SYSTEM AND METHOD OF HAEMODIALYSIS

Abstract

The present disclosure provides a method of removing a target substance from blood of a patient, the method comprising steps of: providing a complexing agent, especially a supra-molecular compound or core particle, adapted for selectively binding a target molecule or target entity in the blood of the patient in a complex, e.g. a supra-molecular complex; administering the complexing agent into the patient's blood, preferably into an extracorporeal blood flow pathway, for binding with the target molecule or the target entity; conveying the blood having the complexing agent through a treatment zone of an extracorporeal blood flow pathway for a predetermined period of time to bind or incorporate the target molecule or target entity within the blood in a complex, such as a supra-molecular complex; and removing the complex (e.g. supra-molecular complex) from the blood by haemodialysis, which preferably includes one or more of filtration, ultrafiltration, convection, or adsorption. The disclosure thus also provides a system (1) for removing a target substance from blood of a patient, the system (1) comprising: an extracorporeal blood flow pathway (2) for connection to a patient and for guiding or conveying a flow of blood from the patient along the pathway; a treatment zone (5) arranged in the extracorporeal blood flow pathway (2) for mixing a complexing agent (C) with the blood adapted to bind a target molecule (M) in a complex (X), especially a supra-molecular complex or core particle complex, as the blood flows through the treatment zone (5); and a haemodialysis unit (4) for separating the complex (X) from the blood via one or more of filtration, ultra-filtration, convection, and membrane adsorption, with or without magnetic assistance.

Claims

1. A method of removing a target substance from blood of a patient, the method comprising steps of: providing a complexing agent, namely a supra molecular compound, adapted for binding or incorporating a target molecule or target entity in the blood of the patient in a complex, namely a supra molecular complex; administering the complexing agent into the patient's blood for binding with the target molecule or the target entity; conveying the blood having the complexing agent through a treatment zone of an extracorporeal blood flow pathway for a predetermined period of time to bind or incorporate the target molecule or target entity within the blood in a supra molecular complex; and removing the supra molecular complex from the blood by haemodialysis, which includes one or more of filtration, ultrafiltration, convection, or adsorption.

2. A method according to claim 1, wherein the target molecule is a mid-sized molecule having a mass in the range of about 500 Da to 50 kDa and/or a size in the range of 1.5 to 3 nm.

3. A method according to claim 1, wherein the complexing agent comprises a supra-molecular compound having an encapsulating supra-molecular structure.

4. A method according to claim 3, wherein the encapsulating supra molecular structure comprises an ultra large cage structure (ULCS) protein.

5. A method according to claim 1, wherein the complexing agent comprises a number of individual molecules adapted to bind to a target molecule and to each other in a form of polymerization or flocculation of a target molecule into clusters or larger aggregates.

6. A method according to claim 1, wherein the supra-molecular compound comprises a ferromagnetic nanoparticle to facilitate extraction of the complex by the application of a magnetic field during the haemodialysis.

7. A method according to claim 1, wherein the predetermined period of time in the extracorporeal blood flow pathway is in the range of 2 to 20 minutes.

8. A method according to claim 1, wherein the administering of the complexing agent into the patient's blood comprises introducing or infusing the complexing agent into extracorporeal blood along the extracorporeal pathway.

9. A method according to claim 1, wherein the administering of the complexing agent into the patient's blood comprises introducing or infusing the complexing agent into the patient's bloodstream one or more hours prior to performing haemodialysis to form the complex in vivo.

10. A method according to claim 1, further comprising altering physical or chemical conditions of blood in the treatment zone to promote complexing of the target molecule with the complexing agent; including altering any one or more of the pH, temperature, and/or composition of the blood in the treatment zone, and/or agitating the blood in the treatment zone.

11. A method according to claim 10, comprising applying electromagnetic radiation (EMR) to the blood in the treatment zone to promote formation of the complex or to cause aggregation or flocculation of multiple complexes into large clusters; wherein the step of applying EMR to the blood in the treatment zone includes applying one or more of: a DC electric current, an AC magnetic field, terahertz radiation, visible light, ultraviolet radiation, X-ray radiation or gamma radiation.

12. A method according to claim 1, comprising a step of introducing one or more adjuvant compound(s) into the blood before it enters the treatment zone to enable a photochemical, electrochemical, or magneto-chemical process in the treatment zone.

13. A method according to claim 1, comprising separating or dividing the blood flow along the extracorporeal blood flow pathway into two streams, wherein a first stream comprises substantially small molecules having a size less than 1.5 nm, including water and electrolytes, and a second stream comprising larger molecules having a size of over 3 nm, including larger proteins, supra-molecular structures and blood cells.

