WO2000057181A1 - Technique permettant d'isoler des erythrocytes - Google Patents

Technique permettant d'isoler des erythrocytes Download PDF

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Publication number
WO2000057181A1
WO2000057181A1 PCT/EP2000/002352 EP0002352W WO0057181A1 WO 2000057181 A1 WO2000057181 A1 WO 2000057181A1 EP 0002352 W EP0002352 W EP 0002352W WO 0057181 A1 WO0057181 A1 WO 0057181A1
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WO
WIPO (PCT)
Prior art keywords
dextran
aggregation
erythrocytes
carrier
sample
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PCT/EP2000/002352
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German (de)
English (en)
Inventor
Herwig Brunner
Eckehard Walitza
Jürgen GERAY
Frank Vitzthum
Günter Tovar
Original Assignee
Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V.
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Publication of WO2000057181A1 publication Critical patent/WO2000057181A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/18—Erythrocytes

Definitions

  • the present invention relates to a method for isolating erythrocytes from a sample and a device for carrying out this method.
  • erythrocytes prove to be inhibitors of chain extension.
  • Erythrocytes are currently separated from human blood generally by centrifugation. However, centrifugation is a laborious process.
  • Another possibility of specifically binding and thereby separating erythrocytes is to bind blood groups to antibodies.
  • the antibodies are applied to magnetic beads, which means that the erythrocytes can be separated using a magnetic field.
  • the binding of the erythrocytes to the antibodies is irreversible.
  • the synthesis of the antibodies represents a process which is complex in terms of laboratory technology and therefore expensive (US Pat. No. 5,466,609).
  • the invention is therefore based on the technical problem of providing an inexpensive and easy to carry out method which is able to specifically isolate erythrocytes from a sample and thereby uses reversible binding of the erythrocytes.
  • the invention solves the problem on which it is based by providing a method for isolating erythrocytes from a sample, the erythrocyte-containing sample being brought into contact with at least one aggregation-promoting substance, in particular a macromolecule such as dextran, the aggregation-promoting substance stimulating the formation of erythrocyte aggregates and the aggregates thus formed are separated from the sample.
  • the separation can be carried out by means of suitable separation processes, for example by means of filtration, chromatography, centrifugation, electrophoretic processes, or, if magnetic beads are used as carriers for the substance which requires aggregation, also by means of a magnetic field.
  • the invention makes use of the effect that, especially in a physiological environment, erythrocytes using at least one substance that requires aggregation, in particular at suitable concentrations adapted to the respective isolation task, aggregates, so-called rouleaux, that is to say roll-like aggregations of individual erythrocytes into a larger one Unity.
  • the aggregation-promoting substance acts as a stimulant or stimulator for the formation of these rouleaux by reversibly binding the erythrocytes to one another.
  • the aggregates or rouleaux thus represent units of money-like units connected to one another via the aggregation-promoting substance.
  • the rouleaux formation and the associated changes in properties, such as volume increase, make it possible to remove erythrocytes in the form of their aggregates from the rest of the sample. separate from the leukocytes.
  • the aggregates can be separated specifically from the remaining constituents of the sample, for example by means of membranes or filters.
  • the invention also has the advantage that no non-specific binding of cells, in particular of leukocytes, viruses or bacteria, to the aggregation-promoting substance takes place.
  • a sample is understood to mean any erythrocyte-containing aqueous solution, aqueous suspension, culture medium, body fluid, mixture or the like, in particular a physiological solution, culture medium or suspension.
  • blood in particular human blood, is used as the sample.
  • the sample can be taken directly from a, preferably human, organism, but can also be of essentially synthetic origin or have been subjected to any pretreatment before the treatment according to the invention.
  • an aggregation-promoting substance is a Understand substance that is able to induce and / or promote the formation of erythrocyte aggregates or rouleaux from individual erythrocytes.
  • the aggregation-promoting substance is a macromolecule, in particular dextran, polyvinylpyrrolidone (PVP), fibrinogen, phytohae agglutinin (lectin), gelatin, globulin, pectin, hydroxyethyl starch, albumin, polylysine or mixtures of these substances.
  • dextran is understood to mean a slimy, high-molecular, neutral biopolysaccharide. In the polysaccharide, in addition to 1,6 and 1,3 linkages between the glucose monomers.
  • both native and partially or completely purified dextran can be used.
  • the dextran used can be of natural or synthetic origin.
