DE3720844A1 - Column for the magnetic separation of cells, cell aggregates and cellular constituents - Google Patents

Column for the magnetic separation of cells, cell aggregates and cellular constituents

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Publication number
DE3720844A1
DE3720844A1 DE19873720844 DE3720844A DE3720844A1 DE 3720844 A1 DE3720844 A1 DE 3720844A1 DE 19873720844 DE19873720844 DE 19873720844 DE 3720844 A DE3720844 A DE 3720844A DE 3720844 A1 DE3720844 A1 DE 3720844A1
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Germany
Prior art keywords
column
separation
column according
plastic
ferromagnetic
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.)
Granted
Application number
DE19873720844
Other languages
German (de)
Other versions
DE3720844C2 (en
Inventor
Stefan Miltenyi
Andreas Dr Radbruch
Walter Weichel
Werner Dr Mueller
Christoph Goettlinger
Klaus Ludwig Meyer
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Miltenyi Biotec GmbH
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Individual
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Application filed by Individual filed Critical Individual
Priority to DE19873720844 priority Critical patent/DE3720844A1/en
Publication of DE3720844A1 publication Critical patent/DE3720844A1/en
Application granted granted Critical
Publication of DE3720844C2 publication Critical patent/DE3720844C2/de
Granted legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28023—Fibres or filaments
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D43/00—Separating particles from liquids, or liquids from solids, otherwise than by sedimentation or filtration
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
    • B01J20/28009—Magnetic properties
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C1/00—Magnetic separation
    • B03C1/02—Magnetic separation acting directly on the substance being separated
    • B03C1/025—High gradient magnetic separators
    • B03C1/031—Component parts; Auxiliary operations
    • B03C1/033—Component parts; Auxiliary operations characterised by the magnetic circuit
    • B03C1/034—Component parts; Auxiliary operations characterised by the magnetic circuit characterised by the matrix elements
    • 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
    • C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
    • C12M47/04—Cell isolation or sorting
    • 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
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54326—Magnetic particles

Abstract

The invention relates to a novel column for the separation of magnetically labelled cells, cell aggregates or cellular constituents in aqueous suspension. For the fractionation, the column is exposed to an external magnetic field while the suspension runs through. Unlabelled elements pass through the column, while labelled elements remain suspended in the matrix. They can be eluted after removal of the magnetic field. The plastic coating on the inner wall of the column results in medium and cell or cell constituents being separated from the ferromagnetic matrix, which protects the constituents to be separated from damage. The coating stabilises the ferromagnetic matrix, and non-magnetic trapping sites are filled with plastic. Hitherto unattainable speeds and quality of separation can be achieved therewith at low expense.

Description

Trennsäule für die magnetische Separierung von Zellen, Zellaggregaten und zellulären Bestandteilen Die erfindungsgemäße Trennsäule dient der Fraktionierung von magnetisch markierten Gemischen aus Zellen, Zellaggregaten oder Zellbestandteilen.Separation column for the magnetic separation of cells, Cell aggregates and cellular components The separation column according to the invention is used for the fractionation of magnetically marked mixtures of cells, cell aggregates or cell components.

Zellen und deren Bestandteile haben von Natur aus bis auf wenige Ausnahmen keine besonderen magnetischen Eigenschaften.Cells and their constituents naturally have up to few exceptions no special magnetic Properties.

Durch die gezielte Ankopplung von magnetischen Strukturen (superparamagnetischen Mikropartikeln, Ferritin, Erythrozyten mit desoxygeniertem oder reduziertem Hämoglobin, oder sonstigen Magnetpartikeln) an bestimmte Zellen, Zellaggregate oder Zellbestandteile, können diese magnetisch markiert werden. Die Ankopplung kann sehr spezifisch über Antikörper oder über andere, an bestimmte Strukturen bin­ dende Substanzen erfolgen.Through the targeted coupling of magnetic structures (superparamagnetic microparticles, ferritin, erythrocytes with deoxygenated or reduced hemoglobin, or other magnetic particles) to certain cells, Cell aggregates or cell components, these can be magnetic be marked. The coupling can be very specific Antibodies or other, to certain structures Ending substances take place.