14. A method according to claim 13, comprising processing the first stream and the second stream of the extracorporeal blood flow pathway separately in a haemodialysis unit via one or more of filtration, ultrafiltration, convection, or adsorption.

15. A system according to claim 13, further comprising re-combining the first stream and the second stream into a unified extracorporeal blood flow prior to returning the blood to the patient.

16. A method according to claim 1, wherein the step of conveying the flow of blood from a patient along the extracorporeal blood flow pathway includes conveying blood through a blood flow circuit, namely a haemodialysis circuit, configured to return the blood to the patient, the treatment zone being arranged in the extracorporeal blood flow pathway upstream of a haemodialysis unit.

17. A system for removing a target substance from blood of a patient, the system comprising: an extracorporeal blood flow pathway for connection to a patient and for guiding or conveying a flow of blood from the patient along the pathway; a treatment zone arranged in the extracorporeal blood flow pathway for mixing a complexing agent with the blood adapted to bind a target molecule in a complex, namely a supra-molecular complex, as the blood flows through the treatment zone; and a haemodialysis unit for separating the complex from the blood via one or more of filtration, ultrafiltration, convection, and membrane adsorption, with or without magnetic assistance.

18. A system according to claim 17, wherein the extracorporeal blood flow pathway is part of a haemodialysis circuit configured to return the blood to the patient.

19. A system according to claim 18, wherein the treatment zone is arranged in the extracorporeal blood flow pathway upstream of the haemodialysis unit.

20. A system according to claim 17, wherein the extracorporeal blood flow pathway for guiding or conveying the flow of blood in the treatment zone is any one or more of extensive, convoluted, serpentine and tortuous.

21. A system according to claim 17, wherein the extracorporeal blood flow pathway for guiding or conveying the flow of blood comprises one or more tube or catheter.

22. A system according to claim 17, comprising at least one applicator device in the treatment zone for applying electromagnetic radiation (EMR) to the blood flowing along the extracorporeal blood flow pathway, the applicator device being adapted to emit or generate and apply any one of: DC electric current, AC magnetic field, terahertz radiation, visible light, ultraviolet light, X-ray or gamma radiation.

23. A system according to claim 17, comprising a plurality of applicator devices in the treatment zone, wherein the applicator devices are configured for applying electromagnetic radiation (EMR) to blood flowing through the treatment zone simultaneously.

24. A system according to claim 23, wherein the applicator devices are adapted to emit or generate and apply the same type of EMR; and/or the applicator devices are adapted to emit or generate and apply different types of EMR.

25.-30. (canceled)

31. A method of removing a target substance from blood of a patient, the method comprising steps of: providing a supra molecular compound as a complexing agent for binding a target molecule or target entity in the blood of the patient in a supra molecular complex; administering the complexing agent into the blood in an extracorporeal blood flow pathway for binding with the target molecule or the target entity; conveying the blood having the complexing agent through a treatment zone of the extracorporeal blood flow pathway for a predetermined period of time to bind or incorporate the target molecule or target entity within the blood in the supra molecular complex; and removing the supra molecular complex from the blood by haemodialysis.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0070] For a more complete understanding of the disclosure and advantages thereof, exemplary embodiments of the disclosure are explained in more detail in the following description with reference to the accompanying drawing figures, in which like reference signs designate like parts and in which:

[0071] FIG. 1 is a schematic view of a system for treating hematologic pathologies including haemodialysis according to a preferred embodiment;

[0072] FIG. 2 shows schematic views of three variants (a) to (c) for conveying blood through a treatment zone in a haemodialysis system according to preferred embodiments;

[0073] FIG. 3 is a schematic view of a treatment zone in a haemodialysis system according to another preferred embodiment;

[0074] FIG. 4 is a schematic view of a treatment zone in a haemodialysis system according to a further preferred embodiment;

[0075] FIG. 5 is a schematic illustration of a supramolecular MM complex in a haemodialysis system and method according to a preferred embodiment;

[0076] FIG. 6 is a flow diagram schematically representing a haemodialysis method according to an embodiment.

[0077] The accompanying drawings are included to provide a further understanding of the present disclosure and are incorporated in and constitute a part of this specification. The drawings illustrate particular embodiments of the disclosure and together with the description serve to explain the principles of this disclosure. Other embodiments of the disclosure and many of the attendant advantages will be readily appreciated as they become better understood with reference to the following detailed description.

