplies, from which the working pressure is removed by appropriately controlled valves.
  • the overpressure or negative pressure supply is selected, in a second valve, by a key, a certain amount of air is transferred between the container and the supply. This results in a time average, which results in the working pressure.
  • Pore direction perpendicular to the surface e.g., by a small membrane thickness relative to the pore size
  • Pore number and density are sufficiently high so that no significant change in properties occurs due to the retentate
  • Possible applications of the invention include cell separation, e.g. for (circulating) tumor cells "CTC" in blood,
  • the filter surface is selected in such a way that the retentate does not significantly change the filter properties during the filtering process under consideration: the number of retained cells is considerably smaller than the number of pores in the membrane; the projected area of the retentate (including retained cells) is much smaller than the filter area.
  • the filter membrane is preferably a circular "track-etched membrane"
  • the feed flow is given by the frequency and volume of the pipetted blood sample. This does not have to be constant. Also, the permeate flow does not have to be constant.
  • Preferred is a level determination in the hopper
  • Filtration properties are ensured. This can be done for example by dividing the volume in the hopper on two or more membranes; Pressure in the respective containers can be regulated individually. It can be different Issues be processed simultaneously (eg.
  • Connection to the permeate container allows further filtering; e.g. by pumping, stacking the arrangement, or a complete filter assembly inside the permeate container of a first arrangement.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Water Supply & Treatment (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Physics & Mathematics (AREA)
  • General Health & Medical Sciences (AREA)
  • Anesthesiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Vascular Medicine (AREA)
  • Biophysics (AREA)
  • Urology & Nephrology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Molecular Biology (AREA)
  • Ecology (AREA)
  • Optics & Photonics (AREA)
  • Manufacturing & Machinery (AREA)
  • Separation Using Semi-Permeable Membranes (AREA)

Abstract

L'invention concerne un ensemble et un procédé de filtration convenant, en particulier, à la filtration de cellules, p. ex. de cellules tumorales, à partir d'un échantillon, p. ex. d'un échantillon de sang. Selon le procédé, une différence de pression entre l'amont et l'aval d'un filtre est déterminée et la différence de pression entre l'amont et l'aval du filtre est réglée, de sorte que cette différence de pression n'excède pas une valeur prédéterminée.
EP12714699.1A 2011-05-20 2012-04-13 Ensemble et procédé de filtration Withdrawn EP2696962A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102011076228A DE102011076228A1 (de) 2011-05-20 2011-05-20 Anordnung und Verfahren zur Filtration
PCT/EP2012/056804 WO2012159821A1 (fr) 2011-05-20 2012-04-13 Ensemble et procédé de filtration

Publications (1)

Publication Number Publication Date
EP2696962A1 true EP2696962A1 (fr) 2014-02-19

Family

ID=45974342

Family Applications (1)

Application Number Title Priority Date Filing Date
EP12714699.1A Withdrawn EP2696962A1 (fr) 2011-05-20 2012-04-13 Ensemble et procédé de filtration

Country Status (4)

Country Link
US (1) US20140110349A1 (fr)
EP (1) EP2696962A1 (fr)
DE (1) DE102011076228A1 (fr)
WO (1) WO2012159821A1 (fr)

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WO2014135432A1 (fr) * 2013-03-05 2014-09-12 Endress+Hauser Conducta Gesellschaft Für Mess- Und Regeltechnik Mbh+Co. Kg Dispositif et procédé pour éliminer un liquide d'une cuve de traitement
ES2818136T3 (es) * 2014-07-02 2021-04-09 Siemens Healthcare Diagnostics Inc Control de retroalimentación para la detección mejorada de células raras
WO2016081737A1 (fr) * 2014-11-19 2016-05-26 The Regents Of The University Of Colorado, A Body Corporate Appareil, procédé et système pour capture de cellules basée sur un filtre et marquage avec zone de dépôt configurable
EP3417267A4 (fr) * 2016-02-18 2019-03-27 Siemens Healthcare Diagnostics Inc. Système d'adaptateur d'orifice d'entrée/sortie de gaz pour dispositif de filtration
ES2877137T3 (es) * 2016-02-18 2021-11-16 Siemens Healthcare Diagnostics Inc Bastidor para un dispositivo de filtración
WO2018038943A1 (fr) 2016-08-11 2018-03-01 Siemens Healthcare Diagnostics Inc. Dispositif de chauffage pour ensemble de filtration
DE102018132710A1 (de) * 2018-12-18 2020-06-18 Analytik Jena Ag Filtrierverfahren geeignet zur Isolierung und/oder Quantifizierung zumindest einer zu untersuchenden Substanz aus einer Probe
CN111773781B (zh) * 2020-09-04 2020-12-18 天津中新智冠信息技术有限公司 压滤机补料系统的控制方法、装置、控制柜及存储介质
CN112795478A (zh) * 2021-01-27 2021-05-14 广州安方生物科技有限公司 细胞分离装置及细胞分离方法和应用
CN112899146B (zh) * 2021-01-27 2023-06-13 广州安方生物科技有限公司 一种全自动细胞分离系统

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Also Published As

Publication number Publication date
US20140110349A1 (en) 2014-04-24
WO2012159821A1 (fr) 2012-11-29
DE102011076228A1 (de) 2012-11-22

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