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Title:
ASSEMBLY FOR MAGNETIC SEPARATION-BASED BODY FLUID PURIFICATION
Document Type and Number:
WIPO Patent Application WO/2020/058136
Kind Code:
A1
Abstract:
The present invention provides an assembly for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles, comprising a first magnetic separation element and a second magnetic element where the second magnetic element is in fluid connection with the first magnetic separation element, wherein the first magnetic separation element of the assembly has an inner surface area Sf and the second magnetic separation element has an inner surface area Ss, and wherein in the first magnetic separation element, the lumen of said assembly is free of an in-line magnetic filter element, and wherein in the second magnetic separation element, the lumen of said assembly comprises an in-line magnetic filter element, and wherein the surface area Sf is inferior to the surface area Ss.

Inventors:
METZGER JEAN-CLAUDE (CH)
LANGENEGGER LUKAS (CH)
Application Number:
PCT/EP2019/074573
Publication Date:
March 26, 2020
Filing Date:
September 13, 2019
Export Citation:
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Assignee:
HEMOTUNE AG (CH)
International Classes:
A61M1/36; B03C1/032; B03C1/033; B03C1/034; B03C1/28
Domestic Patent References:
WO2015023573A22015-02-19
Foreign References:
US5439586A1995-08-08
US6241894B12001-06-05
US20180028990A12018-02-01
DE10127068A12002-11-28
US20180028990A12018-02-01
Attorney, Agent or Firm:
ISLER & PEDRAZZINI AG et al. (CH)
Download PDF:
Claims:
CLAIMS

1. An assembly for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles in an extracorporeal circuit, comprising

a first magnetic separation element and a second magnetic separation element where the second magnetic separation element is in fluid connection with the first magnetic separation element,

wherein the first magnetic separation element of the assembly comprises one or more first tubular separation segments having an inner surface area Sf and the second magnetic separation element comprises one or more second tubular separation segments having an inner surface area Ss, and

wherein in the first magnetic separation element, the lumen of the first tubular separation segment is free of a lumenal magnetic filter element, and

wherein in the second magnetic separation element, the lumen of the second tubular separation segment comprises a lumenal magnetic filter element, and

wherein the inner surface area Sf is inferior to the inner surface area Ss.

2. The assembly according to claim 1 , wherein the assembly further comprises

an inlet element comprising a tubular inlet segment in fluid connection with the one or more first magnetic separation element of the assembly and having an inner cross sectional area Di for guiding a flow of body fluid to the first magnetic separation element, with Di being preferably inferior to the inner cross sectional area Df of the one or more first tubular separation segment, and/or equal to Do an outlet element comprising or more tubular outlet segment in fluid connection with the second magnetic separation element of the assembly and having an inner cross sectional area Do for guiding a flow of body fluid away from the second magnetic separation element, with Do being preferably inferior to the inner cross sectional area Ds of the one or more second tubular separation segment and/or equal to Di.

3. The assembly according to claim 1 or 2, wherein the first magnetic separation element consists of a plurality of first tubular separation segments having an overall surface area Sf.

4. The assembly according to claim 1 or 2, wherein the first magnetic separation element consists of a single first tubular separation segment having a surface area Sf.

5. The assembly according to any of the preceding claims, wherein the one or more first tubular separation segments of the first magnetic separation element have an outer cross-sectional shape that is quadrilateral, preferably rectangular and/or an inner cross-sectional shape that is quadrilateral, preferably rectangular, wherein preferably any of the sides of the quadrilateral inner cross-section are of least 0.2 mm.

6. The assembly according to any of the preceding claims, wherein the one or more second tubular separation segments of the second magnetic separation element comprises a lumenal magnetic filter element is a high gradient magnetic separator (HGMS).

7. The assembly according to claim 6, wherein the high gradient magnetic separator is in the form of a packed bed of magnetisable spheres, preferably having a diameter in excess of 1 mm.

8. A device for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles, comprising

an assembly according to any of claims 1 to 7,

a first purification unit and a second purification unit,

wherein the first purification unit capable of receiving the first magnetic separation element of the assembly and creating a magnetic field across the lumen of the one or more first tubular separation segments of the first magnetic separation element of the assembly when the one or more first tubular separation segments of the first magnetic separation element of the assembly are received in the first purification unit, and

wherein the second purification unit capable of receiving the second magnetic separation element of the assembly and creating a magnetic field across the lumen of the one or more second magnetic separation segments of the second magnetic separation element of the assembly and to magnetize the lumenal magnetic filter element of the one or more second magnetic separation segments when said second magnetic separation element of the assembly is received in the second purification unit.

9. The device for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles according to claim 8, wherein the first purification unit comprises a Halbach cylinder, in which Halbach cylinder the first magnetic separation element is received or comprises a linear Halbach array, on which the first magnetic separation element is received.

