RU2776944C1 - Simplified regeneration of apheresis columns - Google Patents

Abstract

FIELD: medical equipment.

SUBSTANCE: apheresis apparatus for extracorporeal removal of C-reactive protein (CRP) from the blood comprises an extracorporeal circulation system for blood, a tool for forming and controlling the blood flow in the extracorporeal circulation system, a cell separator for separating blood into plasma and cellular components, an apheresis column for removing CRP from the blood by affinity chromatography. The extracorporeal circulation system comprises an arterial line to the cell separator, a plasma line from the cell separator to the apheresis column, a plasma line for CRP-depleted plasma from the apheresis column to point P1, a cell mass line for the separated cellular components from the cell separator to point P1, and a venous line originating from point P1. The central processing unit is used to control the apheresis apparatus. A connecting line is used to connect a liquid container to the arterial line or to the cell separator. A bypass line branches off the plasma line and is connected to the plasma line. A waste line diverges directly from the apheresis column or from the plasma line, in the direction of the flow before the bypass line connection point. A regeneration line diverges from the liquid container or from the connecting line and passes to the plasma line, in the direction of the flow to or after the bypass line branching point, or directly to the apheresis column. Disclosed are an alternative variant of the apparatus and variants of the method for regenerating the apheresis column in apparatus.

EFFECT: simplified regeneration of apheresis columns.

14 cl, 16 dwg

Description

The present invention relates to an apheresis device (1) for removing C-reactive protein from a patient's blood, the apheresis device being connected to the patient's circulatory system. The blood is pumped through the part of the extracorporeal circulation system (2) of the apheresis device (1) according to the invention into the cell separator (7) for separating the blood into blood plasma and cellular components. Through the first outlet of the cell separator (7), the separated blood plasma is sent through the plasma line (8A) to the apheresis column (4) to remove C-reactive protein from the blood plasma by affinity chromatography. After removal of the C-reactive protein from the patient's blood plasma, said already purified blood plasma is mixed with the cellular components of the blood using a plasma line (8B). Furthermore, the apheresis device (1) according to the invention comprises a bypass line (12) which runs from the plasma line (8A) to the plasma line (8B), bypassing the apheresis column (4). The apheresis device (1) according to the invention also comprises a regeneration line (14) which extends to the plasma line (8A) or directly to the apheresis column (4).

In addition, the present invention contains a method for simplified regeneration of the apheresis column.

State of the art invention

According to the World Health Organization (WHO), in 2008 about 17,000,000 people died from cardiovascular diseases. This makes cardiovascular diseases the most common cause of death among noncommunicable diseases and responsible for approximately one third of all deaths worldwide each year. The number is estimated to increase to approximately 23,000,000 deaths per year by 2030.

Thus, cardiovascular diseases are and will remain not only the leading cause of death in the world, but also lead to huge medical costs for national health systems and health insurance. Two of the most common and most devastating manifestations of cardiovascular disease are the occurrence of atherosclerosis and thrombosis, which, in turn, are among other causes of heart attacks and angina attacks.

In recent years, significant progress has been made in the treatment of cardiovascular diseases. This progress has been made possible not only by the growing understanding of the mechanisms that cause the disease, but also by the early recognition of patients at risk. Indeed, disease risk recognition and early treatment are important features of modern medical practice. Over the past 25 years, various factors and clinical parameters have been identified that correlate with either the current state of the disease or the likelihood of future cardiovascular disease. Such risk factors may be measurable biochemical or physiological parameters such as serum cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL) and fibrinogen levels, but may also include behavioral patterns such as overweight and smoking. In cases where the risk factor does not simply characterize the disease or its development, but, in fact, is involved in its development as a cause, the therapeutic effect on the mentioned risk factor may affect the course of the disease or may reduce the risk of its development.

As an acute phase protein, C-reactive protein (CRP) is part of the innate immune system and is formed in the liver during inflammatory reactions and released into the blood. The formation of C-reactive protein (CRP) is induced mainly by cytokines that are expressed during an acute or chronic inflammatory response. The strongest stimulator of CRP formation is interleukin-6 (IL-6). Therefore, blood levels of CRP as well as IL-6 are indicators of a local or systemic inflammatory response. As expected, chronic inflammation is one of the underlying and concomitant pathological phenomena in cardiovascular diseases. At the same time, it is increasingly believed that CRP not only predicts cardiovascular disease, but also, as a cause, is involved in its development or may influence the course of the disease.

As shown in Yeh (Clin Cardiol., 2005, 28: 408-412), the level of CRP can be used to predict the risk of cardiovascular disease, moreover, CRP is an indicator of inflammatory responses, and that inflammation provokes all stages of atherosclerosis. Zoccali et al., (Semin. Nephrol., 2005, 25: 358-362) show that CRP levels predict the risk of cardiovascular mortality in patients with end-stage renal failure. According to Nurmohamed et al., (Neth. J. Med., 2005, 63: 376-381), the level of CRP predicts the risk of cardiovascular mortality for hemodialysis patients.

In the publication of Sola et al., (J. Card. Fail., 2005, 11: 607-612) it can be seen that statin therapy can be used to reduce the level of CRP and, therefore, reduce mortality and the incidence of complications caused by cardiovascular disease. . However, this form of therapy is not sufficient to significantly reduce the high levels of CRP (up to 1000 times normal) that occur after a heart attack, or the high levels of CRP in the blood of dialysis patients.

Publications by Slagman et al. 2011 (Specific Removal of C-reactive protein by Apheresis in a Porcine Cardiac Infarction Model, Blood Purif 2011; 31:9-17), Sheriff et al. 2014 (C-reactive protein adsorber therapies: new ideas and concepts; LECTURE NOTES OF THE ICB SEMINAR: ADVANCES IN MEMBRANE AND ADSORBOR TECHNOLOGY IN LIFE SCIENCES, Warsaw, April 2014), Sheriff et al. 2015 (Selective Apheresis of CRP: A New Therapeutic Option in Myocardial Infarction? Journal of Clinical Apheresis 30:15-21 (2015)) is also devoted to this topic.

Consequently, there is an ever-increasing interest in therapeutic methods for lowering CRP levels in the blood of patients.

Application WO 90/12632 discloses a method and apparatus for the extracorporeal treatment of biological fluids to remove CRP as well as antiphosphocholine antibodies from these biological fluids for the purpose of antitumor therapy. The phosphocholine-containing matrix used for this purpose may consist of, for example, silica, sepharose, acrylic beads or agarose, whereby both CRP and anti-phosphocholine antibodies are bound by the contained phosphocholine.

WO 2007/076844 discloses a method for extracorporeal removal of CRP from blood plasma by means of apheresis in order to reduce the patient's risk caused by elevated blood levels of CRP. According to the invention, a column containing a matrix to which phosphocholine derivatives are bound is used for this purpose in order to bind and remove CRP from plasma and therefore to treat and/or prevent autoimmune diseases, cardiovascular diseases, diabetes as well as kidney failure. .

The normal level of CRP in human blood varies from person to person, but averages approximately 0.8 mg CRP per liter of blood, however, can rise well above 100 mg CRP per liter of blood in case of acute or chronic inflammatory reactions (for example, bacterial infections, atherosclerosis, after a heart attack). Since the half-life of CRP in the blood (approximately 19 hours) is a constant value and, therefore, does not depend on the state of health of the patient, only the rate of CRP synthesis is responsible for regulating the level of CRP in the blood (Pepys & Hirschfield, J. Clin. Invest., 2003, 111: 1805-1812). Therefore, the dramatically accelerated synthesis of CRP in acute pathological conditions places special demands on therapeutic methods for removing CRP from patients (patients with high-risk or severely ill patients), since a significant amount of CRP must be removed in order to reduce blood levels of CRP to normal levels. . Thus, there is a need for particularly effective devices for removing CRP from the blood of patients.

DE 102005061715 A1 discloses a method for reducing the risk of elevated levels of C-reactive protein (CRP) by performing extracorporeal perfusion of blood plasma through a device, for example a column, which contains an adsorbent matrix including lipids, peptides, polypeptides, phosphocholine (PC) or PC derivatives to remove the C-reactive protein. The possibility of column regeneration is not disclosed.

From the prior art, reusable adsorbers are known, which consist of a body filled with a carrier substance and a binding factor connected to it. Reusable adsorbers are usually regenerable because, after passing through them a plasma, the amount of which depends on the concentration of the substance to be adsorbed, the adsorber is "saturated" and the binding of the substance can no longer occur. As a result, the adsorber is washed to remove bound substances with various regeneration solutions and thus again prepared for a new filling with plasma. The permissible number of regenerations is set by the manufacturers. The reusable adsorber can only be used with the same patient. To prevent the development of pathogenic microorganisms in adsorbers, they must be filled with a preservation liquid at the end of each treatment procedure, which must be washed off before each subsequent therapy. However, their repeated use can save significant costs. The operation of existing devices (combinations of two or more medical devices) is overly complex and labor intensive. In addition, devices are rarely fully utilized.

Application DE 102005019406 A1 discloses a method and apparatus for the automatic release of flushing fluid during apheresis therapy. Also disclosed is the use of auxiliary devices by means of which the two adsorbers are filled and washed alternately and repeatedly. These accessories have their own peristaltic pumps, flexible tube clamps and controls. Despite the effectiveness of these known devices and methods, their disadvantage is the simultaneous operation of two devices, which, as mentioned above, are used inconsistently due to their complexity. According to the disclosure of DE 102005019406 A1, the aim of the application was to reduce the number of switching operations between liquid outlet and liquid recirculation during therapy, in order to allow the operation of the adsorber itself, without an additional device on the cell separator. In this context, DE 102005019406 A1 discloses a combination of collecting containers and control valves to enable, for example, switching of filling from the first adsorber to the second adsorber by means of a 3-way valve in the feed tube system. Thus, DE 102005019406 A1 discloses an alternative device with two apheresis columns. The disadvantage of the increase in cost due to the second apheresis column, which in this case can only be used with the same patient, is not eliminated by the invention disclosed in the application DE 102005019406 A1.

WO 2012/143103 discloses a device for extracorporeal blood purification and for controlling the flow of liquids in this device, wherein the flow of liquids is switched between cleansing mode and filling and rinsing mode using a switching clamp. In the fill and wash mode, the wash solution is collected in the collection bag, and, in the purge mode, it must be ensured that the purified plasma does not fall into the collection bag. Therefore, it is necessary to check the correct functioning of the switching terminal. The control of the flow of liquids is carried out by determining the change in the weight of the prefabricated package. In WO 2012/143103, an estimator for monitoring the change in weight of a prefabricated package is shown as an additional feature and contributes to the complexity of the structure of the disclosed subject matter. Qualified personnel using the disclosed device must measure a predetermined time interval so that the lines of the fluid system can be completely filled with flushing fluid. Only when the lines of the fluid system are completely filled with flushing fluid can we expect an increase in the weight of the collection bag. At the same time, qualified personnel must carefully monitor the various audible and / or optical signals generated by the control unit. Therefore, the device disclosed in WO 2012/143103 requires a very high level of training from the staff of the healthcare facility. In addition, although WO 2012/143103 discloses a blood purification unit (10) comprising one or more filters or adsorbers, it does not disclose either the fluids by which the blood purification unit is regenerated, or whether the plasma flow is interrupted during regeneration. . Thus, in the application WO 2012/143103, the presence of a bypass highway is not disclosed or proposed.

Document DE 4338858 C1 also discloses a device for regenerating an apheresis column. DE 43 38 858 C1 proposes the use of a reservoir in which plasma is temporarily stored during regeneration of the apheresis column. Regeneration of the apheresis column occurs with the combined use of glycine, NaCl solution and PBS (phosphate buffered saline) known from the prior art. Therefore, document DE 4338858 C1 does not contain any reference to the use of an anticoagulant solution or a plasma separator wash solution as a regeneration solution for an apheresis column according to the device of the invention. In addition, document DE 4338858 C1 does not disclose a bypass line that allows the plasma flow to be diverted to bypass the apheresis column during its regeneration.

International patent application WO 2012141697 A1 discloses an apheresis device for extracorporeal removal of CRP from blood. There is no description of regeneration of the apheresis column during apheresis, without stopping the cleansing.

European patent application EP 0834329 A1 relates to a device for removing cholesterol from the blood. No specific columns or column materials are mentioned in this application. Removal of CRP is not described. Columns for the removal of cholesterol by affinity chromatography do not exist. In principle, cholesterol is removed by lipoprotein apheresis. Columns are used that are only partially selective for LDL (low density lipoprotein) cholesterol, i. LDL cholesterol binds with a higher affinity to the matrix in the apheresis column than to other substances present in the blood. However, other substances are also removed from the blood or blood plasma in a high percentage. The columns disclosed in EP 0834329 A1 are not suitable for the selective removal of CRP from blood. European patent application EP 0111696 A2 discloses a device for removing anti-factor VII or IX antibodies. CRP removal is not disclosed. Therefore, in particular, apheresis columns for removing CRP by affinity chromatography are not disclosed, i.e., CRP does not bind to the matrix in the apheresis column with a higher affinity than other substances present in the blood, but there is antibody specificity. The columns disclosed in EP 0834329 A1 are not suitable for the selective removal of CRP from blood.

The aim of the present invention is to provide a device for simplified regeneration of apheresis columns, while minimizing certain disadvantages of known devices. In other words, the aim of the present invention is to provide a device for simplified regeneration of apheresis columns, and in particular an apheresis column for selective removal of CRP from blood, which can be used by personnel with less training and, therefore, with less staff labor and reduced overall costs.

This problem is solved using the principles set forth in the independent claims. Additional preferred embodiments arise from the description, examples and the following claims.

Surprisingly, by providing a regeneration line that either runs directly into the apheresis column or is connected to the plasma line before the apheresis column but after the bypass line, it is possible to regenerate the apheresis column more easily while minimizing the disadvantages of the prior art.

Description of the invention

The present invention relates to an apheresis device (1) for extracorporeal removal, and preferably for extracorporeal selective removal of CRP from a patient's blood, the apheresis device being connected to the patient's circulatory system. The blood is pumped through the part of the extracorporeal circulation system (2) of the apheresis device (1) according to the invention into the cell separator (7) for separating the blood into blood plasma and cellular components. Through the first outlet of the cell separator (7), the separated blood plasma is directed through the plasma line (8A) to the apheresis column (4) to remove CRP by affinity chromatography from the blood plasma. After removal and preferably after selective removal of CRP from the patient's blood plasma, said already purified blood plasma is combined with the cellular components of the blood via a plasma manifold (8B). Furthermore, the apheresis device (1) according to the invention comprises a bypass line (12) which runs from the plasma line (8A) to the plasma line (8B), bypassing the apheresis column (4). The apheresis device (1) according to the invention further comprises a regeneration line (14) which extends to the plasma line (8A), in the direction of flow to or preferably after the connection point of the bypass line (12), or directly to the apheresis column (four).

In addition, the present invention includes a method for simplified regeneration of an apheresis column.

Device

The present invention relates to an apheresis device (1) for extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

at least one apheresis column (4) to remove CRP by affinity chromatography from blood,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4), a plasma line (8B) for CRP-poor blood plasma from apheresis column (4) to point (P1), line (9) of cell mass for separated cellular components from cell separator (7) to point (P1) and venous line (6) starting from point (P1),

central processor (10) to control the device (1) for apheresis,

at least one connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass line (12) branches off from the plasma line (8A) and is connected to the plasma line (8B),

the waste line (13) departs directly from the apheresis column (4) or from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and

at least one regeneration line (14) departs from at least one container (F) for liquids or from at least one connecting line (11) and passes to the plasma line (8A), in the direction of flow towards point or after the branch point of the bypass line (12), or connected directly to the apheresis column (4).

As explained above, the apheresis device (1) according to the invention for the extracorporeal removal of CRP from blood is connected to the patient's circulatory system. From a vascular access on the patient (usually a venous access), the blood is pumped into the cell separator (7) through part of the extracorporeal circulation system (2) of the apheresis device (1) according to the invention. The part of the extracorporeal circulation system (2) which directs the blood out of the patient and into the cell separator (7), directs the blood away from the patient and therefore away from the patient's heart and is therefore referred to as the " arterial highway " (5), as terminologically accepted for vessels human body.

The patient's blood is directed through the inlet of the cell separator (7) into the cell separator (7) and separated by the latter into blood plasma (sometimes also referred to simply as "plasma") and cellular blood components. At the same time, it must be taken into account that the separation into blood plasma and cellular components is not completely performed, but only, preferably, 10-90% of the entire blood plasma is separated from cellular components. Through the first outlet of the cell separator (7), the separated blood plasma is directed through the plasma line (8A) to the apheresis column (4) for removal of CRP by affinity chromatography from the blood (or from blood plasma). After removing or reducing the level of CRP in the patient's blood plasma, said already purified blood plasma (also referred to as "poor blood plasma") is sent to the point (P1) via the highway (8B) of the plasma. Through the second outlet of the cell separator (7) and along the connecting highway (the so-called highway (9) of the cell mass), the cellular components of the blood bypass the apheresis column (4) and go to the point (P1). At this point, the cellular components mix with the depleted blood plasma. After mixing the cellular components with the depleted blood plasma, the already purified blood is returned to the patient through the further part of the extracorporeal circulation system (2) of the present invention. The part of the extracorporeal circulation system (2) which directs the purified blood from the point (P1) of the extracorporeal circulation system (2) back to the patient, directs the blood towards the patient and therefore also to the patient's heart, and is therefore referred to as the " venous highway " (6) as terminologically accepted for the vessels of the human body.

In an alternative embodiment of the present invention, it is also possible that the cellular components are fed back into the patient immediately after separation from the plasma, through the second outlet of the cell separator and through the connecting line, and only purified plasma is fed back to the patient through the venous line.

In order to be able to prevent coagulation of blood in the extracorporeal circulation system or to allow flushing or pre-rinsing of the extracorporeal circulation system (for example, with saline), the apheresis device according to the invention comprises at least one line (the so-called connecting line (11) ) which allows the connection of at least one fluid container (F) and hence the supply of the fluid (eg anticoagulant or saline) contained in the fluid container (F) to the extracorporeal circulation system. In this context, it should also be mentioned that the connecting line (11) for connecting at least one container (F) for liquids is fluidly connected to the extracorporeal circulation system, i.e. the liquid from the liquid container can be supplied to the extracorporeal circulation system through the connecting line (11). In preferred embodiments of the present invention, at least one connecting line (11) is connected to the extracorporeal circulation system (2) before the cell separator, i. to the arterial line (5) or directly to the cell separator (7).

It is clear to the skilled person that the container(s) (F) for fluids should not themselves be part of the apheresis device according to the invention, since said containers are usually disposable items, for example in the form of conventional infusion bags. , which are connected to the connecting trunk by technical staff (for example, a staff doctor or nurse) depending on the specific application.

According to the invention, it is possible to have a single connection line (11) for connecting a container for liquids. However, it can also be assumed that there is a single connecting line (11) to which two or three, preferably more liquid containers can be connected. Also possible are embodiments of the apheresis device according to the invention with two, preferably three, or preferably more connecting lines (11', 11'', 11''', etc.) for connecting, each, with, at least one container for liquids, as a result of which a solution is preferable when said two, preferably three or preferably more connecting lines can be independently connected to the arterial line (5) or directly to the cell separator (7). "Independently of each other" means, in this context, for example, that in an embodiment of the apheresis device according to the invention with two connecting lines (11', 11''), one connecting line (11') can be connected to an arterial lines (5), and another connecting line (11'') can be connected directly to the cell separator (7), but also that both connecting lines (11', 11'') can be connected to the arterial line (5), or that both connecting lines (11', 11'') can be connected directly to the cell separator (7).

According to an embodiment of the present invention, it is particularly preferred that the apheresis device (1) according to the invention comprises two connecting lines (11', 11'') each for connecting at least one container for liquids, wherein the connecting lines (11', 11'') are connected independently of each other to the arterial line (5) or directly to the cell separator (7). Therefore, both connecting lines (11', 11'') are connected to the arterial line (5), or both connecting lines (11', 11'') are connected directly to the cell separator (7), or, especially preferably, one connecting a line (11') is connected to the arterial line (5) and another connecting line (11'') is connected directly to the cell separator (7). This makes it possible to connect the two connecting lines (11', 11'') to different liquid containers. It is especially preferred that one of the two connecting lines (eg 11') is connected to a liquid container containing saline solution (eg NaCl solution) and the second of the two connecting lines (eg 11'') is connected to a liquid container, containing citrate solution.

Thus, it is particularly preferred that the apheresis device (1) comprises a connecting line (11') for connecting a container (F1) for liquids and a connecting line (11'') for connecting a container (F2) for liquids, and a connecting line (11 ') is connected to the arterial line (5) or to the cell separator (7), and the connecting line (11'') is connected to the arterial line (5) or to the cell separator (7), or to the connecting line (11') and, therefore, eventually also to the arterial line (5) or to the separator (7) of the cells.

Therefore, the present invention also relates to an apheresis device (1) for extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

at least one apheresis column (4) to remove CRP by affinity chromatography from blood,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4), a plasma line (8B) for CRP-poor blood plasma from apheresis column (4) to point (P1), line (9) of cell mass for separated cellular components from cell separator (7) to point (P1) and venous line (6) starting from point (P1),

central processor (10) to control the device (1) for apheresis,

two connecting lines (11', 11'') each for connecting at least one fluid container to an arterial line (5) or cell separator (7),

characterized in that

the bypass line (12) branches off from the plasma line (8A) and is connected to the plasma line (8B),

the waste line (13) departs directly from the apheresis column (4) or from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and

at least one regeneration line (14) passes to the plasma line (8A), downstream to or after the branch point of the bypass line (12), or is connected directly to the apheresis column (4).

A significant advantage of the apheresis device of the present invention is that the apheresis column, which is naturally limited in cleansing capacity, can be regenerated during operation , i. without the need to draw blood and feed it to a cell separator. For this purpose, a bypass line (12, also referred to as a “shunt”) is provided, which allows the plasma flow to be redirected to bypass the apheresis column (4). This bypass line (12) allows the apheresis column (4) to be temporarily disconnected from the plasma flow and thus the apheresis column (4) to be regenerated, without the need to interrupt the flow of blood or blood plasma into the device according to the invention. The bypass line branches off from the plasma line (8A), while the point on the plasma line (8A) at which the bypass line branches off is designated as point (P2), and is preferably connected to the plasma line (8B), and the point on the line (8B) plasma, in which the bypass line (12) is connected, is indicated as a dot (P6). In yet another possible embodiment, the bypass line (12) is connected to the line (9) of the cell mass, and not to the line (8B) of the plasma, while the point on the line (9) of the cell mass, where the bypass line (12) is connected, labeled as a dot (P3).

The regeneration solution necessary for the regeneration of the apheresis column is supplied to the extracorporeal circulation system (2) through the regeneration line (14), while the regeneration line (14) either passes directly to the apheresis column (4) or is connected to the plasma line (8A) ( in the direction of flow) before the apheresis column (4), but (in the direction of flow) after the branch of the bypass line, i.e. after the point (P2).

In order to remove the regeneration solution from the system after flowing through the apheresis column (4) (instead of being delivered to the patient), a waste line (13) is provided that branches off from the plasma line (8B), while a point on the line (8B) of the plasma from which waste line (13), marked as point (P4). In embodiments in which the bypass line (12) is connected to the cell mass line (9), point (P4) is preferably located in the area from the apheresis column (4) to point (P1). In embodiments in which the bypass line (12) is connected to the plasma line (8B), point (P4) is preferably located in the region from the apheresis column (4) to point (P6). Of course, the collection container, for example, can be connected to said waste line (13). For example, physiological saline solution, tris-glycine solution or citrate solution can be used as a regeneration solution.

In addition to the regeneration solution, a washing solution can also be used. The wash solution may, but not necessarily, also serve to regenerate the apheresis column (4), but its main function is to remove blood plasma from the plasma highway (8A) in the area from the P2 point to the apheresis column (4), from the apheresis column (4) and from the plasma line (8B) from the apheresis column (4) to point P4 before the regeneration solution is used, and then it is drained through the waste line (13) after flowing through the apheresis column (4). On the other hand, the wash solution can be supplied to the patient at least partially, as well as completely and not necessarily drained, at least provided that no regeneration solution is contained in the wash solution. Preferably, saline NaCl is used as the wash solution. Physiological NaCl solution is even more preferable to use as a wash solution if a citrate solution is used as a regeneration solution.

Therefore, the present invention also relates to an apheresis device for in vitro removal, and preferably for selective extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

at least one apheresis column (4) to remove CRP by affinity chromatography from blood,

at the same time, the extracorporeal circulation system (2) contains an arterial line (5) to the cell separator (7) for separating blood into blood plasma and cellular components, a plasma line (8A) from the cell separator (7) to the apheresis column (4) for removal CRP by affinity chromatography from blood, plasma route (8B) for CRP-poor plasma from apheresis column (4) to point (P1), cell mass route (9) for separated cellular components from cell separator (7) to point (P1 ) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (1) for apheresis,

at least one connecting line (11) for connecting at least one container for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass line (12) branches off from the plasma line (8A) and is connected to the plasma line (8B),

the waste line (13) departs directly from the apheresis column (4) or from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and

at least one regeneration line (14) is supplied to the extracorporeal circulation system (2) in the area from the connection point of the bypass line (12) on the plasma line (8A) to the apheresis column (4).

