WO2026030193A1 - System and method to manipulate magnetic particles in liquid suspension - Google Patents

Abstract

Described herein are systems and methods to manipulate magnetic particles in liquid suspension. The system comprises at least two magnets of different magnetic strengths, wherein a weaker magnet coated with an inert protective layer maybe immersed into and pulled out of liquid suspension contained in a vessel, and a strong magnet located outside of the vessel may be activated to reverse the magnetic force exerted by the weaker magnet. Microparticles in the liquid suspension are attracted to the inner surface of the vessel when the strong magnet is activated and otherwise are attracted to the surface of the weaker magnet. Among other applications, the invention can be used in biotechnology to separate magnetic particles from a liquid suspension in a vessel as well as to transfer magnetic particles among a variety of liquid suspensions in multiple vessels.

Description

SYSTEM AND METHOD TO MANIPULATE MAGNETIC PARTICLES IN LIQUID SUSPENSION Background of the Invention Magnetic microparticles and nanoparticles can be separated from liquid suspension using magnetic force and have been widely used in biotechnology for the extraction, purification and analysis of DNA, RNA, proteins, cells, viruses, bacteria, exosomes and other types of biological samples. One common method to separate magnetic particles from a liquid suspension is to create a magnetic sediment or pellet by placing a magnet in the vicinity of a vessel, and then to remove the liquid in the vessel by aspiration. However, this common method suffers from the risk of either particle loss or insufficient liquid removal. An alternative method proposed in US Patent 6207463 and commercialized in the KingFisher sample separation system uses permanent magnetic rods with removable tips to collect magnetic particles from liquid suspensions, and then release them into successive vessels. Unfortunately, the skinny rod and the moving mechanism are difficult to manufacture and failure prone. It is also bulky and incompatible with the trend of modern biotechnology toward miniaturization. Furthermore, the releasing of the magnetic particles relies on the passive dispersion of the magnetic particles from the surface of the removable tip. However, this can be problematic because dispersion cannot always overcome the physical absorption of magnetic particles onto the surface of the removable tip, particularly with biologically labeled magnetic nano or micro particles in biological suspensions. Consequently, a magnetic particle separation system that is robust, compact, and able to forcibly release magnetic particles into a liquid suspension would be desirable. Brief Summary of the Invention This invention relates to systems and methods to manipulate magnetic particles in a liquid suspension. Referring to Figure 1, in the exemplary primary embodiment of the present invention, a system and a method are proposed for magnetic particle manipulation, comprising a vessel (1) containing magnetic particles in a liquid suspension (2); a magnetic tip (3) wherein the portion of its surface that may be exposed to liquid suspension is coated with a thin layer of material inert to the liquid suspension; and a strong magnet (4) that when it is activated will reverse the magnetic force exerted by the magnetic tip (3). When the protected portion of the magnetic tip (3) is immersed into the liquid suspension (2) and the strong magnet (4) is deactivated, the magnetic particles in the liquid suspension (2) are attracted to the portion of the tip (3) coated with a protective layer, forming a pellet on the coated surface of the tip (3) that can be either moved around with the tip (3) within the liquid suspension (2) contained in the vessel (1); or pulled outside of the liquid suspension (2) in the vessel (1); or transferred between a variety of liquid suspensions in multiple vessels. When the strong magnet (4) is activated, its magnetic strength overwhelms the magnetic strength of the tip (3). Consequently, all magnetic particles within the liquid suspension (2) are attracted to the strong magnet (4), forming a pellet (5) on the inner surface of the vessel (1) at the location where the magnetic field is strongest. In summary, the exemplary primary embodiment of the present invention provides a system and a method to manipulate magnetic particles in a liquid suspension; to extract magnetic particles out of a liquid suspension; to release magnetic particles into a liquid suspension; or to transfer magnetic particles between a variety of liquid suspensions in multiple vessels. Brief Description of the Drawings An exemplary embodiment of the present invention is illustrated by way of example in the accompanying drawings wherein like reference numbers indicate the same or similar elements and wherein: Figure 1 is a diagrammatic representation of an exemplary embodiment within which the present invention of a magnetic particle manipulation system may be deployed that includes: a) A vessel (1) containing liquid suspension, b) A magnetic tip (3) wherein the portion of its surface that may be exposed to the said liquid suspension (2) is coated with an inert material, c) A strong magnet (4) that in Figure 1A is placed far away from the vessel (1), and in Figure 1B is placed outside the vessel (1) in the vicinity of the tip (3). Figure 