  • the term dextran is of course also understood to mean dextran fragments or dextran derivatives, such as dextran modifications or, for example with halohydrins, crosslinked dextrans, provided that they are suitable for stimulating erythrocytes to form aggregates.
  • dextran with a molecular weight of 0.5 • 10 4 to 2 • 10 8 daltons, in particular 1.5 • 10 4 to 5 • 10 7 daltons, in particular 6.9 • 10 4 to 2.0 • 10 5 is particularly preferred Dalton.
  • the aggregation-demanding substance in particular the dextran, can be used in any form, for example immobilized on suitable supports, such as a filter, a membrane, a Fleece, foams, porous supports, beads, or a test strip, preferably made of nylon.
  • suitable supports such as a filter, a membrane, a Fleece, foams, porous supports, beads, or a test strip, preferably made of nylon.
  • the carrier used according to the invention can be made of nylon, polyurethane, silicone, cellulose, polyvinylidene di-fluoride, polycarbonate, polypropylene, polyethylene, polybutylene, polystyrene, polyethylene terephthalate, polytetrafluoroethylene, fluoropolymers, polysulfones, glass, silicate, aluminosilicate, silicon or aluminum oxides, zeolites , Carbon or mixtures of two or more of these substances or contain them in substantial parts.
  • the carrier coated with the aggregation-promoting substance, in particular the dextran-coated carrier is added to the sample so that the aggregation-promoting substance, in particular the dextran, can come into contact with the erythrocytes.
  • the aggregation-demanding substance, in particular dextran can also be brought into contact with the sample in free form as an aqueous solution, suspension, suspension or in dried form, for example by mixing or simply adding, with a subsequent incubation time of 1 to 10 minutes. , in particular 3 min., is preferred before the rouleaux are separated from the solution and the remaining constituents of the sample.
  • the dextran is used in free form, that is to say not immobilized, lower and upper limits for the dextran concentration in the solution are preferred, depending on the type of dextran used, ie the molecular weight of the dextran. These limits can be determined by simple routine experiments by observing the Rouleaux formation, ie the erythrocyte aggregation, as a function of the dextran concentration for a certain type of dextran. It happens below the lower limit no rouleaux formation, while above the upper limit the erythrocytes bound in the rouleaux separate again.
  • the preferred concentration range according to the invention is 3 to 7% by weight of dextran in physiological solution or PBS (phosphate-buffered, physiological saline). With higher molecular weights of dextran, comparatively lower dextran concentrations are preferred, for example with dextran 200 in the range from 1 to 5% by weight of dextran in physiological solution or PBS.
  • the invention therefore provides for the aggregation-promoting substance, in particular the dextran, to be brought into contact with the sample in a free form which is not immobilized on a carrier, that is to say the aggregation-promoting substance, in particular the dextran, preferably with thorough mixing into the To give a sample, which then forms, preferably dextran-bound, erythrocyte aggregates which are bound to the aggregation-promoting substance and which can then be separated off, for example, by filtration.
  • the erythrocytes can be separated again, for example by using shear forces, caused, for example, by pressure filtration or corresponding flow conditions or by using increased dextran concentrations or concentrations of aggregation-promoting substance in a solution surrounding the carrier, that is to say a concentration which is a dextran detachment or detach the aggregation-promoting substance from the erythrocytes.
  • the invention provides for the aggregation-promoting substance, in particular the dextran, to be brought into contact with the sample in immobilized form, with incubation times of 1 to 10 minutes, in particular 3 minutes. are preferred before the remaining constituents of the sample and the solution are separated from the rouleaux bound to the support.
  • any suitable materials can be considered as carriers for the immobilized aggregation-promoting substance, in particular the immobilized dextran, for example beads or beads, which can also be in the form of magnetic beads, in order, according to the invention, to magnetically separate those bound to the aggregation-promoting substance, in particular that Dextran-bound to allow aggregates from the sample.
  • immobilization-promoting substance, in particular dextran immobilized on a membrane or a filter is used.
  • Nylon membranes or filters are preferably used, it being possible for the aggregation-promoting substance, in particular the dextran, to be covalently bound to this membrane or filter by wet-chemical methods.
  • the dextran graft density on the support depends on the density of the n-methylol groups activated by, for example, formaldehyde in the nylon membrane and the incubation time in the dextran solution used for the loading, which for example 10 to 60 min. can be.
  • Dextran plug densities preferred according to the invention are in the range from 0.02 mg / cm 2 to 2.4 mg / cm 2 .
