Liquid purification or separation – Processes – Using magnetic force
Reexamination Certificate
2000-08-07
2002-06-25
Horlick, Kenneth R. (Department: 1656)
Liquid purification or separation
Processes
Using magnetic force
C210S222000, C210S416100, C209S224000, C209S232000, C436S526000, C435S006120
Reexamination Certificate
active
06409925
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns a device and system for the transfer and/or manipulation of liquids or particles. The present invention further concerns a method of detection of biological entities using magnetic particles.
BACKGROUND OF THE INVENTION
In recent years, with the advance of automatization in laboratory techniques, many assays, reactions, diagnostic procedures and synthesis techniques, are carried out by the transfer of a plurality of liquid samples, simultaneously, from one array of liquid-containing wells to another. Typically, these are arrays of 5, 8, 16, 25, 96, 384, or 1536 liquid-containing wells. In order to transfer, add, collect or mix liquids, or particles to present in all the wells in the array simultaneously, various multi-collector systems have been devised. The most commonly used is a multi-pipetor which collects liquid from an array of source wells to an array of target wells, simultaneously, by application or release of application, respectively, of vacuum force. However, in all known multi-pipetor devices, each individual pipetor capable of collecting or releasing liquid from the well is connected by vacuum force to all other pipetors so that all samples in the well are collected and released at once (Valerio et al.,
Analytical Biochemistry
, 197:168-177 (1991)).
Magnetic particles are used for a variety of separation, purification, and isolation techniques in connection with chemical or biological molecules. In those techniques, a magnetic particle is coupled to a molecule capable of forming a specific binding (hereinafter “affinity binding”) with a molecule in a biological sample, which is to be isolated, purified or separated. The biological sample is then brought into contact with the magnetic particle and those biological molecules which bind to the magnetic particles are then isolated by application of a magnetic field.
Such magnetic separation techniques have been employed to sort cells, to recover antibodies or enzymes from a solution, to purify proteins using affinity techniques, and to remove unwanted particles from suspension, for example, to remove cancer cells ex vivo, from a cell preparation which is then injected into a patient (Pourfarzaneh, M. et al., “
The use of magnetizable particles in solid phase immunoassay in methods of biochemical analysis
” 28:267-295 (1982)).
For the purpose of using magnetic particles, various devices have been developed in order to transfer the magnetic particles from one location to another, for example from one reaction vessel to another reaction vessel.
U.S. Pat. No. 4,292,920 discloses a device for transferring, by bio-magnetic attraction, antigen-antibody adsorbent material from one reaction mixture to the other. The device may comprise a single or multipin arrangement, corresponding to a well arrangement, which is capable of attracting by magnetic force magnetic particles. By one embodiment, the pin is connected to an electromagnet, and by turning the electromagnet on and off the pin becomes magnetized, or non-magnetized, respectively.
U.S. Pat. No. 5,567,326 discloses an apparatus and method for separating magnetically responsive particles from a nonmagnetic test medium in which they are suspended. The device comprises a plurality of nonmagnetic pins (termed “magnetic field directing elements”) arranged in an array, and a magnet positioned normal to said array. Placing the magnet on the array of pins, renders all the pins in the array magnetic causing particles to be attracted to them, and thus collecting them; and removing the magnet causes the pins to become non-magnetic, and consequently the magnetic particles are released from the pins.
The drawbacks of the above devices and apparatuses reside in the fact that the magnetic pins come into direct contact with the magnetic particles, so that if rinsing and sterilization is required, the whole apparatus or device has to be washed which procedure is expensive and time consuming. Furthermore, the collection of particles is not efficient since in such a construction, due to surface tension forces, some of the particles remain in the suspension.
Another drawback of the prior art devices reside in the fact that where a multi pin device is used to collect magnetic particles from a plurality of wells, the particles from all the wells have to be collected at once in an “all or none” fashion, and it is not possible to selectively collect particles only from some wells in an array.
Magnetic particles were also used for detection purposes, for example for DNA purification for detection purposes, using a method similar to reverse hybridization blot system. However here the specific oligonucleotide probe was attached to a paramagnetic particle instead of a sheet membrane. The target DNA, which contains the complementary sequence of the probe, hybridizes to the probe that is attached to the bead and is then magnetically removed from the solution, washed and collected (Fry et al.,
Bio Techniques
, 13(1) 124-131 (1992)). Coupling of the polynucleotides to the magnetic particles can be carried out for example according to the teaching of Day et al. (Biochem. J. 278, 735-740 (1991)). Immobilization of nucleic acid sequences on magnetic beads can also be carried out utilizing the streptavidin—bioten technology (Uhlen M., Nature, 340, 773-739 (1989)).
GLOSSARY
The following terms will be used at times throughout the specification:
“Material”—the contents of a vessel which is tranferred from a first plurality of vessels termed “source vessels” (see below) to a second plurality of vessels termed “target vessels” (see below). Typically, a “material” is a small amount of liquid, solid particles (such as beads), for example contained in a liquid or magnetic particles.
“Plurality of vessels”—two or more material-holding vessels. The plurality can be present in one “array of vessels” (see below), for example each plurality may be a line or column in a single array. Alternatively, the plurality may be the array of vessels itself for example a 96-well array.
“Array of vessels”—a plurality of voids present in a single construct which holds the material. Typically the array of vessels is an array of wells. State of the art wells have an 8, 16, 25, 96, 384 or 1536—well arrangement.
“Source vessels”—a plurality of vessels from which material is collected.
“Target vessels”—a plurality of vessels to which material is released.
“Transfer”—an action of withdrawing and holding (i.e. collecting) the material from one plurality of vessels (source) and releasing the material to another plurality of vessels (target).
“Collecting member”—a component of the system of the invention capable of collecting (upon activation) and releasing (upon deactivation) material from a single vessel for example from a single well. The system comprises a plurality of individual collecting members each capable of being activated and deactivated independently.
“Activated state” (“activated”) “deactivated state”“Deactivate”—a change of property of the individual collecting member which can cause it to collect or release material, respectively, for example, by application and removal of vacuum force. Another example is creation of an activated state by placing a magnetic-field providing member in a fist position where it is present at the distal-collecting end of the device and deactivated state is created by moving said member to a second position where it is spaced from said distal-collecting end. In the first position magnetic particles (the material) one collected and in the second position magnetic particles are relevant. Another option is a collecting member comprising an electromagnet when the electromagnet is turned on, magnetic particles are collected and the collecting member is the activated state. When the electromagnetic is turned off, the magnetic particles are released and the collecting member is in the deactivated state.
“Manipulation”—a collection and release of magnetic particles resulting in their transfer from one location to the other as well as the movements of
Gombinsky Moshe
Khatskina Anna
Bio-Magnetics Ltd.
Horlick Kenneth R.
Spiegler Alexander H.
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