2 are schematics that illustrate the magnetic field lines near the pole of two magnets with respect to a vessel. In Figure 2A, the strong magnet is placed far away and in Figure 2B outside the vessel in the vicinity of the tip (3). Figure 3 depicts schematically the method of the current invention to extract magnetic particles from a liquid suspension in one vessel. Figure 4 depicts schematically the method of the current invention to release magnetic particles into a liquid suspension in one vessel. Figure 5 depicts schematically the method of the current invention to extract magnetic particles from liquid suspensions in an array of vessels. Figure 6 depicts schematically the method of the current invention to release magnetic particles into liquid suspensions in an array of vessels. Detailed Description In one of the preferred embodiments of the present invention illustrated in Figure 1, the activation of the strong magnet (4) is accomplished by controlling its distance to the magnetic tip (3). When the strong magnet (4) is far away, as illustrated in Figure 1A, the magnetic particles in the liquid suspension (2) form a pellet (5) on the surface of the magnetic tip (3). Moving the tip (3) around in the liquid can therefore increase the exposure of the particle surface to the surrounding liquid. Further, magnetic particles can be extracted by lifting the tip (3) together with the pallet (5) out of the liquid suspension (2). On the other hand, when the strong magnet (4) is placed in the vicinity of the tip (3) outside of the vessel (1), as illustrated in Figure 1B, the magnetic strength of the strong magnet (4) overwhelms that of the tip (3). Magnetic particles on the surface of the tip (3) are therefore forcibly released into the liquid and subsequently form a pallet (5) on the inner surface of the vessel (1) nearest to the strong magnet (4). In summary, the preferred embodiment of the current invention provides a simple system and method to forcibly move magnetic particles around within a liquid suspension, as well as into and out of a liquid suspension. It should be obvious to those of ordinary skill in the art that the magnetic tip (3) could be comprised of any magnetic object with an inert protective coating, so long as the protective portion of the tip can be immersed into the liquid suspension (2) in the vessel (1). It should also be noted that in the context of the present invention, magnetic particles are any objects that fit inside of a vessel and can be attracted to a magnet, including objects that are attached, enclosed or covered with additional physical, chemical or biological molecules, species or other materials and objects. Further, a magnetic material may be composed of permanent magnetic, ferromagnetic, ferrimagnetic, electromagnetic or a mixture of these materials. In addition, a strong magnet is one that when activated can generate a force that is stronger than and overwhelms the magnetic force of the tip (3). An example of which is a permanent magnet (4) that is made of the same material as the magnetic portion of the tip (3), but 10 times its size, although 10 should not be considered in a limiting sense. The activation mechanism may be either mechanical, for example by moving a permanent magnet to the outside of the vessel (1) in the vicinity of the tip (3), or electrical, for example by switching on an electromagnet placed outside the vessel (1) in the vicinity of the tip (3). The mechanism that two magnets of different magnetic strengths can be used to manipulate the behavior of magnetic particles in liquid suspension is illustrated in Figure 2. The direction of magnetic force is depicted by magnetic field lines (206) originated from the pole of a magnet. The denser the field line, the stronger the magnet force. In other words, the magnetic particles would always move towards location where the magnetic field lines are closest to each other. As illustrated in Figure 2A, in the absence of the strong magnet (204), the magnetic particles will move towards the pole of the magnetic tip (203) to form a pellet on the tip surface. As the strong magnet (204) is moved to the vicinity of the magnetic tip (203), as shown in Figure 2B, the magnetic field lines (206) redistribute. Magnetic particles are therefore pulled away from the magnetic tip (203) and form a pellet on the inner surface of the vessel (201) closest to the pole of the strong magnet (204). By moving the strong magnet close to or away from the vicinity of the tip (203), the magnetic particles in liquid suspension can be manipulated deterministically, for example either dragged by the varying magnetic force back and forth inside the liquid or pulled out of the liquid with the tip (203). The magnetic particles on a tip (203) may also be released into the liquid suspension in another vessel when a strong magnet (204) is placed nearby. It should be noted that although the tip (203) and the strong magnet (204) attract each other in Figure 2B, the same principle applies to the situation wherein the tip and the strong magnet repel each other. In both cases, the magnetic field gradient between the tip (203) and the magnet (204) always points towards the latter when the two are close to each other. Figure 3 illustrates schematically a preferred embodiment of the current invention for the extraction of magnetic particles from liquid suspension. Due to the relatively weak magnetic