EP1227888A1 - Carte haute densite, de preparation d'echantillons, coulee sur place - Google Patents

Carte haute densite, de preparation d'echantillons, coulee sur place

Info

Publication number
EP1227888A1
EP1227888A1 EP00961767A EP00961767A EP1227888A1 EP 1227888 A1 EP1227888 A1 EP 1227888A1 EP 00961767 A EP00961767 A EP 00961767A EP 00961767 A EP00961767 A EP 00961767A EP 1227888 A1 EP1227888 A1 EP 1227888A1
Authority
EP
European Patent Office
Prior art keywords
housing
sample
substrate
reservoir
sample preparation
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.)
Ceased
Application number
EP00961767A
Other languages
German (de)
English (en)
Other versions
EP1227888A4 (fr
Inventor
William Kopaciewicz
Cheryl Brucato
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.)
EMD Millipore Corp
Original Assignee
Millipore 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 Millipore Corp filed Critical Millipore Corp
Publication of EP1227888A1 publication Critical patent/EP1227888A1/fr
Publication of EP1227888A4 publication Critical patent/EP1227888A4/fr
Ceased legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples
    • B01L3/50255—Multi-well filtration
    • 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
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/141—Preventing contamination, tampering
    • 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
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0829—Multi-well plates; Microtitration plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • B01L2400/049—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics vacuum