10. A method for purifying a flow of body fluid loaded with magnetic particles in a magnetic separation-based body fluid purification device according to claim 8 or 9, comprising

a first purification step in a first purification unit of the device, said step comprising receiving the first magnetic separation element of the assembly in the first purification unit and creating a magnetic field across the lumen of the one or more first tubular separation segments of the first magnetic separation element of the assembly and guiding the flow of body fluid to be purified through the lumen of the one or more first tubular separation segments of the first magnetic separation element of the assembly and withholding a first fraction of the magnetic particles in the one or more first tubular separation segments and on the inner wall the one or more first tubular separation segments of the first magnetic separation element of the assembly, and

receiving the second magnetic separation element of the assembly in the second purification unit and creating a magnetic field across the lumen of the one or more second tubular separation segments of the second magnetic separation element of the assembly, magnetising the lumenal magnetic filter element, guiding the flow of body fluid to be purified through the lumen of the one or more second tubular separation segments of the second magnetic separation element of the assembly, and withholding a second fraction of the magnetic particles in the one or more second tubular separation segments and on the lumenal magnetic filter element of the one or more second tubular separation segments of the second magnetic separation element of the assembly,

wherein the first fraction of the magnetic particles is larger than the second fraction of the magnetic particles.

1 1. The method for purifying a flow of body fluid loaded with magnetic particles in a magnetic separation-based body fluid purification device according to claim 10, wherein the first fraction of the magnetic particles is at least 10-fold, more preferably 100-fold larger than the second fraction of the magnetic particles.

12. The method for purifying a flow of body fluid loaded with magnetic particles in a magnetic separation-based body fluid purification device according to claim 10 or 1 1, wherein the flow of body fluid loaded with magnetic particles is between 80 and 400 ml/min.

Description:
TITLE

ASSEMBLY FOR MAGNETIC SEPARATION-BASED BODY FLUID

PURIFICATION

TECHNICAL FIELD

The present invention relates to a preferably disposable assembly for magnetic separation- based body fluid purification of a body fluid loaded with magnetic particles, which magnetic particles are functionalized such as to bind to unwanted substances or cells found in the body fluid, as well as to a device incoiporating said tubing. Furthermore, the present invention relates to a method of purifying a body fluid in such device.

PRIOR ART

It has been well-known in the art to contact body fluids with functionalized magnetic particles, such as for example magnetic beads in order to isolate certain targets to which the magnetic particles bind from said body fluids. For example, it is well-known to isolate cells of a certain type or certain substances using immunomagnetic separation beads.

It has therefore become possible to selectively“sort out” the targets from body fluids for either analytical or preparative purposes, thereby in principle enabling diagnostic or even therapeutic applications.

However, in the therapeutic domain, it is of utmost importance that in addition to the selective binding of the target to the magnetic particle, the magnetic particle binding the target is not returned to the patient. It is thus important to provide means by which the magnetic particles binding the target can be separated from the body fluid with which it was contacted for the purpose of binding the target. This problem is further exacerbated by the use of magnetic nanoparticles which due to their size can be hard to completely separate from the body fluid without imparting too much of shear stress on the constituents of a body fluid. This is especially the case where the body fluid is treated in an extracorporeal circuit as in the case of blood apheresis, where blood is subjected to significant shear stress which can negatively influence blood cell viability.

In the case where the body fluid is contacted with the magnetic particles, the strategy for separating the magnetic particles from the body fluid can be to remove the magnetic particles by applying a magnetic field across the body fluid. The resulting magnetic force will deviate the magnetic particle towards the inner wall of the conduit through which it flows and the magnetic particle will be trapped for as long as the magnetic field is held. However, this strategy does not remove all of the magnetic particles from the body fluid, since the distance between the magnetic particles in the body fluid and the magnet from which the magnetic field emanates, even if it is merely in the range of millimeters due to the wall of the assembly, is too significant to warrant 100% removal of the magnetic particles. Therefore this approach, when taken alone, cannot be used in the therapeutic context such as for example in blood apheresis because clinical guidelines require that essentially no magnetic particles may be returned to the patient’s body. Another strategy can be that of separating the magnetic particles by passing the body fluid loaded with the magnetic particles across a filtering element such as for example a packed bed of spheres or a mesh filter. However, while this strategy will allow the removal of all of the magnetic particles from the body fluid, the filtering on one hand have a propensity to clog and must therefore be over-dimensioned in the sense that their cross sectional area is increased and on the other hand create a pressure increase in the body fluid due to the resistance to the flow that can damage the cells in the body fluid.

US2018/0028990 Al describes an assembly which includes a first rotating Halbach array for magnetizing and mixing magnetic particles loaded in a fluid being guided across the lumen of the Halbach array and which magnetic particles are subsequently partially removed in a single high gradient magnetic separator (HGMS) element. There exists thus a need to provide a method, and a device for use in such method, in which method the magnetic particles can be separated from the body fluids with essentially total separation efficiency and in which the cells of the body fluid are not exposed to intolerable shear stress.