[0078] It will be appreciated that common and/or well understood elements that may be useful or necessary in a commercially feasible embodiment are not necessarily depicted in order to facilitate a more abstracted view of the embodiments. The elements of the drawings are not necessarily illustrated to scale relative to each other. It will also be understood that certain actions and/or steps in an embodiment of a method may be described or depicted in a particular order of occurrences while those skilled in the art will understand that such specificity with respect to sequence is not actually required.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0079] With reference firstly to FIG. 1 of the drawings, a schematic representation of a haemodialysis system 1 for the removal of metabolic waste products and/or undesirable compounds from the blood of a patient, especially for treating patients suffering chronic renal failure (CRF). The system 1 comprises an extracorporeal blood flow pathway 2 for connection to a patient (not shown) via vascular access obtained in the usual way for conveying a flow of blood from the patient along the pathway 2. In this regard, the extracorporeal blood flow pathway 2 is part of a haemodialysis circuit 3 incorporating a haemodialysis unit 4 and is configured to return the blood to the patient. The system 1 further includes a treatment zone 5 arranged in the extracorporeal blood flow pathway 2 upstream of the dialysis unit 4, with the treatment zone 5 having an infusion device 6 for introducing a complexing agent, such as a supramolecular compound C into the blood flowing through the treatment zone 5 along the extracorporeal blood flow pathway 2. The supramolecular compound C is adapted to bind selectively with a target molecule M in the blood to form a supramolecular complex X which is then to be removed from the blood in the haemodialysis unit 4.

[0080] With reference briefly to drawing FIG. 5, the supra-molecular compound C may be supra-molecular structure in the form of a molecular cage, e.g. an ultra-large cage structure (ULCS) protein. The supra-molecular compound C may thus have an opening of a size and binding affinity for the specific target molecule M. Under correct conditions, therefore, it is possible for the ULCS to selectively bind the target molecule M for which it has been designed. In an alternative embodiment, the complexing agent may include a number of individual molecules adapted to bind to the target molecule M and to each other in a kind of polymerization or flocculation of the target molecule M into a complex of clusters or larger aggregates. In another embodiment, the complexing agent may also comprise a core particle in the form of a superparamagnetic iron oxide nanoparticle (SPION), a magnetic microbead (MMB) or non-magnetic organic particle. Such anchor or core particles (e.g. SPIONs of 20-150 nm) can be synthesized coated with receptors or binding sites, such as zeolites, adapted for specific target molecules M that require removal and a number of target molecules M could then bind to each particle to form a complex. Regardless of which form the complexing agent takes (in this case, a supra-molecular compound C) it acts to bind or to incorporate the target molecules M in a complex X (e.g. a supra-molecular complex X) thereby to enlarge or ‘upsize’ the target molecule M for removal in the haemodialysis unit 4.

[0081] The extracorporeal blood flow pathway 2 for guiding or conveying the flow of blood along the haemodialysis circuit 3 comprises tubing 9; e.g. in the form of one or more tubes or catheters. In the treatment zone 5, the tubing 9 of the extracorporeal blood flow pathway 2 defines an extensive and convoluted generally flat spiral pathway such that the blood remains within the treatment zone 5 for a prolonged period of time, preferably in the range of about 2 to 10 minutes, as it flows along the pathway 2. This extended duration for the blood to traverse the treatment zone 5 provides time for the complexing agent (i.e., supra-molecular compound C) to mix with the blood and to bind the target molecule M in the supra-molecular complex X. To facilitate this process, the system and method may involve altering physical or chemical conditions of the blood in the treatment zone 5 to promote complexing of the target molecule M with the agent or supramolecular compound C. For example, the temperature of the blood in the treatment zone 5 may be raised or lowered to promote formation of the supramolecular complex X. Further, the treatment zone 5 may be agitated (e.g. vibrated) and/or some form of electromagnetic radiation (EMR) may be applied to the treatment zone 5 to promote formation of the complex X and/or to cause aggregation or flocculation of multiple complexes into large clusters.

[0082] To this end, with reference to drawing FIGS. 3 and 4, EMR 7 may be applied by an applicator device 8 to treat the blood. Indeed, the EMR 7 may result, either directly or indirectly, in preferential inactivation or neutralisation of pathogens in the blood. The at least one applicator device 8 applies the EMR 7 via an applicator head 8′ to the blood flowing through the treatment zone 5 along the extracorporeal blood flow pathway 2. The EMR 7 (e.g. DC electric current, AC magnetic field, terahertz radiation, visible light, UV radiation, X-ray and/or gamma radiation) is applied to the blood via the or each applicator head 8′ to promote formation of the supramolecular complex X or aggregation or flocculation of multiple complexes X into large clusters, and to inactivate or neutralise microorganisms, pathogens, and/or molecular structures as the blood flows through the treatment zone 5.