Definitions

  • Test plates for chemical or biochemical analysis which contain a plurality of individual wells or reaction chambers are well known laboratory tools. Such devices have been employed for a broad variety of purposes and assays, and are exemplified in U.S. Patent No. 4,734,192 and • 5, 009, 780, for example. Microporous membrane filters and filtration devices containing the same have become especially useful with many of the recently developed cell culture techniques, assays, and sample preparation methods, especially in the fields of virology, immunology, genetics, drug discovery, etc. Typically, a 96-well filtration plate is used to conduct multiple sample preparations or assays simultaneously.
  • membrane type, well geometry and layout are important criteria in choosing the appropriate sample preparation device for a particular operation.
  • analytical techniques such as matrix assisted laser desorption ionization, time of flight, mass spectrometry (MALDI TOF MS) and 96X capillary electrophoresis systems require only a small amount of sample for analysis.
  • Traditional 96-well devices often contain far more volume than is required for these high performance analytical instruments.
  • the structures are monolithic and/or continuous.
  • the invention is applicable to a variety of particular sizes and configurations, and provides a means of affixing chromatographic media in a variety of volumes and layouts.
  • the invention enables the inclusion of a substantial (relative to the increase in surface area of the precipitated polymeric structure) amount of media in the polymer composite matrix.
  • the composite structures comprise particles entrapped within a porous polymeric substrate, and are cast in-place into a planar or substantially planar insert having one or more recesses, thereby providing an effective platform for high throughput micromass handling.
  • particle chemistry With the appropriate selection of particle chemistry, virtually any separation or purification operation can be conducted in multiplicity, including selective bind/elute chromatography operations, on sample mass loads less than 1 microgram in volumes of a few microliters or less, as well as larger mass loads and volumes.
  • These structures preferably are self- retaining and/or self-supporting.
  • si tu into one or more wells in a suitable insert can be
  • either the filled or unfilled structures which may be self-retaining and/or self-supporting are derived from inorganic materials such as metals or ceramics .
  • Figure 3C is an exploded view of a spout of the underdrain of Figure 3B;
  • Figures 4A and 4B are graphs of the mass spectrum of desalted peptides in accordance with Example 4; .
  • Figures 5A and 5B are graphs of the mass spectrum of desalted peptides in accordance with Example 5;.
  • Figure 8A is a graph of the mass spectrum of peptides in accordance with Example 8.
  • Figures 8D and 8E are graphs of the mass spectrum of recombinant his-tagged protein in accordance with Example 8 ;
  • Figure 9A is a graph of the mass spectrum of phosphopeptides in accordance with Example 9.
  • membrane as used herein includes permeable and semi-permeable three dimensional structures with or without particles, having a porosity suitable for the desired application.
  • composite structure as used herein includes filled membranes.
  • Suitable adsorptive composite structures are polymer bound, particle laden adsorptive membrane structures, such as those comprised of chromatographic beads which have been adhered together with a binder.
  • a suitable particle loaded structure is comprised of about 80% w/w C18 silica and 20% w/w polysulfone binder, and is produced by Millipore Corporation.
  • Functional composite structures comprising other micron-size (e.g., 1-30 microns) resin particles derivatized with other functional groups are also beneficial, including styrenedivinyl -benzene-based media
  • silica-based media unmodified or derivatized with C 2 , C 4 , C 6 , C 8 , or C l ⁇ or ion exchange functionalities
  • C 2 , C 4 , C 6 , C 8 , or C l ⁇ or ion exchange functionalities to accommodate a variety of applications for peptides, proteins, nucleic acids, and other organic compounds.
  • selectivities e.g., hydrophobic interaction, affinity, etc.
  • particles as used herein is intended to encompass particles having ' regular (e.g., spherical) or irregular shapes, as well as shards, fibers and powders, including metal powders, plastic powders (e.g., powdered polystyrene) , silica and activated carbon.
  • metal powders e.g., metal powders, plastic powders (e.g., powdered polystyrene) , silica and activated carbon.
  • silica into a polysulfone polymer results in increased active surface area and is suitable for various applications.
  • Polysulfone sold under the name UDEL P3500 and P1700 by Amoco is particularly preferred in view of the extent of the adherence of the resulting composite structure to the housing (e.g., the walls of the apertures of the inserts) , including polypropylene, polyethylene, polystyrene, polycarbonate, etc., and mixtures thereof.
  • polystyrene and polystyrene/acrylonitrile copolymer examples include polyethersulfone, cellulose acetate, cellulose acetate butyrate, acrylonitrile PVC copolymer (sold commercially under the name “DYNEL”), polyvinylidene fluoride (PVDF, sold commercially under the name “KYNAR”), polystyrene and polystyrene/acrylonitrile copolymer, etc.
  • Any castable, membrane-forming polymer (such as nylon) can be used in the invention although viscosity may need to be adjusted and/or the use of mechanical supports may be needed to keep the material m place until precipitated.
  • Adhesion to the housing can be enhanced or an analogous effect achieved with these composite structures by means known to those skilled in the art, including etching of the housing, such. as with plasma treatment or chemical oxidation; mechanical aids such as rims inside the housing; and inclusion of additives into the housing material that promote such adhesion. Adhesion allows uniform precipitation during casting.
  • the formed structures are cast in the preferred method.
  • the membranes or composite structures formed as defined by the well geometry have an aspect "ratio (average diameter to average thickness) of less than about 20, more preferably less than about 10, especially less than 2, most preferably from about 0.5 to about 2.
  • ratio average diameter to average thickness
  • an aspect ratio within these ranges provides for suitable residence times of the sample in the composite structure during operation.
  • N-methyl-pyrolidone is a suitable solvent for polysulfones, polyethersulfones and polystyrene.
  • polystyrene pellets can be dissolved in N-methyl- pyrolidone and cast-in-place.