The present invention also relates to an apheresis device (1) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood or blood plasma, comprising:

an extracorporeal circulation system (2) for blood or blood plasma connected to the patient's circulatory system,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

at least one apheresis column (4) to remove CRP by affinity chromatography from blood or blood plasma,

wherein the extracorporeal circulation system (2) contains an arterial line (5) from the patient to the cell separator (7),

a plasma line (8A) for the separated blood plasma coming from the cell separator (7) and fluidly connected to the apheresis column (4) for removing CRP by affinity chromatography from the blood,

highway (8B) plasma, coming from the apheresis column (4), for CRP-poor blood plasma,

highway (9) of the cell mass, coming from the separator (7) of cells, for the separated cellular components, which is connected to the highway (8B) of the plasma at the point (P1),

and

venous line (6) from the point (P1) to the patient;

central processor (10) to control the device (1) for apheresis,

at least one connecting line (11) for connecting at least one container for liquids, fluidly connected to the extracorporeal circulation system,

characterized in that the device (1) for apheresis further comprises:

a bypass line (12) that runs from a point (P2) on the line (8A) of the plasma to a point (P3) on the line (9) of the cell mass or to a point (P6) on the line (8B) of the plasma,

line (13) waste, which branches off from the point (P4) on line (8B) plasma,

at least one regeneration line (14), which is connected to the extracorporeal circulation system (2) in the area from the point (P2) to the apheresis column (4),

and point (P4) is before points (P1) and (P6), or point (P4) coincides with point (P6).

The present invention also relates to an apheresis device (1) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood or blood plasma, comprising:

an extracorporeal circulation system (2) for blood or blood plasma connected to the patient's circulatory system,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

at least one apheresis column (4) to remove CRP by affinity chromatography from blood or blood plasma,

wherein the extracorporeal circulation system (2) contains an arterial line (5) from the patient to the cell separator (7),

a plasma line (8A) for the separated blood plasma coming from the cell separator (7) and fluidly connected to the apheresis column (4) for removing CRP by affinity chromatography from the blood,

highway (8B) plasma, coming from the apheresis column (4), for CRP-poor blood plasma,

highway (9) of the cell mass, coming from the separator (7) of cells, for the separated cellular components, which is connected to the highway (8B) of the plasma at the point (P1),

and

venous line (6) from the point (P1) to the patient,

central processor (10) to control the device (1) for apheresis,

two connecting lines (11', 11''), each for connecting at least one container for liquids connected in fluid medium with the extracorporeal circulation system,

characterized in that the device (1) for apheresis further comprises:

a bypass line (12) that runs from a point (P2) on the line (8A) of the plasma to a point (P3) on the line (9) of the cell mass or to a point (P6) on the line (8B) of the plasma,

line (13) waste, which branches off from the point (P4) on line (8B) plasma,

at least one line (14) of regeneration, which is connected to the extracorporeal circulation system (2) in the area from the point (P2) to the apheresis column (4),

and point (P4) is before points (P1) and (P6), or point (P4) coincides with point (P6).

Therefore, according to an embodiment of the present invention, it is preferable that the apheresis device (1) according to the invention comprises at least two connecting lines (11), each for connecting at least one container (F) for fluids to the arterial line (5) or separator (7) of cells.

Moreover, embodiments of the apheresis device (1) are preferred, in which the apheresis device (1) comprises at least two connecting lines (11), each for connecting at least one container (F) for liquids. to the arterial line (5) or cell separator (7), and at the same time there is a regeneration line (14) for each container (F) for liquids, which departs from the corresponding container (F) for liquids or its connecting line (11), and each of which passes to the highway (8A) plasma or directly into the apheresis column (4).

It is also possible that at least two connecting lines (11) are combined before the point of their connection, i.e. merge into one highway. It is also possible that the regeneration lines (14) are combined before the point of their connection, i. e. merge into one highway.

If the present application describes that a device feature is located in the area from the first position in the device to the second position in the device, or extends into this area, or branches off from this area, then this should be understood in such a way that both the first position and the second position, so and the section located between them are inside this area. This is illustrated by the following example: The wording that "the regeneration line (14) is connected to the extracorporeal circulation system (2) in the area from the point (P2) to the apheresis column (4)" means that the regeneration line (14) is connected to the area of the system (2 ) extracorporeal circulation, which includes not only the section between the point (P2) and the apheresis column (4), but also includes the point itself (P2) as well as the apheresis column (4). This means that the regeneration line (14) can be connected at the point (P2) or to the apheresis column (4), or even to the section of the plasma line (8A) which is located between the point (P2) and the apheresis column (4).

Point (P1) is the nodal point in the extracorporeal circulation system (2) at which the plasma line (8B) joins with the venous line (6). Point (P2) is the nodal point in the extracorporeal circulation system (2) at which the bypass line (12) branches off from the plasma line (8A). The point (P3) is the nodal point in the extracorporeal circulation system (2) at which the bypass line (12) is connected to the cell mass line (9). Point (P4) is a nodal point in the extracorporeal circulation system (2) in which the waste line (13) branches off from the plasma line (8B). The point (P5) is the nodal point in the extracorporeal circulation system (2) at which the line (14) is connected to the connecting line (11). The point (P6) is the nodal point in the extracorporeal circulation system (2) at which the bypass line (12) is connected to the plasma line (8B).

The present invention also relates to an apheresis device (1) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood or blood plasma, comprising:

an extracorporeal circulation system (2) for blood or blood plasma connected to the patient's circulatory system,

means (3) for forming and regulating the flow of blood or blood plasma in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

at least one apheresis column (4) to remove CRP by affinity chromatography from blood or blood plasma,

wherein the extracorporeal circulation system (2) contains an arterial line (5) from the patient to the cell separator (7),

a plasma line (8A) for the separated blood plasma coming from the cell separator (7) and fluidly connected to the apheresis column (4) to remove CRP by affinity chromatography,

highway (8B) plasma coming from the apheresis column (4) for CRP-poor blood plasma,

highway (9) of the cell mass, coming from the separator (7) of cells, for the separated cellular components, which is connected to the highway (8B) of the plasma at the point (P1),

and

venous line (6) from the point (P1) to the patient,

central processor (10) to control the device (1) for apheresis,

at least one connecting line (11) for connecting at least one container for liquids to the arterial line (5) or cell separator (7),

characterized in that the device (1) for apheresis further comprises:

a bypass line (12) that runs from a point (P2) on the line (8A) of the plasma to a point (P3) on the line (9) of the cell mass or to a point (P6) on the line (8B) of the plasma,

line (13) waste, which branches off from the point (P4) on line (8B) plasma,

at least one regeneration line (14), which is connected to the plasma line (8A) or directly to the apheresis column (4) after the point (P2),

and point (P4) is before points (P1) and (P6), or point (P4) coincides with point (P6).

In accordance with a preferred embodiment of the present invention, the connecting line (11) is connected to the arterial line (5). According to a further preferred embodiment of the present invention, the connecting line (11) is connected directly to the cell separator (7).

As already described, the apheresis device according to the invention comprises at least one line (the so-called regeneration line (14)), which allows the regeneration solution (for example, citrate solution, Tris-glycine solution or NaCl solution) to be fed into extracorporeal circulation system, preferably directly before the apheresis column (4) or directly into the apheresis column (4). In this context, it is also mentioned that the regeneration line (14) for connecting at least one container (F) for liquids is fluidly connected to the extracorporeal circulation system, i.e. the liquid from the liquid container can be supplied to the extracorporeal circulation system through the regeneration line.

According to a preferred embodiment of the present invention, the regeneration line (14) is connected to the plasma line (8A) after point (P2), i. between the point (P2) and the apheresis column (4). According to another preferred embodiment of the present invention, the regeneration line (14) is connected to the plasma line (8A) at point (P2). In accordance with a further preferred embodiment of the present invention, the regeneration line (14) passes directly into the apheresis column (4).

It should be obvious to the skilled person that a container (F) for fluids for connection to the regeneration line itself does not have to be included in the apheresis device according to the invention, since said containers are usually disposable products, for example in the form of conventional infusion bags, which are connected to the interconnecting trunk by technical staff (for example, a staff doctor or nurse), depending on the specific application.

According to the invention, it is possible to have a single regeneration line (14) for connecting a container (F) for liquids. In this case, for example, it can be assumed that a separate container for liquids, for example, an infusion bag with a NaCl solution, can be connected to the regeneration line (14). However, it can also be assumed that the end of the regeneration line (14) that allows the connection of a container for liquids is located spatially close to the end of the connecting line (11) that allows the connection of a container for liquids, so that the container for liquids (with at least , two alternative connection options or with an appropriate adapter) can be connected to both the connecting line (11) and the regeneration line (14).

According to the invention, it is possible to have a single regeneration line (14) and particularly preferably 1 or 2 regeneration lines. It is also possible to implement the apheresis device according to the invention with two, three or more connecting lines (11', 11'', 11''', etc.), in which case these two, three or more regeneration lines can be connected to the extracorporeal circulation system (2) independently from each other in the region from the branch of the bypass line (12) on the plasma line (8A) (i.e. from point P2) to the apheresis column (4). "Independent" in this context means, for example, that, in an embodiment of the apheresis device according to the invention with two regeneration lines (14', 14''), one regeneration line (14') is connected to the line (8A ) of plasma between the point (P2) and the apheresis column (4), and the other line (14'') of regeneration goes directly to the apheresis column (4), but also that both lines (14', 14'') of regeneration can be connected to plasma lines (8A) between point (P2) and apheresis column (4). It is also possible that one regeneration line (14') is connected to another regeneration line (14''). However, if there are two or more lines (14', 14'', 14''', etc.) of regeneration, it is particularly preferred that all lines (14', 14'', 14''', etc.) .) regenerations were connected to the extracorporeal circulation system (2) at the same point in the area from the point (P2) to the apheresis column (4), and even more preferably, all lines (14', 14'', 14''' etc.) regenerations were connected to the extracorporeal circulation system (2) at the point (P2).

According to the invention, it is particularly advantageous if the connecting line (11) and the regeneration line (14) use the same source of fluid, since this not only saves space, but also minimizes the labor required to operate and maintain the apheresis device according to the invention. with invention. At the same time, existing apheresis systems can also be modified or supplemented without the need to connect a separate additional device of large dimensions. Therefore, in the preferred embodiments of the present invention, the regeneration line (14) branches off from the connecting line (11), the point on the connecting line (11) from which the regeneration line (14) branches off is designated as point (P5).

Therefore, according to some embodiments of the present invention, it is preferred that at least one regeneration conduit (14) leading to the plasma conduit (8A) or directly to the apheresis column (4) originate from a point (P5) on, at least one connecting line (11).

In embodiments in which there is more than one connecting line (11', 11'', 11''', etc.), and the regeneration line (14) is connected to several connecting lines (11', 11'', 11 ''', etc.), the symbols of the points (P5', P5'', P5''', etc.) of the junction are based on the symbols of the connecting trunks (11', 11'', 11''' etc.). That is, for example, in the case of a regeneration line (14) that fits or connects to two existing connecting lines (11', 11''), the point at which the regeneration line (14) connects to the connecting line (11') is denoted as a point (P5'), and the point at which the regeneration line (14) is connected to the connecting line (11'') is designated as a point (P5'').

The apheresis device (1) is preferred, in which the apheresis device (1) comprises two connecting lines (11', 11'') each for connecting one container (F1, F2) for fluids to the arterial line (5) or cell separator (7), and at the same time two regeneration lines (14', 14'') depart from two containers (F1, F2) for liquids or two connecting lines (11', 11'') and pass to the line (8A ) plasma or directly into the apheresis column (4).

It is also possible to contemplate embodiments in which the regeneration line (14) which passes to the plasma line (8A) or directly to the apheresis column (4) and which originates from the point (P5) on at least one connecting line (11 ), has at least one additional connection for a container for liquids (see Fig. 7).

In embodiments with a number of connecting lines greater than the number of regeneration lines, with each regeneration line forming a connection with at least one connecting line, it being possible that each regeneration line is connected to one connection line, and the excess(s) the connecting line(s) connect(s) only to the arterial line or cell separator, or that more numerous connecting lines converge on the regeneration lines, i. e. several connecting lines are connected to one regeneration line. Mixed options are also possible.

There are various possibilities for adjusting the flow rates in the part of the connecting line (11) after the point (P5) and in the regeneration line (14). This can be done, for example, by means of independently controlled pumps in the part of the connecting line (11) after the point (P5) and in the regeneration line (14). Another possibility would be a pump located in the connecting line (11) before point (P5), whereby the distribution of flow rates after point (P5) is either fixed by the diameters of the regeneration line (14) and the connecting line (11), or can be adjusted by a suitable means ( clamps, valves) (e.g. by changing the diameter of the respective line). Of course, adjusting the flow rates is especially important when a solution (for example, citrate solution) must be fed into the system through the connecting line (11) (for example, for blood anticoagulation) and, at the same time, must enter the apheresis column through the line ( 14) regeneration (for regeneration). With such mechanisms, for example, the supply of solution through the connecting line (11) can be kept constant (for example, for permanent anticoagulation), even if the solution branches off in the regeneration phases of the apheresis column into the regeneration line (14).

Compared to other systems, the apheresis device (1) operates with a maximum of 8, preferably 7, preferably 6 and most preferably 5 pumps.

Therefore, the present invention also relates to an apheresis device (1) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood or blood plasma, comprising:

an extracorporeal circulation system (2) for blood or blood plasma connected to the patient's circulatory system,

means (3) for forming and regulating the flow of blood or blood plasma in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

at least one apheresis column (4) to remove CRP by affinity chromatography from blood or blood plasma,

wherein the extracorporeal circulation system (2) contains an arterial line (5) from the patient to the cell separator (7),

a plasma line (8A) for the separated blood plasma coming from the cell separator (7) and fluidly connected to the apheresis column (4) to remove CRP by affinity chromatography,

highway (8B) plasma, coming from the apheresis column (4), for CRP-poor blood plasma,

highway (9) of the cell mass, coming from the separator (7) of cells, for the separated cellular components, which is connected to the highway (8B) of the plasma at the point (P1),

and

venous line (6) from the point (P1) to the patient,

central processor (10) to control the device (1) for apheresis,

at least one connecting line (11) for connecting at least one container for liquids, fluidly connected to the extracorporeal circulation system (2),

characterized in that the device (1) for apheresis further comprises:

a bypass line (12) that runs from a point (P2) on the line (8A) of the plasma to a point (P3) on the line (9) of the cell mass or to a point (P6) on the line (8B) of the plasma,

line (13) waste, which branches off from the point (P4) on line (8B) plasma,

at least one regeneration line (14) originating from point (P5) on at least one connecting line that passes into the extracorporeal circulation system (2) in the area from point (P2) to apheresis column (4),

and point (P4) is before points (P1) and (P6), or, in the case where bypass line (12) is connected at point (P3), point (P1) is the same as point (P4), or, in case when the bypass line (12) is connected at point (P6), point (P4) is the same as point (P6).

The present invention also relates to an apheresis device (1) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood or blood plasma, comprising:

an extracorporeal circulation system (2) for blood or blood plasma connected to the patient's circulatory system,

means (3) for forming and regulating the flow of blood or blood plasma in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

at least one apheresis column (4) to remove CRP by affinity chromatography from blood or blood plasma,

wherein the extracorporeal circulation system (2) contains an arterial line (5) from the patient to the cell separator (7),

a plasma line (8A) for the separated blood plasma coming from the cell separator (7) and fluidly connected to the apheresis column (4) to remove CRP by affinity chromatography,

highway (8B) plasma, coming from the apheresis column (4), for CRP-poor blood plasma,

highway (9) of the cell mass, coming from the separator (7) of cells, for the separated cellular components, which is connected to the highway (8B) of the plasma at the point (P1),

and

venous line (6) from the point (P1) to the patient,

central processor (10) to control the device (1) for apheresis,

at least one connecting line (11) for connecting at least one container for liquids to the arterial line (5) or to the cell separator (7),

characterized in that the device (1) for apheresis further comprises:

a bypass line (12) that runs from a point (P2) on the line (8A) of the plasma to a point (P3) on the line (9) of the cell mass or to a point (P6) on the line (8B) of the plasma,

line (13) waste, which branches off from the point (P4) on line (8B) plasma,

at least one regeneration line (14) originating from the point (P5) on at least one connecting line and connected to the plasma line (8A) after the point (P2) or directly to the apheresis column (4),

and point (P4) is before points (P1) and (P6), or, in the case where bypass line (12) is connected at point (P3), point (P1) is the same as point (P4), or, in case when the bypass line (12) is connected at point (P6), point (P4) is the same as point (P6).

In embodiments of the present invention with several connecting lines (11', 11'', 11''', etc.) and several lines (14', 14'', 14''', etc.) regeneration, one connecting line can be connected to one regeneration line in each case, which, in turn, is connected to the plasma line (8A) or directly to the apheresis column (4) after the point (P2). In this case, each regeneration line can be connected to the plasma line (8A) or directly to the apheresis column (4) at point after point (P2), independently of other regeneration lines. However, it is preferred that all regeneration lines are connected to the plasma line (8A) or directly to the apheresis column (4) at the same point after point (P2), even more preferably to the apheresis column (4) and most preferably at point (P2). One such exemplary embodiment can be explained with reference to FIG. 6: In this case, the device (1) for apheresis contains the first connecting line (11'), which, firstly, passes to the arterial line (5), and from which, secondly, the first line (14') of regeneration branches off. at the point (P5'). The apheresis device (1) also contains a second connecting line (11'') which, firstly, passes directly into the cell separator (7), and from which, secondly, the second regeneration line (14'') branches off in point (P5''). In this embodiment, both regeneration lines (14', 14'') are connected to the extracorporeal circulation system (2) at point (P2).

Therefore, an apheresis device (1) is preferred, in which the apheresis device (1) comprises two connecting lines (11', 11''), each for connecting at least one container (F) for fluids to the arterial line (5) or separator (7) cells, and at the same time, at least one line (14) regeneration leading to line (8A) plasma or directly to the apheresis column (4), joins at one point (P5') to connecting line (11') and at one point (P5'') to the connecting line (11'').

Thus, embodiments of the apheresis device (1) are particularly preferred, in which the apheresis device (1) comprises two connecting lines (11', 11''), each for connecting at least one container (F1, F2 ) for fluids to the arterial line (5) or cell separator (7), and at the same time, at least one regeneration line (14) leading to the plasma line (8A) or directly to the apheresis column (4) is connected at the point (P5') to the connecting line (11') and at the point (P5'') to the connecting line (11''), and moreover, the regeneration line (14') extends from the container (F1) for liquids or from the connecting line (11 '), which extends from the container (F1) for liquids, into the apheresis column (4) or to the plasma line (8A) or to the regeneration line (14'').

In a preferred embodiment, the liquid container (F1) contains saline NaCl solution and the liquid container (F2) contains a citrate solution.

Thus, it is particularly preferred that the apheresis device (1) comprises a connecting line (11') for connecting a container (F1) for liquids and a connecting line (11'') for connecting a container (F2) for liquids, and a connecting line (11 ') is connected to the arterial line (5) or to the cell separator (7), and the connecting line (11'') is connected to the arterial line (5) or to the cell separator (7) or to the connecting line (11') and therefore , ultimately also to the arterial line (5) or to the cell separator (7), and the regeneration line (14'), which runs from the container (F1) for fluids or from the connecting line (11') to the apheresis column (4 ) or to the plasma line (8A), and the regeneration line (14'') which passes from the container (F2) for liquids or from the connecting line (11'') to the apheresis column (4) or to the plasma line (8A), or in the line (14') regeneration.

In a preferred embodiment, the liquid container (F1) contains saline NaCl solution and the liquid container (F2) contains a citrate solution.

Therefore, embodiments of the apheresis device (1) are particularly preferred, in which the apheresis device (1) comprises a connecting line (11') for connecting a container (F1) for fluids to an arterial line (5) or cell separator (7) and connecting line (11'') for connecting the container (F2) for fluids to the arterial line (5) or cell separator (7), and at the same time the regeneration line (14') departs from the container (F1) for liquids or the connecting line (11 ') and is connected, downstream at or preferably downstream of the bypass line (12), to the plasma line (8A) or directly to the apheresis column (4), and the regeneration line (14'') departs from the container ( F2) for liquids or the connecting line (11'') and runs, in the direction of flow to a point, or preferably after a branch point of the bypass line (12), to the plasma line (8A) or to the line (14 ') regeneration or directly into the apheresis column (4).

Therefore, particularly preferred is an apheresis device (1) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood or blood plasma, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

at least one apheresis column (4) to remove CRP by affinity chromatography from blood,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4), a plasma line (8B) for CRP-poor blood plasma from the apheresis column (4) to point (P1), the line (9) of cell mass for separated cellular components from the cell separator (7) to point (P1), and the venous line (6) coming from point (P1),

central processor (10) to control the device (1) for apheresis,

connecting line (11') for connecting at least one container (F1) for liquids to the arterial line (5) or cell separator (7) and connecting line (11'') for connecting at least one container (F2) for fluids to the arterial line (5) or to the cell separator (7),

characterized in that:

the bypass line (12) branches off from the plasma line (8A) and is connected to the plasma line (8B),

the waste line (13) departs directly from the apheresis column (4) or from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and the regeneration line (14') departs from the container (F1) for liquids or connecting line (11') and passes, in the direction of flow to a point or, preferably, after a branch branch of the bypass line (12), to the line (8A) of the plasma or directly to the apheresis column (4), and the line (14'') regeneration departs from the container (F2) for liquids or connecting line (11'') and passes, in the direction of flow to the point or preferably after the branch point of the bypass line (12), to the plasma line (8A) or to the apheresis column (4) or combined with the line (14') regeneration.

Preferably, the liquid container (F1) is a physiological saline container and the liquid container (F2) is a citrate solution container.

In other words, therefore, according to one embodiment, an apheresis device (1) is preferred, in which the apheresis device (1) comprises two connecting lines (11', 11''), each for connecting at least , one container for fluids to the arterial line (5) or cell separator (7), and at the same time, at least one regeneration line (14), passing to the plasma line (8A) or directly to the apheresis column (4), installs connection with the connecting line (11') at the point (P5') and with the connecting line (11'') at the point (P5''). Thus, it should be understood that one line (14) regeneration is a connecting element between the connecting lines (11', 11'') on the one hand and line (8A) plasma or apheresis column (4) on the other hand. Therefore, liquid from one of the liquid containers (F) connected to one of the two connecting lines (11', 11'') can flow through the regeneration line (14) into the plasma line (8A) after point (P2) or directly into apheresis column (4).

Therefore, the present invention also relates to an apheresis device (1) for extracorporeal removal of CRP from blood or blood plasma, comprising:

an extracorporeal circulation system (2) for blood or blood plasma connected to the patient's circulatory system,

means (3) for forming and regulating the flow of blood or blood plasma in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

at least one apheresis column (4) to remove CRP by affinity chromatography from blood or blood plasma,

wherein the extracorporeal circulation system (2) contains an arterial line (5) from the patient to the cell separator (7),

a plasma line (8A) for the separated blood plasma coming from the cell separator (7) and fluidly connected to the apheresis column (4) to remove CRP by affinity chromatography,

highway (8B) plasma, coming from the apheresis column (4), for CRP-poor blood plasma,

highway (9) of the cell mass, coming from the separator (7) of cells, for the separated cellular components, which is connected to the highway (8B) of the plasma at the point (P1),

and

venous line (6) from the point (P1) to the patient,

central processor (10) to control the device (1) for apheresis,

two connecting lines (11', 11''), each for connecting at least one container for liquids connected in fluid medium with the extracorporeal circulation system (2),

characterized in that the device (1) for apheresis further comprises:

a bypass line (12) that runs from a point (P2) on the line (8A) of the plasma to a point (P3) on the line (9) of the cell mass or to a point (P6) on the line (8B) of the plasma,

line (13) waste, which branches off from the point (P4) on line (8B) plasma,

at least one regeneration line (14) which is connected to the extracorporeal circulation system (2) in the area from the point (P2) to the apheresis column (4), and which establishes a connection with the connecting line (11') at the point (P5' ) and with connecting line (11'') at point (P5''),

and point (P4) is before points (P1) and (P6) or, in the case where bypass line (12) is connected at point (P3), point (P1) is the same as point (P4), or, in case when bypass line (12) is connected at point (P6), point (P4) coincides with point (P6).

The present invention also relates to an apheresis device (1) for extracorporeal removal of CRP from blood or blood plasma, comprising:

an extracorporeal circulation system (2) for blood or blood plasma connected to the patient's circulatory system,

means (3) for forming and regulating the flow of blood or blood plasma in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

at least one apheresis column (4) to remove CRP by affinity chromatography from blood or blood plasma,

wherein the extracorporeal circulation system (2) contains an arterial line (5) from the patient to the cell separator (7),

a plasma line (8A) for the separated blood plasma coming from the cell separator (7) and fluidly connected to the apheresis column (4) to remove CRP by affinity chromatography,

highway (8B) plasma, coming from the apheresis column (4), for CRP-poor blood plasma,

highway (9) of the cell mass, coming from the separator (7) of cells, for the separated cellular components, which is connected to the highway (8B) of the plasma at the point (P1),

and

venous line (6) from the point (P1) to the patient,

central processor (10) to control the device (1) for apheresis,

two connecting lines (11', 11'') each for connecting at least one fluid container to an arterial line (5) or cell separator (7),

characterized in that the device (1) for apheresis further comprises:

a bypass line (12) that runs from a point (P2) on the line (8A) of the plasma to a point (P3) on the line (9) of the cell mass or to a point (P6) on the line (8B) of the plasma,

line (13) waste, which branches off from the point (P4) on line (8B) plasma,

at least one regeneration line (14) which is connected to the plasma line (8A) or directly to the apheresis column (4) and which connects to the connecting line (11') at point (P5') and to the connecting line ( 11'') at point (P5''),

and point (P4) is before points (P1) and (P6) or, in the case where bypass line (12) is connected at point (P3), point (P1) is the same as point (P4), or, in case when bypass line (12) is connected at point (P6), point (P4) coincides with point (P6).

According to one embodiment of the present invention, it is preferred that the apheresis device (1) according to the invention comprises two connecting lines (11', 11''), wherein the first connecting line (11') for connecting at least one fluid container (preferably a fluid container designed for or containing a NaCl solution) is connected (i.e. fluidly connected) to the arterial line (5), and a second connecting line (11'') for connecting at least at least one liquid container (preferably a liquid container intended for or containing a citrate solution) is connected (ie fluidly connected) directly to the cell separator (7). Furthermore, it is advantageous when the apheresis device (1) according to the invention comprises a single regeneration line (14) which, after point (P2), is connected to the plasma line (8A) or directly to the apheresis column (4), and which, however, originates from or is connected to both the first connecting line (11') and the second connecting line (11'') (see FIG. 5). This means that the regeneration line (14) is connected to the first connecting line (11') at the point (P5') and to the second connecting line (11'') at the point (P5'') and then passes into the plasma line (8A) or directly into the apheresis column (4), after the point (P2). By means of suitable valves or clamps for flexible tubes, the liquid can be directed, if necessary, through the regeneration line (14) from the liquid container connected to the first connecting line (11'), to the apheresis column (4) or, after the point (P2) , into the plasma line (8A), or the liquid can also be directed from the liquid container connected to the second connecting line (11'').