  • Erythrocytes and Erythrocytenaggre- gates, i.e. Rouleaux, are reversibly bound to the dextran-immobilized membrane or the membrane containing the aggregation-promoting substance.
  • the bond strength to the dextran molecules depends on the molecular weight of the dextran used and the dextran density on the membrane.
  • erythrocytes and erythrocyte aggregates are bound to the membrane or filter provided with the aggregation-promoting substance, in particular to the dextran-immobilized membrane or the filter.
  • the erythrocytes or rouleaux can be separated from the sample in a one-step, very specific process.
  • the erythrocytes can then be separated again using shear forces in the order of magnitude of the binding forces, or they can be detached from the support and separated. These shear forces can be generated by using, for example, pressure filtration or using appropriate flow conditions.
  • a separation can also take place by adding an increased dextran concentration to the dextran-bound erythrocytes, that is to say a concentration which brings about the dextran detachment from the erythrocytes.
  • an increased dextran concentration to the dextran-bound erythrocytes, that is to say a concentration which brings about the dextran detachment from the erythrocytes.
  • the dextran concentration required for this depends, among other things, on the molecular weight of the dextran type and is, for example, at least 8% by weight of dextran in physiological solution or PBS in the case of dextran 70 and at least 6% by weight in physiological solution or PBS in the case of dextran 200.
  • erythrocytes that are not immobilized on a support can also be separated using these methods.
  • detachment can be achieved by increasing the concentration of the respective aggregation-promoting substance.
  • the aggregation-promoting macromolecule in free and at the same time also in a form immobilized on a support for the specific isolation and separation of erythrocytes.
  • the invention also relates to a device for isolating erythrocytes or erythrocyte aggregates from a sample, comprising an aggregation-promoting substance bound to a support, in particular a membrane, beads, a fleece, a foam, a porous support or a filter, preferably covalently. especially dextran.
  • a device for isolating erythrocytes or erythrocyte aggregates from a sample comprising an aggregation-promoting substance bound to a support, in particular a membrane, beads, a fleece, a foam, a porous support or a filter, preferably covalently. especially dextran.
  • a device can be designed as a test strip, which can optionally be used for subsequent analyzes.
  • the carrier can be made of nylon, polyurethane, silicone, cellulose, polyvinylidene difluoride, Polycarbonate, polypropylene, polyethylene, polybutylene, polystyrene, polyethylene terephthalate, polytetrafluoroethylene, fluoropolymer, polysulfones, glasses, silicate, aluminosilicate, silicon or aluminum oxides, carbon, zeolite or mixtures of two or more of these substances exist or contain them.
  • the invention also relates to the use of aggregation-promoting substance immobilized on a carrier, in particular immobilized dextran, for stimulating the formation of aggregates of erythrocytes, in particular human erythrocytes, in particular the use of aggregation-promoting substance immobilized on a carrier, in particular immobilized dextran, for promoting the reversible binding of Erythrocytes among themselves, so that aggregates or rouleaux form.
  • a carrier in particular immobilized dextran
  • the invention also relates to the use of an aggregation-promoting substance immobilized on a carrier, in particular immobilized dextran, for promoting the reversible binding of erythrocytes and / or erythrocyte aggregates to the carrier having the immobilized aggregation-promoting substance, in particular the dextran carrier, that is to say, for example, a membrane, beads or a filter.
  • a carrier in particular immobilized dextran
  • the present invention can serve both to remove disruptive erythrocytes from a sample to be analyzed further and to isolate and purify erythrocytes to be analyzed further from a sample which is otherwise of no interest.
  • the invention is explained in more detail with reference to the examples and the associated figures.
  • FIG. 1 the aggregate formation of erythrocytes among one another caused by dextran
  • FIG. 2 shows the separation of erythrocyte aggregates from a sample using a filter
  • FIG. 3 shows the binding and separation of erythrocytes and erythrocyte aggregates bound to immobilized dextran from a biological sample by means of a membrane
  • FIG. 4 shows a graph for the separation of erythrocytes on (A) (untreated membrane), (B) (dextran 70-treated membrane) and (C) (dextran 200-treated membrane) and
  • FIG. 5 calibration lines for the density determination of dextran 70 and 200.
  • Fresh venous whole human blood was always used for the experiments described below.
  • the blood was made non-coagulable with K-EDTA.
  • a PBS solution with a pH of 7.4 was used to dilute the blood.
  • 250 ⁇ l of whole blood in 5 ml of PBS or 5 ml of 4% (% by weight in PBS) dextran 70 solution (dilution 1:20) were prepared at room temperature.
  • Example 1 Separation of erythrocytes from human blood using free dextran.