  • the resulting structure shows good adhesion to the walls of the wells in the insert, particularly when the insert is plastic, and has adsorption characteristics similar to polysulfone.
  • Dimethylsulfoxide (DMSO) , dimethylformamide, butyrolactone, and sulfalane are also suitable solvents.
  • Suitable particle sizes include particles in the range of from about 100 nanometers to about 100 microns in average diameter with or without porosity.
  • the material of construction for the housing is not particularly limited, but should be made of a material which will not deleteriously react with the reagents used during the sample preparation procedure or any subsequent procedure.
  • the material also must withstand the conditions typical of the method, particularly where pressure is used as the fluid driving force. ' Suitable materials include plastics
  • polyolefins especially polyethylene and polypropylene; PVC and polystyrene
  • glass and stainless steel glass and stainless steel.
  • the housing 10 and number of recesses or apertures therein are not critical. Where a plurality of apertures are present, the housing forms a high- density sample array.
  • the housing shown is a 3.365" x 5.030" planar card or plate, containing 384 recesses or apertures 12, and is 0.090 inches thick.
  • the apertures 12 penetrate through the housing. Smaller or larger housings can be used, as can thicker or thinner housings.
  • the housing is planar or substantially planar.
  • the apertures 12 can be formed in the housing by any suitable means, such as drilling, punching or molding. Preferably the apertures 12 are evenly spaced.
  • the apertures 12 have a diameter of about 0.060 inches and are spaced at about 0.178" centers.
  • Figure IB shows another embodiment with 96 apertures 12, each with a diameter of 0.150 inches and spaced 0.354 inch centers. The card of Figure IB is 0.09 inches thick.
  • the preferred configuration of the recesses or apertures 12 is substantially cylindrical, as the flow vectors during operation are substantially straight, similar to chromatography, thereby minimizing or avoiding dilutional washing that might occur with non-cylindrical configurations.
  • the recesses Preferably have an open top and an open bottom opposing and spaced from the open top, and thus are coplanar with the top and bottom surfaces of the housing.
  • the composite structure contained in the recesses preferably fills each recess, but can occupy less than the total volume of each recess if desired.
  • the composite structure is preferably coterminous with both sides of the recess, but can fill less than the entire recess so as to form a distribution well for the introduction of liquid sample, for example.
  • the structures of the present invention have a final bed height of from about 0.005 to about 0.5 inches.
  • the ideal bed heights will depend upon the application and are readily determined by those skilled in the art.
  • ' Bed height is predominantly controlled by the housing thickness; the structures are preferably coterminous with the two sides of the housing that communicate with the recess or recesses.
  • the housing is planar such as a plate, the structures are preferably coplanar with the two sides of the housing that communicate with the recess or recesses.
  • the structures of the present invention are not filled with particles, symmetrical or asymmetrical semi-permeable structures, or a combination of symmetrical and asymmetrical semi-permeable polymeric structures, can be formed.
  • the preferred method of formation is casting in si tu in the wells of the
  • a self-retaining, self-supporting structure suitable for separations based on size or adsorption (depending on polymer identity).
  • Recess geometry e.g., ribbed, hourglass or conical
  • Functionality can be either intrinsic or added to such a membrane to perform adsorption separations without the use of particles.
  • cellulose acetate can be treated with base to form cellulose, followed by an oxidant to render it reactive .
  • the preferred method of formation involves precipitation by means of solvent exchange, such as by introducing the casting solution into the apertures of the inserts by any suitable means, as discussed above.
  • the insert is held to the substrate by mechanical means or by adhesion (e.g., taping).
  • adhesion e.g., taping
  • the casting solution in the recesses is contacted with a liquid in which the polymer is insoluble, preferably water, so that the polymer precipitates in the recesses.
  • the inserts are placed on a flat substrate, such as a steel or glass plate, thereby forming a floor or bottom to each recess in the insert.
  • the casting solution is then applied to the insert and the recesses therein filled.
  • the insert (and substrate) is immersed in the liquid in which the polymer precipitates. Through the exchange of water for the solvent, the structure precipitates. The substrate is then removed from the insert.
  • the solvent used to prepare the casting solution and the non-solvent can contain a variety of additives.
  • One particular example is a casting solution containing 30% (w/w) C18 silica solids (15 ⁇ m) in a 9% (w/w) Udel P3500 (polysulfone dissolved in N- methylpyrrolidone) solution which has a viscosity of about 800 cps.
  • This solution is suitable for use in holes of about 0.080 in diameter and about the same in length.
  • the viscosity of this solution can be increased to above about 20,000 cps by increasing the C18 solids content to about 40% (w/w) .
  • the relationship between solids content and viscosity will vary with particle type.
  • the semi-permeable barrier can be optionally left in place, especially if slightly recessed (e.g., 0.010 inches recessed) from the top surface of the recess, to carry out size-based separations with unfilled structures, as the barrier acts as a micro- or ultra-filtration membrane.
  • the cast in-place structure assumes the shape of the recesses 12 and results in a self-retaining homogeneous structure akin to a chromatographic column, providing a large surface area (e.g., when particles are included in the polymer matrix) suitable for bind/elute chromatography or for other analytical or biochemical techniques.
  • Suitable driving forces include centrifugation, gravity, capillary action, pressure or vacuum.
  • FIG. 2 illustrates one suitable device 20 that forms the sample preparation device of the present invention.
  • the device 20 includes a sample reservoir 22 and a collection reservoir 23 in fluid communication with the sample reservoir 22 through the preferably planar insert or card 10.