[0083] Referring now to drawing FIGS. 2(a) to (c), three variations of the tubing 9 for the blood flow pathway 2 in the treatment zone 5 of the system 1 are shown schematically. FIG. 2(a) illustrates the convoluted and generally flat spiral pathway 2 for the blood in the treatment zone 5 also shown in FIG. 1. FIG. 2(b) illustrates an array of interconnected parallel tubes 9 that are arranged to extend side-by side through the treatment zone 5. FIG. 2(c), on the other hand, illustrates a stacked 3×3 array of tubing 9. In this particular case, however, the tubing 9 represents a single flexible tube that is bent in a serpentine configuration—the cross-sectional end view in FIG. 2(c) showing the lengths of tubing 9 in which the flow is directed “out of the page” by a central point, and the lengths in which the flow is directed “into the page” by a central cross. Those lengths are then joined by 180-degree bends in the tubing at adjacent ends of the lengths of the tubing 9 joined by a dash. In this way, referring to the perspective view in FIG. 2(c), the blood enters the 3×3 stacked array via the upper, right-hand-side length of tubing 9 (as shown by arrow) and leaves the 3×3 stacked array via the lower, left-hand-side length of tubing 9 (as shown by the arrow).

[0084] With reference to drawing FIG. 3, an example of treatment zone 5 in a system 1 according to a preferred embodiment is illustrated. In this example, treatment zone 5 includes a blood flow path 2 formed by four interconnected parallel tubes 9 that extend side-by side, as in FIG. 2(b). A magnet 10, e.g. a DC electromagnet, arranged to apply an essentially constant magnetic field over an area below the treatment zone 5. This attracts red blood cells towards that area by virtue of their iron (Fe.sup.++) ions and thereby creates a profile of blood components with the pathogens most superficially or uppermost in the tubing 9, as illustrated by the accumulation of darker (haemoglobin) cells in a lower part of that tubing 9. The EMR 7 applied from above thus treats this superficial layer with greatest activity, thereby partially sparing deeper layers containing healthy components. Thus, a roughly vertical (non-homogenous) gradient is generated through the blood, with microorganisms, pathogens and the target molecule M located superficially and mainly red blood cells (RBCs) in a lowermost layer towards the magnet. If therapeutic EMR 7 is applied to encounter the superficial layer (with higher concentrations of pathogens), the selectivity of the treatments is enhanced, especially with shorter wavelength and higher frequency EMRs 7.

[0085] Referring now to drawing FIG. 4, a further embodiment of a treatment zone 5 in a system 1 for treating hematologic pathologies is illustrated. In this particular example, the treatment zone 5 incorporates an extracorporeal blood flow pathway 2 having a 3×3 stacked array of tubing 9 corresponding to the example shown in FIG. 2(c). The laterally arranged applicator devices 8, each connected to a control unit and power source 11, include an electromagnetic coil (e.g. an orthogonal pancake coil of wound copper wire) for generating and applying an AC oscillating magnetic field (OMF) 7 via applicator heads 8′ arranged adjacent sides of the 3×3 stacked array of tubing 9. In addition, the treatment zone 5 includes further upper and lower applicator devices 8″, each having a control unit and power source 11″, for applying supplemental EMR 7′ (typically of a type different to OMF) to the blood in the treatment zone 5. By applying AC electric current of certain frequencies through the two OMF coils with correct alternating sequencing, an OMF is produced that passes through the treatment zone 5. The field may be pulsed multiple times over the treatment period and combined with the other EMR 7′ applied orthogonally simultaneously in combinations determined to inactivate or kill a pathogen most effectively.

[0086] With reference to FIG. 6 of the drawings, a flow diagram is shown to illustrate schematically the steps in a method of haemodialysis for removing a target substance from the blood of a patient pursuant to the disclosure using a system 1 described above with reference to the embodiments in FIGS. 1 to 4. In this example, the disclosure is employed in a haemodialysis circuit. In this regard, the first box i of FIG. 6 represents the step of connecting an infected patient to an extracorporeal blood flow pathway 2, e.g. in a haemodialysis circuit 3, for conveying a flow of blood from the patient along the pathway 2. To this end, the vascular access is obtained in the patient in the usual way to facilitate haemodialysis in an intensive care unit (ICU). The patient will likely need to be anticoagulated. The blood is conveyed from the patient along the extracorporeal blood flow pathway 2 but does not go directly to the haemodialysis unit 4. Rather, it rather proceeds along the pathway through a treatment zone 5, which is arranged in such a way that it results in a transit time in the range of about 1 minute to 5 minutes for a blood volume in the range of about 100 mL to 300 mL of whole blood. The second box ii represents a step of infusing or administering a complexing agent, such as a supra-molecular compound C or core particle, into the blood in the extracorporeal blood flow pathway 2 adapted for binding with a target molecule M.