Such embodiments with two (or even more) connecting lines are ideally suitable for using different regeneration solutions to regenerate the apheresis column (4) and to feed them sequentially to the apheresis column (4). For example, such a device is theoretically suitable for introducing first a NaCl solution to displace the plasma contained in the apheresis column, then a citrate solution for efficient and rapid regeneration of the adsorber, and finally again a NaCl solution to displace the citrate solution contained in the apheresis column, before how to reinject plasma into the apheresis column.

Therefore, a particularly preferred embodiment of the present invention relates to an apheresis device (1) for extracorporeal removal and preferably selective extracorporeal removal of CRP from blood or blood plasma, comprising:

an extracorporeal circulation system (2) for blood or blood plasma connected to the patient's circulatory system,

means (3) for forming and regulating the flow of blood or blood plasma in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

at least one apheresis column (4) to remove CRP by affinity chromatography from blood or blood plasma,

wherein the extracorporeal circulation system (2) contains an arterial line (5) from the patient to the cell separator (7),

a plasma line (8A) for the separated blood plasma coming from the cell separator (7) and fluidly connected to the apheresis column (4) to remove CRP by affinity chromatography,

highway (8B) plasma, coming from the apheresis column (4), for CRP-poor blood plasma,

highway (9) of the cell mass, coming from the separator (7) of cells, for the separated cellular components, which is connected to the highway (8B) of the plasma at the point (P1),

and

venous line (6) from the point (P1) to the patient,

central processor (10) to control the device (1) for apheresis,

the first connecting line (11') for connecting at least one fluid container to the arterial line (5) and the second connecting line (11'') for connecting at least one fluid container directly to the separator (7) cells;

characterized in that the device (1) for apheresis further comprises:

a bypass line (12) that runs from a point (P2) on the line (8A) of the plasma to a point (P3) on the line (9) of the cell mass or to a point (P6) on the line (8B) of the plasma,

line (13) waste, which branches off from the point (P4) on line (8B) plasma,

at least one regeneration line (14) which is connected to the plasma line (8A) or directly to the apheresis column (4) after the point (P2) and which establishes a connection at the point (P5') with the connecting line (11') and at point (P5'') with connecting line (11''),

and point (P4) is located before points (P1) and (P6).

In embodiments of the apheresis device according to the invention, in which the bypass line (12) extends to the point (P6) on the line (8B) of the plasma, preferably when the point (P6) is located before (in the direction of flow) the point (P1) ( see figures 1-3).

In accordance with a preferred embodiment of the present invention, the connecting line is connected to the arterial line. In accordance with another preferred embodiment of the present invention, the connecting line is connected directly to the cell separator.

According to a preferred embodiment of the present invention, the regeneration line (14) is connected to the plasma line (8A) after point (P2), i. between the point (P2) and the apheresis column (4). In accordance with a further preferred embodiment of the present invention, the regeneration line (14) passes directly into the apheresis column (4).

In order to reduce the dead volume of the system according to the invention, it is particularly advantageous when, in the apheresis device (1) according to the invention, at least one regeneration line (14) is connected to the extracorporeal circulation system (2) at point (P2) . In embodiments where there is more than one regeneration line (14', 14'', 14''', etc.) it is particularly preferred that all existing lines (14', 14'', 14''' and etc.) regenerations are connected to the extracorporeal circulation system (2) at the point (P2) or are connected to the plasma line (8A) at the point (P2).

Therefore, the present invention also relates to an apheresis device (1) according to the invention, wherein the bypass line (12) extends from a point (P2) on the plasma line (8A) to a point (P6) on the plasma line (8B), and waste line (13) exits at point (P4) from plasma line (8B), and at least one regeneration line (14) is connected to plasma line (8A) at point (P2).

To further reduce the dead volume of the system, it is even more preferable that not only the regeneration line (14) is connected to the plasma line (8A) at point (P2), at which, in addition, the bypass line (12) branches off from the plasma line (8A), but also when the waste line (13) branches off from the same point on the plasma line (8B) to which the bypass line (12) is also connected. In other words, it is preferable that the point (P6) at which the bypass line (12) is connected to the plasma line (8B) and the point (P4) at which the waste line (13) branches off from the plasma line (8B) coincide, i.e. .e. when P4=P6 (see also Fig. 2 and Fig. 3).

Therefore, the present invention also relates to an apheresis device (1) according to the invention, in which the bypass line (12) extends from a point (P2) on the plasma line (8A), to a point (P6) on the plasma line (8B), and the waste line (13) exits from the point (P4) on the plasma line (8B), and at least one regeneration line (14) is connected to the plasma line (8A) at the point (P2), and the point (P6 ) and point (P4) are identical.

In the device according to the invention, a cell separator is installed, which separates the patient's blood supplied to it (via the arterial line) into blood plasma and cellular components and transfers the said fractions to the respective lines, i.e., respectively, the plasma line and the cell line masses. In this case, as already mentioned, it must be taken into account that the separation into blood plasma and cellular components by means of the cell separators used is not completely carried out, but only, preferably, 10-90% of the entire blood plasma is separated from the cellular components. When centrifugal cell separators are used, preferably 70% to 90%, more preferably 80% to 87% of the total blood plasma is separated from the cellular components. When membrane cell separators are used, preferably 10% to 30%, more preferably 13% to 25%, even more preferably 15% to 20% of the total blood plasma is separated from the cellular components.

Possible types of cell separators that can be used in connection with the present invention include centrifugal cell separators, membrane cell separators, for example, membrane cell separators with semi-permeable membranes and membrane cell separators with rotating membranes.

Therefore, the present invention also relates to an apheresis device for extracorporeal removal of CRP from blood, in which the cell separator (7) is either a centrifugal cell separator or a membrane cell separator.

When in this application the position of one or more components of the apheresis device according to the invention relative to another component of the apheresis device according to the invention is described by the terms " before " or " after " (or "before in the direction of flow" and "after in the direction of flow" ), such a description refers to the general direction of blood or plasma flow in the apheresis device according to the invention. "Before" in relation to a device component according to the invention means, therefore, against the general direction of blood or plasma flow, and "after" in relation to a device component according to the invention, therefore, is consistent with the general direction of blood or plasma flow blood. Preferably, the direction of flow in the apheresis device is not reversed or reversed by means for shaping and controlling the flow.

According to the present invention, an apheresis device for extracorporeal removal of CRP from blood according to the invention comprises an apheresis column (4) for removing CRP by affinity chromatography from blood or blood plasma, the purpose of which is to bind CRP that is present in blood or plasma the patient's blood, which is passed through the apheresis column (4).

The term " affinity chromatography " in relation to the removal of CRP in the context of this application means that the removal of CRP occurs through specific binding between CRP and components of the apheresis column (4) to remove CRP. In this context, one can also speak of "selective CRP removal" or "selective CRP apheresis". Such specific binding between CRP and components of the apheresis column (4) is based on the structural properties of the CRP protein and includes, for example, the characteristic binding of CRP to phosphocholine as well as its derivatives, or the binding of CRP to antibodies directed to the CRP epitope. Selective or molecular specific removal of CRP involves binding CRP with higher affinity to the matrix in the apheresis column (4) than to other structures/molecules. In addition, CRP binds with a higher affinity to the matrix in the apheresis column (4) than to other substances present in the blood, ie, the matrix is CRP specific or the matrix is CRP specific. The matrix, preferably a solid phase modified with phosphocholine, preferably binds CRP selectively, i.e. binds almost exclusively to CRP and no other blood components such as LDL cholesterol, antibodies or uremic toxins bind. Thus, "removal of CRP", disclosed in this application, preferably means the selective removal of CRP.

In principle, the design or construction of such an apheresis column (or cartridge or cassette) is state of the art and can be taken from EP 0237659 B1, for example. The exact dimensions of the cartridge, column or cassette used in accordance with the invention (as a device for selective removal of CRP) depend to a large extent on the intended use of the device in accordance with the invention. The apheresis column (4) for removing CRP by affinity chromatography usually contains a housing, for example, in the form of a cartridge or cassette, which is connected in fluid medium with the extracorporeal circulation system through at least one inlet and at least one outlet , and which contains a matrix for removing CRP by affinity chromatography or adsorption.

The matrix for removing CRP by affinity chromatography (or adsorption) contains a carrier matrix material, to which, in turn, compounds are associated that have the property of specific binding of CRP. In accordance with a preferred embodiment of the present invention, the matrix is formulated or immobilized in the apheresis column (4) for CRP removal by affinity chromatography such that the matrix cannot be washed out of the column by the blood plasma flow. Depending on the embodiment, this can be implemented, for example, in the form of filters on the inlet and outlet of the device.

In principle, all inert chromatography materials or columns are suitable as matrix carrier materials for the preparation of a matrix which, in particular, do not react with blood or blood plasma or do not alter or contaminate blood or blood plasma in such a way that that the blood or blood plasma can no longer be returned to the patient after contact with the matrix. Therefore, suitable matrix carrier materials according to the invention include, but are not limited to, Eupergite, polyvinylpyrrolidone, methacrylate, methacrylate resins, agarose, sepharose, acrylic beads, cellulose matrices, ceramic matrices, glass beads and/or solid phase silica or their mixtures and/or derivatives. The solid phase silica matrix may contain virtually any form of silica particles, including amorphous silicas such as colloidal silica, silica gels, precipitated silicas, and aerosol powdered or fumed silicas; microcrystalline silicas such as diatomaceous earth; and crystalline silicas such as quartz. According to the invention, compounds that bind to matrix carrier materials that have the property of specific CRP binding are selected from the group consisting of lipids, lysophospholipids, lysophosphatidylcholine, peptides, peptides containing charged amino acids, peptides containing the ArgProArg sequence, polypeptides, antibodies , monoclonal antibodies, antibody fragments, engineered antibodies, phosphocholine, phosphocholine derivatives, DNA, DNA derivatives, RNA, RNA derivatives, L-ribonucleic acid aptamers such as Spiegelmere® (an RNA-like molecule composed of L-ribose units) and aptamers .

Ca2+-dependent ligands for CRP

As already mentioned several times, for the removal of CRP by affinity chromatography from biological fluids, for example, from blood or blood plasma, a column material containing phosphocholine and / or its derivatives is used, allowing Ca2+-dependent binding of CRP to the mentioned functionalized column material.

For this purpose, phosphocholine and/or its derivatives are immobilized on the column material. This is usually done by an organic linker group, whereby the phosphocholine or its derivatives are bound to the column material by adsorption, or even more preferably by covalent bonding. This results in a so-called " functionalized column material " where the chemical group responsible for the Ca2+-dependent CRP binding is exposed to the outside so that the CRP that is in the body fluid also has access to said chemical group.

In other words, the term " functionalized column material " as used herein refers to an affinity chromatography column material that is provided with a functional chemical group. In this case, the functional chemical group can be connected to the column material through adsorption or ionic interactions, but preferably through a covalent bond. Of course, it is important that the functional chemical group be associated with the column material in such a way that the functional group is active and exposed to the outside so that its functionality is maintained. This enables the group (here: ω-phosphonooxyalkylammonium group and/or ω-ammoniumalkoxyhydroxyphosphoryloxy group) attached to the column material to interact or bind with the ligand (here: CRP) from the sample (here: biological fluid such as blood or plasma blood).

Depending on whether phosphocholine or its derivative binds to the column material through an ammonium group or through a phosphate group, using an organic linker, a distinction is made between a column material functionalized with an ω-phosphonooxyalkylammonium group (bond with an ammonium group) and a column material a column functionalized with an ω-ammonium alkoxyhydroxyphosphoryloxy group (linked via a phosphate group).

Linkage to the column material (using an organic linker, if necessary) is shown in Formulas (I) and (II) below by a dotted line on either the nitrogen of the ammonium group or the oxygen of the phosphate group.

The term "ω- phosphonooxyalkylammonium group " as used herein can be used as a synonym for "omega-phosphonooxyalkylammonium" and describes compounds with the following general formula (I).

where

n is selected from 2 and 3;

R ¹ and R ² are independently selected from: -H, -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -C ₄ H ₉ , -C ₅ H ₁₁ , -C ₆ H ₁₃ , or R ¹ and R ² together with the nitrogen atom to which they are attached may form a heterocycle selected from:

,

,

,

,

,

,

where one or more hydrogen atoms can be replaced by (a) fluorine atom(s).

Preferred ω-phosphonooxyalkylammonium groups contain compounds of the general formula (I)

where

n is 2 and 3;

R ¹ and R ² are independently selected from: -H, -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , or R ¹ and R ² together with the nitrogen atom to which they are attached may form a heterocycle , which is selected from:

, и

.

, and

.

Particularly preferred ω-phosphonooxyalkylammonium groups comprise compounds of the general formula (I)

where

n is 2;

R ¹ and R ² are selected from: -H, -CH ₃ , -C ₂ H ₅ , and particularly preferably from -CH ₃ , -C ₂ H ₅ , or R ¹ and R ² together with the nitrogen atom to which they attached, can form a heterocycle from:

,

.

,

.

Preferred compounds containing the above-described ω-phosphonooxyalkylammonium group and suitable for the functionalization of the corresponding column material include, for example:

2-[2-(2-aminoethoxy)ethyl-diethyl-ammonio]ethyl hydrogen phosphate, 2-[4-[2-(2-aminoethoxy)ethyl]morpholin-4-ium-4-yl]ethyl hydrogen phosphate, 2-[1- [2-(2-aminoethoxy)ethyl]piperidin-1-ium-1-yl]ethyl hydrogen phosphate, 2-[2-(2-aminoethoxy)ethyl-dimethyl-ammonio]ethyl hydrogen phosphate, 2-[3-aminopropyl-( dimethyl) ammonio] ethyl hydrogen phosphate, 2-[dimethyl (4-sulfanylbutyl) ammonio] ethyl hydrogen phosphate, 2-[4-azidobutyl (dimethyl) ammonio] ethyl hydrogen phosphate, 2-[dimethyl (pent-4-ynyl) ammonio] ethyl hydrogen phosphate, 2-[ 3-(6-Aminohexanoylamino)propyldiethylammonio]ethyl hydrogen phosphate, 2-[1-[2-[2-(6-aminohexanoylamino)ethoxy]ethyl]piperidin-1-ium-1-yl]ethyl hydrogen phosphate, 2-[4- [2-[2-[3-(6-aminohexanoylamino)propanoylamino]ethoxy]ethyl]morpholin-4-ium-4-yl]ethyl hydrogen phosphate, 2-[1-[2-[2-[6-(6-aminohexanoylamino )hexanoylamino]ethoxy]ethyl]pyrrolidin-1-ium-1-yl]ethylhydrogen phosphate, 2-[2-allyloxyethyl(dimethyl)ammonio]ethylhydrophosphate, 2-[2-allyloxyethyl(diethyl)ammonio]ethylhydrogenphosphate, 2-[4- (2-allyloxyethyl)morpholin-4-ium-4-yl]ethyl hydrogen phosphate, 2-[1-(2-allyloxyethyl)piperidine-1-u m-1-yl]ethyl hydrogen phosphate, 2-[2-[2-(6-aminohexanoylamino)ethoxy]ethyldimethylammonio]ethyl hydrogen phosphate, 2-[2-[2-[3-(6-aminohexanoylamino)propanoylamino]ethoxy]ethyldimethylammonio]ethyl hydrogen phosphate . )ethoxy]ethyldimethylammonio]ethyl hydrogen phosphate, 2-[2-[2-[6-(allyloxycarbonylamino)hexanoylamino]ethoxy]ethyldimethylammonio]ethyl hydrogen phosphate, 2-[2-(6-aminohexanoylamino)ethyldimethylammonio]ethyl hydrogen phosphate, 2-[dimethyl-[3 -[6-(prop-2-inoxycarbonylamino)hexanoylamine]propyl]ammonio]ethyl hydrogen phosphate and 2-[3-(6-aminohexanoylamino)propyldimethylammonio]ethyl hydrogen phosphate.

The term "ω- ammonium alkoxyhydroxyphosphoryloxy " as used herein can be used as a synonym for "omega-ammonium alkoxyhydroxyphosphoryloxy" and describes compounds with the following general formula ( II )

where

n is selected from 2 and 3;

R ¹ , R ² and R ³ are independently selected from: -H, -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -C ₄ H ₉ , -C ₅ H ₁₁ , -C ₆ H ₁₃ ,

or R ¹ and R ² together with the nitrogen atom to which they are attached may form a heterocycle selected from:

,

,

,

,

,

,

and

R ³ is selected from: -H, -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -C ₄ H ₉ , -C ₅ H ₁₁ , -C ₆ H ₁₃ , and preferably -H;

where one or more hydrogen atoms can be replaced by (a) fluorine atom(s).

Preferred "ω-ammoniumalkoxyhydroxyphosphoryloxy groups" contain compounds with the general formula ( II ),

where

n is selected from 2 and 3;

R ¹ , R ² and R ³ are independently selected from: -H, -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ ,

or R ¹ and R ² together with the nitrogen atom to which they are attached may form a heterocycle selected from:

,

,

,

,

and R³ is -H.

Within the scope of the present invention, it is particularly preferred if the ω-ammoniumalkoxyhydroxyphosphoryloxy group is a ω-trialkylammoniumalkoxyhydroxyphosphoryloxy group.

Thus, particularly preferred ω-ammonium alkoxyhydroxyphosphoryloxy groups contain compounds with the general formula ( II ),

where

n is 2;

and R ¹ , R ² and R ³ are selected from: -H, -CH ₃ , -C ₂ H ₅ , and particularly preferably from -CH ₃ and -C ₂ H ₅ .

It is also particularly preferred if the ω-ammonium alkoxyhydroxyphosphoryloxy groups are ω-trimethylammonium methoxyhydroxyphosphoryloxy groups or ω-trimethylammonium propoxyhydroxyphosphoryloxy groups.

Preferred compounds containing the above-described ω-ammoniumalkoxyhydroxyphosphoryloxy group and suitable for the functionalization of the corresponding column material contain, for example: ) or p-nitrophenyl-6-(O-phosphocholine)hydroxyhexanoate.

In one exemplary embodiment of the present invention, the ω-ammoniumalkoxyhydroxyphosphoryloxy group is phosphoester bonded to the hydroxy group of the glycerol molecule (as an organic linker), the resulting glycerol ester being further bonded to the column material via a second glycerol hydroxy group. In such an embodiment, it is also possible that the remaining hydroxy group is either esterified with a fatty acid or esterified with a second ω-ammonium alkoxyhydroxyphosphoryloxy group. Moreover, the position of the corresponding esterification on the glycerol molecule can change. Suitable fatty acids are conventional saturated, monoolefinic, polyolefinic, monoacetylenic, unsaturated linear and/or branched fatty acids having 8-28 carbon atoms. Preferred fatty acid residues are palmitic acid, arachidonic acid, levulinic acid, glutaric acid, isoprostanic acid epoxy, and steparic acid.

Column material

For the preparation of column material functionalized with ω-phosphonooxyalkylammonium and/or ω-ammoniumalkoxyhydroxyphosphoryloxy groups, in principle all inert chromatography materials or column materials are suitable, such as materials which, in particular, do not react with blood or blood plasma or do not alter or contaminate the blood or blood plasma in such a way that the blood or blood plasma, after contact with the column material, can no longer be injected into the patient. Therefore, column materials useful in the present invention include, but are not limited to: Eupergite®, polyvinylpyrrolidone (PVP), polysulfone (PS), polyethersulfone (PES), polyarylethersulfone (PAES), polyacrylate, methacrylate, methacrylate resins such as poly(methyl methacrylate ) (PMMA) and poly(glycidyl methacrylate) (PGMA), poly(hydroxy methacrylate), polystyrene (PS), polytetrafluoroethylene (PTFE), polyacrylamide, polyacrolein, acrylonitrile butadiene styrene (ABS), polyacrylonitrile (PAN), polyurethane (PU), Sepharose® ( sepharose), acrylic beads, agarose, cellulose matrices, polyethylene glycol (PEG), alginate, carrageenan, chitin, starch, nitrocellulose, ceramic matrices, glass beads and/or solid phase silica, or mixtures and/or derivatives of these substances. The solid phase silica matrix may contain virtually any form of silica particles, including amorphous silica such as colloidal silica, silica gel, precipitated silica, and aerosol powdered or fumed silica; microcrystalline silica such as diatomaceous earth; and crystalline silica such as quartz. The silica has a particle size in the range of about 45 to 120 mesh (about 345 µm to 125 µm), preferably in the range of about 45 to 60 mesh (about 345 µm to 212 µm).

Often, functionalization with ω-phosphonooxyalkylammonium and/or ω-ammoniumalkoxyhydroxyphosphoryloxy groups uses column material that has already been "pre-functionalized", i. was provided with a chemical group which then, in turn, allows covalent attachment of ω-phosphonooxyalkylammonium and/or ω-ammoniumalkoxyhydroxyphosphoryloxy groups.

This "pre-functionalization" of the column material is achieved by methods well known to those skilled in the art (Chin. J, Chem. 2012, 30, 2473, Polym. Int. 2013, 62, 991). In addition, some already "pre-functionalized" column materials are commercially available, such as Toyopearl® AF-epoxy, Toyopearl® AF-amino, Toyopearl® AF-tresyl, TSKgel® tresyl, Sepharose® 6B epoxy-activated Sepharose® 6B (GE Healthcare Life Sciences), CNBr-activated Sepharose® 4 fast flow (GE Healthcare Life Sciences), ECH Sepharose® 4B (GE Healthcare Life Sciences), NHS-activated Sepharose® 4 fast flow (GE Healthcare Life Sciences) Sepharose® 4 fast flow vinyl sulfone (Affiland), Separopore® aldehyde (agarose) 4B, ECH Separopore® (agarose) 4B (Separopore), agarose from Sterogene Bioseparations, Inc., e.g. Epoxy-UltraFlow-4 Agarose (Sterogene Bioseparations, Inc.), Epoxy-UltraFlow-6 Agarose (Sterogene Bioseparations, Inc), agarose from emp Biotech GmbH, Epoxy-UltraFlow-4 Agarose (EMP Biotech GmbH), Epoxy-UltraFlow-6 Agarose (EMP Biotech GmbH), activated agaroses with any degree stitching. Columns for the selective removal of cholesterol (LDL cholesterol) and anti-factor VII or IX antibodies are in principle not suitable and cannot be used for the removal of CRP by affinity chromatography and in particular for the selective removal of CRP by affinity chromatography from blood.

Columns consisting of protein A bound to a carrier matrix material are suitable for antibody purification by affinity chromatography, i.e. the column is specific for antibodies but not for CRP.

A well-known example of a matrix for LDL cholesterol removal by affinity chromatography is polyacrylamide beads with polyacrylic acid covalently bound to their surface (also known by the trade names Dali beads, where DALI stands for "direct lipid adsorption"). Only small proteins (lipoproteins such as LDL with a diameter of 25 nm) diffuse through the pores (100-200 nm in diameter) into the sponge-like structure of the granules due to their size.

Pumps

In accordance with the present invention, in an apheresis device for extracorporeal removal of CRP from blood in accordance with the invention, means are provided for forming and regulating the flow of blood (or blood plasma) in the extracorporeal circulation system. For this, one or more pumps or pumping systems are usually used, which allow the controlled flow of blood (or blood plasma or also regenerating solution or anticoagulant solution) in the extracorporeal circulation system and the components of the device according to the invention, which are fluidly connected to the system. .

In accordance with the invention, the preferred direction of flow in the extracorporeal circulation system and the components of the device according to the invention which are fluidly connected to the system is from the access point on the patient, through which blood enters the device according to the invention, along the arterial line of the system extracorporeal circulation to the venous line of the extracorporeal circulation system, and to the access site on the patient, in which the purified blood is returned to the patient.

The means used in accordance with the invention for generating and regulating the flow in the extracorporeal circulation system are preferably pumps in the form of peristaltic pumps (also called peristaltic pumps), piston pumps, pneumatic pumps, hydraulic pumps or other types of pumps known to the person skilled in the art. Therefore, the term "means for generating and regulating the flow" and the term "pump" can be used interchangeably in this application.

According to the invention, it is preferable that the means used to form and regulate the flow of blood (or blood plasma, or also regeneration solution or anticoagulant solution) in the extracorporeal circulation system do not have direct physical contact with blood (or blood plasma, or also regeneration solution). or anticoagulant solution) in the device according to the invention. This is particularly useful for hygienic reasons and prevents complex medical components such as the pump from being contaminated with blood, and of course also the blood with the flow agent used.

Therefore, in a particularly preferred embodiment of the present invention, the means for generating and regulating the flow in the extracorporeal circulation system is one or more peristaltic pumps.

The exact location of the means for shaping and regulating the flow in the extracorporeal circulation system, i. e. one or more pumps is not essential to the present invention. Embodiments of the present invention are possible using only one pump, with the pump located in the area of the arterial line of the apheresis device according to the invention for the extracorporeal removal of CRP from the blood, i.e. before the cell separator. In accordance with the invention, if several means are provided in the extracorporeal circulation system for shaping and regulating the flow, i. several pumps, it is preferable if the pumps can be controlled and controlled independently of each other (for example, by means of a central processor). Depending on the particular application, different flow rates within the extracorporeal circulation system may be useful or required. It can also be assumed that different flow rates may be desirable in different components of the device according to the invention, in a particular application.