SUMMARY OF THE INVENTION

The present invention provides an assembly for use in the magnetic separation-based body fluid purification of a body fluid, preferably in, or as a part of, an extracorporeal blood treatment circuit such an extracorporeal blood apheresis circuit, loaded with magnetic particles which allow separating magnetic particles from a body fluid with essentially 100% efficiency and in which the cells of the body fluid are not exposed to intolerable shear stress.

It is understood that in the context of the present invention, the term“inner cross sectional area” refers to the area defined by the outline of the inner dimensions of the segment, i.e. the area delimited by the outline of the lumen. It is further understood that in the context of the present invention, the term“outer cross sectional area” refers to the area defined by the outline of the outer dimensions of the segment or element.

It is understood that in the context of the present invention, the term“inner surface area” refers to the area corresponding to the surface area of the lumen (i.e. of the tube interior surface) over a given length of segment or element.

It is an object of the present invention to provide an assembly for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles, comprising a first magnetic separation element and a second magnetic separation element where the second magnetic separation element is in fluid connection with the first magnetic separation element,

wherein the first magnetic separation element of the assembly comprises one or more first tubular separation segments having an inner surface area Sf and the second magnetic separation element comprises one or more second tubular separation segments having an inner surface area Ss, and wherein in the first magnetic separation element, the lumen of the first tubular separation segment is free of a lumenal or in-line magnetic filter element, and

wherein in the second magnetic separation element, the lumen of the first tubular separation segment comprises a lumenal or in-line magnetic filter element, and

wherein the inner surface area Sf is inferior to the inner surface area Ss. In a preferred embodiment, the inner surface area Sf is inferior to the inner surface area Ss by a factor of from 10 to 500, more preferably of from 30 to 100.

In a preferred embodiment, the assembly further comprises an inlet element comprising a tubular inlet segment in fluid connection with the one or more first magnetic separation element of the assembly and having an inner cross sectional area Di for guiding a flow of body fluid to the first magnetic separation element, with Di being preferably inferior to the inner cross sectional area Df of the first tubular separation segment, and/or equal to Do, and/or comprises an outlet element comprising one or more tubular outlet segment in fluid connection with the second magnetic separation element of the assembly and having an inner cross sectional area Do for guiding a flow of body fluid away from the second magnetic separation element, with Do being preferably inferior to the inner cross sectional area Ds of the second tubular separation segment and/or equal to Di.

The first magnetic separation element and a second magnetic separation element may be in fluid connection for example via a tubing.

In a preferred embodiment of the assembly for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles, the first magnetic separation element consists of a plurality of first tubular separation segments having an overall inner surface area Sf.

The plurality of first tubular separation segments can be achieved by including a manifold element upstream of the first magnetic separation element and by including a manifold element downstream of the first magnetic separation element, wherein the upstream manifold element is in fluid connection with the downstream manifold element via the plurality of first tubular separation segments, and that said plurality of first tubular separation segments has a combined inner surface area Sf. In a preferred embodiment of the assembly for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles, the first magnetic separation element consists of a single first tubular separation segment having an inner surface area Sf.

In a preferred embodiment of the assembly for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles, the one or more first tubular separation segments of the first magnetic separation element have an outer cross-sectional shape that is quadrilateral, preferably rectangular and/or an inner cross-sectional shape that is quadrilateral, preferably rectangular, wherein preferably any of the sides of the quadrilateral inner cross-section are of least 0.2 mm.

In a preferred embodiment of the assembly for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles, the one or more second tubular separation segments of the second magnetic separation element comprises a lumenal or inline magnetic filter element is a high gradient magnetic separator (HGMS).

In a preferred embodiment of the assembly for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles, the high gradient magnetic separator (HGMS) is in the form of a packed bed of magnetisable spheres, preferably having a diameter in excess of 1 mm.

It is a further object of the present invention to provide a device for magnetic separation- based body fluid purification of a body fluid loaded with magnetic particles, comprising an assembly according to the above and a first and a second purification unit,

wherein the first purification unit capable of receiving the first magnetic separation element of the assembly and creating a magnetic field across the lumen of the one or more first tubular separation segments of the first magnetic separation element of the assembly when the one or more first tubular separation segments of the first magnetic separation element of the assembly are received in the first purification unit, and

wherein the second purification unit capable of receiving the second magnetic separation element of the assembly and creating a magnetic field across the lumen of the one or more second magnetic separation segments of the second magnetic separation element of the assembly and to magnetize the lumenal magnetic filter element of the one or more second magnetic separation segments when said second magnetic separation element of the assembly is received in the second purification unit.

In a preferred embodiment of the device for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles, the first purification unit comprises a Halbach cylinder, in which Halbach cylinder the first magnetic separation element is received or comprises a linear Halbach array, on which the first magnetic separation element is received.