Eine Auftrennung erfolgt in einem inhomogenen Magnetfeld. Das Gemisch wird in zwei Fraktionen aufgeteilt, eine, deren Elemente magnetische Strukturen gebunden haben, somit selbst magnetisierbar geworden sind, und eine unmagnetische. Die magnetische (positive) Fraktion ist oft von besonderem Interesse.Separation takes place in an inhomogeneous magnetic field. The mixture is divided into two fractions, one of which Elements bound to magnetic structures, thus themselves have become magnetizable, and a non-magnetic. The magnetic (positive) fraction is often special Interest.

Bisherige Verfahren verwenden meist nur Permanentmagnete zur Auftrennung, die an die Wandung des Gefäßes, das die zu trennende Suspension enthält, gehalten werden. Nur wenige nutzen die wesentlich stärkeren Magnetkräfte einer Hochgra­ dientenanordnung HGM. Bei dem besonders aus der Erzaufberei­ tung bekannten HGM-Verfahren erzeugen feine ferromagnetische Strukturen, wie etwa Metalldrähte, in ihrer Umgebung sehr große Magnetfeldgradienten. Sie sind in großer Menge in eine Säule gepackt. Beim Anlegen eines äußeren Magnetfeldes funktioniert die Säule wie ein Filter. Magnetisierbare Partikel werden von den Drähten angezogen und zurückgehal­ ten. Previous methods mostly only use permanent magnets Separation, which on the wall of the vessel, which the separating suspension contains. Only a few use the much stronger magnetic forces of a Hochgra service arrangement HGM. Especially from the ore processing tion known HGM processes produce fine ferromagnetic Structures, such as metal wires, are very close to them large magnetic field gradients. They are in large quantities in one Packed column. When applying an external magnetic field the column works like a filter. Magnetizable Particles are attracted to the wires and held back ten.  

HGM-Anordnungen haben viele Vorzüge, im Vergleich zu anderen Verfahren:HGM arrangements have many advantages over others Method:

  • -Starke Kräfte auf Partikel, auch schon mit kleinen Magneten- Strong forces on particles, even with small ones Magnets
  • -In kleinen Volumina große Abscheideflächen- Large separation areas in small volumes
  • -keine prinzipiellen Mengenbegrenzungen, da Filter sehr groß gebaut werden können-no basic quantity limits, because filters can be built very large
  • -schnellere und bessere Trennungen als bei anderen Verfahren- faster and better separations than others method

Besonders die Kombination eines HGM Systemes mit superpara­ magnetischen Markierungspartikeln kann sehr effektiv funktionieren, da diese Partikel im Vergleich zu nur para­ magnetischen Stoffen (Ferritin, modifizierte Erythrozyten) schon bei kleinen Feldern sehr stark angezogen werden.Especially the combination of an HGM system with superpara magnetic marker particles can be very effective work because these particles are only para magnetic substances (ferritin, modified erythrocytes) be very strongly attracted even in small fields.

Allerdings führt der unmittelbare Kontakt und die großen wirkenden Kräfte zwischen den Bestandteilen der magnetischen Fraktion und der Drahtoberfläche in bisher bekannten Trenn­ säulen zu Schädigungen der Zellmembranen oder der Zellbe­ standteile. Besonders Säugerzellen und Zellorganellen sind sehr empfindlich. Die Verletzungen bzw. die großen Zellver­ luste begrenzen bisher die Anwendbarkeit dieses Verfahrens auf paramagnetisch markierte Stoffe. Aber auch dort können bisher nur beständige, ferromagnetische Materialien mit sehr glatter Oberfläche verwendet werden. Aber gerade die Edel­ stähle, die sich durch ihre magnetischen Eigenschaften zur HGM-Trennung eignen, korrodieren in chloridhaltigen Trennmedien. Die nach kurzer Zeit entstehende Rauheit führt zu einer verstärkten Schädigung. Andererseits bieten gerade rauhe Fasern viele besonders starke magnetische Anheftungs­ punkte, korrosionsempfindliche oder toxische Materialien bessere magnetische Eigenschaften. However, the direct contact and the big ones forces acting between the components of the magnetic Fraction and the wire surface in previously known separations pillars to damage the cell membranes or the cell components. Especially mammalian cells and cell organelles are very sensitive. The injuries or the big cell ver So far, losses limit the applicability of this method on paramagnetically marked substances. But also there so far only stable, ferromagnetic materials with very smooth surface can be used. But just the noble steels, which are characterized by their magnetic properties HGM separation are suitable, corrode in chloride-containing Separation media. The roughness that arises after a short time leads to an increased damage. On the other hand, just offer rough fibers have many particularly strong magnetic attachments points, corrosion-sensitive or toxic materials better magnetic properties.  