In accordance with the invention, several means for shaping and controlling the flow (ie pumps) can also be included in the apheresis device according to the invention. Thus, it is possible that the means for shaping and regulating the flow are located in the arterial line (5) and/or in the plasma line (8A) and/or in the plasma line (8B) and/or in the venous line (6), and /or in the bypass line (12), and/or in the line (9) of the cell mass, and/or in the connecting line (11) and/or in the connecting lines (11', 11'', 11''', etc.). etc.), and/or in the line (14) regeneration or lines (14', 14'', 14''', etc.) regeneration. As mentioned above, according to the embodiment of the present invention, in which the regeneration line (14) branches off from the connecting line (11) at point (P5), it is preferable that a means for forming and controlling the flow (inorganic salt solutions) be provided in the connecting line (11) before point (P5).

According to a further embodiment of the present invention, in which the regeneration line (14) branches off from the connecting line (11) at point (P5), it is preferable that means for generating and controlling the flow be provided in the connecting line (11) after point (P5 ), and a means for shaping and regulating the flow was provided in the regeneration line (14).

In addition, the apheresis device (1) preferably comprises at least one particle filter, which is provided downstream of the apheresis column (4) in the plasma line (8B) or venous line (6).

In addition, the apheresis device (1) preferably comprises at least one bubble catcher provided downstream of the apheresis column (4) in the plasma line (8B) or venous line (6).

In the case of a centrifuge as a cell separator (7), the apheresis device (1) preferably comprises at least one plasma reservoir provided after the centrifuge (7) and before the apheresis column (4) in the plasma line (8A).

In additional embodiments, an apheresis device according to the invention for extracorporeal removal of CRP from blood or blood plasma may comprise one or more pressure sensors that serve to measure or control the pressure in a particular section of the device according to the invention. This serves not only to monitor and adjust the operating parameters of the apheresis device according to the invention, but is also useful in that, in the event of a malfunction (for example, blockage of the tube or filter of the device), operation can be stopped in order to avoid dangerous consequences for the patient. The exact mode of operation and installation location in the device according to the invention are prior art and are known to the person skilled in the art. In a preferred embodiment of the present invention, at least one pressure sensor is located in the arterial line of the apheresis device according to the invention, and at least one pressure sensor is located in the venous line of the apheresis device according to the invention. In a further preferred embodiment of the present invention, such pressure sensors are incorporated in the means used to generate and control flow in the extracorporeal circulation system of the apheresis device of the invention.

In order to be able to control the direction of flow in the system at the nodal points of the extracorporeal circulation system, i.e. at the points where the plurality of conduits converge or diverge from one another, means are preferably provided which determine the flow of the solution (eg blood, plasma or regenerant solution). Such means may be valves, multi-way valves, clamps, or valves in the form of check valves, control valves, pressure valves, directional valves, or other types of valves known to those skilled in the art that allow flow in one direction and block it in another direction. . Such flow control means (e.g. valves) are preferably located at point (P1) and/or at point (P2) and/or at point (P3) and/or at point (P4) and/or at point ( P5), and/or at a point (P6). It is also possible that, for example, at one point, two or more valves are connected in series to allow more complex flow control.

It is also particularly advantageous if the means for regulating the flow (eg valves) can be controlled electronically, i.e. their position may depend on the CPU (10).

Therefore, the present invention also relates to an apheresis device for extracorporeal removal of CRP from blood, in which valves are provided at points (P1), (P2), (P4), (P5), (P6), (P7) and (P8). with electronic control.

In addition, it is possible and according to the invention it is possible that the valves are not located directly at the points (P1, P2, P4, P5, P6, P7 and P8) of the branching, but are located in the incoming and/or outgoing lines and from these positions they control flow of solutions in the extracorporeal circulation system. Hose clamps can also be used for this purpose. It is particularly advantageous if these valves or hose clamps are controlled electronically.

Another advantage of the present invention, which is due to the fact that apheresis and regeneration of the apheresis column are implemented in a single device, is that the device as a whole can be controlled by only one central processing unit (CPU). Thus, various programs during an apheresis session, such as normal operation, during which the blood plasma is passed through the apheresis column, and the regeneration operation, during which the blood plasma is passed around the apheresis column along the bypass line, and the apheresis column is washed with regeneration solution, may run under the control of a single processor or software installed in it. This facilitates the automation of many processes and thus reduces the scale of human operator error. In prior art devices, on the other hand, it is necessary to combine different complex systems (a primary system for separating blood into plasma and cellular components; and an auxiliary system for apheresis and regeneration), with each system controlled separately.

Therefore, the present invention also relates to an apheresis device for extracorporeal removal of CRP from blood, in which the entire device is under the control of one central processor (10).

A further aspect of the present invention relates to an apheresis device in which a second apheresis column (4'') is connected to a bypass or the bypass contains a second apheresis column. The second apheresis column (4'') is preferably contained in the bypass line. Thus, the apheresis devices of the invention described herein for the extracorporeal removal of CRP from blood may comprise a second apheresis column (4'') with the second apheresis column (4'') contained in the bypass line. The apheresis column (4'') is contained in the bypass line when the bypass section (12') in the bypass line (12) is connected to the second apheresis column (4''), and the other section (12'') of the bypass line in the bypass line (12) extends from the outlet of the apheresis column (4'').

Therefore, a further aspect of the present invention is an apheresis device (II) for in vitro removal, and preferably for selective in vitro removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1), the line (9) of the cell mass for the separated cellular components from the cell separator (7) to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (1) for apheresis,

a connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

different in that

the bypass line (12) branches off from the plasma line (8A) and is connected to the plasma line (8B), and the bypass line (12) contains a second apheresis column (4''),

the waste line (13) departs directly from the apheresis column (4') or from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and

at least one regeneration line (14) departs from at least one container (F) for liquids or from at least one connecting line (11) and passes to the plasma line (8A), in the direction of flow in point or after the branch point of the bypass line (12), or passes directly into the apheresis column (4'), and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') can only be used alternately, i.e. cannot be used simultaneously to remove CRP.

The above-mentioned embodiments of the apheresis device (1) according to the invention are to be converted into the apheresis device (II) according to the invention.

With said apheresis device (II) according to the invention it is possible to remove CRP from the blood more efficiently than with previous devices during the same treatment time. When using two apheresis columns connected in parallel, which can only be used to remove CRP alternately, one apheresis column can be used by means of the apheresis device according to the invention to remove CRP from the blood, while the second apheresis column can be replaced by another apheresis column, or the second apheresis column can be regenerated during an ongoing apheresis session. Thus, a high clinical throughput can also be achieved with the apheresis device. Moreover, the use of the apheresis device according to the invention is not limited to dead volume. Typically, oversized apheresis columns, as well as apheresis columns connected in series, are severely limited in apheresis applications due to their large dead volume. In addition, the volume of the apheresis device, and hence the volume of the series of apheresis columns connected in series, determines the amount of blood flow from the person. Apheresis devices with apheresis columns connected in parallel and used simultaneously cannot be effectively used to remove CRP from blood without risk to the patient due to large dead volume. Accordingly, the bypass line (12) can be used as a plasma line.

The apheresis device (II) according to the invention described in the present application is characterized in that the second apheresis column is connected in parallel with the first apheresis column (4'). "Parallel" in this context means that the different blood flows in a closed circuit occur side by side within the extracorporeal circulation system (2), i.e., for example, the first apheresis column (4') with a plasma manifold (8A) for separated plasma and with a manifold (8B) plasma for CRP-poor plasma is the first circulation system of the extracorporeal circulation system (2), and the second apheresis column (4'') with the bypass section (12') in the bypass line (12) and the section (12'' ) bypass line in the bypass line (12) is the second circulation system of the extracorporeal circulation system (2). "Parallel" also means that the two apheresis columns are not connected in series, i.e., not one after the other, and the output stream of the first apheresis column is not fed into the second apheresis column. Due to the parallel arrangement of the apheresis columns, their throughputs also do not add up.

From the above-described connection should be distinguished serial connection of apheresis columns, which does not correspond to the invention. "Serial" means that several apheresis columns are in only one circulation circuit of the extracorporeal circulation system (2), i.e., for example, the first apheresis column (4') and the second apheresis column (4'') together with the manifold (8A ) plasma and plasma manifold (8B) form only one circulation circuit of the extracorporeal circulation system (2), i.e., will be connected or arranged in series.

According to the invention, two apheresis columns (4', 4''), connected in parallel to each other or arranged in parallel, can only be used alternately. "Alternately" means that the separated blood plasma is passed either through the apheresis column (4') or through the apheresis column (4''), but not simultaneously through both apheresis columns (4', 4''). "Sequential" work in this context means the therapeutic removal of CRP. Both apheresis columns (4' and 4'') cannot be used simultaneously to remove CRP. Of course, one of the two apheresis columns can be regenerated while the other is being used to remove CRP at the same time. Excluded only simultaneous therapeutic work to remove CRP using both apheresis columns.

Therefore, the following modes are possible. Blood plasma is passed through one apheresis column to remove the CRP. At the same time, the second apheresis column is ready for use, and the plasma flow can be redirected to this second apheresis column as soon as the capacity of the first apheresis column is exhausted, or there are other problems with the first apheresis column, or the second apheresis column has already been used. to remove CRP and require replacement or regeneration, or the second apheresis column is being regenerated while the first apheresis column is removing CRP.

Therefore, in the embodiments of the present invention, the apheresis device (II) with two apheresis columns is designed such that the apheresis columns can only be used alternately.

Thus, according to an embodiment of the apheresis device (II) according to the invention, the blood plasma can be passed at the same time either only through the first apheresis column (4') or only through the second apheresis column (4'' ). Therefore, in further embodiments of the device according to the invention, the apheresis device is designed such that blood plasma can be passed at the same time either only through the first apheresis column (4') or only through the second apheresis column (4' ').

Therefore, an embodiment of the present invention relates to an apheresis device (II) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1), the line (9) of the cell mass for the separated cellular components from the cell separator (7) to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (1) for apheresis,

a connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass line (12) branches off from the plasma line (8A) and is connected to the plasma line (8B), and the bypass line (12) contains a second apheresis column (4''),

the waste line (13) departs directly from the apheresis column (4') or from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and

at least one regeneration line (14) departs from at least one container (F) for liquids or from at least one connecting line (11) and passes to the plasma line (8A), in the direction of flow in point or after the branch point of the bypass line (12), or passes directly into the apheresis column (4'), and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') can only be used alternately to remove CRP, and moreover, blood plasma can only be passed through the first apheresis column column (4') or only through the second apheresis column (4'') at the same time.

During the alternating operation of the two apheresis columns (4', 4''), no blood plasma is passed through either the apheresis column (4') or the apheresis column (4''). As a result, it is possible to change one of the two apheresis columns from the apheresis device while the apheresis device is in operation. "Replacement" in this context means replacing one of the two apheresis columns with a fresh apheresis column or regenerating one of the two apheresis columns. Regeneration of one of the two apheresis columns can be performed, for example, by washing with a citrate solution. For the regeneration of apheresis columns, it is preferable to use a citrate solution. "During operation" in this context means that the removal of CRP from the blood continues.

Therefore, the embodiment of the apheresis devices (II) of the invention described in the present application relates to an apheresis device in which the first apheresis column (4') can be replaced during operation of the second apheresis column (4''), and the second apheresis column the column (4'') can be replaced during operation of the first apheresis column (4').

Embodiments are also possible in which the first apheresis column (4') can be regenerated during operation of the second apheresis column (4'') and the second apheresis column (4'') can be regenerated during operation of the first apheresis column (4').

Thus, in an embodiment of the present invention, the apheresis device (II) is designed such that the first apheresis column (4') can be replaced or regenerated during operation of the second apheresis column (4''), and the second apheresis column (4' ') can be replaced or regenerated during operation of the first apheresis column (4').

Therefore, an embodiment of the present invention relates to an apheresis device (II) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1), the line (9) of the cell mass for the separated cellular components from the cell separator (7) to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (1) for apheresis,

a connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass line (12) branches off from the plasma line (8A) and is connected to the plasma line (8B), and the bypass line (12) contains a second apheresis column (4''),

the waste line (13) departs directly from the apheresis column (4') or from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and

at least one regeneration line (14) which departs from at least one container (F) for liquids or from at least one connecting line (11) and passes to the plasma line (8A), in the direction flow to or after the branch point of the bypass line (12) or passes directly into the apheresis column (4'), and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') can only be activated alternately at the same time, and moreover, the first apheresis column (4 ') can be replaced or regenerated during operation of the second apheresis column (4''), and the second apheresis column (4'') can be replaced or regenerated during operation of the first apheresis column (4').

The present invention further relates to an apheresis device (II) for extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1), the line (9) of the cell mass for the separated cellular components from the cell separator (7) to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (1) for apheresis,

a connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass line (12) branches off from the plasma line (8A) and is connected to the plasma line (8B), and the bypass line (12) contains a second apheresis column (4''),

the waste line (13) departs directly from the apheresis column (4') or from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and

at least one regeneration line (14) departs from at least one container (F) for liquids or from at least one connecting line (11) and passes to the plasma line (8A), in the direction of flow in point or after the branch point of the bypass line (12), or passes directly into the apheresis column (4'), and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') cannot be used simultaneously to remove CRP, and wherein one of the apheresis columns (4' , 4'') can be regenerated simultaneously with CRP removal with another apheresis column.

Therefore, according to an embodiment of the present invention, the apheresis device (II) is designed such that the first apheresis column (4') can be replaced while the second apheresis column (4'') is in operation, and the apheresis column is configured such that it is regenerable, and the second apheresis column (4'') can be changed during operation of the first apheresis column (4'), and the apheresis column (4'') is designed such that the apheresis column (4'') is regenerable.

The second apheresis column (4'') connected in parallel with the first apheresis column (4') can be integrated into the bypass line, i. e. the bypass line (12) is composed of a section (12') of the bypass line and a section (12'') of the bypass line, while the second apheresis column (4'') is located between said sections of the bypass line.

Therefore, the present invention also relates to an apheresis device (II) for extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1),

line (9) of the cell mass for the separated cellular components from the separator (7) of cells to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (1) for apheresis,

a connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass section (12') in the bypass line (12) branches off from the plasma line (8A) and is connected to the second apheresis column (4''), and the bypass line section (12'') in the bypass line (12) issuing from apheresis column (4''), connects to the plasma manifold (8B),

the waste line (13) departs directly from the apheresis column (4') or from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and

at least one regeneration line (14) departs from at least one container (F) for liquids or from at least one connecting line (11) and passes to the plasma line (8A), in the direction of flow in point or after the branch point of the bypass line (12), or passes directly into the apheresis column (4'), and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') cannot be used simultaneously to remove CRP.

Therefore, an embodiment of the present invention relates to an apheresis device (II) for in vitro removal, and preferably for selective in vitro removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1), the line (9) of the cell mass for the separated cellular components from the cell separator (7) to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (1) for apheresis,

two connecting lines (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass line (12) branches off from the plasma line (8A) and is connected to the plasma line (8B), and the bypass line (12) contains a second apheresis column (4''),

the waste line (13) departs directly from the apheresis column (4') or from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and

at least one regeneration line (14) departs from at least one container (F) for liquids or from at least two connecting lines (11) and passes to the plasma line (8A), in the direction of flow in point or after the branch point of the bypass line (12), or passes directly into the apheresis column (4'), and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') cannot be used simultaneously to remove CRP (i.e., can only be used alternately).

According to an embodiment of the present invention, it is especially preferred that the apheresis device (II) according to the invention comprises two connecting lines (11', 11'') each for connecting at least one container (F) for liquids , wherein the connecting lines (11', 11'') are connected independently of each other to the arterial line (5) or directly to the cell separator (7). Therefore, both connecting lines (11', 11'') are connected to the arterial line (5), or both connecting lines (11', 11'') are connected directly to the cell separator (7) or, especially preferably, one connecting line (11') is connected to the arterial line (5) and another connecting line (11'') is connected directly to the cell separator (7). This allows two connecting lines (11', 11'') to be connected to different liquid containers. It is especially preferred that one of the two connecting lines (eg 11') is connected to a liquid container containing physiological salt solution (eg NaCl solution), the second of the two connecting lines (eg 11'') is connected to the liquid container containing citrate solution.

A further embodiment of the present invention is an apheresis device (II) for in vitro removal, and preferably for selective in vitro removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1), the line (9) of the cell mass for the separated cellular components from the cell separator (7) to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (1) for apheresis,

two connecting lines (11', 11''), each for connecting at least one container (F) for fluids to the arterial line (5) or cell separator (7),

different in that

the bypass line (12) branches off from the plasma line (8A) and is connected to the plasma line (8B), and the bypass line (12) contains a second apheresis column (4''),

the waste line (13) departs directly from the apheresis column (4') or from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and

at least one regeneration line (14) departs from at least one container (F) for liquids or from at least one connecting line (11) and passes to the plasma line (8A), in the direction of flow in point or after the branch point of the bypass line (12), or passes directly into the apheresis column (4'), and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') cannot be used simultaneously to remove CRP, i.e. can only be used sequentially.

According to a further embodiment of the present invention, the apheresis device (II) comprises a waste line (13') that exits directly from the apheresis column (4') or departs from the plasma line (8B), in the direction of flow before the section connection point ( 12'') of the bypass line in the bypass line on the plasma line (8B), and the waste line (13'') that extends directly from the apheresis column (4'') or from the section (12'') of the bypass line, in the direction of flow in front of the connection point on the line (8B) of the plasma.

Thus, the present invention also relates to an apheresis device (II) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1),

line (9) of the cell mass for the separated cellular components from the separator (7) of cells to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (1) for apheresis,

a connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass section (12') in the bypass line (12) branches off from the plasma line (8A) and is connected to the second apheresis column (4''), and the bypass line section (12'') in the bypass line (12) issuing from apheresis column (4''), connects to the plasma manifold (8B),

the waste line (13') exits directly from the apheresis column (4') or departs from the plasma line (8B), in the direction of flow before the connection point of the bypass section (12'') in the bypass line on the plasma line (8B), and the line (13'') waste exits directly from the apheresis column (4'') or from the bypass section (12'') in the bypass line (12), in the direction of flow before the connection point on the plasma line (8B),

and

at least one regeneration line (14) departs from at least one container (F) for liquids or from at least one connecting line (11) and passes to the plasma line (8A) or to the section (12 ') of the bypass, downstream to or after the branch point of the bypass section (12') in the bypass (12), or passes directly into the apheresis column (4') or into the apheresis column (4''), and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') cannot be used simultaneously to remove CRP, i.e. can only be used sequentially.

According to a further embodiment of the present invention, the apheresis device (II) further comprises at least one regeneration line (14) which extends from at least one container (F) for liquids or at least one connecting line (11) and passes into the plasma line (8A) or into the section (12') of the bypass line in the bypass line (12) or passes directly into the apheresis column (4'), or passes directly into the apheresis column (4'' ). According to a further embodiment of the present invention, the apheresis device (II) further comprises at least one regeneration line (14) which is connected to the bypass section (12') in the region between the point (P2) and the apheresis column ( 4') or to the plasma conduit (8A) in the region between the point (P2) and the apheresis column (4'') or passes directly into the apheresis column (4') or directly into the apheresis column (4'').

In a particularly preferred embodiment of the present invention, the apheresis device (II) comprises a waste line (13') that exits directly from the apheresis column (4') or departs from the plasma line (8B), in the direction of flow before the connection point of the section (12 '') bypass line in bypass line (12), and at least one regeneration line (14) that extends from at least one container (F) for liquids or at least one connecting line ( 11) and passes to the bypass section (12') or to the plasma line (8A), or passes directly into the apheresis column (4') or directly into the apheresis column (4'').

Particularly preferred is an apheresis device (II) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1), the line (9) of the cell mass for the separated cellular components from the cell separator (7) to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (1) for apheresis,

a connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

different in that

the bypass section (12') in the bypass line (12) branches off from the plasma line (8A) and is connected to the second apheresis column (4''), and the bypass line section (12'') in the bypass line (12) issuing from apheresis column (4''), connects to the plasma manifold (8B),

the waste line (13) exits directly from the apheresis column (4') or departs from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and

at least one regeneration line (14) departs from at least one container (F) for liquids or from at least one connecting line (11) and passes to the plasma line (8A), in the direction of flow in to or after the branch point of the bypass section (12') in the bypass line (12), or to the bypass section (12') in the bypass line (12) or passes directly into the apheresis column (4') or into the apheresis column (4 ''), and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') cannot be used simultaneously to remove CRP.

In a particularly preferred embodiment of the present invention, the apheresis device (II) comprises a waste line (13') that exits directly from the apheresis column (4') or departs from the plasma line (8B), in the direction of flow before the connection point of the section (12 '') of the bypass line in the bypass line, the waste line (13'') that exits directly from the apheresis column (4''), or that departs from the section (12'') of the bypass line in the bypass line (12), in the direction flow before the connection point of the bypass line section (12') in the bypass line, and at least one regeneration line (14) that exits from at least one container (F) for liquids or at least one connecting line (11) and passes to the plasma line (8A) or to the section (12') of the bypass line in the bypass line (12) or passes directly into the apheresis column (4') or directly into the apheresis column (four'').

A particularly preferred embodiment of the basic invention relates to an apheresis device (II) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1),

line (9) of the cell mass for the separated cellular components from the separator (7) of cells to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (1) for apheresis,

a connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass section (12') in the bypass line (12) branches off from the plasma line (8A) and is connected to the second apheresis column (4''), and the bypass line section (12'') in the bypass line (12) issuing from apheresis column (4''), connected to the plasma line (8B),

the waste line (13') exits directly from the apheresis column (4') or departs from the plasma line (8B), in the direction of flow before the connection point of the bypass section (12'') in the bypass line (12), line (13'' ) waste departs directly from the apheresis column (14'') or from the bypass section (12'') in the bypass line (12), in the direction of flow before the connection point of the bypass section (12'') in the bypass line (12),

and

at least one regeneration line (14) departs from at least one container (F) for liquids or from at least one connecting line (11) and passes to the plasma line (8A), in the direction of flow in to or after the branch point of the bypass section (12') in the bypass line (12), or to the bypass section (12') in the bypass line (12) or passes directly into the apheresis column (4') or into the apheresis column (4 ''),

and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') cannot be used simultaneously to remove CRP.

In addition, embodiments of the apheresis device (II) according to the invention are possible, in which at least one regeneration line (14) is connected at point (P7), and from point (P7) line (14') passes to point (P2) or is connected to the plasma line (8A), and from the point (P7) the line (14'') passes to the plasma line (8A) (see Fig. 11 ).

In the case where at least one regeneration line (14) for the wash solution is connected to the plasma line (8A) between the point (P2) and the apheresis column (4'), or in the case where at least one line (14) regeneration is connected to the section (12') of the bypass line in the bypass line (12) between the point (P2) and the apheresis column (4''), the wash solution can be used either only for the apheresis column (4') or for the apheresis column columns (4''). Thus, the regeneration line (14) is either selective for the apheresis column (4') or selective for the apheresis column (4'').

Also possible are embodiments of the apheresis device (II) according to the invention with two, three or more lines (14'. 14'', 14''', etc.) of regeneration, in which, in such cases, the said two , three or more regeneration lines are connected independently of each other to the plasma line (8A) [i.e. from the point (P2) to the apheresis column (4')] or to the section (12') of the bypass line [i.e. from the point (P2) to the apheresis column (4'')], or to the apheresis column (4'), or to the apheresis column (4''). "Independent" in this context means, for example, that, in an embodiment of the apheresis devices according to the invention with two regeneration lines (14', 14''), one regeneration line (14') is connected to the line (8A ) of plasma between the point (P2) and the apheresis column (4'), and another line (14'') of regeneration passes directly into the apheresis column (4''), but also that both lines (14', 14'') of regeneration can be connected to the plasma line (8A) between the point (P2) and the apheresis column (4'). An additional possibility is that one regeneration line (14') is connected to the extracorporeal circulation system (2) at point (P2), and the other regeneration line (14'') is connected to the bypass line section (12') in the bypass line ( 12) between the point (P2) and the apheresis column (4''). It is also possible that one regeneration line (14') is connected to the extracorporeal circulation system at point (P2) and the other regeneration line (14'') passes into the apheresis column (4''). It is also possible that one regeneration line (14') is connected to another regeneration line (14''). However, if there are two or more lines (14', 14'', 14''', etc.) of regeneration, it is preferable that all lines (14', 14'', 14''', etc.) ) regenerations were connected to the extracorporeal circulation system (2) at the point (P2).

Moreover, it is preferable that one regeneration line (14') is connected to the bypass section (12') in the bypass line (12) between the point (P2) and the apheresis column (4'), and the other regeneration line (14'') connects to the bypass section (12') in the bypass line (12) between the P2 point and the apheresis column (4''). Moreover, it is preferable that a regeneration line (14') is connected to an apheresis column (4') and another regeneration line (14'') is connected to an apheresis column (4''). Here, the regeneration line (14') is selective with respect to the first apheresis column (4'), and the regeneration line is selective with respect to the second apheresis column (4'').

Therefore, according to a particularly preferred embodiment of the present invention, the apheresis device (II) further comprises a regeneration line (14') for a wash solution selective with respect to the first apheresis column (4') and/or further comprises a line (14'' ) regeneration for a wash solution selective for the second apheresis column (4'').

Therefore, an embodiment of the present invention relates to an apheresis device (II) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1), the line (9) of the cell mass for the separated cellular components from the cell separator (7) to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (1) for apheresis,

a connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass line (12) branches off from the plasma line (8A) and is connected to the plasma line (8B), and the bypass line (12) contains a second apheresis column (4''),

the waste line (13') exits directly from the apheresis column (4') or departs from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and

the wash solution regeneration line (14') is selective with respect to the first apheresis column (4'), and/or the wash solution regeneration line (14'') is selective with respect to the second apheresis column (4''),

and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') cannot be used simultaneously to remove CRP, i.e. can only be used sequentially.