strength of the tip (303), it is preferable to first apply a strong magnetic field to the liquid suspension such that a pallet (305) is formed near the bottom of the vessel (301) prior to extraction, for example by activating the strong magnet (304). Although, to those of ordinary skill in the art, it is clear that the formation of a pellet (305) prior to particle extraction is not a prerequisite of the current invention. In addition, many alternative ways may be used to form a magnetic pellet prior to particle extraction, such as by gravitation or centrifuge. In any case, in the absence of the strong magnet (304), the magnetic particles, either in the liquid suspension (302) or in the pre-formed pellet near the bottom of the inner surface of the vessel (301) are attracted to the tip (303) and form a pellet on its surface. The pellet (305) can therefore be extracted together with the tip (303) from the liquid suspension (302), leaving all other components of the liquid behind. As shown in Figure 4, the pellet removed from the suspension can be released into another vessel (401) containing different liquid suspension (402). As shown, during the magnetic particle release, the strong magnet (404) is placed outside of the vessel (401) near its bottom. Once the tip (403) containing the pellet (405) is immersed into the liquid suspension (402), the magnetic particles will start to move away from the tip (403) and finally form a new pellet (405) on the inner surface of the vessel (401) closest to the strong magnet (404). The empty tip (403) is then pulled out of the liquid suspension (402), completing the pellet-releasing process. It should be noted that the movement of the pellet (305, 405) in the liquid suspension is affected only by the activation state of the strong magnet (304, 404). It is for the convenience of illustration that a time sequence is used to describe the immersion and activation processes. It should be obvious to those skill in the art that the combination of the systems and methods depicted in Figure 3 and Figure 4 of the current invention comprises a robust and compact system that can be used to forcibly transfer magnetic particles between liquid suspensions in multiple vessels. The present invention to manipulate magnetic particles in liquid suspension can be readily extended to applications involving a plurality or array of vessels. For convenience, “array” and “a plurality” will be used interchangeably without distinction in the current context. An exemplary embodiment of the present invention for collective extraction of microparticles from liquid suspensions in a plurality of vessels is illustrated in Figure 5. The system comprises a plurality of tips (503), wherein each tip is of the type of tip (3) depicted in Figure 1, and a plurality of strong magnets (504), wherein each magnet is of the type of strong magnet (4) depicted in Figure 1. It should be noted that a single magnet or a group of magnets capable of generating a magnetic force strong enough to overwhelm every tip (3) in the plurality of tips (503) may also serve the purpose. In other words, multiple tips may share one strong magnet. Like the system and method depicted in Figure 1, the strong magnets (504) are placed near the bottom of the plurality of vessels (501), to speed up the formation of a magnetic pellet in each vessel of the array. Once the strong magnets (504) are moved away, the magnetic tips (503) immersed in the liquid suspensions contained in the plurality of vessels will attract the magnetic particles and pellets toward them. The plurality of pellets (505) can then be pulled out of the corresponding liquid suspensions (502), ready to be released into another array of vessels containing different types of liquid suspensions. Figure 6 shows an embodiment of the current invention that releases collectively a plurality of pellets (605) from an array of magnetic tips (603) into a plurality of vessels (601). The release is accomplished by placing an array of strong magnets (604) near the bottom of each vessel in the array, therefore pulling the pellets (605) away from the tips (603). The clean tips (603) can then be pulled out of the liquid suspensions to complete the pellets-releasing process. As noted previously, the effect created by an array of strong magnets placed near the bottom of each vessel may also be realized by a large magnet, or a group of magnets. It should be obvious to those skilled in the art that the combination of the systems and methods depicted in Figure 5 and Figure 6 of the current invention comprises a magnetic particle transfer process between successive array of vessels. Although one embodiment of the present disclosure of a system and method to manipulating magnetic particles in a liquid suspension has been described in some detail, and several other equally advantageous embodiments have also been described, it will be apparent to those of ordinary skill in the art that many modifications and variations of the described embodiment are possible in the light of the above teachings without departing from the principles and concepts of the disclosure as set forth in the claims. Although the present invention has been described in terms of the presently preferred embodiment, it is to be understood that such disclosure is purely illustrative and is not to be interpreted as limiting. Consequently, without departing from the spirit and scope of the disclosure, various alterations, modifications and/or alternative applications of the disclosure will, no doubt, be suggested to those skilled in the art after having read the preceding disclosure. Accordingly, it is intended that the following claims be interpreted as encompassing all alterations, modifications and/or alternative applications as fall within the true spirit and scope of the disclosure. /// /// /// /// /// /// /// /// /// /// /// /// /// /// /// /// /// /// /// ///