In a preferred embodiment of the device for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles, the magnetic field created across the lumen of the one or more first and/or second tubular separation segments by the first and/or second purification unit is a temporal constant magnetic field in the sense that the magnetic field strength is varying throughout the spatial positions within the lumen of the magnetic separation element but is kept at this magnetic field strength over time. Thus, the first and second magnet assemblies from which a magnetic field emanates in the respective purification unit are fixed, i.e. not varying over time.

It is yet a further object of the present invention to provide a method for purifying a flow of body fluid loaded with magnetic particles in a magnetic separation-based body fluid purification device according to the above, the method comprising the steps of, in this order, a first purification step in a first purification unit of the device, said step comprising receiving the first magnetic separation element of the assembly in the first purification unit and creating a magnetic field across the lumen of the one or more first tubular separation segments of the first magnetic separation element of the assembly and guiding the flow of body fluid to be purified through the lumen of the one or more first tubular separation segments of the first magnetic separation element of the assembly and withholding a first fraction of the magnetic particles in the one or more first tubular separation segments and on the inner wall the one or more first tubular separation segments of the first magnetic separation element of the assembly, and receiving the second magnetic separation element of the assembly in the second purification unit and creating a magnetic field across the lumen of the one or more second tubular separation segments of the second magnetic separation element of the assembly, magnetising the lumenal magnetic filter element, guiding the flow of body fluid to be purified through the lumen of the one or more second tubular separation segments of the second magnetic separation element of the assembly, and withholding a second fraction of the magnetic particles in the one or more second tubular separation segments and on the lumenal magnetic filter element of the one or more second tubular separation segments of the second magnetic separation element of the assembly,

wherein the first fraction of the magnetic particles is larger than the second fraction of the magnetic particles.

In a preferred embodiment of the method for purifying a flow of body fluid loaded with magnetic particles in a magnetic separation-based body fluid purification device according to the present invention, the first fraction of the magnetic particles is at least 10-fold, more preferably 100-fold larger than the second fraction of the magnetic particles.

In a preferred embodiment of the method for purifying a flow of body fluid loaded with magnetic particles in a magnetic separation-based body fluid purification device according to the present invention, the flow of body fluid loaded with magnetic particles is between 80 and 400 ml/min, preferably between 80 and 200 ml/min and may be about 100 ml/min.

Further embodiments of the invention are laid down in the dependent claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred embodiments of the invention are described in the following with reference to the drawings, which are for the purpose of illustrating the present preferred embodiments of the invention and not for the puipose of limiting the same ln the drawings,

Fig. 1 shows a schematic representation of the method according to the invention. Fig. 2 shows a schematic representation of the individual parts of the assembly (1) according to the present invention. The inlet segment (2) having a cross- sectional diameter of Di is fluidly connected to the first magnetic separation element (3) comprising a first tubular separation segment (4) having a rectangular cross-sectional shape of width (w), height (h) and an inner surface area over its length (1) of Sf of [2 ((wr) x (If)) + 2 ((hr) x (If)) + 2 ((wr) x (hr))] . A first permanent magnet assembly (5), from which a magnetic field emanates, is positioned on one side of the first tubular separation segment (4) such as to attract the magnetic particles towards the side of the first tubular separation segment (4) closest to the magnet assembly (5) and withhold the majority of magnetic particles loaded into the body fluid. The body fluid exits the first magnetic separation element (3) and flows to the fluidly connected second magnetic separation element (6) comprising a second tubular separation segment (7) having a rectangular cross-sectional shape and inner surface area Ss, where a packed bed of metal spheres (8) of radius r forming an in-line HGMS filter in the second tubular separation segment (7) is magnetized by a second permanent magnet assembly (9). In the case of the second tubular separation segment (7), the inner surface area Ss is generally obtained by adding the inner surface of the walls delimiting the second tubular separation segment [2 ((w s ) x (l s )) + 2 ((h s ) x (l s )) + 2 ((w s ) x (h s ))] and adding the surface of the filter element, i.e. the bed of metal spheres (h s ) x (l s ) x (w s )/ (r) x p / v/2. The in-line HGMS filter removes the magnetic particles that have eluded the first magnetic separation element (3) and essentially clean body fluid exits the second magnetic separation element via the outlet segment (10). The straight arrow indicates the direction of flow of the body fluid.

DESCRIPTION OF PREFERRED EMBODIMENTS

It is an object of the present invention to provide an assembly for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles, comprising a first magnetic separation element and a second magnetic separation element where the second magnetic separation element is in fluid connection with the first magnetic separation element, wherein the first magnetic separation element of the assembly comprises one or more first tubular separation segments having an inner surface area Sf and the second magnetic separation element comprises one or more second tubular separation segments having an inner surface area Ss, and wherein in the first magnetic separation element, the lumen of the first tubular separation segment is free of a lumenal magnetic filter element, and wherein in the second magnetic separation element, the lumen of the second tubular separation segment comprises a lumenal magnetic filter element, and wherein the inner surface area Sf is inferior to the inner surface area Ss. It is understood that in the second magnetic separation element, the inner surface area Ss of the one or more tubular segment includes not only the surface area of the lumen over the length the one or more tubular segment but also the surface of the in-line or lumenal magnetic filter element.