HGM-Anordnungen zur Zelltrennung verwenden bisher nur Trenn­ säulen, die unbehandelte oder silikonisierte Edelstahldrähte enthalten. Deshalb und durch die nur schwachen paramagne­ tischen Kräfte sind sie nicht effektiv nutzbar.HGM arrangements for cell separation have so far only used separation pillars, the untreated or siliconized stainless steel wires contain. Therefore and because of the only weak paramagne technical forces, they cannot be used effectively.

Kunstoffbeschichtete Säulen werden bisher nicht eingesetzt.Plastic coated columns have not yet been used.

Durch die Beschichtung bzw. den Verguß der ferromagnetischen Matrix werden die oben beschriebenen Probleme beseitigt. Es kann ein zellfreundlicher Kunststoff mit glatter Oberfläche verwendet werden. Der Überzug führt zu einer Abtrennung des Mediums und der Zellen bzw. der Zellbestandteile von der magnetischen Matrix.By coating or casting the ferromagnetic Matrix eliminates the problems described above. It can be a cell-friendly plastic with a smooth surface be used. The coating leads to a separation of the Medium and the cells or the cell components of the magnetic matrix.

Die ferromagnetische Struktur wird durch den Verguß mechanisch stabilisiert, nichtmagnetische Fangstellen (enge Spalten etc.) werden verschlossen.The ferromagnetic structure is made by potting mechanically stabilized, non-magnetic traps (narrow Gaps etc.) are closed.

Besonders in Kombination mit superparamagnetischen Markier­ ungpartikeln ermöglicht die erfindungsgemäße Trennsäule außerordentlich gute Trennergebnisse bei sehr geringer Zellschädigung.Especially in combination with superparamagnetic markers The separation column according to the invention enables particles extraordinarily good separation results with very little Cell damage.

HerstellungsbeispielManufacturing example

Eine 2 ml Insulinspritze (Durchmeser 6.5 mm) wird auf eine Länge von 20 mm mit 150 mg Cr-Mo Stahlwolle (Werkstoff 1.4113 S, Faserdurchmesser 60 µm) gefüllt. Die Hauptfaserrich­ tung fällt mit der Achse der Spritze zusammen. Die Stahl­ wolle wird zunächst benetzt, indem man Lackverdünner (Lesonal V83) durch die Fasern aufzieht. Man läßt den Verdünner ablaufen und zieht anschließend mehrmals angerührten 2- Komponenten Klarlack (Lesonal K 86) durch die Wolle. Nach Abtropfen des überschüssigen Lacks zentrifugiert man die Spritze dann bei 100 g für 1 Minute.A 2 ml insulin syringe (diameter 6.5 mm) is placed on one Length of 20 mm with 150 mg Cr-Mo steel wool (material 1.4113 S, fiber diameter 60 µm). The main grain tion coincides with the axis of the syringe. The steel wool is first wetted by using lacquer thinner (Lesonal V83) through the fibers. The thinner is left run off and then pulls the 2- Components clear coat (Lesonal K 86) through the wool. To The excess paint is drained off and centrifuged Then syringe at 100 g for 1 minute.

Nach 2 Tagen ist der Lack getrocknet. Im Wasserstrahlvakuum wird die innere Kunststoffoberfläche nun silikonisiert. Die nun fertige Trennsäule hat eine Kapazität von 20 cm2, aus­ reichend für ca. 107 Zellen (z.B.Lymphozyten). Sie kann autoklaviert und wiederverwertet werden.The varnish has dried after 2 days. The inner plastic surface is now siliconized in a water jet vacuum. The now finished separation column has a capacity of 20 cm 2 , sufficient for approx. 10 7 cells (e.g. lymphocytes). It can be autoclaved and reused.

Literaturliterature

Whitesides, G. M., Kazlauskas, R. J., Josephson, L.:Whitesides, G.M., Kazlauskas, R.J., Josephson, L .:

Magnetic separations in biotechnology.Magnetic separations in biotechnology.

Trends in Biotechnology Vol. 1, No. 5, 144-148, (1983).Trends in Biotechnology Vol. 1, No. 5, 144-148, (1983).