Claims

The Claims What is claimed is 1. A system for manipulating magnetic particles in liquid suspension comprising: a. A small magnetic object covered by an inert material wherein the object can be immersed into and pulled out of liquid suspension contained in a vessel, wherein the small magnetic object can be fabricated using a permanent magnet, an electromagnet, a ferromagnetic object in touch with a permanent magnet, a ferromagnetic object in touch with an electromagnet, a ferrimagnetic object in touch with a permanent magnet, or a ferrimagnetic object in touch with an electromagnet. b. A strong magnetic object that can be made to switch on and off an attractive magnetic force on magnetic particles in the said liquid suspension, wherein a pallet is formed on the inner surface of the said vessel when the said attractive magnetic force is on, and the said pellet moves to the surface of the said small magnetic object when the said attractive force is off, wherein the strong magnet can be fabricated using a strong permanent magnet, a strong electromagnet, a ferromagnetic object in touch with a strong permanent magnet, a ferromagnetic object in touch with a strong electromagnet, a ferrimagnetic object in touch with a strong permanent magnet, or a ferrimagnetic object in touch with a strong electromagnet. 2. The system of claim 1, wherein the said attractive magnetic force is turned on by placing the said strong magnet in the vicinity outside the said vessel and turned off by placing the said strong magnet far away from the said vessel, or is turned on and off by the said strong electromagnet placed in the vicinity outside the said vessel. 3. The system of claim 2, wherein when the said attractive magnetic force is turned off, magnetic particles are extracted from the said liquid suspension by pulling the said small magnetic object with pellet on its surface out of the vessel; wherein when the said attractive magnetic force is turned on, the magnetic particles are released into the said liquid suspension by immersing the said small magnetic object with the pellet on its surface into the said liquid suspension. 4. The system of claim 3, wherein the strong magnetic force maybe activated and deactivated on the liquid suspensions in two vessels to transfer magnetic particles from one liquid suspension to the other. 5. A system for manipulating magnetic particles in liquid suspensions in an array of vessels comprising: a. A plurality of small magnetic objects covered by inert materials wherein the objects can be immersed collectively into and pulled out of liquid suspensions contained in an array of vessels, wherein each small magnetic object can be fabricated using a permanent magnet, an electromagnet, a ferromagnetic object in touch with a permanent magnet, a ferromagnetic object in touch with an electromagnet, a ferrimagnetic object in touch with a permanent magnet, or a ferrimagnetic object in touch with an electromagnet. b. A plurality of strong magnetic objects that can be made to switch on and off the attractive magnetic force on magnetic particles in said liquid suspensions contained in the said array of vessels, wherein a plurality of pallets is formed when the said attractive magnetic force is on, one pellet on the inner surface of an individual vessel in the said array of vessels; when the said magnetic attractive force is off, each pellet in the said plurality of pellets moves to the surface of an individual small magnetic object in the said plurality of small magnetic objects immersed in the said array of vessles, wherein the plurality of strong magnets can be fabricated using a plurality of strong permanent magnets, strong electromagnets, ferromagnetic objects in touch with strong permanent magnets, ferromagnetic objects in touch with strong electromagnets, ferrimagnetic objects in touch with strong permanent magnets, or ferrimagnetic objects in touch with strong electromagnets. 6. The system of claim 5, wherein the said attractive magnetic force is turned on by placing the plurality of said strong magnets in the vicinity outside each individual vessel in the said array of vessels and turned off by placing the said plurality of strong magnets far away from the said array of vessels, or turned on and off by the said plurality of strong electromagnets. 7. The system of claim 6, wherein when the said attractive magnetic force is turned off, the magnetic particles are extracted from the plurality of said liquid suspensions by pulling the said plurality of small magnetic objects with pellets on their surfaces out of the liquid suspensions in an array of vessels; wherein when the said attractive magnetic force is turned on, the plurality of pellets are released individually into the said liquid suspensions in an array of vessels by immersing the said plurality of small magnetic objects each with a pellet on their surface into the said plurality of liquid suspensions. 