As mentioned above, the regeneration solution required for the regeneration of apheresis columns can be supplied to the extracorporeal circulation system (2) via the regeneration line (14), and therefore, in addition to the washing solution, a regeneration solution (for example, citrate solution, Tris -glycine solution or sodium chloride solution). The wash solution may, but need not, serve to regenerate the first apheresis column (4') and/or the apheresis column (4'') but, in addition to the above function, has the task of expelling the blood plasma from the plasma highway (8A) into area from the point (P2) to the apheresis column (4'), as well as from the highway (8B) of plasma from the apheresis column (4') to the point (P8), or the expulsion of blood plasma from the section (12') of the bypass line to the bypass line (12) plasma in the area from the point (P2) to the apheresis column (4''), as well as from the section (12'') of the bypass line in the bypass line (12) from the apheresis column (4'') to the point (P8) , and therefore passing into the patient's circulatory system, before the regeneration solution is introduced, which, after flowing through one of the two apheresis columns (4', 4''), is drained through the waste line (13', 13'').

Thus, it is possible that the apheresis columns (4', 4'') connected in parallel can not only be operated alternately, but also alternately regenerated.

In the devices (II) for apheresis in accordance with the invention presented in this application, the first apheresis column (4') can be replaced or regenerated during operation of the second apheresis column (4''), and the second apheresis column (4'') can be replace or regenerate during operation of the first apheresis column (4').

Therefore, an embodiment of the present invention relates to an apheresis device (II) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood or blood plasma, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1),

line (9) of the cell mass for the separated cellular components from the separator (7) of cells to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (II) for apheresis,

a connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass section (12') in the bypass line (12) branches off from the plasma line (8A) and is connected to the second apheresis column (4'), and the bypass section (12'') in the bypass line (12) issuing from the apheresis columns (4''), connected to the plasma manifold (8B),

the waste line (13') exits directly from the apheresis column (4') or departs from the plasma line (8B), in the direction of flow before the connection point of the bypass section (12'') in the bypass line (12), line (13'' ) waste departs directly from the apheresis column (14'') or from the bypass section (12'') in the bypass line (12), in the direction of flow before the connection point of the bypass section (12'') in the bypass line (12),

and

at least one regeneration line (14) departs from at least one container (F) for liquids or from at least one connecting line (11) and passes to the plasma line (8A), in the direction of flow in point or after the branch point section (12') of the bypass line in the bypass line (12), or to the section (12') of the bypass line in the bypass line (12) or passes directly into the apheresis column (4') or into the apheresis column (4 ''),

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') can only be used alternately, and the first apheresis column (4') can be replaced or regenerated during operation of the second apheresis column (4''), and the second apheresis column (4'') can be replaced or regenerated during operation of the first apheresis column (4').

In addition, embodiments of the present invention are possible, in which the apheresis device comprises a regeneration line (14) for each liquid container (F) that extends from the corresponding liquid container (F) or its connecting line (11), and each of which passes to the plasma line (8A) or to the bypass section (12') in the bypass line (12) either directly to the apheresis column (4') or directly to the apheresis column (4'').

A particularly preferred embodiment of the present invention relates to an apheresis device (II) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1),

line (9) of the cell mass for the separated cellular components from the separator (7) of cells to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (II) for apheresis,

a connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass section (12') in the bypass line (12) branches off from the plasma line (8A) and is connected to the second apheresis column (4'), and the bypass section (12'') in the bypass line (12) issuing from the apheresis columns (4''), connected to the plasma manifold (8B),

the waste line (13') exits directly from the apheresis column (4') or departs from the plasma line (8B), in the direction of flow before the connection point of the bypass section (12'') in the bypass line (12), line (13'' ) waste departs directly from the apheresis column (14'') or from the bypass section (12'') in the bypass line (12), in the direction of flow before the connection point of the bypass section (12'') in the bypass line (12),

and a regeneration line (14) is provided for each liquid container (F) and departs from the corresponding liquid container (F) or from its connecting line (11), and passes to the plasma line (8A), in the direction of flow to or after branch points of the bypass section (12') in the bypass line (12), or to the bypass section (12') in the bypass line (12) or directly into the apheresis column (4') or into the apheresis column (4'') ,

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') cannot be used simultaneously to remove CRP.

In addition, embodiments of the apheresis device (II) are preferred, in which the apheresis device (II) comprises at least two connecting lines (11), each for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7), and at the same time, each container (F) for liquids has a regeneration line (14), which departs from the corresponding container (F) for liquids or its connecting line (11), and each of which passes to the plasma line (8A) or to the bypass section (12') in the bypass line (12), either directly to the apheresis column (4') or directly to the apheresis column (4'').

According to some embodiments of the present invention, it is preferred that at least one regeneration line (14) extend to the plasma line (8A) or to the bypass section (12') in the bypass line (12) or directly into the apheresis column (4'), or passing directly into the apheresis column (4''), proceeded from the point (P5) on at least one connecting line (11).

Therefore, the present invention also relates to an apheresis device (II) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1),

line (9) of the cell mass for the separated cellular components from the separator (7) of cells to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (II) for apheresis,

a connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass section (12') in the bypass line (12) branches off from the plasma line (8A) and is connected to the second apheresis column (4'), and the bypass section (12'') in the bypass line (12) issuing from the apheresis columns (4''), connected to the plasma manifold (8B),

the waste line (13) departs directly from the apheresis column (4') or departs from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and

at least one regeneration line (14) departs from the point (P5) on at least one connecting line (11) for connecting at least one container (F) for fluids to the arterial line (5) or separator (7) cells and passes to the highway (8A) plasma, in the direction of flow to or after the branch point of the bypass section (12') in the bypass line (12), or to the section (12') of the bypass line in the bypass line (12 ) or passes directly into the apheresis column (4') or into the apheresis column (4''),

and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') cannot be used simultaneously to remove CRP.

Preferred is an apheresis device (II) in which the apheresis device (II) comprises two connecting lines (11', 11'') each for connecting one container (F1, F2) for fluids to an arterial line (5) or a separator (7) cells, and two lines (14', 14'') of regeneration, which depart from two containers (F1, F2) for liquids or two connecting lines (11', 11'') and pass to the line (8A) of plasma or to the section (12') of the bypass line in the bypass line (12), or directly into the apheresis column (4'), or directly into the apheresis column (4'').

Therefore, a particularly preferred embodiment of the basic invention relates to an apheresis device (II) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1),

line (9) of the cell mass for the separated cellular components from the separator (7) of cells to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (II) for apheresis,

two connecting lines (11', 11'') for connecting two containers (F1, F2) for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass section (12') in the bypass line (12) branches off from the plasma line (8A) and is connected to the second apheresis column (4''), and the bypass line section (12'') in the bypass line (12) issuing from apheresis column (4''), connects to the plasma manifold (8B),

the waste line (13') exits directly from the apheresis column (4') or departs from the plasma line (8B), in the direction of flow before the connection point of the bypass section (12') in the bypass line (12), line (13'') waste leaves directly from the apheresis column (14'') or from the bypass section (12'') in the bypass line (12), in the direction of flow before the connection point of the bypass section (12'') in the bypass line (12),

and

two lines (14', 14'') of regeneration depart from two containers (F1, F2) for liquids or two connecting (11', 11'') lines and pass to the plasma line (8A) in the direction of flow, to a point or after branch points section (12') of the bypass line in the bypass line (12), or to the section (12') of the bypass line in the bypass line (12) or pass directly into the apheresis column (4') or into the apheresis column (4'') ,

and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') cannot be used simultaneously to remove CRP, i.e. can only be used sequentially.

Embodiments are also possible in which the regeneration line (14) which passes to the plasma line (8A) or to the bypass section (12') in the bypass line (12), either directly into the apheresis column (4'), or directly into an apheresis column (4''), and which starts from a point (P5) on at least one connecting line (11), has at least one additional connection for a container for liquids (Fig. 16).

In embodiments of the present invention with several connecting lines (11', 11'', 11''', etc.) and several lines (14', 14'', 14''', etc.), regeneration is possible that one connecting line simultaneously communicates with one regeneration line, which, in turn, goes, after point (P2), to the plasma line (8A) or to the bypass section (12') in the bypass line (12), or directly into the apheresis column (4'), or directly into the apheresis column (4''). In this case, each regeneration line can be connected to the plasma line (8A) or to the bypass section (12') in the bypass line (12), or directly to the apheresis column (4'), or directly to the apheresis column (4'' ), independently of other regeneration lines. Preferably, however, all regeneration lines are connected to apheresis columns (4'; 4''), preferably at point (P2) in the extracorporeal circulation system (2). One such exemplary embodiment is explained with reference to FIG. 7. Here, the device (II) for apheresis contains the first connecting line (11'), which passes, firstly, to the arterial line (5), and from which, secondly, the first line (14') of regeneration branches off at the point (P5'). The apheresis device (II) also contains a second connecting line (11'') which, firstly, passes directly into the cell separator (7), and from which, secondly, the second regeneration line (14'') branches off in point (P5''). In this embodiment, both regeneration lines are connected to the extracorporeal circulation system (2) at point (P2).

Therefore, an apheresis device (II) is preferred which comprises two connecting lines (11', 11'') each for connecting at least one container (F) for fluids to the arterial line (5) or separator (7 ) cells, and at the same time, at least one highway (14) regeneration, which passes to the highway (8A) plasma or section (12') of the bypass line in the bypass line (12), or directly into the apheresis column (4' ), or directly into the apheresis column (4''), is connected at point (P5') to the connecting line (11') and at point (P5'') to the connecting line (11'').

Therefore, a preferred embodiment of the basic invention relates to an apheresis device (II) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1),

line (9) of the cell mass for the separated cellular components from the separator (7) of cells to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (II) for apheresis,

two connecting lines (11', 11''), each for connecting at least one container (F) for fluids to the arterial line (5) or cell separator (7),

characterized in that

the bypass section (12') in the bypass line (12) branches off from the plasma line (8A) and is connected to the second apheresis column (4'), and the bypass section (12'') in the bypass line (12) issuing from the apheresis columns (4''), connected to the plasma manifold (8B),

the waste line (13') exits directly from the apheresis column (4') or departs from the plasma line (8B), in the direction of flow before the connection point of the bypass section (12') in the bypass line (12), line (13'') waste leaves directly from the apheresis column (14'') or from the bypass section (12'') in the bypass line (12), in the direction of flow before the connection point of the bypass section (12') in the bypass line (12),

and

at least one line (14) regeneration,

which passes to the plasma line (8A) or section (12') of the bypass line in the bypass line (12) or passes directly into the apheresis column (4') or into the apheresis column (4''), is connected to the connecting line (11') at point (P5') and to the connecting line (11'') at point (P5''),

which departs from at least one container (F) for liquids or at least one connecting line (11) and passes to the line (8A) of the plasma, in the direction of flow to the point or, preferably, after the branch point of the section ( 12') of the bypass line in the bypass line (12), or to the section (12') of the bypass line in the bypass line (12) or passes directly into the apheresis column (4') or into the apheresis column (4''),

and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') cannot be used simultaneously to remove CRP.

Thus, embodiments of the apheresis device are particularly preferred, in which the apheresis device (II) comprises two connecting lines (11', 11'') each for connecting one container (F1, F2) for fluids to the arterial line (5 ) or cell separator (7), and at least one regeneration line (14) passes to the plasma line (8A) or to the bypass section (12') in the bypass line (12), or directly to the apheresis column (4'), or directly into the apheresis column (4''), is connected at point (P5') to the connecting line (11') and at point (P5'') to the connecting line (11''), and the line (14') regeneration passes from the container (F1) for liquids or from the connecting line (11') exiting the container (F1) for liquids, to the apheresis column (4') or to the apheresis column (4''), or to plasma lines (8A') or plasma lines (8A'') and air regeneration line (14'') From the fluid container (F2) or from the connecting line (11'') coming from the fluid container (F2) to the apheresis column (4') or to the apheresis column (4'') or to the line (8A) plasma, or to section (12') of the bypass line in the bypass line (12), or line (14') regeneration.

The liquid container (F1) preferably contains a saline solution and the liquid container (F2) contains a citrate solution.

Thus, it is particularly preferred that the apheresis device (II) comprises a connecting line (11') for connecting a container (F1) for liquids and a connecting line (11'') for connecting a container (F2) for liquids, and a connecting line (11 ') is connected to the arterial line (5) or to the cell separator (7) and the connecting line (11'') is connected to the arterial line (5) or to the cell separator (7) or to the connecting line (11') and, hence ultimately to the arterial line (5) or to the cell separator (7) and the regeneration line (14') passes from the fluid container (F1) or from the connecting line (11') to the apheresis column (4') or to the apheresis column (4''), or to the plasma line (8A), or to the plasma line (8A''), and the regeneration line (14'') extends from the fluid container (F2) or from the connecting line (11 '') into the apheresis column (4') or into the apheresis column (4''), or and to the plasma line (8A'), or to the bypass section (12') in the bypass line (12), or to the regeneration line (14').

Therefore, embodiments of the apheresis device (II) are particularly preferred, in which the apheresis device (II) comprises a connecting line (11') for connecting a container (F1) for fluids to an arterial line (5) or cell separator (7) and connecting line (11'') for connecting the container (F2) for fluids to the arterial line (5) or cell separator (7), and at the same time the regeneration line (14') departs from the container (F1) for liquids or from the connecting line ( 11') and passes to the plasma line (8A) or bypass section (12') in the bypass line (12), either directly to the apheresis column (4'), or directly to the apheresis column (4''), and the line ( 14'') of regeneration departs from the container (F2) for liquids or connecting line (11'') and passes to the plasma line (8A) or to the section (12') of the bypass line in the bypass line (12), or to the line (14 ') regeneration, or immediately directly into the apheresis column (4'), or directly into the apheresis column (4'').

A preferred embodiment of the basic invention relates to an apheresis device (II) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1),

line (9) of the cell mass for the separated cellular components from the separator (7) of cells to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (II) for apheresis,

a connecting line (11') for connecting a container (F1) for fluids to an arterial line (5) or a cell separator (7), and a connecting line (11'') for connecting a container (F2) for liquids to an arterial line (5) or separator (7) cells,

characterized in that

the bypass section (12') in the bypass line (12) branches off from the plasma line (8A) and is connected to the second apheresis column (4'), and the bypass section (12'') in the bypass line (12) issuing from the apheresis columns (4''), connected to the plasma manifold (8B),

the waste line (13') exits directly from the apheresis column (4') or departs from the plasma line (8B), in the direction of flow before the connection point of the bypass section (12') in the bypass line (12), line (13'') waste flows directly from the apheresis column (14'') or from the bypass section (12'') in the bypass line (12), in the direction of flow before the connection point, the bypass section (12') in the bypass line (12),

and

line (14') regeneration departs from the container (F1) for liquids or connecting line (11') and passes, in the direction of flow to the point or, preferably, after the branch point of the section (12') of the bypass line in the bypass line (12), to the plasma line (8A) or to the bypass section (12') in the bypass line (12) either directly into the apheresis column (4') or directly into the apheresis column (4''), and the regeneration line (14'') departs from the container (F2) for liquids or the connecting line (11'') and passes, in the direction of flow to a point, or preferably after the branch point of the bypass section (12') in the bypass line (12), to the line (8A) plasma or to the section (12') of the bypass line in the bypass line (12) or passes directly into the apheresis column (4') or directly into the apheresis column (4'').

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') cannot be used simultaneously to remove CRP.

Preferably, the liquid container (F1) is a physiological saline container and the liquid container (F2) is a citrate solution container.

Therefore, the present invention also relates to an apheresis device (II) according to the invention, in which the plasma line (8A) and the bypass section (12') in the bypass line (12) diverge from point (P2), and the line (8B ) plasma and bypass section (12'') at bypass line (12) converge at point (P6), and waste line (13') departs from plasma line (8B) at point (P4), and line (13'' ) waste leaves the bypass section (12'') at the bypass line (12) at point (P8), and at least one regeneration line (14) is connected to the extracorporeal circulation system (2) at point (P2).

A preferred embodiment of the basic invention relates to an apheresis device (II) for extracorporeal removal and preferably for selective extracorporeal removal of CRP from blood, comprising:

system (2) extracorporeal circulation for blood,

means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2),

separator (7) of cells for separating blood into blood plasma and cellular components,

two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood plasma,

wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1),

line (9) of the cell mass for the separated cellular components from the separator (7) of cells to the point (P1) and the venous line (6) coming from the point (P1),

central processor (10) to control the device (II) for apheresis,

a connecting line (11') for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7),

characterized in that

the bypass section (12 '' ) in the bypass line (12) branches off from the plasma line (8A) and connects to the second apheresis column (4'), and the bypass section (12 '' ) in the bypass line (12) originates from the apheresis columns (4''), connected to the plasma manifold (8B),

the waste line (13') exits directly from the apheresis column (4') or departs from the plasma line (8B), in the direction of flow before the connection point of the bypass section (12') in the bypass line (12), line (13'') waste departs directly from the apheresis column (14'') or from the section (12'') of the bypass line in the bypass line (12), in the direction of flow before the connection point of the section (12'') of the bypass line in the bypass line (12), and plasma line (8A) and bypass section (12') in bypass line (12) diverge from point (P2), and plasma line (8B) and bypass line section (12'') in bypass line (12) converge at point (P6), and

at least one regeneration line (14) departs from at least one container (F) for liquids or at least one connecting line (11) and passes, in the direction of flow, to or preferably after the point branches of the bypass section (12') in the bypass line (12), to the plasma line (8A) or to the bypass section (12') in the bypass line (12) or passes directly into the apheresis column (4') or directly into the apheresis column (4''), and

the waste line (13') departs directly at point (P4) from the plasma line (8B), and the waste line (13'') departs at point (P8) from the bypass section (12'') in the bypass line (12), and

at least one regeneration line (14) is connected to the extracorporeal circulation system (2) at point (P2), and

moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') cannot be used simultaneously to remove CRP, i.e. can only be used sequentially.

To further reduce the dead volume of the system, it is even more preferable that not only the regeneration line (14) is connected to the extracorporeal circulation system at the point (P2) from which the plasma line (8A) and the bypass line section (12') diverge in the bypass line ( 12), but when the waste lines (13', 13'') also branch off from the same point (P6) where the plasma line (8B) and the bypass line section (12'') converge in the bypass line (12). In other words, preferably, when the point (P6) at which the plasma line (8B) and the bypass section (12'') converge in the bypass line (12), the point (P8) at which the waste line (13'') branches off , and the point (P4) at which the waste line (13') branches off coincide, ie when P8=P4=P6 (see FIG. 12 and FIG. 13).

Therefore, the present invention also relates to an apheresis device (II) according to the present invention, in which the plasma line (8B) and the bypass section (12'') in the bypass line (12) converge at point (P6), the line ( 13'') of the waste departs at point (P8) from the section (12'') of the bypass line in the bypass line (12), and the line (13') of the waste departs at point (P4) from the line (8B) of the plasma, and, along at least one regeneration line (14) is connected to the extracorporeal circulation system (2) at point (P2), and point (P6), point (P4) and point (P8) are identical.

According to the present invention, an embodiment of the apheresis device (II) for extracorporeal removal of CRP from blood according to the present invention comprises two apheresis columns (4', 4'') for removing CRP by affinity chromatography from blood or blood plasma, the purpose which consists in binding CRP, which is present in the blood or plasma of patients, which is passed through apheresis columns (4') or (4'').

Way

The present invention also relates to a method for regenerating an apheresis column (4) for removing CRP by affinity chromatography in an apheresis device (1), wherein the method enables regeneration during operation and is characterized in that it comprises the following steps:

(A) start redirecting the separated plasma from the plasma line (8A) to the bypass line (12), while stopping the supply of the separated plasma from the plasma line (8A) to the apheresis column (4),

(B) start supplying the regeneration solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(C) start redirecting the flow of fluid flowing from the apheresis column (4) from the plasma line (8B) to the waste line (13),

(D) stop supplying the regeneration solution and stop redirecting the separated plasma from the plasma line (8A) to the bypass line (12), while supplying the separated plasma from the plasma line (8A) to the apheresis column (4),

(E) block off the waste line (13) and direct the flow of fluid flowing from the apheresis column (4) into the venous line (6).

The expression "cutting off the supply of separated plasma" in accordance with step (A) can be understood to mean, depending on the embodiment of the present invention, the use of hose clamps, controls, valves and/or peristaltic pumps to prevent further flow of blood plasma into the line (8A) plasma or into the bypass section (12') in the bypass line (12), or into the apheresis column (4') or (4'').

The expression "stopping the supply of regenerant solution" in accordance with step (D) can be understood to mean, depending on the embodiment of the present invention, the use of hose clamps, controls, valves and/or peristaltic pumps to prevent further flow of regenerant solution into the line (8A) plasma or into an apheresis column (4). It should be understood here that, in embodiments in which only one regeneration solution is used, its supply is stopped. In embodiments in which several regenerants are supplied in succession, said expression means that the supply of the last used regeneration solution is stopped and therefore that any regeneration solution is also stopped.

The expression "shut off the waste line (13)" according to step (E) can be understood to mean, depending on the embodiment of the present invention, the use of hose clamps, controls, valves and/or peristaltic pumps to prevent further flow of liquid flowing from the apheresis column (4). It should be understood here that, in embodiments in which only one regeneration solution is used, its supply is stopped. In embodiments in which several regenerants are supplied in succession, said expression means that the supply of the last used regeneration solution is stopped and therefore that any regeneration solution is also stopped.

By "directing the flow of fluid flowing out of the apheresis column (4)" according to step (E), the separated plasma subsequently flows back into the plasma manifold (8B) after flowing through the apheresis column (4), and from there further along the venous lines (6) back to the patient. Depending on the embodiment of the present invention, hose clamps, controls, valves and/or peristaltic pumps can be used to change the direction of the flow of fluid flowing from the apheresis column (4).

The present invention further relates to a method for regenerating an apheresis column (4) for removing CRP by affinity chromatography in the apheresis device (1) described above, wherein the method enables regeneration during operation by switching from an apheresis mode to a regeneration mode, wherein, in the apheresis mode, the plasma separated from the blood by the cell separator (7) is sent to the apheresis column (4) via the plasma line (8A), and the flow of fluid flowing from the apheresis column (4) is directed to the venous line (6) via the line (8B) plasma;

and moreover, the regeneration mode differs in that it contains the following steps:

(A) start redirecting the separated plasma from the plasma line (8A) to the bypass line (12), while stopping the supply of the separated plasma from the plasma line (8A) to the apheresis column (4),

(B) start supplying the regeneration solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(C) start redirecting the flow of fluid flowing from the apheresis column (4) from the plasma line (8B) to the waste line (13),

(D) stop supplying the regeneration solution and stop redirecting the separated plasma from the plasma line (8A) to the bypass line (12), while supplying the separated plasma from the plasma line (8A) to the apheresis column (4),

(E) block the waste line (13) and direct the flow of fluid flowing from the apheresis column (4) into the venous line (6) and thus switch back to apheresis mode.

With respect to the two methods described above, the regeneration solution is preferably saline or saline NaCl.

In addition, methods are preferred in which step (C) is started after a full volume X of the regeneration solution(s) has been supplied to the plasma manifold (8A) and/or directly to the apheresis column (4), while X corresponds to at least 75% of the volume of the device between the point at which the regeneration line (14) is connected to the extracorporeal circulation system (2), in the direction of flow, at or preferably after the branch point of the bypass line (12), and the point at which the waste line (13) starts from the extracorporeal circulation system (2). In this case, the regeneration solution is, for example, a saline solution or saline solution.

Also preferred are methods in which step (E) is started after a volume Y of plasma has been delivered to the plasma manifold (8A) or directly to the apheresis column (4), with Y corresponding to at least 90% of volume of the device between the point at which the regeneration line (14) is connected to the extracorporeal circulation system (2), in the direction of flow, at or preferably after the branch point of the bypass line (12), and the point at which the waste line (13) starts from the system (2) extracorporeal circulation.

The expression " during operation " in the context of the present application means that, in order to carry out the regeneration method of the apheresis column (4) in accordance with the invention, blood sampling and supply, as well as the operation of the cell separator, do not need to be suspended. In other words, when performing the method of regeneration of the apheresis column (4) in accordance with the invention, continuously sampled plasma is combined with cellular components through a bypass line (12), while bypassing the apheresis column (4), and is fed into the patient. During the time that the plasma is redirected along the bypass line (12), the apheresis column (4), which normally loses capacity, is regenerated. Thus, the patient's circulation is not stressed, since the continuously withdrawn blood is returned to the patient without delay.

The expression "during operation" in the context of the present application, accordingly, does not mean that the continuous sampling must be interrupted in order to carry out the method according to the invention for the regeneration of the apheresis column (4). Furthermore, it also does not mean that a decrease in the CRP level occurs during the regeneration of the apheresis column.

Thus, in both the above methods and the methods disclosed generally in the present application, it is preferable that the regeneration solution supply comprises the supply of one regeneration solution or the successive supply of several regeneration solutions.

For a person skilled in the art it is quite obvious that before the implementation of the method in accordance with the invention should be the initial operation of washing the adsorber or the entire system. This operation is associated with the pre-filling of the entire tube system. To do this, in some cases additional compounds may be present in the system, which allow flushing the entire system. After the patient is disconnected from the tubing system, the adsorber can be preserved so that it can be used again for further treatment of the same patient.

In other words, the present invention also relates to a method according to the invention for regenerating an apheresis column (4) for removing CRP by affinity chromatography in an apheresis device (1), wherein the method enables regeneration during operation, and is characterized in that it contains the following stages:

(A) redirecting the separated plasma from the plasma line (8A) to the bypass line (12),

(B) feeding the regeneration solution from the liquid container on the connecting line (11) through the regeneration line (14) into the plasma line (8A) or directly into the apheresis column (4),

(C) redirecting the flow of fluid flowing from the apheresis column (4) from the plasma line (8B) to the waste line (13),

(D) redirect the separated plasma from the plasma line (8A) to the apheresis column (4) and stop the supply of the regeneration solution,

(E) block off the waste line (13) and direct the flow of fluid flowing from the apheresis column (4) into the venous line (6).

The term "redirection" in the context of the present application refers to a change in the direction of flow of the respective fluid. In therapy mode, the separated plasma flows through the plasma line (8A) into the apheresis column (4). After exiting the apheresis column (4), the depleted plasma flows through the plasma line (8B) into the venous line (6).