Kemshead, J. T., Ugelstad, J.:.Kemshead, J.T., Ugelstad, J.:.

Magnetic separation techniques: their application to medicine. Molecular and Gellular Biochemistry 67, 11-18 (1985).Magnetic separation techniques: their application to medicine. Molecular and Gellular Biochemistry 67, 11-18 (1985).

Claims (13)

1. Trennsäule für die magnetische Separierung von Zellen, Zellaggregaten und zellulären Bestandteilen, dadurch gekennzeichnet, daß das Säuleninnere feine ferromagnetische Strukturen enthält, die mit einem Kunststoff überzogen sind, wobei manche Bereiche des Säuleninneren ebenfalls mit dem Kunststoff ausgefüllt sind.1. separation column for the magnetic separation of cells, cell aggregates and cellular components, characterized in that the interior of the column contains fine ferromagnetic structures that are coated with a plastic, some areas of the interior of the column are also filled with the plastic. 2. Trennsäulen nach Anspruch 1, dadurch gekennzeichnet, daß es sich bei den ferromagnetischen Strukturen um Stahlwolle handelt.2. separation columns according to claim 1, characterized in that the ferromagnetic structures are Steel wool deals. 3. Trennsäule nach Anspruch 2, dadurch gekennzeichnet, daß es sich bei den ferromagnetischen Strukturen um nichtrostende Stahlwolle handelt.3. separation column according to claim 2, characterized in that the ferromagnetic structures are stainless steel wool. 4. Trennsäule nach Anspruch 1, dadurch gekennzeichnet, daß es sich bei den ferromagnetischen Strukturen um Drähte handelt.4. separation column according to claim 1, characterized in that the ferromagnetic structures are Wires. 5. Trennsäule nach Anspruch 1-4, dadurch gekennzeichnet, daß die ferromagnetischen Fasern im Wesentlichen in Durchflußrichtung verlaufen.5. separation column according to claim 1-4, characterized in that the ferromagnetic fibers are essentially in Flow direction. 6. Trennsäule nach Anspruch 1, dadurch gekennzeichnet, daß es sich bei den ferromagnetischen Strukturen um Kugelschüttungen aus ferromagnetischem Material handelt.6. separation column according to claim 1, characterized in that the ferromagnetic structures are Ball beds made of ferromagnetic material acts. 7. Trennsäule nach Anspruch 1-6, dadurch gekennzeichnet, daß der Kunststoff bei der Herstellung der Säule nach dem Packen der ferromagnetischen Strukturen zur Säule eingebracht wird. 7. separation column according to claim 1-6, characterized in that the plastic in the manufacture of the column after packing the ferromagnetic structures to the column is introduced.   8. Trennsäule nach Anspruch 1-7, dadurch gekennzeichnet, daß der Kunststoff bei der Herstellung der Säule in einer flüssigen oder suspendierten Form in die Säule eingebracht wird.8. separation column according to claim 1-7, characterized in that the plastic in the manufacture of the column a liquid or suspended form in the column is introduced. 9. Trennsäule nach Anspruch 8, dadurch gekennzeichnet, daß überschüssiger Kunstoff durch Einwirken von Kräften noch im flüssigen oder suspendierten Zustand aus der Säule entfernt wird.9. separation column according to claim 8, characterized in that excess plastic by the action of Powers still in a liquid or suspended state is removed from the column. 10. Trennsäule nach Anspruch 1-8, dadurch gekennzeichnet, daß die Beschichtung bei der Herstellung in Gegenwart von magnetisierbaren Flüssigkeiten und magnetischen Feldern erfolgen kann.10. separation column according to claim 1-8, characterized in that the coating is present in the manufacture of magnetizable liquids and magnetic Fields can be done. 11. Trennsäule nach Anspruch 1-10, dadurch gekennzeichnet, daß das ferromagnetische Material vor der Beschichtung, zur Verbesserung seiner magnetischen Eigenschaften oder zur Verbesserung der Haftung und Benetzung mit dem Kunststoff geeignet, vorbehandelt wird.11. Separating column according to claims 1-10, characterized in that the ferromagnetic material before coating, to improve its magnetic properties or to improve liability and wetting with the Suitable for plastics, pretreated. 12. Trennsäule nach Anspruch 1-11, dadurch gekennzeichnet, daß die Kunstoffschicht mit weiteren Stoffen behandelt oder überzogen ist.12. Separating column according to claims 1-11, characterized in that the plastic layer is treated with other substances or coated. 13. Trennsäule nach Anspruch 12, dadurch gekennzeichnet, daß es sich bei der Behandlung um eine Silikonisierung handelt.13. Separating column according to claim 12, characterized in that that the treatment is siliconization acts.
DE19873720844 1987-06-24 1987-06-24 Column for the magnetic separation of cells, cell aggregates and cellular constituents Granted DE3720844A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE19873720844 DE3720844A1 (en) 1987-06-24 1987-06-24 Column for the magnetic separation of cells, cell aggregates and cellular constituents