  • the insert or card 10 could be applied directly, or can be sealed to a housing 20 by any suitable means, such as mechanically with seal 26, by gluing, welding, such as ultrasonic welding, impulse welding or thermal welding, ensuring that all sample passes through the insert or card (via the filled recesses 12) into the collection reservoir during operation.
  • a mechanical lock down plate 25 coupled to a pair of tie rods actuated by cam lever can be used to secure the device 20 together during operation, but other mechanical means are possible and within the scope of the present invention, such as suitable lock down hardware 27 as shown.
  • Figure 3A illustrates a design that can be bonded together as a single unit that can fit into a conventional vacuum housing ( Figure 3B) used for 96 or 384 well filter plates.
  • the upper sample chamber array 30, which contains a plurality of wells 33 (which for a 96X device, can be spaced by 0.36 inch centers; for a 384X device, can be spaced by 0.178 inch centers, etc.) is bonded to the insert 31 along an underdrain assembly 32.
  • the underdrain 32 is an array of spouts 34 (preferably in a single part) that is bonded to the underside of the insert 31 and serves to direct the filtrate liquid into a collection vessel or collection reservoir 23.
  • the spouts 34 are sized according to the size of the wells in the insert.
  • suitable means e.g., glue, such as cyanomethacrylate, UV curable glue, epoxy, silicone, etc., thermal or ultrasonic welding, etc.
  • glue such as cyanomethacrylate, UV curable glue, epoxy, silicone, etc., thermal or ultrasonic welding, etc.
  • the three pieces now form a disposable housing that when placed in a suitable vacuum manifold (with a collection plate 35) will operate as a multiwell (96, 384, 1536X, etc.) sample preparation device ( Figure 3B) .
  • the upper chamber and lower spout assemblies can be comprised of a variety of plastics, including polypropylene, polycarbonate, polystyrene, etc.
  • FIG. 3B the vacuum chamber for operating the plate assembly unit of Figure 3A is shown in Figure 3B.
  • a lower chamber 52 is provided which houses the collection plate 35 as shown.
  • a removable lid 53 is configured to mate with the side walls 54 of the lower chamber 52, and includes elastomeric seals 55 to seal against the side walls and against which the plate assembly unit seals. Once the plate assembly unit is sealed in the device, vacuum or other driving force can be applied to effectuate flow.
  • the device of Figure 3A may be assembled by turning the upper housing 30 upside down and precisely dispensing an adhesive onto the partition using a computer controlled liquid delivery device. Onto this, the insert 31 is laid, while taking care to maintain the proper orientation. Once the adhesive in this sub-assembly cures, additional adhesive is applied to the partitions on the side of the insert opposite that adhered to the upper housing 30. The underdrain 32 is set upon this additional adhesive and carefully oriented for axial alignment of recesses. The result after curing is a disposable, high throughput, sample preparation device ready to fit into current state-of-the-art robotics.
  • the device 20 can be adapted to accommodate more than a single insert at any given time.
  • two or more inserts can be aligned so that their respective recesses are in fluid communication with one another.
  • one or more holes in a single insert can be filled with media having different chemistries.
  • a desorbing matrix can be applied to the sample bound to the structure in the insert, such as a matrix including acetonitrile, which desorbs the sample for MALDI TOF mass spectrometry, and also helps mediate the effect of the laser so that the sample is not destroyed.
  • the unit was removed and a razor blade was used to remove excess polymer.
  • the card was then removed from the glass plate and was re-immersed in the water for an additional 0.5 hours to complete solvent exchange.
  • the insert was then removed from the water and allowed to air dry.
  • the card After the structure is precipitated and desolvenated (about 1 hour) , the card is removed and the excess polymer above the plane of the card surface is removed such as with a razor blade or wiping with a cloth. The card is then re- immersed and agitated in a water bath for about 5 minutes to remove particulate matter, and is then removed and allowed to dry.
  • Example 3
  • oligonucleotides were desalted using a ZipTip ⁇ C18 ⁇ and eluted from tip using 2 ⁇ l of
  • Example 4 Using the device described in Example 4, 2 ⁇ l of methanol were deposited directly onto the free side of the structure and allowed to pass into the plug by capillary action. This step was followed by the addition of 5 ⁇ l of 50 mM triethylamine acetate buffer, pH 7.0, which entered the plug in the same way. Onto the equilibrated structure, 3 ⁇ l of 50 mM triethylamine acetate buffer, pH 7.0, containing 5 pmole each of three oligonucleotides (20, 25 and 29 mer) was added and allowed to absorb into the plug by capillary action for about 1 min. Any remaining sample on top of the plug was forced through using positive pressure.
  • the structure was liberally washed with water using positive pressure (see Example 4) . Once washed and air dried, 1.0 ⁇ l of matrix (45 mg/ml hydroxypiccolinic acid, 5 mg/ml ammonium citrate, 45% acetonitrile) was carefully deposited onto the structure and again allowed to air dry. The plastic substrate was then snapped into a PE BioSystems (Framingham, MA) disposable MALDI sample plate holder (P/N V700314) in the same orientation. The carriage was inserted in a PE BioSystems VoyagerTM MALDI-TOF MS mass spectrometer with delayed extraction and the matrix spot was analyzed directly. ( Figure 7) .
  • matrix 45 mg/ml hydroxypiccolinic acid, 5 mg/ml ammonium citrate, 45% acetonitrile
  • a 0.02" cylindrical hole was bored into the center of a 1.75 X 1.75 X 0.04" piece of polypropylene plastic using a sharp point.
  • lacquer was added consisting of 10% (w/w) polystyrene (Dow Chemical, Styron 685D) : 90% (w/w) N-methylpyrrolidone containing 30% (w/w) of imidodiacetic acid coated-200A-15 ⁇ m spherical silica particles using the tip of a spatula.
  • the plastic was then immersed into an ambient temperature water bath for 1 hour to precipitate the polymer. After this period, the plastic substrate was removed and polymer precipitated on the exterior surface was cut off with a sharp razor blade.
  • protein was enriched using a ZipTip Mc " charged with copper ions.
  • the protein was eluted from the tip using 3 ⁇ l of 5% acetic acid directly onto MALDI-TOF MS sample plate and overlaid with matrix (Figure 8E) .
  • Example 8 Using the device described in Example 8 charged with copper ions, 2 ⁇ l of methanol were deposited directly onto the free side of the structure and allowed to pass into the plug by capillary action. Then, 5 ⁇ l of 8 M Urea, 0.1 M NaH 2 P0 4 ,