8. A system of claim 7, wherein the strong magnetic force may be activated or deactivated on the liquid suspensions of two sets of vessel arrays to transfer the magnetic particles from the liquid suspensions in one vessel array to the liquid suspensions in another vessel array. 9. A method to manipulate magnetic particles in liquid suspension using a system comprising: a. A small magnetic object covered by an inert material wherein the object can be immersed into and pulled out of the liquid suspension contained in a vessel, wherein the small magnetic object can be fabricated using a permanent magnet, an electromagnet, a ferromagnetic object in touch with a permanent magnet, a ferromagnetic object in touch with an electromagnet, a ferrimagnetic object in touch with a permanent magnet, or a ferrimagnetic object in touch with an electromagnet. b. A strong magnetic object that can be made to switch on and off an attractive magnetic force on magnetic particles in the said liquid suspension, wherein a pallet is formed on the inner surface of the said vessel when the said attractive magnetic force is on, and the said pellet moves to the surface of the said small magnetic object when the said attractive force is off, wherein the strong magnet can be fabricated using a strong permanent magnet, a strong electromagnet, a ferromagnetic object in touch with a strong permanent magnet, a ferromagnetic object in touch with a strong electromagnet, a ferrimagnetic object in touch with a strong permanent magnet, or a ferrimagnetic object in touch with a strong electromagnet. 10. The method of claim 9, wherein the said attractive magnetic force is turned on by placing the said strong magnet in the vicinity outside the said vessel and turned off by placing the said strong magnet far away from the said vessel, or is turned on and off by the said strong electromagnet placed in the vicinity outside the said vessel. 11. The method of claim 10, wherein when the said attractive magnetic force is turned off, magnetic particles are extracted from the said liquid suspension by pulling the said small magnetic object with pellet on its surface out of the vessel; wherein when the said attractive magnetic force is turned on, the magnetic particles are released into the said liquid suspension by immersing the said small magnetic object with pellet on its surface into the said liquid suspension. 12. The method of claim 11 to transfer magnetic particles from the liquid suspension in one vessel to the liquid suspension in another vessel. 13. A method to manipulate magnetic particles in liquid suspensions in an array of vessels using a system comprising: a. A plurality of small magnetic objects covered by inert materials wherein the objects can be immersed collectively into and pulled out of liquid suspensions contained in an array of vessels, wherein each small magnetic object can be fabricated using a permanent magnet, an electromagnet, a ferromagnetic object in touch with a permanent magnet, a ferromagnetic object in touch with an electromagnet, a ferrimagnetic object in touch with a permanent magnet, or a ferrimagnetic object in touch with an electromagnet. b. A plurality of strong magnetic objects that can be made to switch on and off the attractive magnetic force on magnetic particles in said liquid suspensions contained in the said array of vessels, wherein a plurality of pellets is formed when the said attractive magnetic force is on, one pellet on the inner surface of each individual vessel in the said array of vessels; when the said magnetic attractive force is off, each pellet in the said plurality of pellets moves to the surface of an individual small magnetic object in the said plurality of small magnetic objects immersed in the said array of vessels; wherein the plurality of strong magnets can be fabricated using a plurality of strong permanent magnets, strong electromagnets, ferromagnetic objects in touch with strong permanent magnets, ferromagnetic objects in touch with strong electromagnets, ferrimagnetic objects in touch with strong permanent magnets, or ferrimagnetic objects in touch with strong electromagnets. _{14. The method of claim 13, wherein the said attractive magnetic force is turned on} byplacing the plurality of said strong magnets in the vicinity outside of each individualvessel in the said array of vessels and turned off by placing the said plurality of strongmagnets far away from the said array of vessels, or turned on and off by the saidplurality of strong electromagnets. _{15. The method of claim 14, wherein when the said attractive magnetic force is} turned off,the magnetic particles are extracted from the plurality of said liquid suspensions bypulling the said plurality of small magnetic objects with pellets on their surfaces out ofthe liquid suspensions in an array of vessels; wherein when the said attractive magneticforce is turned on, the plurality of pellets are released individually into the said liquidsuspensions in an array of vessels by immersing the said plurality of small magneticobjects each with a pellet on their surface into the said plurality of liquid suspensions. _{16. The method of claim 15, wherein the strong magnetic force may be activated} ordeactivated on the liquid suspensions of two sets of vessel arrays to transfer themagnetic particles from the liquid suspensions in one vessel array to the liquidsuspensions in another vessel array.