By having a reduced surface area in the one or more first tubular separation segments when compared to the surface area in the one or more second tubular separation segments, the flow resistance encountered by the body fluid is kept low in the one or more first tubular separation segments while at the same removing the bulk of the magnetic particles, whereas in the one or more second tubular separation segments the remaining magnetic particles are removed. A reduced resistance to the body fluid results in a reduction of shear stress on the body fluid.

It is understood that in the context of the present invention, the term“tubular” is not necessarily limiting in the sense that“tubular” segments having a circular or elliptic cross- sectional shape, but also segments having a polygonal, quadrilateral, rectangular, or square cross-sectional shape are included.

It is further understood that“magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles” refers to a phenomenon in which magnetic particles are withheld from further moving along in a flow of body fluid upon interaction with a magnetic field of sufficient strength. The magnetic particles may be formed from magnetized materials which are pre-magnetized or which are magnetized as they interact with a magnetic field of the first or second magnetic separation element. It is understood that the magnetic particles may be formed from any material that can be magnetized in a magnetic field such as for example metals or alloys thereof. In a preferred embodiment, the magnetic particles are ferromagnetic or paramagnetic nanoparticles. In another embodiment, the magnetic particles are ferromagnetic nanoparticles having an average diameter of 20 nm to 200 nm and/or having at least a magnetization of 80% of the saturation magnetization and more preferably having at least a magnetization of 90% of the saturation magnetization.

The magnetic particles may be formed of ferromagnetic carbon-encapsulated iron carbide core (C/Fe 3 C) with high saturation magnetization of 125 emu/g and a size of 20±l2 nm.

The magnetic particles may be functionalized such as to bind and thereby remove unwanted substances from the body fluid into which the magnetic particles are loaded. In a more preferred embodiment, the magnetic particles are functionalized such as to bind and thereby remove bacterial toxins from the body fluid into which they are loaded. Exemplary magnetic particles are magnetic particles functionalized with antibodies binding to the unwanted substance such as bacterial toxins.

In the assembly according to the present invention, the assembly comprises a first magnetic separation element and second magnetic element where the second magnetic element is in fluid connection with the first magnetic separation element. It is understood that the first magnetic element is located upstream of the second magnetic element with respect to the flow of body fluid being guided through the assembly and the second magnetic element is located downstream of the first magnetic element with respect to the flow of body fluid being guided through the assembly.

The first magnetic separation element comprises one or more first tubular separation segments having an inner surface area, or lumenal surface area, through which the body fluids are conveyed and which first tubular separation segment is delimited by a wall, which wall defines the inner and outer surface area of the first tubular separation segment. It is understood that the wall has an inner surface are defined by the inner boundaries and an outer surface area defined by the outer boundaries. In general, the inner cross-sectional shape and an outer cross-sectional shape have the same shape but this is not necessarily so. Thus, in a preferred embodiment, both the inner cross-sectional shape and the outer cross-sectional shape of the first and/or second tubular separation segment may have the same shape, such as for example a quadrilateral shape, rectangular shape or may have a circular or elliptical shape.

It is understood that the one or more first tubular separation segment of the first magnetic separation element may either be formed from a continuous part of material such as for example one or more conduit segments such as a tube segment or may alternatively be formed from two or more separate parts of material, which when assembled, form the one or more first tubular separation segment. For instance, the one or more first tubular separation segments may be formed from two parts of a polymeric material, where each part comprises one or more recesses each forming a part of the one or more first tubular separation segments and forming the first tubular separation segment when the parts are assembled.

It is understood that there are no limitations on the spatial path the one or more first tubular separation segments may extend along. For instance, in the case where a plurality of first tubular separation segments are comprised in the first magnetic separation element, the individual first separation segments can extend in parallel fashion, be it in either rectilinear or curvilinear pattern.

Thus, for example in the case where two or more separate parts of material are assembled into the first magnetic separation element, the recesses may be provided such that the tubular separation segments extend along essentially a rectilinear path or extend along an essentially spiral path.

The one or more first tubular separation segments may be formed from a glass or a polymeric material such as thermoplastic polymers or thermosetting polymers lt is understood that these materials may be used in different thicknesses and that depending on the thickness of the wall of the one or more first tubular separation segments may be either a rigid or a flexible segments in the sense that they may deform or not deform under the internal pressure exerted by the body fluid flowing across the assembly.