By "redirecting" the flow direction of the separated plasma according to step (A), the separated plasma subsequently no longer flows through the apheresis column (4), but is bypassed due to being redirected to the bypass line (12).

The term "supply" in the context of the present application in accordance with step (B) can be understood to mean, depending on the embodiment of the present invention, the supply of at least one regeneration solution (using or actuating hose clamps, controls, valves and/or peristaltic pumps) into the plasma manifold (8A) or into the apheresis column (4).

By "redirecting" the flow direction of the fluid flowing out of the apheresis column (4) according to step (C), the outflowing fluid subsequently flows not into the plasma line (8B) but directly into the waste line (13). In accordance with the invention, it is preferred that the waste line (13) branch off directly from or immediately after the apheresis column (4) in order to minimize the volume of regeneration solution required to regenerate the apheresis column (4). According to the invention, the waste line (13) can also branch off from the plasma line (8B) and therefore need not branch directly from the apheresis column.

By "redirecting" the flow direction of the separated plasma according to step (D), the separated plasma subsequently flows again through the apheresis column (4) and no longer flows into the bypass line (12). In some embodiments, a pump is provided in the bypass line (12), wherein the plasma in the bypass line (12) is pumped into the plasma line (8B) and into the patient via the venous line (6) after being redirected in accordance with step (D ). In this case, preferably, the plasma in the bypass line is displaced by the NaCl solution from the regeneration line (14). This solution is preferably a 0.9% NaCl solution. It is also possible that a separate container for liquids can be connected to the bypass line (12), from which said NaCl solution is supplied for displacement.

Therefore, a particularly preferred embodiment of the present invention relates to a method according to the invention for regenerating an apheresis column (4) for removing CRP by affinity chromatography in an apheresis device (1), wherein the method enables regeneration during operation and is characterized in that contains the steps disclosed in the following method.

Therefore, a method for regenerating the apheresis column (4) for removal by affinity chromatography and preferably for selective in vitro removal of CRP in the apheresis device (1) is particularly preferred, the method being characterized in that it comprises the following steps:

(A) start redirecting the separated plasma from the plasma line (8A) to the bypass line (12), while stopping the supply of the separated plasma from the plasma line (8A) to the apheresis column (4),

(B) starting the supply of the wash solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(C) start redirecting the flow of fluid flowing from the apheresis column (4) from the plasma line (8B) to the waste line (13),

(D) stop the supply of the wash solution and proceed to the supply of the regeneration solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(E) stopping the supply of the regeneration solution and proceeding to the supply of the washing solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(F) stopping the supply of the wash solution and stopping the redirection of the separated plasma from the plasma line (8A) to the bypass line (12), while directing the separated plasma from the plasma line (8A) to the apheresis column (4).

(G) block off the waste line (13) and direct the flow of fluid flowing from the apheresis column (4) into the venous line (6).

Alternatively, a method for regenerating the apheresis column (4) for removal by affinity chromatography and preferably for selective removal of CRP by affinity chromatography in the apheresis device (1) is also particularly preferred, the method being characterized in that it comprises the following steps:

(A) start redirecting the separated plasma from the plasma line (8A) to the bypass line (12), while stopping the supply of the separated plasma from the plasma line (8A) to the apheresis column (4),

(B) starting the supply of the wash solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(C) stopping the supply of the wash solution and proceeding to supply the regeneration solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(D) start redirecting the flow of fluid flowing from the apheresis column (4) from the plasma line (8B) to the waste line (13),

(E) stopping the supply of the regeneration solution and proceeding to the supply of the washing solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(F) blocking the waste line (13) and directing the flow of fluid flowing from the apheresis column (4) into the venous line (6),

(G) stopping the supply of the wash solution and stopping the redirection of the separated plasma from the plasma line (8A) to the bypass line (12), while directing the separated plasma from the plasma line (8A) to the apheresis column (4).

In both of the above methods, a wash solution is used in addition to the regeneration solution. The wash solution is preferably physiologically acceptable and serves primarily to expel the blood plasma from the plasma line (8A) from point P2, from the apheresis column (4) and from the line (8B) plasma to point P4. The wash solution does little or nothing to regenerate the apheresis column (4). Therefore, the wash solution minimizes or even completely prevents plasma loss. Only when the blood plasma is largely or completely expelled from the section of the apheresis device (1) to be washed with the regeneration solution, is the regeneration solution supplied to regenerate the apheresis column (4). After regeneration has taken place, first the section of the apheresis device (1) that has been flushed with the regeneration solution (i.e., in the direction of flow from point P2 and through the apheresis column (4) to point P4) is again injected with the wash solution until the regeneration solution is completely removed through the waste line (13). Only then the bypass line (12) is closed and the blood plasma is again passed through the apheresis column (4). In the above two methods, steps (C) and (D) can be interchanged, i.e., can be performed in any order as well as simultaneously, and can also be combined into one step. However, step (D) is preferably performed before step (C).

In this method, the wash solution is preferably a saline NaCl solution and the regeneration solution is a citrate solution.

The preferred embodiment of the method according to the invention is designed to carry out the method more efficiently, without loss of blood plasma. Due to the simultaneous redirection of the separated plasma and the parallel supply of the washing solution to the apheresis column (4), there is no loss or significant loss of blood plasma. In addition, the preferred embodiment has the advantage that mixing of the regeneration solution and blood plasma is completely avoided. This ensures that the regeneration solution does not enter the patient and, on the other hand, there is no loss of the patient's blood plasma.

Said advantage is provided by the sequential order of steps (B)-(E). Dilution of blood plasma, if at all, occurs only with the wash solution. On the other hand, the mixing of blood plasma with the regeneration solution is completely excluded.

The volume of the wash solution according to step (B) preferably corresponds to 3-4 times the volume of the matrix of the apheresis column (4).

As a minimum, the volume of the wash solution in accordance with step (B) corresponds to the sum of the volume of the line (8A) of plasma from the point P2 to the apheresis column (4), the volume of the matrix of the apheresis column (4) and the volume of the line (8B) of plasma from the apheresis column (4 ) to point P4.

The volume of the regeneration solution according to step (C) preferably corresponds to 2-100 times the volume of the matrix of the apheresis column (4).

The volume of the wash solution according to step (E) preferably corresponds to 2-4 times the volume of the apheresis column matrix (4).

The volume of the wash solution according to step (E) at least corresponds to the sum of the volume of the plasma line (8A) from point P2 to the apheresis column (4), the volume of the matrix of the apheresis column (4) and the volume of the line (8B) of plasma from the apheresis column (4) up to point P4.

According to this even more preferred embodiment, dilution of the plasma is virtually eliminated and mixing with the regeneration solution is completely prevented. The user does not encounter excessive complexity in the operation of the apheresis device (1). Therefore, in an alternative embodiment, the steps of the method can be controlled manually without causing too much difficulty for the user.

The expression "apheresis column matrix volume" in the context of this application means the volume of the solid phase within the column, which, in turn, contains the carrier matrix material and its associated compounds that have the property of specific CRP binding. Distinguished from the reduced volume is the "dead volume of the apheresis column", i.e. the space inside the column available for the mobile phase (eg plasma). The "dead volume of the apheresis column" is equal to the difference between the volume bounded by the body of the apheresis column and the volume occupied by the swollen matrix (i.e., the "volume of the matrix of the apheresis column").

Another aspect of the present invention relates to a method for regenerating an apheresis column (4') for removal by affinity chromatography and preferably for selective removal of CRP by affinity chromatography during operation of the second apheresis column (4'') in an apheresis device (II), comprising the following stages:

(A) Starting with blood plasma flowing through the apheresis column (4''), start feeding the separated plasma from the plasma manifold (8A) into the apheresis column (4') and direct the CRP-poor blood plasma into the venous manifold (6), with termination , while supplying the separated plasma through the bypass section (12') in the bypass line (12) to the apheresis column (4''),

(B) start supplying the regeneration solution through at least one regeneration line (14) to the bypass section (12') in the bypass line (12) or directly to the apheresis column (4''),

(C) start redirecting the flow of fluid flowing from the apheresis column (4'') from the bypass section (12') in the bypass line (12) to the waste line (13''),

(D) start feeding the separated plasma through the bypass section (12') in the bypass line (12) to the apheresis column (4'') and send the CRP-poor plasma to the venous line (6) while stopping the supply separated plasma via the plasma line (8A) into the apheresis column (4'),

(E) shut off the waste line (13'') and start redirecting the flow of fluid flowing from the apheresis column (4') from the plasma line (8B) into the waste line (13').

In the above two methods, the regeneration solution is preferably saline or saline NaCl.

The expression " during operation " in the context of the present application means that, in order to carry out the method according to the invention for the regeneration of the apheresis column (4') or the regeneration of the apheresis column (4''), the collection and supply of blood and the operation of the cell separator do not need to be suspended . Thus, the patient's circulation is not stressed, since the continuously withdrawn blood is returned to the patient without delay.

In other words, in an embodiment, the present invention relates to a method for regenerating an apheresis column (4') for removal by affinity chromatography and preferably for selective removal of CRP by affinity chromatography during operation of the second apheresis column (4'') in the device (II ) apheresis, containing the following steps:

(A) starting with the blood plasma flowing through the apheresis column (4''), feed the separated plasma from the plasma manifold (8A) into the apheresis column (4') and direct the CRP-poor blood plasma into the venous manifold (6), with termination, at the same time, supplying the separated plasma through the bypass section (12') in the bypass line (12) to the apheresis column (4''),

(B) supplying the regeneration solution via at least one regeneration line (14) to the bypass section (12') in the bypass line (12) or directly to the apheresis column (4''),

(C) redirecting the flow of fluid flowing from the apheresis column (4'') from the bypass section (12') in the bypass line (12) to the waste line (13''),

(D) feeding the separated plasma through the bypass section (12') in the bypass line (12) to the apheresis column (4'') and directing the CRP-poor plasma to the venous line (6) while stopping the supply of the separated plasma via the plasma line (8A) into the apheresis column (4'),

(E) shut off the waste line (13'') and start redirecting the flow of fluid flowing from the apheresis column (4') from the plasma line (8B) into the waste line (13').

In addition, the present invention relates to a method for regenerating two apheresis columns (4', 4'') for removal by affinity chromatography and preferably for selective removal of CRP by affinity chromatography in an apheresis device (II), the method making possible the regeneration during operation and differs in that it contains the following steps:

(A) Starting with blood plasma flowing through the apheresis column (4''), start feeding the separated plasma from the plasma manifold (8A) into the apheresis column (4') and direct the CRP-poor blood plasma into the venous manifold (6), with termination , while supplying the separated plasma through the bypass section (12') in the bypass line (12) to the apheresis column (4''),

(B) start supplying the wash solution through at least one regeneration line (14) to the bypass section (12') in the bypass line (12) or directly to the apheresis column (4''),

(C) start redirecting the flow of fluid flowing from the apheresis column (4'') from the bypass section (12') in the bypass line (12) to the waste line (13''),

(D) stop the supply of the wash solution and proceed to the supply of the regeneration solution through at least one regeneration line (14) to the bypass section (12') in the bypass line (12) or directly to the apheresis column (4''),

(E) stopping the supply of the regeneration solution and proceeding to the supply of the washing solution through at least one regeneration line (14) to the bypass section (12') in the bypass line (12) or directly to the apheresis column (4''),

(F) start feeding the wash solution into the plasma line (8A) and through the apheresis column (4'), while starting the separated plasma supply through the bypass section (12') in the bypass line (12) into the apheresis column (4 ''),

(G) block off the waste line (13'') and direct the flow of fluid flowing from the apheresis column (4'') into the venous line (6),

(H) start redirecting the flow of fluid flowing from the apheresis column (4') from the plasma line (8B) to the waste line (13'),

(I) stop the supply of the wash solution and proceed to the supply of the regeneration solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4').

(J) stopping the supply of the regeneration solution and proceeding to supply the wash solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4').

In both of the above methods, the wash solution is used in addition to the regeneration solution. The flushing solution is preferably physiologically acceptable and serves primarily to expel blood plasma from the plasma line (8A) or section (12') of the bypass line in the bypass line (12) from point P2, from the apheresis column (4') or apheresis column (4'') and from the bypass section (12'') to the bypass line (12) to point P3 and the plasma line (8B) to point P4. The wash solution does little or nothing to regenerate the apheresis column (4') or apheresis column (4''). Therefore, the wash solution minimizes or even completely prevents plasma loss. Only when the blood plasma is largely or completely expelled from the section of the apheresis device (II) to be washed with the regeneration solution, is the regeneration solution supplied to regenerate the apheresis column (4') or the apheresis column (4''). After regeneration has taken place, first into the section of the apheresis device (II) that has been flushed with regeneration solution, (i.e., downstream from P2 and through the apheresis column (4'') to P8 or through the apheresis column (4') up to point P4) again enter the wash solution until the regeneration solution is completely removed through the line (13', 13'') waste.

In this method, the wash solution is preferably a saline NaCl solution and the regeneration solution is a citrate solution.

The preferred embodiment of the method according to the invention is designed to carry out the method more efficiently, without loss of blood plasma. Due to the simultaneous redirection of the separated plasma and the parallel supply of the washing solution to the apheresis column (4''), there is no loss or significant loss of blood plasma. In addition, the preferred embodiment has the advantage that mixing of the regeneration solution and blood plasma is completely avoided. This ensures that the regeneration solution does not enter the patient and, on the other hand, there is no loss of the patient's blood plasma.

This ensures that the regeneration solution does not enter the patient and, on the other hand, there is no loss of the patient's blood plasma.

Said advantage is provided by the sequential order of steps (B)-(E). Dilution of blood plasma, if at all, occurs only with the wash solution. On the other hand, the mixing of blood plasma with the regeneration solution is completely excluded.

Said advantage is provided by the sequential order of steps (B)-(E). Dilution of blood plasma, if at all, occurs only with the wash solution. On the contrary, the mixing of blood plasma with the regeneration solution is completely excluded.

The volume of the wash solution according to step (B) preferably corresponds to 3-4 times the volume of the apheresis column matrix (4''). At a minimum, the volume of the wash solution in accordance with step (B) corresponds to the sum of the volume of the bypass section (12') in the bypass line (12) from point P2 to the apheresis column (4''), the volume of the apheresis column matrix (4'') and the volume of the section (12'') of the bypass line in the bypass line (12) from the apheresis column (4'') to the point (P3).

The volume of the wash solution according to step (F) preferably corresponds to 3-4 times the volume of the matrix of the apheresis column (4'). At a minimum, the volume of the wash solution according to step (B) corresponds to the sum of the volume of the plasma line (8A') from the point (P2) to the apheresis column (4'), the volume of the apheresis column matrix (4') and the volume of the plasma line (8B) from the apheresis column to the point (P4).

The volume of the regeneration solution according to step (D) preferably corresponds to 2-100 times the volume of the apheresis column matrix (4'').

The volume of the regeneration solution according to step (I) preferably corresponds to 2-100 times the volume of the matrix of the apheresis column (4').

The volume of the wash solution according to step (E) preferably corresponds to 2-4 times the volume of the apheresis column matrix (4'').

At least the volume of the wash solution in accordance with step (E) corresponds to the sum of the volume of the section (12') of the bypass line in the bypass line (12) from point P2 to the apheresis column (4''), the volume of the matrix of the apheresis column (4'' ) and the volume of the section (12') of the bypass line in the bypass line (12) from the apheresis column (4') to point P3.

The volume of the wash solution according to step (E) preferably corresponds to 2-4 times the volume of the apheresis column matrix (4'').

The volume of the wash solution according to step (J) preferably corresponds to 2-4 times the volume of the apheresis column matrix (4').

At least the volume of the wash solution according to step (E) corresponds to the sum of the volume of the plasma line (8A) from the point P2 to the apheresis column (4'), the volume of the matrix of the apheresis column (4') and the volume of the line (8B) of the plasma from the apheresis column (4') to point P4.

Regeneration solution

In particular, the regeneration solution is a citrate solution, a tris-glycine solution, a NaCl solution, a saturated electrolyte solution or an EDTA solution, preferably a citrate solution, a Tris-glycine solution or a NaCl solution, more preferably a citrate solution. or NaCl solution, and most preferably citrate solution.

Therefore, the present invention also relates to a method according to the invention for regenerating an apheresis column, wherein the regeneration solution is selected from the group consisting of: NaCl solution, NaCl solution with citrate addition, citrate solution alone, Tris-glycine solution and EDTA solution.

In accordance with this embodiment, an anticoagulant solution already present in the system can be used as a regeneration solution. Therefore, regeneration can be carried out without additional liquids.

The term " citrate solution " in the context of this application includes aqueous solutions containing at least one citrate compound.

The term " citrate " in the context of this application refers to the citrate anion, i.e. salt of citric acid or, in other words, an organic tricarboxylate with the following chemical formula:

Citrate can be in various forms (or compounds), for example, as citric acid (singly to triple protonated form), as a salt of citric acid in combination with other (other than H+) inorganic cations (for example, as a metal salt together with metal cations or as an ammonium salt together with ammonium ions), but also as a partial ester of citric acid. In this context, the present application also uses the term " citrate compound ".

If the salt of citric acid, i.e. citrate anion complexed with an inorganic cation, the term " citric acid salt " is also used in this application as a special form of the citrate compound. Thus, the term "citrate compound" in the context of the present application includes both citric acid and its salts.

Preferably according to the invention, the citrate solution contains at least one of the citrate compounds selected from the group containing or consisting of citric acid, sodium dihydrogen citrate, disodium hydrogen citrate, trisodium citrate, trisodium citrate dihydrate, potassium dihydrogen citrate, dipotassium citrate, tripotassium citrate, lithium dihydrogencitrate, dilithium hydrocitrate, trilithium citrate, ammonium dihydrogencitrate, diammonium hydrocitrate, triammonium citrate, tricalcium dicitrate (calcium citrate), trimagnesium dicitrate (magnesium citrate) and/or partial esters of citric acid.

When the rather general term "sodium citrate" is used in this application, the term includes various protonated forms of sodium citrate, i.e. both non-protonated (trisodium citrate), and singly protonated (disodium hydrocitrate) or doubly protonated form (sodium dihydrogen citrate). When the rather general term "potassium citrate" is used in this application, the term includes various protonated forms of potassium citrate, i.e., both unprotonated (tripotassium citrate), singly protonated (dicalium hydrogen citrate) or doubly protonated form (potassium dihydrogen citrate) . When the rather general term "lithium citrate" is used in this application, this term includes various protonated forms of lithium citrate, i.e., both unprotonated (trilithium citrate), singly protonated (dilithium hydrocitrate) or doubly protonated form (lithium dihydrogen citrate) . When the rather general term "ammonium citrate" is used in this application, this term includes various protonated forms of ammonium citrate, i.e., both unprotonated (triammonium citrate), and singly protonated (diammonium hydrocitrate) or doubly protonated form (ammonium dihydrogen citrate) .

A citrate solution consisting of citric acid, trisodium citrate, D-glucose and water is also called " citrate-dextrose acid solution (ACD solution) ". Preferred variants of the citrate solution used in accordance with the invention relate to ACD solutions containing from 22.9 mM to 38.0 mM citric acid, and 44.9 mM to 74.8 mM trisodium citrate, from 74.2 mM to 123 .6 mM D-glucose and water. A particularly preferred citrate solution used in accordance with the invention relates to an ACD solution containing 38 mM citric acid, 74.8 mM trisodium citrate, 123.6 mM D-glucose and water. This solution is also referred to as "ACD-A solution".

A citrate solution consisting of citric acid, trisodium citrate, sodium hydrogen phosphate, D-glucose and water is also called " citrate-phosphate-dextrose (CPD) solution ". A preferred citrate solution used in accordance with the invention refers to a CPD solution containing 15.6 mM citric acid, 89.4 mM trisodium citrate, 128.7 mM D-glucose, 16.1 mM sodium hydrogen phosphate and water. A citrate solution consisting of citric acid, trisodium citrate, sodium hydrogen phosphate, D-glucose, adenine and water is also called " citrate-phosphate-adenine-dextrose (CPDA) solution ". The preferred citrate solution used in accordance with the invention refers to a CPDA solution containing 15.6 mM citric acid, 89.4 mM trisodium citrate, 128.7 mM to 160.9 mM D-glucose, 16.1 mM hydrogen phosphate sodium, 2 mM adenine and water. A preferred citrate solution used in accordance with the invention relates to a CPDA solution containing 15.6 mM citric acid, 89.4 mM trisodium citrate, 128.7 mM D-glucose, 16.1 mM sodium hydrogen phosphate, 2 mM adenine and water. A particularly preferred citrate solution used according to the invention relates to a CPDA solution containing 15.6 mM citric acid, 89.4 mM trisodium citrate, 160.9 mM D-glucose, 16.1 mM sodium hydrogen phosphate, 2 mM adenine and water.

The term " NaCl solution " in the context of this application contains aqueous solutions containing sodium chloride (ie NaCl, also called table salt) as the main ingredient. "Main ingredient" in the context of this application means that the molar concentration of sodium chloride in the NaCl solution exceeds the molar concentration of all other compounds in the NaCl solution, except water. The NaCl solution preferably contains 0.1-5 wt. % sodium chloride, particularly preferably 0.9 wt. %. The wash solution is preferably such a NaCl solution.

The term "tris-glycine solution" in the context of this application includes aqueous solutions containing tris(hydroxymethyl)aminomethane (2-amino-2-(hydroxymethyl)propane-1,3-diol; TRIS) and glycine. The "Tris-glycine solution" is preferably a TRIS-glycine buffer. Particularly preferably, the triglycine solution is a TRIS-glycine buffer pH 8.3 from a solution of TRIS (25 mM) and glycine (192 mM). In a further preferred embodiment, the triglycine solution is a TRIS-glycine buffer pH 8.3 from a TRIS solution (25 mM), glycine (192 mM) and SDS (sodium lauryl sulfate) solution (0.1% w/v). The pH level preferably corresponds to the pH level at 25°C.

In a preferred specific embodiment, the wash solution is saline or saline, or PBS (phosphate buffered saline), or a combination of saline and PBS, sequentially or simultaneously, and the regeneration solution is a citrate solution.

Thus, a preferred specific embodiment relates to a method for regenerating an apheresis column (4) for removal by affinity chromatography and preferably for selective removal of CRP by affinity chromatography in an apheresis device (1), the method being characterized in that it comprises the following steps :

(A) start redirecting the separated plasma from the plasma line (8A) to the bypass line (12), while stopping the supply of the separated plasma from the plasma line (8A) to the apheresis column (4),

(B) starting the supply of saline through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(C) start redirecting the flow of fluid flowing from the apheresis column (4) from the plasma line (8B) to the waste line (13),

(D) stopping the supply of saline and proceeding to the supply of citrate solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(E) stopping the supply of citrate solution and stopping the redirection of the separated plasma from the plasma line (8A) to the bypass line (12), while supplying the separated plasma from the plasma line (8A) to the apheresis column (4),

(F) block off the waste line (13) and direct the flow of fluid flowing from the apheresis column (4) into the venous line (6).

Alternatively, a preferred specific embodiment relates to a method for regenerating an apheresis column (4) for removal by affinity chromatography and preferably for selective removal of CRP by affinity chromatography in an apheresis device (1), the method being characterized in that it comprises the following stages:

(A) start redirecting the separated plasma from the plasma line (8A) to the bypass line (12), while stopping the supply of the separated plasma from the plasma line (8A) to the apheresis column (4),

(B) starting the supply of saline through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(C) stopping the supply of saline and proceeding to the supply of citrate solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(D) start redirecting the flow of fluid flowing from the apheresis column (4) from the plasma line (8B) to the waste line (13),

(E) stopping the supply of citrate solution and proceeding to the supply of saline solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(F) blocking the waste line (13) and directing the flow of fluid flowing from the apheresis column (4) into the venous line (6);

(G) stopping the saline supply and stopping the redirection of the separated plasma from the plasma line (8A) to the bypass line (12), while feeding the separated plasma from the plasma line (8A) to the apheresis column (4).

In the above two methods, steps (C) and (D) can be interchanged, i.e., can be performed in any order as well as simultaneously, and can also be combined into one step.

The regeneration methods according to the invention are preferably carried out in such a way that first the plasma is expelled from the apheresis column (4) with a flushing solution, e.g. saline or saline, and fed back into the patient until almost saline alone is fed back . Only then is the saline solution introduced into the waste line (13), and into the plasma line (8A), in the direction of flow in place or, preferably after the bypass line (12), a regeneration solution is supplied, for example, a citrate solution, which displaces the saline solution, regenerates the apheresis column (4), is completely fed into the waste line (13) and removed. After the apheresis column (4) has been regenerated with the regeneration solution supplied in the volume of several volumes of the apheresis column, the wash solution, for example, saline or saline, is fed again until the regeneration solution is completely expelled from the device (1) for apheresis and not removed. Only then is the waste line (13) closed, the wash solution is returned to the patient, the bypass line (12) is closed, and the plasma is again fed through the plasma line (8A) into the apheresis column (4), with the actions performed simultaneously or immediately one after the other, the order of the stages can be rearranged.

A further preferred specific embodiment relates to a method for regenerating an apheresis column (4) for removal by affinity chromatography and preferably for selective removal of CRP by affinity chromatography in an apheresis device (1), the method being characterized in that it comprises the following steps:

(A) start redirecting the separated plasma from the plasma line (8A) to the bypass line (12), while stopping the supply of the separated plasma from the plasma line (8A) to the apheresis column (4),

(B) starting the supply of saline through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(C) start redirecting the flow of fluid flowing from the apheresis column (4) from the plasma line (8B) to the waste line (13),

(D) stopping the supply of saline and proceeding to the supply of citrate solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(E1) stop the supply of citrate solution and proceed to the supply of saline solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(E2) stop the supply of saline and proceed to the supply of the PBS solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(E3) stop the supply of the PBS solution and proceed to the supply of saline through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(F) stopping the supply of saline and stopping the redirection of the separated plasma from the plasma line (8A) to the bypass line (12), while supplying the separated plasma from the plasma line (8A) to the apheresis column (4);

(G) block off the waste line (13) and direct the flow of fluid flowing from the apheresis column (4) into the venous line (6).