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Application Number Priority Date Filing Date Title
DE19873720844 DE3720844A1 (en) 1987-06-24 1987-06-24 Column for the magnetic separation of cells, cell aggregates and cellular constituents

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DE3720844A1 true DE3720844A1 (en) 1989-01-05
DE3720844C2 DE3720844C2 (en) 1991-01-10

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US5439586A (en) * 1993-09-15 1995-08-08 The Terry Fox Laboratory Of The British Columbia Cancer Agnecy Magnetic filter with ordered wire array
US5503801A (en) * 1993-11-29 1996-04-02 Cobe Laboratories, Inc. Top flow bubble trap apparatus
US5591251A (en) * 1993-11-29 1997-01-07 Cobe Laboratories, Inc. Side flow bubble trap apparatus and method
US6020210A (en) * 1988-12-28 2000-02-01 Miltenvi Biotech Gmbh Methods and materials for high gradient magnetic separation of biological materials
US6190870B1 (en) * 1995-08-28 2001-02-20 Amcell Corporation Efficient enrichment and detection of disseminated tumor cells
EP1308211A2 (en) 1995-02-27 2003-05-07 Miltenyi Biotec Inc. Improved magnetic separation apparatus and method
US8264684B2 (en) 2007-12-19 2012-09-11 Singulex, Inc. Scanning analyzer for single molecule detection and methods of use
US8450069B2 (en) 2009-06-08 2013-05-28 Singulex, Inc. Highly sensitive biomarker panels
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US9040305B2 (en) 2004-09-28 2015-05-26 Singulex, Inc. Method of analysis for determining a specific protein in blood samples using fluorescence spectrometry
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Cited By (21)

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US6020210A (en) * 1988-12-28 2000-02-01 Miltenvi Biotech Gmbh Methods and materials for high gradient magnetic separation of biological materials
US6417011B1 (en) 1988-12-28 2002-07-09 Miltenyi Biotec Gmbh Methods and materials for improved high gradient magnetic separation of biological materials
US5439586A (en) * 1993-09-15 1995-08-08 The Terry Fox Laboratory Of The British Columbia Cancer Agnecy Magnetic filter with ordered wire array
US5503801A (en) * 1993-11-29 1996-04-02 Cobe Laboratories, Inc. Top flow bubble trap apparatus
US5591251A (en) * 1993-11-29 1997-01-07 Cobe Laboratories, Inc. Side flow bubble trap apparatus and method
US5674199A (en) * 1993-11-29 1997-10-07 Cobe Laboratories, Inc. Top flow bubble trap method
EP1308211A2 (en) 1995-02-27 2003-05-07 Miltenyi Biotec Inc. Improved magnetic separation apparatus and method
US6190870B1 (en) * 1995-08-28 2001-02-20 Amcell Corporation Efficient enrichment and detection of disseminated tumor cells
US9040305B2 (en) 2004-09-28 2015-05-26 Singulex, Inc. Method of analysis for determining a specific protein in blood samples using fluorescence spectrometry
US8685711B2 (en) 2004-09-28 2014-04-01 Singulex, Inc. Methods and compositions for highly sensitive detection of molecules
US9063131B2 (en) 2004-09-28 2015-06-23 Singulex, Inc. Methods and compositions for highly sensitive detection of molecules
US9823194B2 (en) 2004-09-28 2017-11-21 Singulex, Inc. Methods and compositions for highly sensitive detection of molecules
US8462339B2 (en) 2007-12-19 2013-06-11 Singulex, Inc. Scanning analyzer for single molecule detection and methods of use
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