In the one or more first tubular separation segments of the first magnetic separation element, the magnetic particles can be withheld by applying a magnetic field across the lumen of the first tubular separation segments of the first magnetic separation element of the assembly. The purpose of the first magnetic element is to first remove the bulk of magnetic particles in the one or more first tubular separation segments without imparting significant shear stress on the cells and/or components of the body fluid, which is why the lumen of said assembly is free of an in-line magnetic filter element that would otherwise impart stress on a body fluid being diverted by it.

It has further been found that to further reduce shear stress on the cells and/or components of the body fluid, it is advantageous to decrease the flow rate of body fluids in both the first and second tubular separation segments, which is why the one or more tubular separation segments of either magnetic separation element of the assembly have an enlarged cross sectional area, which allows a slower flow rate compared to tubular segments in which the cross sectional area is inferior to the cross sectional area of either magnetic separation element of the assembly.

For instance, the assembly may further comprise an inlet element comprising a tubular inlet segment in fluid connection with the one or more first magnetic separation element of the assembly having a cross sectional area Di which is inferior to Df, and where the flow rate of the body fluid is then decreased as it passes from the inlet element to the first magnetic element. This also means that the residence time of the body fluid loaded with the magnetic particles within the first magnetic element is increased by the widening from Di to Df.

In the assembly according to the present invention, and in particular in the case where the first magnetic separation element includes a single first tubular separation segment, the first magnetic separation element may have a quadrilateral outer cross-sectional shape such as rectangular shape. One reason for this is that in order to provide efficient removal of the larger fraction of magnetic particles in the first magnetic separation element, the first tubular separation segment should closely fit to the first purification unit, and in particular the magnetic surface of the purification unit, which surface has a flat separator surface from which the magnetic field emanates such as for example in the case of a magnetic chuck or a linear Halbach array. Preferably, in the case where the single first tubular separation segment has a quadrilateral outer cross-sectional shape such as rectangular shape, the inner cross- sectional shape thereof is equally quadrilateral such as rectangular.

In the assembly according to the present invention, and in particular in the case where the first magnetic separation element includes a single first tubular separation segment, the single first tubular separation segment preferably has a rectangular inner cross-sectional shape having a width (w) and a height (h) and where the single first tubular separation segment extends over a separation length (1), where the inner surface area Sf is equal to 2[(w) x (1) + (h) x (1) + (w) x (h)]. The width (w) is defined as being the dimension of the rectangular cross-section shape being normal to the plane of the flat separator surface of the first purification unit and should be kept at a minimum, since the width also determines the maximum distance a magnetic particle has to travel until it contacts and gets trapped on the side of the first tubular separation segment closest to the flat separator surface of the first purification unit and since for a first tubular separation segment volume Vf, small values of width (w) mean that the a separation length (1) is increased when keeping the height (h) constant and vice versa. However, it should be understood that the width (w) should be chosen such that it is not inferior to 0.2 mm, i.e. 0.2 mm or more since below 0.2 mm cells, and especially blood cells comprised in bodily fluids such as blood or lymph are damaged when passing such narrow spaces. In the case where the first tubular separation segment has a quadrilateral outer and/or inner cross-sectional shape such as a rectangular cross-section, the width should therefore be chosen from about 0.2 mm to about 5 mm and preferably from about 0.2 mm to about 3 mm. The first tubular separation segment may have a volume Vf of about 50 to 200 ml, preferably of from 75 ml to 150 ml and more preferably of from 100 to 150 ml, in particular in the case the body fluid is blood.

Generally, the first tubular separation segment may be from a single material or from a combination of materials. For instance, in the case where the first tubular separation segment has an outer cross-sectional shape that is a quadrilateral such as rectangular, the first tubular separation segment may be formed from a single material or by a combination of materials. In a preferred embodiment of the single tubular separation segment having an outer cross- sectional shape that is quadrilateral or rectangular, the first tubular separation segment is formed by a combination of materials. The first material of the first tubular separation segment may have an essentially U-shaped cross-sectional shape and of a second material may span the legs of the U such as to form a first tubular separation segment having a quadrilateral or rectangular shaped cross-section. The second material may preferably be a polymer film, because its reduced thickness will allow to further increase the separation efficiency of the first tubular separation segment. Thus three sides of the first tubular separation segment may be formed from a rigid material whereas the remaining side is formed from a polymer film preferably having a thickness in the range of from 0.02 mm to 0.2 mm. An example of a rigid material is PMMA, whereas an example of a polymer film is polycarbonate or PET.