An alternative preferred specific embodiment relates to a method for regenerating an apheresis column (4) for removal by affinity chromatography and preferably for selective removal of CRP by affinity chromatography in an apheresis device (1), the method being characterized in that it comprises the following steps:

(A) start redirecting the separated plasma from the plasma line (8A) to the bypass line (12), while stopping the supply of the separated plasma from the plasma line (8A) to the apheresis column (4),

(B) starting the supply of saline through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(C) stopping the supply of saline and proceeding to the supply of citrate solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(D) start redirecting the flow of fluid flowing from the apheresis column (4) from the plasma line (8B) to the waste line (13),

(E1) stop the supply of citrate solution and proceed to the supply of saline solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(E2) stop the supply of saline and proceed to the supply of the PBS solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(E3) stop the supply of the PBS solution and proceed to the supply of saline through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4),

(F) blocking the waste line (13) and directing the flow of fluid flowing from the apheresis column (4) into the venous line (6);

(G) stopping the saline supply and stopping the redirection of the separated plasma from the plasma line (8A) to the bypass line (12), while feeding the separated plasma from the plasma line (8A) to the apheresis column (4).

In the above two methods, steps (C) and (D) can be interchanged, i.e., can be performed in any order as well as simultaneously, and can also be combined into one step.

Thus, the present invention relates to a method for regenerating two apheresis columns (4', 4'') for removal by affinity chromatography and preferably for selective removal of CRP by affinity chromatography in an apheresis device (II), the method making possible the regeneration during operation and differs in that it contains the following steps:

(A) Starting with blood plasma flowing through the apheresis column (4''), start feeding the separated plasma from the plasma manifold (8A) into the apheresis column (4') and direct the CRP-poor blood plasma into the venous manifold (6), with termination , while supplying the separated plasma through the bypass section (12') in the bypass line (12) to the apheresis column (4''),

(B) starting the supply of saline through at least one regeneration line (14) to the bypass section (12') in the bypass line (12) or directly to the apheresis column (4''),

(C) start redirecting the flow of fluid flowing from the apheresis column (4'') from the bypass section (12') in the bypass line (12) to the waste line (13''),

(D) stopping the supply of saline and proceeding to the supply of citrate solution through at least one regeneration line (14) to the bypass section (12') in the bypass line (12) or directly to the apheresis column (4''),

(E) stopping the supply of citrate solution and proceeding to the supply of saline solution through at least one regeneration line (14) to the bypass section (12') in the bypass line (12) or directly to the apheresis column (4''),

(F) starting the supply of saline into the plasma line (8A) and through the apheresis column (4'), and, at the same time, supply the separated plasma through the bypass section (12') in the bypass line (12) to the apheresis column (4''),

(G) block off the waste line (13'') and direct the flow of fluid flowing from the apheresis column (4'') into the venous line (6),

(H) start redirecting the fluid flow from the apheresis column (4') from the plasma line (8B) to the waste line (13').

(I) stop the supply of the wash solution and proceed to the supply of the citrate solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4'),

(J) stop the supply of citrate solution and proceed to the supply of saline through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4').

The regeneration methods according to the invention are preferably carried out so that the plasma is first expelled from the apheresis column (4'') by a flushing solution, e.g. saline or saline, and fed back into the patient until almost saline alone is fed back. Only then is the brine injected into the waste line (13''), and the bypass section (12') of the bypass line (12), downstream at point P2, is supplied with a regeneration solution, for example, citrate solution, which displaces the brine, regenerates the apheresis column (4''), is completely fed into the waste line (13'') and removed. After the apheresis column (4'') has been regenerated with the regeneration solution supplied in the volume of several volumes of the apheresis column, the wash solution, a solution such as saline or saline, is fed again until the regeneration solution is completely expelled from the device (II) for apheresis and not removed. Only then is the plasma line (8A) closed, the wash solution is returned to the patient, and the plasma is again fed through the bypass section (12') in the bypass line (12) to the apheresis column (4''), with the actions being performed simultaneously or immediately one after another.

Another preferred specific embodiment relates to a method for regenerating two apheresis columns (4', 4'') for removal by affinity chromatography and preferably for selective removal of CRP by affinity chromatography in the apheresis device (II), wherein the method enables regeneration during operation and differs in that it contains the following steps:

(A) Starting with blood plasma flowing through the apheresis column (4''), start feeding the separated plasma from the plasma manifold (8A) into the apheresis column (4') and direct the CRP-poor blood plasma into the venous manifold (6), with termination , while supplying the separated plasma through the bypass section (12') in the bypass line (12) to the apheresis column (4''),

(B) starting the supply of saline through at least one regeneration line (14) to the bypass section (12') in the bypass line (12) or directly to the apheresis column (4''),

(C) start redirecting the flow of fluid flowing from the apheresis column (4'') from the bypass section (12') in the bypass line (12) to the waste line (13''),

(D) stopping the supply of saline and proceeding to the supply of citrate solution through at least one regeneration line (14) to the bypass section (12') in the bypass line (12) or directly to the apheresis column (4''),

(E1) stop the supply of citrate solution and proceed to the supply of saline solution through at least one regeneration line (14) to the bypass section (12') in the bypass line (12) or directly to the apheresis column (4''),

(E2) stop the supply of saline and proceed to the supply of the PBS solution through at least one regeneration line (14) to the bypass section (12') in the bypass line (12) or directly to the apheresis column (4''),

(E3) stop the supply of the PBS solution and proceed to the supply of saline solution through at least one regeneration line (14) to the bypass section (12') in the bypass line (12) or directly to the apheresis column (4''),

(F) starting the flow of saline into the plasma line (8A) and through the apheresis column (4') and feeding the separated plasma along the bypass section (12') in the bypass line (12) into the apheresis column (4'' )

(G) block off the waste line (13'') and direct the flow of fluid flowing from the apheresis column (4'') into the venous line (6),

(H) start redirecting the fluid flow from the apheresis column (4') from the plasma line (8B) to the waste line (13').

(I) stop the supply of the wash solution and proceed to the supply of the citrate solution through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4'),

(J) stop the supply of citrate solution and proceed to the supply of saline through at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4').

Examples

Application example:

The term "matrix volume" (abbreviated MV) in the context of the present application refers to the volume of the matrix contained within the adsorber.

The term "adsorber volume" (abbreviated as AV) in the context of this application refers to the volume of the adsorber body.

Example 1: Apheresis using a bypass line and an apheresis column

Training:

A suitable tubing system is installed in the apheresis device (1) for extracorporeal removal of CRP from the patient's blood, as shown in FIG. 3 using a plasma centrifuge as a cell separator (7). A bag with 5 l of 0.9% NaCl solution and a bag with 500 ml of ACD-A solution are connected to the connecting line. Two 3 liter waste bags are connected to the waste line (13) (eg via a 3-way valve).

The arterial (5) and venous (6) lines are connected to each other using an adapter. The plasma lines (8A and 8B) before and after the adsorber are also connected to an adapter (without an adsorber in between) to form a closed system.

The entire system is filled with NaCl solution by preflushing with a 1 liter volume of 0.9% NaCl solution (200 ml/min); the air present is forced out into the first waste bag. A CRP shaker adsorber (MV 20 ml, AV 30 ml) is then installed in the plasma lines (8A and 8B) in place of the adapter. The adsorber is pre-washed with a 1-liter volume of NaCl solution (100 ml/min). The NaCl solution is also sent to the first waste bag.

At the last stage of preparation, the plasma centrifuge is pre-filled with 0.9% NaCl solution and ACD-A solution diluted 1:15. The required volume consists of the volume of the tubing in the plasma centrifuge (7), the connecting line (11) to the plasma centrifuge and the plasma line between the plasma centrifuge and point P2. The displaced NaCl solution is directed to the first waste bag via points P4/P6.

Apheresis:

1. After finishing the preparation, switch to the second waste bag. The patient is connected to the arterial (5) and venous (6) lines. At the start of apheresis, blood is sent to a centrifuge (60-80 ml/min). During therapy, ACD-A solution is mixed into the blood in a ratio of 1:15 (1 ml of ACD-A solution per 15 ml of blood) via a connecting line (11).

The NaCl solution thus displaced is directed to the second waste bag via point P2, bypass line (12) and points P4/P6. When the plasma separation begins, after a volume corresponding to the tubes from the plasma centrifuge to the point P4/6, the system is switched so that the plasma flows into the venous line (6) and hence back into the patient. After a constant plasma flow of approximately 30 ml/min is reached in 3 minutes, the first cycle can begin.

2. The bypass line (12) is closed and the plasma is passed through the adsorber (fill). As a consequence, the NaCl solution present in the plasma lines (8A and 8B) and the adsorber is passed through P4/P6 into the second waste bag up to a volume consisting of the sum of the volume of the plasma lines (8A and 8B) and AV. The adsorber is then filled with a plasma volume of 50-100 MV (1000-2000 ml). Then the regeneration starts.

3. To do this, the plasma is returned to the patient via the bypass line (12).

After that, the adsorber is washed with a 0.9% NaCl solution (30 ml/min) passed through the regeneration line (14) and the plasma lines (8A and 8B). The volume required for this is calculated from the AV and the volume of the lines (8A and 8B) of the plasma. Plasma from the plasma lines (8A and 8B) and adsorber is also returned to the patient up to a volume consisting of AV and 75% of the plasma lines (8A and 8B). Subsequently, P4/P6 is switched to direct the solutions to the second waste bag.

In the next step, the adsorber is regenerated using 3 MV (60 ml) of a 0.9% NaCl solution and, after that, a 1:15 ACD-A solution (100 ml/min). After that, the adsorber is washed with 0.9% NaCl solution (100 ml/min). The volume required for this is calculated from the AV and the volume of the regeneration line (14) and the plasma lines (8A and 8B).

Step 2 (filling) can then be performed again, followed by step 3. If necessary, replace the ACD-A solution bag.

4. After the last filling, a final regeneration is performed. At the same time, the arterial line (5) is blocked. Using 0.9% NaCl solution (30 ml/min), expel the blood from the plasma centrifuge (7) through the cell mass line (9), as well as the remaining plasma from the plasma line to P2 and bypass line (12) and feed back into patient through the connecting line (11). The volume required for this consists of the volume of the centrifuge (7) of plasma and the volume of the plasma line up to P2, the bypass line (12), the line (9) of the cell mass and the venous line (6). The patient can then be disconnected from the apheresis device.

5. If desired, the NaCl solution bag can now be replaced with a preservation solution bag (eg PBS solution with sodium azide). The adsorber is flushed by supplying 10 MV of conservation solution through the regeneration line (to the second waste bag). Then the adsorber is removed, hermetically sealed and stored. The tubing system is removed from the apheresis device and discarded.

Example 2: Alternate use of an apheresis column connected in parallel

Training:

A suitable tubing system is installed in the apheresis device (II) for in vitro removal of CRP from the patient's blood, as shown in FIG. 13 using a plasma centrifuge as a cell separator (7). A bag with 5 l of 0.9% NaCl solution and a bag with 500 ml of ACD-A solution are connected to the connecting line. Two 3 liter waste bags are connected to the waste line (13) (eg via a 3-way valve).

The arterial (5) and venous (6) lines are connected to each other using an adapter. Similarly, the plasma lines (8A and 8B) before and after the adsorber are also connected to the adapter (without the adsorber between them), and the sections (12' and 12'') of the bypass line in the bypass line (12) before and after the adsorber are connected to the adapter ( without an adsorber in between) to form a closed system.

The entire system is filled with NaCl solution by preflushing with a 1 liter volume of 0.9% NaCl solution (200 ml/min); the air present is forced out into the first waste bag. Then, in the bypass section (12' and 12'') and in the plasma line (8A and 8B), a CRP shaker adsorber (MV 20 ml, AV 30 ml) is installed instead of the adapter. The adsorber is pre-washed with a 1-liter volume of NaCl solution (100 ml/min). The NaCl solution is also sent to the first waste bag.

At the last stage of preparation, the plasma centrifuge is pre-filled with 0.9% NaCl solution and ACD-A solution diluted 1:15. The required volume consists of the volume of the tubing in the plasma centrifuge (7), the connecting line (11) to the plasma centrifuge and the plasma line between the plasma centrifuge and point P2. The displaced sodium chloride is directed to the first waste bag via points P8/P4/P6.

Apheresis:

1. After finishing the preparation, switch to the second waste bag. The patient is connected to the arterial (5) and venous (6) lines. At the start of apheresis, blood is sent to a centrifuge (60-80 ml/min). During therapy, ACD-A solution is mixed into the blood in a ratio of 1:15 (1 ml of ACD-A solution per 15 ml of blood) via a connecting line (11).

The NaCl solution thus displaced is sent to the second waste bag via point P2, bypass section 12' and points P8/P4/P6. When plasma separation begins, after a volume equal to that of the tubes from the plasma centrifuge to P8/P4/P6, the system is switched so that the plasma flows back into the venous line (6) and therefore back into the patient. After a constant plasma flow of approximately 30 ml/min is reached in 3 minutes, the first cycle can begin.

2. The plasma conduit (8A) in the area between the nodal point (P2) and the adsorber (4') is closed and the plasma is passed through the adsorber (4'') (filling). As a consequence, the NaCl solution present in sections (12' and 12'') of the bypass line and adsorber is passed through P3/P4/P6 into the second waste bag up to a volume consisting of the sum of the volumes of sections (12' and 12'' ) bypass highway and AV. Then the adsorber (4'') is filled with a plasma volume of 50-100 MV (1000-2000 ml). Then the blood plasma is displaced from the adsorber (4'') with sodium chloride solution.

3. Switching to the second adsorber is performed and the bypass section (12') is closed in the area between the nodal point (P2) and the adsorber (4''). The plasma is directed through the adsorber (4') (fill). During this process, the sodium chloride solution present in the sections (12' and 12'') of the bypass line and adsorber (4') is transferred to the second waste bag via P8/P4/P6 up to a volume consisting of the volume of the lines ( 8A and 8B) plasma and AV. The adsorber (4') is then filled with a plasma volume of 50-100 MV (1000-2000 ml). The blood plasma is then displaced from the adsorber (4') with sodium chloride solution and fed into the patient.

After that, step 2 (filling) can be performed again, and after it step 3. If necessary, replace the ACD-A solution bag.

4. After the last filling, a final regeneration is performed. At the same time, the arterial line (5) is blocked. With the help of 0.9% NaCl solution (30 ml/min), the blood is expelled from the centrifuge (7) of the plasma via the cell mass line (9) and fed back to the patient via the connecting line (11). The volume required for this consists of the volume of the centrifuge (7) of the plasma and the volume of the line (9) of the cell mass and the venous line (6). The patient can then be disconnected from the apheresis device.

5. If desired, the sodium chloride solution bag can now be replaced with a preservation solution bag (eg PBS solution with sodium azide). The adsorber is flushed by supplying 10 MV of conservation solution through the regeneration line (to the second waste bag). Then the adsorber is removed, hermetically sealed and stored. The tubing system is removed from the apheresis device and discarded.

Example 3: Sequential use of apheresis columns (4 ' , 4 '' ) connected in parallel and regeneration during operation

Training:

A suitable tubing system is installed in the apheresis device (II) for in vitro removal of CRP from the patient's blood, as shown in FIG. 5 using a plasma centrifuge as a cell separator (7). A bag with 5 l of 0.9% NaCl solution and a bag with 500 ml of ACD-A solution are connected to the connecting line. Two 3 liter waste bags are connected to the waste line (13) (eg via a 3-way valve).

Arterial (5) and venous (6) lines are connected to the adapter. Similarly, sections (12' and 12'') of the bypass line upstream and downstream of the adsorber are connected to the adapter (no adsorber in between), and the plasma lines (8A and 8B) upstream and downstream of the adsorber are connected to the adapter (no adsorber in between) to form a closed system.

The entire system is filled with NaCl solution by preflushing with a 1 liter volume of 0.9% NaCl solution (200 ml/min); the air present is forced out into the first waste bag. Then, in the bypass section (12' and 12'') and in the plasma line (8A and 8B), a CRP shaker adsorber (MV 20 ml, AV 30 ml) is installed instead of the adapter. The adsorber is pre-washed with a 1-liter volume of NaCl solution (100 ml/min). The NaCl solution is also sent to the first waste bag.

At the last stage of preparation, the plasma centrifuge is pre-filled with 0.9% NaCl solution and ACD-A solution diluted 1:15. The required volume consists of the volume of the tubing in the plasma centrifuge (7), the connecting line (11) to the plasma centrifuge and the plasma line between the plasma centrifuge and point P2. The displaced sodium chloride solution is directed to the first waste bag via points P8/P4/P6.

Apheresis:

1. After finishing the preparation, switch to the second waste bag. The patient is connected to the arterial (5) and venous (6) lines. At the start of apheresis, blood is sent to a centrifuge (60-80 ml/min). During therapy, ACD-A solution is mixed into the blood in a ratio of 1:15 (1 ml of ACD-A solution per 15 ml of blood) via a connecting line (11).

The NaCl solution thus displaced is sent to the second waste bag via point P2, bypass section 12' and points P8/P4/P6. When plasma separation begins, after a volume equal to that of the tubes from the plasma centrifuge to P8/P4/P6, the system is switched so that the plasma flows back into the venous line (6) and therefore back into the patient. After a constant plasma flow of approximately 30 ml/min is reached in 3 minutes, the first cycle can begin.

2. The plasma line (8A) is closed and the plasma is directed through the adsorber (4'') (filling). As a consequence, the NaCl solution present in the sections (12' and 12'') of the bypass line and adsorber (4'') is directed through P3/P4/P6 to the second waste bag up to a volume consisting of the sum of the volumes of the sections (12 ' and 12'') bypass line and AV. Then the adsorber (4'') is filled with a plasma volume of 50-100 MV (1000-2000 ml). Then the blood plasma is displaced from the adsorber (4'') with sodium chloride solution.

3. Switching to the second adsorber is performed and the bypass section (12') is closed in the area between the nodal point (P2) and the adsorber (4''). The plasma is directed through the adsorber (4') (fill). During this process, the sodium chloride solution present in the sections (12' and 12'') of the bypass line and adsorber (4') is directed to the second waste bag via P8/P4/P6 up to a volume consisting of the volume of the lines ( 8A and 8B) plasma and AV. The adsorber (4') is then filled with a plasma volume of 50-100 MV (1000-2000 ml). The blood plasma is then displaced from the adsorber (4') with sodium chloride solution and fed into the patient.

At the same time, the adsorber (4'') is flushed (30 ml/min) with 0.9% NaCl solution through the regeneration line (14) and bypass sections (12' and 12''). The volume required for this is calculated from the AV and the volume of the bypass sections (12' and 12''). Plasma present in sections (12' and 12'') of the bypass line and adsorber (4'') is also redirected to the patient up to a volume consisting of AV and 75% of the volume of lines (8A and 8B) of plasma. Subsequently, P4/P6 is switched to direct the solutions to the second waste bag.

In the next step, the adsorber is regenerated using 3 MV (60 ml) of a 0.9% NaCl solution and, after that, a 1:15 ACD-A solution (100 ml/min). After that, the adsorber is washed with 0.9% NaCl solution (100 ml/min). The volume required for this is calculated from the AV and the volume of the regeneration line (14) and the plasma lines (8A and 8B).

Step 2 (filling) can then be performed again, followed by step 3. If necessary, replace the ACD-A solution bag.

4. After the last filling, a final regeneration is performed. At the same time, the arterial line (5) is blocked. With the help of 0.9% NaCl solution (30 ml/min), the blood is expelled from the centrifuge (7) of the plasma via the cell mass line (9) and fed back to the patient via the connecting line (11). The volume required for this consists of the volume of the centrifuge (7) of plasma and the volume of the line (9) of the cell mass and the arterial line (6). The patient can then be disconnected from the apheresis device.

5. If desired, the sodium chloride solution bag can now be replaced with a preservation solution bag (eg PBS solution with sodium azide). The adsorber is flushed by supplying 10 MV of conservation solution through the regeneration line (to the second waste bag). Then the adsorber is removed, hermetically sealed and stored. The tubing system is removed from the apheresis device and discarded.

Description of figures

Fig. 1: Schematic representation of an embodiment of an apheresis device (1) according to the invention for extracorporeal removal of CRP from blood. The arterial line (5), in which the means (3) for forming and regulating the blood flow (eg, a peristaltic pump) is located, brings the patient's blood to the cell separator (7, for example, a centrifugal cell separator). From this separator, the plasma line (8A) passes to an apheresis column (4) to remove CRP from the blood by affinity chromatography. From the apheresis column, the plasma highway (8B) passes to the nodal point (P1). The other highway, the cell mass highway (9), runs from the cell separator (7) to the nodal point (P1). A venous line (6) also departs from the nodal point (P1), which directs the purified blood back to the patient. In addition, to connect the container (F1) for liquids, there is a connecting line (11), which is connected to the arterial line (5) or, alternatively, connected directly to the cell separator (7) (dotted line). The bypass line (12) branches off from the plasma line (8A) at the nodal point (P2) and connects to the plasma line (8B) at the nodal point (P6). The waste line (13) branches off from the plasma line (8B) at the nodal point (P4). In addition, the regeneration line (14) for connecting the liquid container (F2) is connected to the plasma line (8A) in the area between the nodal point (P2) and the apheresis column (4). Alternatively, the regeneration line (14) may also pass directly into the apheresis column (4) (not shown). For the sake of clarity, the central processing unit (10), which is also part of the apheresis device according to the invention, is not shown.

Fig. 2: Schematic representation of an embodiment of an apheresis device according to the invention for in vitro removal of CRP from blood. The arterial line (5), in which the means (3) for forming and regulating the blood flow (eg, a peristaltic pump) is located, brings the patient's blood to the cell separator (7, for example, a centrifugal cell separator). From this separator, the plasma line (8A) passes to an apheresis column (4) to remove CRP from the blood by affinity chromatography. From the apheresis column, the plasma highway (8B) passes to the nodal point (P1). The other highway, the cell mass highway (9), runs from the cell separator (7) to the nodal point (P1). A venous line (6) also departs from the nodal point (P1), which directs the purified blood back to the patient. In addition, there is a connecting line (11) which is connected to the arterial line (5) or alternatively connected directly to the cell separator (7) (dotted line). The bypass line (12) branches off from the plasma line (8A) at the nodal point (P2) and connects to the plasma line (8B) at the nodal point (P6). The waste line (13) branches off from the plasma line (8B) at the nodal point (P6). In addition, a regeneration line (14) is connected to the plasma line (8A) at the nodal point (P2). For the sake of clarity, the central processing unit (10), which is also part of the apheresis device according to the invention, is not shown.

Fig. 3: Schematic representation of an embodiment of an apheresis device according to the invention for in vitro removal of CRP from blood. The arterial line (5), in which the means (3) for forming and regulating the blood flow (eg, a peristaltic pump) is located, brings the patient's blood to the cell separator (7, for example, a centrifugal cell separator). From this separator, the plasma line (8A) passes to an apheresis column (4) to remove CRP from the blood by affinity chromatography. From the apheresis column, the plasma highway (8B) passes to the nodal point (P1). The other highway, the cell mass highway (9), runs from the cell separator (7) to the nodal point (P1). A venous line (6) also departs from the nodal point (P1), which directs the purified blood back to the patient. In addition, there is a connecting line (11) for connecting the container (F) for liquids, which is connected to the arterial line (5) or, alternatively, connected directly to the cell separator (7) (dotted line). The bypass line (12) branches off from the plasma line (8A) at the nodal point (P2) and connects to the plasma line (8B) at the nodal point (P6). The waste line (13) branches off from the plasma line (8B) at the nodal point (P6). In addition, the regeneration line (14), which branches off from the connecting line (11) at point (P5), is connected to the plasma line (8A) at the node point (P2). For the sake of clarity, the central processing unit (10), which is also part of the apheresis device according to the invention, is not shown.

Fig. 4: Schematic representation of an embodiment of an apheresis device according to the invention for in vitro removal of CRP from blood. The arterial line (5), in which the means (3) for forming and regulating the blood flow (eg, a peristaltic pump) is located, brings the patient's blood to the cell separator (7, for example, a centrifugal cell separator). From this separator, the plasma line (8A) passes to an apheresis column (4) to remove CRP from the blood by affinity chromatography. From the apheresis column, the plasma highway (8B) passes to the nodal point (P1). The other highway, the cell mass highway (9), runs from the cell separator (7) to the nodal point (P1). A venous line (6) also departs from the nodal point (P1), which directs the purified blood back to the patient. In addition, there is a connecting line (11) which is connected to the arterial line (5) or, alternatively, passes directly to the cell separator (7) (dotted line). The bypass line (12) branches off from the plasma line (8A) at the nodal point (P2) and connects to the cell mass line (9) at the nodal point (P3). The waste line (13) branches off from the plasma line (8B) at the nodal point (P1). In addition, the regeneration line (14), which branches off from the connecting line (11) at point (P5), is connected to the plasma line (8A) at the node point (P2). For the sake of clarity, the central processing unit (10), which is also part of the apheresis device according to the invention, is not shown.

Fig. 5: Schematic representation of an embodiment of an apheresis device according to the invention for in vitro removal of CRP from blood. The arterial line (5), in which the means (3) for forming and regulating the blood flow (eg, a peristaltic pump) is located, brings the patient's blood to the cell separator (7, for example, a centrifugal cell separator). From this separator, the plasma line (8A) passes to an apheresis column (4) to remove CRP from the blood by affinity chromatography. From the apheresis column, the plasma highway (8B) passes to the nodal point (P1). The other highway, the cell mass highway (9), runs from the cell separator (7) to the nodal point (P1). A venous line (6) also departs from the nodal point (P1), which directs the purified blood back to the patient. In addition, there is a connecting line (11') that is connected to the arterial line (5), but can also go directly to the cell separator (7), as well as a connecting line (11'') that is connected to the cell separator (7) , but may also be connected to the arterial line (5). The bypass line (12) branches off from the plasma line (8A) at the nodal point (P2) and connects to the plasma line (8B) at the nodal point (P6). The waste line (13) branches off from the plasma line (8B) at the nodal point (P6). In addition, the regeneration line (14), which communicates with the connection line (11') at point (P5') and communicates with the connection line (11'') at point (P5'), is connected to the plasma line (8A) at the node point (P2). For the sake of clarity, the central processing unit (10), which is also part of the apheresis device according to the invention, is not shown.