[0087] The third box iii of FIG. 6 represents the step of conveying the blood with the complexing agent (i.e., supra-molecular compound C) through a treatment zone 5 of the extracorporeal blood flow pathway 2 for a predetermined period of time, typically 5 to 15 mins, for binding or incorporating the target molecule M in a supra-molecular complex X and optionally applying electro-magnetic radiation (EMR) 7 to the blood passing through the treatment zone 5 during the transit time. The blood may thus be exposed to one or more type of EMR 7 selected from the group of: DC electric current, AC oscillating magnetic field (OMF), visible light, UV radiation, X-ray radiation, gamma radiation, and terahertz radiation. The EMR 7 may be applied by one or more applicator device 8 via a respective applicator head 8′ arranged adjacent the tubing 9 defining the blood flow pathway 2 in the treatment zone 5. An adjuvant may be added to the blood prior to the blood entering the treatment zone 5, so that a desired photochemical, electrochemical, or magneto-chemical treatments may occur in the treatment zone 5. Upon exiting the treatment zone, any such adjuvant process will then cease.

[0088] The final box iv in FIG. 6 of the drawings represents the step of passing the blood through a dialysis/filtration unit 4 and removing the supra-molecular complex X from the blood via haemodialysis, preferably via one or more of filtration, ultrafiltration, convection, or membrane adsorption. Thus, break-down products or complexes formed during the treatment with EMR 7 are filtered out of the blood. After filtration, the treated blood completes its traverse of the extracorporeal blood flow pathway or circuit and returns into the patient. The step of passing the blood through the haemodialysis unit 4 may comprise separating or dividing the blood flow along the extracorporeal blood flow pathway 2 into two streams, with a first stream comprising substantially small molecules typically having a size less than 1.5 nm, including water and electrolytes, and a second stream comprising larger molecules typically having a size of over 3 nm and up to many microns, including larger proteins, supra-molecular structures X and blood cells. In this way, the two steams are then be processed/filtered separately in the dialysis unit. The first stream will desirably include albumen, which at a size of about 2.5 nm qualifies as a mid-sized molecule. But it is preferable not to remove albumen from the plasma due to its importance in maintaining plasma oncotic pressure. The first stream and the second stream are the re-combined into a unified extracorporeal blood flow 2 prior to returning the blood to the patient.

[0089] Approximately 20-30 such treatments may be necessary to treat an entire adult blood volume, and a further series of 20-30 such treatments may be needed as returned blood of earlier treatments mixes with blood in the patient that has not yet been treated.

[0090] Although specific embodiments of the disclosure are illustrated and described herein, it will be appreciated by persons of ordinary skill in the art that a variety of alternative and/or equivalent implementations exist. It should be appreciated that each exemplary embodiment is an example only and is not intended to limit the scope, applicability, or configuration in any way. Rather, the foregoing summary and detailed description will provide those skilled in the art with a convenient road map for implementing at least one exemplary embodiment, it being understood that various changes may be made in the function and arrangement of elements described in an exemplary embodiment without departing from the scope as set forth in the appended claims and their legal equivalents. Generally, this application is intended to cover any adaptations or variations of the specific embodiments discussed herein.

[0091] It will also be appreciated that the terms “comprise”, “comprising”, “include”, “including”, “contain”, “containing”, “have”, “having”, and any variations thereof, used in this document are intended to be understood in an inclusive (i.e. non-exclusive) sense, such that the process, method, device, apparatus, or system described herein is not limited to those features, integers, parts, elements, or steps recited but may include other features, integers, parts, elements, or steps not expressly listed and/or inherent to such process, method, process, method, device, apparatus, or system. Furthermore, the terms “a” and “an” used herein are intended to be understood as meaning one or more unless explicitly stated otherwise. Moreover, the terms “first”, “second”, “third”, etc. are used merely as labels, and are not intended to impose numerical requirements on or to establish a certain ranking of importance of their objects. In addition, reference to positional terms, such as “lower” and “upper”, used in the above description are to be taken in context of the embodiments depicted in the figures, and are not to be taken as limiting this disclosure to the literal interpretation of the term but rather as would be understood by the skilled addressee in the appropriate context.