In the case where the first tubular separation segment has a quadrilateral outer cross-sectional shape such as rectangular, the first tubular separation segment can be fixed in the device according to the present invention to the flat separator surface of the purification unit from which the magnetic field emanates by means of a fixing element, which can be spring- loaded. The fixing element can be comprised in the device according to the present invention, and in general impedes a bulging or deformation of the first tubular separation segment, in the case where it is made at least partially from a flexible material that can be deformed by the pressure of the body fluid flowing through the first tubular separation segment. This then means that the first tubular separation segment cannot fit closely to the flat separator surface of the first purification unit. Generally, the fixing element can be adjusted such that the resulting internal width (w) in the compressed first tubular separation segment is in excess of 0.2 mm but below 3 nun, preferably of from 0.2 mm to 2 mm and most preferably such as to be about 1 mm. In a preferred embodiment of the assembly according to the present invention, the device is further equipped with a fixing element capable of pressing down the first magnetic separation element such that the first tubular separation segment may closely fit the flat separator surface of the first purification unit. Exemplary fixing elements may be vise-type fixing elements comprising one fixing surface having preferably at least the dimensions (h) x (1), which fixing surface can be fastened onto the side of the first tubular separation segment opposed to the side of the first tubular separation segment closest to the separator surface of the first magnetic separator. Alternatively, the fixing elements may be spring-loaded fixing elements, comprising one fixing surface having preferably at least the dimensions (h) x (1), which fixing surface can be pressed onto the side of the first tubular separation segment opposed to the side of the first tubular separation segment closest to the separator surface of the first purification unit via either a compressed or an extended spring. In the assembly according to the present invention, the first tubular separation segment may preferably have a circular or elliptic cross-section. Alternatively, the first tubular separation segment may preferably have a semi-circular or semi-elliptic cross-section, i.e. having one flat side to closely fit to the first purification unit which generally has a flat separator surface from which the magnetic field emanates.

In the assembly according to the present invention, the one or more first tubular separation segments may either essentially extend along essentially a rectilinear path, preferably in parallel to the flat surface of the separator surface and its longitudinal axis (L) or extend along an essentially spiral path, preferably around its height axis (H).

In the case where the one or more first tubular separation segments extend along an essentially spiral path, the one or more first tubular separation segments are rolled up in a spiral fashion with the upstream end in the periphery of the spiral and the downstream end in the center of the spiral, such that the body fluid is guided from the outer periphery of the roll towards the center of the roll. This allows placing the first magnetic separation element comprising the rolled-up one or more first tubular separation segments into a cylindrical Halbach assembly, in particular into its cylindrical receiving chamber. It is however not preferred to guide the body fluid in an opposing direction, i.e. from the center to the periphery. When body fluid is guided from the outer periphery of the roll towards the center of the roll, it becomes possible to more efficiently magnetize the magnetic particles loaded into the body fluid in the initial windings of the roll in order to increase the magnetic force with which the magnetic particles are attracted outwards against the side of the first tubular separation segment closest to the inner cylindrical surface of the cylindrical Halbach assembly from which the magnetic field emanates.

In the case where the one or more first tubular separation segments extend along an essentially spiral path, the one or more first tubular separation segments may be formed from two or more separate parts of material, which when assembled, form the one or more first tubular separation segment. For instance, the one or more first tubular separation segments may be formed from two parts of a polymeric material, where each part comprises two or more recesses each forming a part of two or more first tubular separation segments and forming the first two or more tubular separation segments when the parts are assembled. In the case where a plurality of first tubular separation segments extend along an essentially spiral path, the first tubular separation segments may be formed from two or more separate parts of material, which when assembled, form the plurality of first tubular separation segments. In this case the upstream ends of each of the individual first tubular separation segments extending along an essentially spiral path are located in the periphery of the spiral, preferably spaced about the periphery such that they are evenly spaced from another and the downstream ends of each of the individual first tubular separation segments extending along an essentially spiral path are located at the center of the spiral and preferably converge in a central bore acting as outlet. For instance, the one or more first tubular separation segments may be formed from two parts of a polymeric material, where each part comprises one or more recesses each forming a part of the first tubular separation segments and forming the plurality of first tubular separation segment when the parts are assembled.

The one or more second tubular separation segments may be formed from a glass or a polymer material such as thermoplastic polymers or thermosetting polymers. It is understood that these materials may be used in different thicknesses and that depending on the thickness the first magnetic separation element may be either a rigid or a flexible structure in the sense that it can deform or not defonn under the internal pressure exerted by the body fluid flowing across the assembly. In a preferred embodiment the one or more second tubular separation segments is a rigid that does not deform under the internal pressure exerted by the body fluid flowing across the assembly.

In the in-line magnetic filter element of the one or more second tubular separation segments, the magnetic particles are withheld by applying a magnetic field across the lumen of the one or more second tubular separation segments of the second element. The in-line magnetic filter element is magnetized by the magnetic field. The purpose of the second magnetic element is to withhold and remove the residual fraction of magnetic particles which has not been withheld and removed at the first magnetic separation element, which is why the lumen of the one or more second tubular separation segments of said assembly is equipped with an in-line magnetic filter element that is capable of reliably removing any remaining magnetic particles, thereby ensuring that the body fluid exiting the second magnetic separation element is essentially free of magnetic particles, i.e. that with respect to the total amount of magnetic particles loaded into the body fluid, 99.9 % or more, preferably more than 99.95% are removed.