  • the dextran used was Dextran T70 from Pharmacia and Dextran 200 from Serva.
  • the molecular weight of the dextran 70 was 69,000 daltons, determined by means of gel filtration.
  • the molecular weight of dextran 200 was 200,000 to 300,000 daltons.
  • Sefar 03-10 / 2 nylon membranes were used for the filtration process. It was a polyamide (6.6) fabric with a mesh size of 9 - 11 ⁇ m. The fabric thickness was 45 ⁇ m and the open screen area was 2%. The weight per unit area of the membrane fabric used was 40 g / m 2 . The bubble point was determined to be 540 - 660 mm water column and the air permeability to 100 - 200 I N / m 2 s.
  • a 4% (w / w) dextran 70 solution in PBS was prepared. This solution was added to the blood sample and 3 min. incubated at room temperature. In the process, aggregates, so-called Rouleaux, were formed, ie erythrocytes reversibly connected to one another via dextran molecules (see FIG. 1). These rouleaux can be separated on a membrane whose pore diameter is larger than that of an individual erythrocyte or leukocyte (see FIG. 2). This ensures that only the erythrocytes bound by dextran are retained. are removed while all other components in the blood are removed.
  • Example 2 Removal of erythrocytes from human blood using immobilized dextran.
  • the supports designed as nylon membranes were coated with dextran. As a result, their surface was changed in such a way that erythrocytes were bound to the membrane via the dextran by the same mechanism as in the Rouleaux formation described in Example 1.
  • the nylon membranes used corresponded to those of Example 1, but were covered with dextran as follows.
  • the PA6.6 membranes are covered by wet chemistry.
  • the amino groups of the nylon are first activated by formaldehyde, to which the dextran is then covalently bound.
  • the reaction sequence of dextran immobilization on the nylon membrane is based on the knowledge of Beeskow et al. [Beeskow, T .; Kroner, K.H .; Anspach, F. B .: Nylon-based affinity me branes: impacts of surface modification on protein adsorption. J. Colloid Interface 196 (2), (1997), pp. 278-291.]:
  • the dextran graft density depends on the density of the formaldehyde-activated N-methylol groups on the nylon membrane.
  • the dextran graft density depends on the incubation time in the dextran solution. The greater the molecular weight of the dextran, the higher the absolute mass of the covalently bound dextran. However, the number of bound molecules simultaneously drops by the same order of magnitude. According to Beeskow [a. a. Determine as follows:
  • the membrane is incubated in 10 ml of 2M HCl at 90 ° C for 4 h. As a result, the dextran is hydrolyzed and glucose monomers are formed. The mixture is then neutralized with 21 ml of 1M NaOH and 1 ml of BCA reagent (from Sigma) is added to 0.5 ml of this solution and at 37 ° C. for 30 min. incubated.
  • BCA reagent bicinchoninic acid assay (protein determination): Detection of Cu (I), the glucose monomer reduces Cu (II) to Cu (I)). An absorption measurement at 562 nm follows (see FIG. 5).
  • the rouleaux formation on the membranes covered in this way took place after about 3 minutes of incubation of the blood sample at room temperature. It was then filtered through the nylon membrane.
  • FIG. 3 shows that dextran immobilized on a membrane binds erythrocytes and rouleaux, while the remaining blood components, such as leukocytes, are not retained by the membrane.
  • FIG. 4 shows the number of retained red blood cells on an untreated membrane (A), a dextran 70-treated membrane (B) and a dextran 200-treated membrane (C). It can be seen that the dextran-treated membranes (filled bars) have a considerably higher deposition rate for erythrocytes than untreated membranes (white bars). It also shows that the molecular weight of the dextran influences the deposition rate. The higher molecular weight dextran of 200,000 had one higher deposition rate for erythrocytes than dextran with a molecular weight of 70,000.
  • dextran 70 solution instead of the PBS solution used as a control to a blood sample leads to erythrocyte separation from the rest of the sample even when untreated membranes are used.
  • this is due to the fact that the non-immobilized dextran also stimulates the rouleaux formation of the erythrocytes and thus enables size filtration on a membrane.
  • a quantification of the erythrocyte aggregation can be carried out by means of various methods, which also serve, for example, to determine the concentrations of aggregation-promoting substance in which Rouleaux formation takes place according to the invention.
  • Red blood cells are monodisperse in isotonic saline solution (PBS solution).
  • PBS solution isotonic saline solution
  • a cell unit consists of either a monodisperse cell or from an aggregate.
  • the cell units in dextran-free PBS solution are divided by the number of cell units in the dextran solution.
  • the MAY is defined by:
  • N s number of cell units in dextran-free PBS
  • RAI Reflectometric Aggregation Index
  • RAI 1-R I / R 200 ;
  • the light reflection at a given shear rate of, for example, i 0.5 l / s is compared with the reflection at a shear rate of 200 l / s.
  • the method is based on the assumption that cells are monodisperse at 200 l / s.