Abstract

L'invention concerne une pièce rapportée (31) à placer dans un dispositif de filtration à alvéoles de microtitration, qui présente des ouvertures remplies d'une matrice de filtration. Ladite matrice contient éventuellement des particules d'adsorption.
EP00961767A 1999-09-13 2000-09-11 Carte haute densite, de preparation d'echantillons, coulee sur place Ceased EP1227888A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US15360699P 1999-09-13 1999-09-13
US153606P 1999-09-13
US19578000P 2000-04-10 2000-04-10
US195780P 2000-04-10
PCT/US2000/024855 WO2001019520A1 (fr) 1999-09-13 2000-09-11 Carte haute densite, de preparation d'echantillons, coulee sur place

Publications (2)

Publication Number Publication Date
EP1227888A1 true EP1227888A1 (fr) 2002-08-07
EP1227888A4 EP1227888A4 (fr) 2006-05-24

Family

ID=26850698

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00961767A Ceased EP1227888A4 (fr) 1999-09-13 2000-09-11 Carte haute densite, de preparation d'echantillons, coulee sur place

Country Status (2)

Country Link
EP (1) EP1227888A4 (fr)
WO (1) WO2001019520A1 (fr)

Families Citing this family (14)

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WO2002096541A1 (fr) 2001-05-25 2002-12-05 Waters Investments Limited Plaque de dessalage pour spectrometrie de masse maldi
EP1390539A4 (fr) * 2001-05-25 2007-06-27 Waters Investments Ltd Plaques de desorption-ionisation par impact laser assiste par matrice (maldi) de concentration d'echantillons pour la spectrometrie de masse maldi
GB0120131D0 (en) 2001-08-17 2001-10-10 Micromass Ltd Maldi target plate
US20030143124A1 (en) * 2002-01-31 2003-07-31 Roberts Roger Q. Unidirectional flow control sealing matt
US20040050787A1 (en) * 2002-09-13 2004-03-18 Elena Chernokalskaya Apparatus and method for sample preparation and direct spotting eluants onto a MALDI-TOF target
CA2467131C (fr) * 2003-05-13 2013-12-10 Becton, Dickinson & Company Appareil et methode de traitement d'echantillons biologiques et chimiques
CA2467164A1 (fr) * 2003-05-13 2004-11-13 Becton, Dickinson & Company Appareil et methode de purification et de dessalage d'echantillons biologiques
US7824623B2 (en) * 2003-06-24 2010-11-02 Millipore Corporation Multifunctional vacuum manifold
SE0302074D0 (sv) * 2003-07-15 2003-07-15 Simon Ekstroem Device and method for analysis of samples using a combined sample treatment and sample carrier device
US20050236318A1 (en) * 2004-04-23 2005-10-27 Millipore Corporation Low holdup volume multiwell plate
EP1854540A1 (fr) * 2006-05-12 2007-11-14 F. Hoffmann-la Roche AG Dispositif de filtration à puits multiples
EP1854542B1 (fr) * 2006-05-12 2011-03-30 F. Hoffmann-La Roche AG Dispositif filtrant multipuits
EP3289856A1 (fr) * 2016-09-05 2018-03-07 Deutsche Saatveredelung AG Dispositif de culture et de prélèvement d'échantillon pour plantes
EP3784368A4 (fr) * 2018-04-25 2022-01-26 Optofluidics, Inc. Collecteur à vide pour microscopie à filtration

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US6048457A (en) * 1997-02-26 2000-04-11 Millipore Corporation Cast membrane structures for sample preparation

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Also Published As

Publication number Publication date
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WO2001019520A1 (fr) 2001-03-22

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