The in-line magnetic filter element may be formed either of a packed bed of magnetizable packing material, which packing material may be in the form of for example of spheres or granules. The in-line magnetic filter element may alternatively be formed from metal wire mesh, which may be stacked on top of each other in either random or oriented order.

In a preferred embodiment, the in-line magnetic filter element is formed by packed metal spheres preferably having a diameter in excess of 1 mm, more preferably having a diameter of from about 1 mm to 3 mm or from about 1.2 mm to 1.7 mm. If the diameter in the spheres is below 1 mm, the interstices between the packed spheres become so small that the cells and/or constituents of the body fluid can be damaged as they pass across the in-line magnetic filter element, whereas when the diameter of the diameter is in excess of 3 mm, the separation efficiency of the in-line magnetic filter element becomes insufficient to attain the removal of 99.9 % or more, preferably more than 99.95% of the total amount of magnetic particles loaded into the body fluid.

It is a further object of the present invention to provide a device for magnetic separation- based body fluid purification of a body fluid loaded with magnetic particles, comprising an assembly according to the above and a first and a second purification unit,

wherein the first purification unit capable of receiving the first magnetic separation element of the assembly and creating a magnetic field across the lumen of the one or more first tubular separation segments of the first magnetic separation element of the assembly when the one or more first tubular separation segments of the first magnetic separation element of the assembly are received in the first purification unit, and

wherein the second purification unit capable of receiving the second magnetic separation element of the assembly and creating a magnetic field across the lumen of the one or more second magnetic separation segments of the second magnetic separation element of the assembly and to magnetize the lumenal magnetic filter element of the one or more second magnetic separation segments when said second magnetic separation element of the assembly is received in the second purification unit. The first purification unit capable of receiving the first magnetic separation element of the assembly and creating a magnetic field across the lumen of the one or more first tubular separation segments of the first magnetic separation element comprises a magnet assembly having a magnetic separator surface from which the magnetic field emanates from, which can be a flat surface or a cylindrical surface.

In a preferred embodiment of the device for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles, the first purification unit comprises a Halbach assembly such as a Halbach cylinder, in which Halbach cylinder the first magnetic separation element is received or comprises a Halbach assembly such as a linear Halbach array, on which the first magnetic separation element is received.

The device for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles may further comprise a suitable pump for displacing the body fluid through the assembly, positioned upstream of the first magnetic separation element.

The device for magnetic separation-based body fluid purification of a body fluid loaded with magnetic particles may further comprise a suitable dosing unit for dosing the magnetic particles into the body fluid, positioned upstream of the first magnetic separation element. The dosing unit is fluidly connected to the assembly such as to deliver the magnetic particles into the stream of body fluid upstream the first magnetic separation element.

It is yet a further object of the present invention to provide a method for purifying a flow of body fluid loaded with magnetic particles in a magnetic separation-based body fluid purification device according to the above, the method comprising the steps of, in this order, a first purification step in a first purification unit of the device, said step comprising receiving the first magnetic separation element of the assembly in the first purification unit and creating a magnetic field across the lumen of the one or more first tubular separation segments of the first magnetic separation element of the assembly and guiding the flow of body fluid to be purified through the lumen of the one or more first tubular separation segments of the first magnetic separation element of the assembly and withholding a first fraction of the magnetic particles in the one or more first tubular separation segments and on the inner wall the one or more first tubular separation segments of the first magnetic separation element of the assembly, and

receiving the second magnetic separation element of the assembly in the second purification unit and creating a magnetic field across the lumen of the one or more second tubular separation segments of the second magnetic separation element of the assembly, magnetising the lumenal magnetic filter element, guiding the flow of body fluid to be purified through the lumen of the one or more second tubular separation segments of the second magnetic separation element of the assembly, and withholding a second fraction of the magnetic particles in the one or more second tubular separation segments and on the lumenal magnetic filter element of the one or more second tubular separation segments of the second magnetic separation element of the assembly, wherein the first fraction of the magnetic particles is larger than the second fraction of the magnetic particles.

In a preferred embodiment of the method for purifying a flow of body fluid loaded with magnetic particles in a magnetic separation-based body fluid purification device according to the present invention, the first fraction of the magnetic particles is at least 10-fold, more preferably 100-fold larger than the second fraction of the magnetic particles.

In a preferred embodiment of the method for purifying a flow of body fluid loaded with magnetic particles in a magnetic separation-based body fluid purification device according to the present invention, the flow of body fluid loaded with magnetic particles is of from 80 to 200 ml/min, which corresponds to a comparatively high throughput. Under such a high throughput the targeted separation efficiency can only be achieved by combining the two different magnetic separation elements in series as described for the assembly of the present invention. LIST OF REFERENCE SIGNS assembly element

inlet segment 7 secondary tubular separation first magnetic separation segment

element 8 magnetic spheres first tubular separation 9 second permanent magnet segment assembly

first magnet assembly 10 outlet segment

second magnetic separation