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Abstract

L'invention concerne une technique améliorée permettant d'isoler les composants d'intérêt d'échantillons biologiques, qui consiste à fixer de manière réversible lesdits composants sur des macromolécules.
PCT/EP2000/002352 1999-03-18 2000-03-16 Technique permettant d'isoler des erythrocytes WO2000057181A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19912120A DE19912120A1 (de) 1999-03-18 1999-03-18 Verfahren zur Isolierung von Erythrozyten
DE19912120.6 1999-03-18

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WO2000057181A1 true WO2000057181A1 (fr) 2000-09-28

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5212060A (en) * 1990-04-27 1993-05-18 Genesis Labs, Inc. Dry test strip comprising a dextran barrier for excluding erythrocytes
WO1994027140A1 (fr) * 1993-05-12 1994-11-24 Medisense, Inc. Detecteurs electrochimiques
US5466609A (en) * 1990-10-31 1995-11-14 Coulter Corporation Biodegradable gelatin-aminodextran particle coatings of and processes for making same
US5652148A (en) * 1993-04-20 1997-07-29 Actimed Laboratories, Inc. Method and apparatus for red blood cell separation
EP0790494A1 (fr) * 1996-02-15 1997-08-20 Bayer Ag Matrices de fibres de graphite comme couches fonctionnelles dans des kits d'essais diagnostiques
US5660798A (en) * 1993-04-20 1997-08-26 Actimed Laboratories, Inc. Apparatus for red blood cell separation
US5766552A (en) * 1993-04-20 1998-06-16 Actimed Laboratories, Inc. Apparatus for red blood cell separation
WO1998032840A1 (fr) * 1997-01-24 1998-07-30 Asahi Medical Co., Ltd. Procede de separation des cellules

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5212060A (en) * 1990-04-27 1993-05-18 Genesis Labs, Inc. Dry test strip comprising a dextran barrier for excluding erythrocytes
US5466609A (en) * 1990-10-31 1995-11-14 Coulter Corporation Biodegradable gelatin-aminodextran particle coatings of and processes for making same
US5652148A (en) * 1993-04-20 1997-07-29 Actimed Laboratories, Inc. Method and apparatus for red blood cell separation
US5660798A (en) * 1993-04-20 1997-08-26 Actimed Laboratories, Inc. Apparatus for red blood cell separation
US5766552A (en) * 1993-04-20 1998-06-16 Actimed Laboratories, Inc. Apparatus for red blood cell separation
WO1994027140A1 (fr) * 1993-05-12 1994-11-24 Medisense, Inc. Detecteurs electrochimiques
EP0790494A1 (fr) * 1996-02-15 1997-08-20 Bayer Ag Matrices de fibres de graphite comme couches fonctionnelles dans des kits d'essais diagnostiques
WO1998032840A1 (fr) * 1997-01-24 1998-07-30 Asahi Medical Co., Ltd. Procede de separation des cellules
EP0987325A1 (fr) * 1997-01-24 2000-03-22 ASAHI MEDICAL Co., Ltd. Procede de separation des cellules

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