Fig. 6: Schematic representation of an embodiment of an apheresis device according to the invention for in vitro removal of CRP from blood. The arterial line (5), in which the means (3) for forming and regulating the blood flow (eg, a peristaltic pump) is located, brings the patient's blood to the cell separator (7, for example, a centrifugal cell separator). From this separator, the plasma line (8A) passes to an apheresis column (4) to remove CRP from the blood by affinity chromatography. From the apheresis column, the plasma highway (8B) passes to the nodal point (P1). The other highway, the cell mass highway (9), runs from the cell separator (7) to the nodal point (P1). A venous line (6) also departs from the nodal point (P1), which directs the purified blood back to the patient. In addition, there is a connecting line (11') that is connected to the arterial line (5) but can also go directly to the cell separator (7), as well as a connecting line (11'') that is connected to the cell separator (7), but can also be connected to the arterial line (5). The bypass line (12) branches off from the plasma line (8A) at the nodal point (P2) and connects to the plasma line (8B) at the nodal point (P6). The waste line (13) branches off from the plasma line (8B) at the nodal point (P6). In addition, the first regeneration line (14') which branches off from the connecting line (11') at point (P5') and the second regeneration line (14'') which branches off from the connecting line (11'') at point ( P5''), both are connected to the plasma line (8A) at the nodal point (P2). For the sake of clarity, the central processing unit (10), which is also part of the apheresis device according to the invention, is not shown.

Fig. 7: Schematic representation of an embodiment of an apheresis device according to the invention for in vitro removal of CRP from blood, similar to that described in FIG. 3, but with the difference that in this embodiment there is an additional connection for the container for liquids, extending from the regeneration line (14). The connecting line (11) is connected to the arterial line (5) and can, however, also pass directly into the cell separator (7), as shown by the dotted line. This time, the regeneration line (14) has an additional connection for the liquid container, while this connection is after the cell separator (7) in the direction of flow, and therefore the liquid from this additional liquid container cannot be supplied to the cell separator (7) and cannot be supplied to the arterial line (5) before the cell separator (7), but can only be supplied to the plasma line (8A) in the direction of flow, after the cell separator (7) or directly to the apheresis column (4).

Fig. 8: Schematic representation of the regeneration method according to the invention.

(A) In normal operation, crude blood (dark gray and dashed arrow) from a patient is separated into crude plasma (dark gray arrow) and cellular components (white and dashed arrow) in the cell separator (7). The crude plasma is sent to the apheresis column (4) via the plasma line (8A) and the CRP is removed in the column. Plasma thus purified (light gray arrow) is passed through the plasma manifold (8B) to the point (P1) where the plasma combines with cellular components. Purified blood (light gray and dotted arrow) is sent back to the patient through the venous line.

(B) By switching the valve at point (P2), the crude plasma is redirected to the bypass line (12) and the regeneration solution (white arrow) is fed into the apheresis column. Most of the displaced plasma is returned to the patient.

(C) After flowing through the apheresis column (4), the regenerant solution is redirected to the waste line (13) by switching the valve at point (P6) and thus removed.

(D) Subsequently, the supply of the regeneration solution is stopped by switching the valve at point (P2), and the crude plasma is again fed into the apheresis column (4). Most of the displaced regeneration solution is removed via the waste line (13). Subsequent switching of the valve at point (P6) switches back to normal operation (A).

Fig. 9: Schematic representation of an embodiment of an apheresis device (II) according to the invention for extracorporeal removal of CRP from blood. The arterial line (5), in which the means (3) for forming and regulating the blood flow (eg, a peristaltic pump) is located, brings the patient's blood to the cell separator (7, for example, a centrifugal cell separator). From this separator, the plasma line (8A) passes into an apheresis column (4') for CRP removal by affinity chromatography. The bypass line section (12') in the bypass line (12) branches off from the plasma line (8A), passes into an apheresis column (4'') for removal of CRP by affinity chromatography from blood. From the apheresis column (4''), the section (12'') of the bypass line in the bypass line (12) for CRP-poor blood plasma passes to the nodal point (P1), and the plasma line (8B) for CRP-poor blood plasma passes from the apheresis column (4') to the nodal point (P1). The other highway, the cell mass highway (9), runs from the cell separator (7) to the nodal point (P1). A venous line (6) also departs from the nodal point (P1), which directs the purified blood back to the patient. In addition, there is a connecting line (11) for connecting a container (F1) for liquids, which is connected to the arterial line (5) or, alternatively, goes directly to the cell separator (7) (dotted line). The plasma line (8A) and the bypass line section (12') in the bypass line (12) diverge at the nodal point (P2), and the bypass line section (12'') in the bypass line (12) and the plasma line (8B) converge at anchor point (P6). For the sake of clarity, the central processing unit (10), which is also part of the apheresis device according to the invention, is not shown.

Fig. 10: Schematic representation of an embodiment of an apheresis device according to the invention for in vitro removal of CRP from blood. The arterial line (5), in which the means (3) for forming and regulating the blood flow (eg, a peristaltic pump) is located, brings the patient's blood to the cell separator (7, for example, a centrifugal cell separator). From this separator, the plasma line (8A) passes into an apheresis column (4') for CRP removal by affinity chromatography. The bypass line section (12') in the bypass line (12) branches off from the plasma line (8A), passes into an apheresis column (4'') for removal of CRP by affinity chromatography from blood. From the apheresis column (4''), the section (12'') of the bypass line in the bypass line (12) for CRP-poor blood plasma passes to the nodal point (P1), and the plasma line (8B) for CRP-poor blood plasma passes from the apheresis column (4') to the nodal point (P1). The other highway, the cell mass highway (9), runs from the cell separator (7) to the nodal point (P1). A venous line (6) also departs from the nodal point (P1), which directs the purified blood back to the patient. In addition, there is a connecting line (11) for connecting a container (F1) for liquids, which is connected to the arterial line (5) or, alternatively, goes directly to the cell separator (7) (dotted line). The bypass section (12') in the bypass line (12) and the plasma line (8A) diverge at the nodal point (P2), and at the nodal point (P6) the bypass line section (12'') in the bypass line (12) and the line ( 8B) the plasmas converge. The waste line (13'') branches off from the bypass section (12') at the bypass line (12) at the nodal point (P8), and the waste line (13') branches off from the plasma line (8B) at the nodal point (P4). In addition, the regeneration line (14) for connecting the liquid container (F2) is connected to the extracorporeal circulation system (2) at the nodal point (P2). For the sake of clarity, the central processing unit (10), which is also part of the apheresis device according to the invention, is not shown.

Fig. 11: Schematic representation of an embodiment of an apheresis device according to the invention for in vitro removal of CRP from blood. The arterial line (5), in which the means (3) for forming and regulating the blood flow (eg, a peristaltic pump) is located, brings the patient's blood to the cell separator (7, for example, a centrifugal cell separator). From this separator, the plasma line (8A) passes into an apheresis column (4') for CRP removal by affinity chromatography. The bypass line section (12') in the bypass line (12) branches off from the plasma line (8A), passes into an apheresis column (4'') for removal of CRP by affinity chromatography from blood. From the apheresis column (4''), the section (12'') of the bypass line in the bypass line (12) for CRP-poor blood plasma passes to the nodal point (P1), and the plasma line (8B) for CRP-poor blood plasma passes from the apheresis column (4') to the nodal point (P1). The other highway, the cell mass highway (9), runs from the cell separator (7) to the nodal point (P1). A venous line (6) also departs from the nodal point (P1), which directs the purified blood back to the patient. In addition, there is a connecting line (11) for connecting a container (F1) for liquids, which is connected to the arterial line (5) or, alternatively, goes directly to the cell separator (7) (dotted line). The bypass line section (12') in the bypass line (12) and the plasma line (8A) diverge at the nodal point (P2), and at the nodal point (P6) the bypass line section (12'') in the bypass line (12) and the line (8B) The plasmas converge. The waste line (13'') branches off from the bypass line section (12'') at the bypass line (12) at the nodal point (P8), and the waste line (13') branches off from the plasma line (8B) at the nodal point (P4) . In addition, the regeneration line (14) for connecting the liquid container (F2) extends to the nodal point (P7). Two lines (15', 15'') branch off at a node (P7). The line (15') is connected to the extracorporeal circulation system (2) at the nodal point (P2), and the line (15'') is connected to the area between the nodal point (P2) and the apheresis column (4''). For the sake of clarity, the central processing unit (10), which is also part of the apheresis device according to the invention, is not shown.

Fig. 12: Schematic representation of an embodiment of an apheresis device according to the invention for in vitro removal of CRP from blood. The arterial line (5), in which the means (3) for forming and regulating the blood flow (eg, a peristaltic pump) is located, brings the patient's blood to the cell separator (7, for example, a centrifugal cell separator). From this separator, the plasma line (8A) passes into an apheresis column (4') for CRP removal by affinity chromatography. The bypass line section (12') in the bypass line (12) branches off from the plasma line (8A), passes into an apheresis column (4'') for removal of CRP by affinity chromatography from blood. From the apheresis column (4''), the section (12'') of the bypass line in the bypass line (12) for CRP-poor blood plasma passes to the nodal point (P1), and the plasma line (8B) for CRP-poor blood plasma passes from the apheresis column (4') to the nodal point (P1). The other highway, the cell mass highway (9), runs from the cell separator (7) to the nodal point (P1). A venous line (6) also departs from the nodal point (P1), which directs the purified blood back to the patient. In addition, there is a connecting line (11) for connecting a container (F1) for liquids, which is connected to the arterial line (5) or, alternatively, goes directly to the cell separator (7) (dotted line). The bypass line section (12') in the bypass line (12) and the plasma line (8A'') diverge at the nodal point (P2), and at the nodal point (P6) the bypass line section (12'') in the bypass line (12) and the highway (8B'') of the plasma diverge. The waste line (13) branches off from the extracorporeal circulation system (2) at the nodal point (P6). In addition, the regeneration line (14) for connecting the liquid container (F2) is connected to the extracorporeal circulation system (2) at the nodal point (P2). For the sake of clarity, the central processing unit (10), which is also part of the apheresis device according to the invention, is not shown.

Fig. 13: Schematic representation of an embodiment of an apheresis device according to the invention for in vitro removal of CRP from blood. The arterial line (5), in which the means (3) for forming and regulating the blood flow (eg, a peristaltic pump) is located, brings the patient's blood to the cell separator (7, for example, a centrifugal cell separator). From this separator, the plasma line (8A) passes into an apheresis column (4') for CRP removal by affinity chromatography. The bypass line section (12') in the bypass line (12) branches off from the plasma line (8A) and passes into an apheresis column (4'') to remove CRP by affinity chromatography from the blood. From the apheresis column (4''), the section (12'') of the bypass line in the bypass line (12) for CRP-poor blood plasma passes to the nodal point (P1), and the plasma line (8B) for CRP-poor blood plasma passes from the apheresis column (4') to the nodal point (P1). The other highway, the cell mass highway (9), runs from the cell separator (7) to the nodal point (P1). A venous line (6) also departs from the nodal point (P1), which directs the purified blood back to the patient. In addition, there is a connecting line (11) for connecting the container (F) for liquids, which is connected to the arterial line (5) or, alternatively, goes directly to the cell separator (7) (dotted line). The bypass line section (12') in the bypass line (12) and the plasma line (8A) diverge at the nodal point (P2), and at the nodal point (P6) the bypass line section (12'') in the bypass line (12) and the line (8B) The plasmas converge. The waste line (13) branches off from the extracorporeal circulation system (2) at the nodal point (P6). In addition, the regeneration line (14), which branches off from the connecting line (11) at point (P5), is connected to the extracorporeal circulation system (2) at the nodal point (P2). For the sake of clarity, the central processing unit (10), which is also part of the apheresis device according to the invention, is not shown.

Fig. 14: Schematic representation of an embodiment of an apheresis device according to the invention for in vitro removal of CRP from blood. The arterial line (5), in which the means (3) for forming and regulating the blood flow (eg, a peristaltic pump) is located, brings the patient's blood to the cell separator (7, for example, a centrifugal cell separator). From this separator, the plasma line (8A) passes into an apheresis column (4') for CRP removal by affinity chromatography. The bypass line section (12') in the bypass line (12) branches off from the plasma line (8A), passes into an apheresis column (4'') for removal of CRP by affinity chromatography from blood. From the apheresis column (4''), the section (12'') of the bypass line in the bypass line (12) for CRP-poor blood plasma passes to the nodal point (P1), and the plasma line (8B) for CRP-poor blood plasma passes from the apheresis column (4') to the nodal point (P1). The other highway, the cell mass highway (9), runs from the cell separator (7) to the nodal point (P1). A venous line (6) also departs from the nodal point (P1), which directs the purified blood back to the patient. In addition, there is a connecting line (11') that is connected to the arterial line (5), but can also go directly to the cell separator (7), as well as a connecting line (11'') that is connected to the cell separator (7) , but may also be connected to the arterial line (5). The bypass line section (12') in the bypass line (12) and the plasma line (8A) diverge at the nodal point (P2), and at the nodal point (P6) the bypass line section (12'') in the bypass line (12) and the line (8B) The plasmas converge. The waste line (13) branches off from the extracorporeal circulation system (2) at the nodal point (P6). In addition, the line (14) regeneration, which communicates with the connecting line (11') at the point (P5') and communicates with the connecting line (11'') at the point (P5'), is connected to the extracorporeal circulation system (2) in anchor point (P2). For the sake of clarity, the central processing unit (10), which is also part of the apheresis device according to the invention, is not shown.

Fig. 15: Schematic representation of an embodiment of an apheresis device according to the invention for in vitro removal of CRP from blood. The arterial line (5), in which the means (3) for forming and regulating the blood flow (eg, a peristaltic pump) is located, brings the patient's blood to the cell separator (7, for example, a centrifugal cell separator). From this separator, the plasma line (8A) passes into an apheresis column (4') for CRP removal by affinity chromatography. The bypass line section (12') in the bypass line (12) branches off from the plasma line (8A), passes into an apheresis column (4'') for removal of CRP by affinity chromatography from blood. From the apheresis column (4''), the section (12'') of the bypass line in the bypass line (12) for CRP-poor blood plasma passes to the nodal point (P1), and the plasma line (8B) for CRP-poor blood plasma passes from the apheresis column (4') to the nodal point (P1). The other highway, the cell mass highway (9), runs from the cell separator (7) to the nodal point (P1). A venous line (6) also departs from the nodal point (P1), which directs the purified blood back to the patient. In addition, there is a connecting line (11') that is connected to the arterial line (5), but can also go directly to the cell separator (7), as well as a connecting line (11'') that goes to the cell separator (7) , but may also be connected to the arterial line (5). The bypass section (12') in the bypass line (12) and the plasma line (8A) diverge at the nodal point (P2), and at the nodal point (P6), the plasma line (8B') and the plasma line (8B'') converge. The waste line (13) branches off from the extracorporeal circulation system (2) at the nodal point (P6). In addition, the first regeneration line (14') which branches off from the connecting line (11') at point (P5') and the second regeneration line (14'') which branches off from the connecting line (11'') at point ( P5''), both are connected to the extracorporeal circulation system (2) at the nodal point (P2). For the sake of clarity, the central processing unit (10), which is also part of the apheresis device according to the invention, is not shown.

Fig. 16: Schematic representation of an embodiment of an apheresis device according to the invention for in vitro removal of CRP from blood. The arterial line (5), in which the means (3) for forming and regulating the blood flow (eg, a peristaltic pump) is located, brings the patient's blood to the cell separator (7, for example, a centrifugal cell separator). From there, the plasma line (8A) passes to an apheresis column (4') for CRP removal by affinity chromatography. The bypass line section (12') in the bypass line (12) branches off from the plasma line (8A) and passes into an apheresis column (4'') to remove CRP by affinity chromatography from the blood. From the apheresis column (4''), the section (12'') of the bypass line in the bypass line (12) for CRP-poor blood plasma passes to the nodal point (P1), and the plasma line (8B) for CRP-poor blood plasma passes from the apheresis column (4') to the nodal point (P1). The other highway, the cell mass highway (9), runs from the cell separator (7) to the nodal point (P1). A venous line (6) also departs from the nodal point (P1), which directs the purified blood back to the patient. In addition, there is a connecting line (11) for connecting the container (F) for liquids, which is connected to the arterial line (5) or, alternatively, goes directly to the cell separator (7) (dotted line). The bypass line section (12') in the bypass line (12) and the plasma line (8A) diverge at the nodal point (P2), and at the nodal point (P6) the bypass line section (12'') in the bypass line (12) and the line (8B) The plasmas converge. The waste line (13) branches off from the extracorporeal circulation system (2) at the nodal point (P6). In addition, the regeneration line (14), which branches off from the connecting line (11) at point (P5), is connected to the extracorporeal circulation system (2) at the nodal point (P2). This time, the inlet line has an additional connection for the liquid container, while this connection is after the cell separator (7) in the direction of flow, and therefore the liquid from this additional liquid container cannot be fed into the cell separator (7) and cannot be fed into the arterial line (5) before the cell separator (7), but can only be fed into the bypass section (12') in the bypass line (12) or into the plasma line (8A), in the direction of flow after the cell separator (7), or directly into the apheresis column (4') or directly into the apheresis column (4''). For the sake of clarity, the central processing unit (10), which is also part of the apheresis device according to the invention, is not shown.

List of conventions

1 - device for apheresis

2 - extracorporeal circulation system

3 - means for forming and regulating the flow of blood (or blood plasma) in the extracorporeal circulation system (pump)

4 - apheresis column for removing CRP by affinity chromatography

4' - apheresis column for removing CRP by affinity chromatography

4'' - apheresis column for removing CRP by affinity chromatography

5 - arterial line

6 - venous line

7 - cell separator

8A - plasma line (before apheresis column)

8B - plasma highway (after apheresis column)

9 - highway cell mass

10 - central processing unit (CPU)

11 - connecting line

12 - bypass line

12' - section of the bypass line in the bypass line

12''- section bypass line in bypass line

13 - waste line

13'- waste line

13''- waste line

14 - regeneration line

14'- regeneration line

14''- regeneration line

F - container for liquids

F1 - container 1 for liquids

F2 - container 2 for liquids

P1 is the nodal point at which the plasma line (8B) is connected to the venous line (6), or the nodal point at which the bypass section (12'') in the bypass line (12) or the plasma line (8B) and the line (9 ) cell mass converge and connect to the venous line (6)

P2 is the nodal point at which the bypass line (12) branches off from the plasma line (8A), or the nodal point at which the bypass line section (12') in the bypass line and the plasma line (8B) diverge

P3 - nodal point at which the bypass line (12) is connected to the line (9) of the cell mass

P4 is the nodal point at which the waste line (13) branches off from the plasma line (8B), or the nodal point at which the waste line (13') branches off from the plasma line (8B)

P5 - nodal point at which the regeneration line (14) branches off from the connecting line (11)

P5, P5' - nodal point at which the regeneration line (14) branches off from the connecting line (11) or (11'), respectively.

P6 is the nodal point at which the bypass line (12) is connected to the plasma line (8B), or the nodal point at which the bypass line section (12'') in the bypass line (12) and the plasma line (8B) converge and run together as bypass section (12'') to bypass line (12) or plasma line (8B) to point P1.

P7 is the nodal point on the regeneration line (14), from which the regeneration line (14) is divided into lines (15') and (15'').

P8 is the nodal point at which the waste line (13'') branches off from the bypass section (12'') in the bypass line.

Claims (54)

1. Device (1) for apheresis for extracorporeal removal of C-reactive protein (CRP) from the blood, containing: system (2) extracorporeal circulation for blood, means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2), separator (7) of cells for separating blood into blood plasma and cellular components, at least one apheresis column (4) to remove CRP by affinity chromatography from blood, wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4), a plasma line (8B) for CRP-poor blood plasma from the apheresis column (4) to the point (P1), the line (9) of the cell mass for the separated cellular components from the cell separator (7) to the point (P1) and the venous line (6) coming from the point (P1), central processor (10) to control the device (1) for apheresis, at least one connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7), different in that the bypass line (12) branches off from the plasma line (8A) and is connected to the plasma line (8B), the waste line (13) departs directly from the apheresis column (4) or from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and at least one regeneration line (14) departs from at least one container (F) for liquids or from at least one connecting line (11) and passes to the plasma line (8A), in the direction of flow in point or after the branch point of the bypass line (12) or passes directly into the apheresis column (4). 2. Device according to claim 1, wherein at least one regeneration line (14) leading to the plasma line (8A) or directly to the apheresis column (4) starts from point (P5) on at least one connecting line (11). 3. The device according to claim 1, in which the device (1) for apheresis contains at least two connecting lines (11), each for connecting at least one container (F) for fluids to the arterial line (5) or cell separator (7), and at the same time there is a regeneration line (14) for each container (F) for liquids, which departs from the corresponding container (F) for liquids or its connecting line (11) and each of which passes to the line ( 8A) plasma or directly into the apheresis column (4). 4. Device according to claim 1, wherein the apheresis device (1) comprises two connecting lines (11', 11''), each for connecting at least one container (F) for fluids to the arterial line (5) or separator (7) cells, and at least one highway (14) regeneration leading to highway (8A) plasma or directly to the apheresis column (4), joins the connecting highway (11') at the point (P5 ') and to the connecting line (11'') at point (P5''). 5. Device according to claim 1, wherein the apheresis device (1) comprises two connecting lines (11', 11''), each for connecting at least one fluid container (F1, F2) to an arterial line ( 5) or cell separator (7), and at the same time two regeneration lines (14', 14'') depart from two containers (F1, F2) for liquids or two connecting lines (11', 11'') and pass to the line (8A) plasma or directly into the apheresis column (4). 6. Device according to claim 1, wherein the apheresis device (1) comprises a connecting line (11') for connecting a container (F1) for fluids to an arterial line (5) or a cell separator (7) and a connecting line (11'' ) to connect the container (F2) for fluids to the arterial line (5) or separator (7) of cells and at the same time the regeneration line (14') departs from the container (F1) for liquids or the connecting line (11') and passes to the line ( 8A) of plasma, in the direction of flow after branching the bypass line (12), or directly into the apheresis column (4) and the regeneration line (14'') departs from the container (F2) for liquids or the connecting line (11'') and passes to line (8A) plasma, in the direction of flow after a branch of the bypass line (12), or line (14') regeneration or directly into the apheresis column (4). 7. The device according to any one of paragraphs. 1-6, wherein the bypass line (12) extends from point (P2) on the plasma line (8A) to point (P6) on the plasma line (8B), and the waste line (13) exits at point (P4) from the line ( 8B) of the plasma, and at least one regeneration line (14) is connected to the plasma line (8A) at point (P2). 8. Device (II) for apheresis for extracorporeal removal of C-reactive protein (CRP) from the blood, containing: system (2) extracorporeal circulation for blood, means (3) for forming and regulating the blood flow in the extracorporeal circulation system (2), separator (7) of cells for separating blood into blood plasma and cellular components, two apheresis columns (4', 4'') for the removal of CRP by affinity chromatography from blood, wherein the extracorporeal circulation system (2) comprises an arterial line (5) to the cell separator (7), a plasma line (8A) from the cell separator (7) to the apheresis column (4'), a plasma line (8B) for CRP-poor plasma blood from the apheresis column (4') to the point (P1), the line (9) of the cell mass for the separated cellular components from the cell separator (7) to the point (P1) and the venous line (6) coming from the point (P1), central processor (10) to control the device (1) for apheresis, at least one connecting line (11) for connecting at least one container (F) for liquids to the arterial line (5) or cell separator (7), different in that the bypass line (12) branches off from the plasma line (8A) and is connected to the plasma line (8B), and the bypass line (12) contains a second apheresis column (4''), the waste line (13) departs directly from the apheresis column (4') or from the plasma line (8B), in the direction of flow before the connection point of the bypass line (12), and at least one regeneration line (14) departs from at least one container (F) for liquids or from at least one connecting line (11) and passes to the plasma line (8A), in the direction of flow in point or after the branch point of the bypass line (12), or passes directly into the apheresis column (4'), and moreover, the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') are connected in parallel with the possibility of alternate use. 9. The method of regeneration of the apheresis column (4) to remove C-reactive protein (CRP) by affinity chromatography in the device (1) for apheresis according to any one of paragraphs. 1-6, wherein the method includes the following steps: (A) start redirecting the separated plasma from the plasma line (8A) to the bypass line (12) while stopping the supply of separated plasma from the plasma line (8A) to the apheresis column (4), (B) start supplying the regeneration solution from at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4), (C) start redirecting the flow of fluid flowing from the apheresis column (4) from the plasma line (8B) to the waste line (13), (D) stopping the supply of the regeneration solution and stopping the redirection of the separated plasma from the plasma line (8A) to the bypass line (12) while supplying the separated plasma from the plasma line (8A) to the apheresis column (4), (E) block off the waste line (13) and direct the flow of fluid flowing from the apheresis column (4) into the venous line (6). 10. The method according to p. 9 for the regeneration of the apheresis column (4) to remove CRP by affinity chromatography in the device (1) for apheresis according to any one of paragraphs. 1-7, wherein the method is characterized in that it comprises the following steps: (A) start redirecting the separated plasma from the plasma line (8A) to the bypass line (12) while stopping the supply of separated plasma from the plasma line (8A) to the apheresis column (4), (B) start feeding the wash solution of at least one regeneration line (14) into the plasma line (8A) or directly into the apheresis column (4), (C) stopping the supply of the wash solution and proceeding to the supply of the regeneration solution of at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4), (D) start redirecting the flow of fluid flowing from the apheresis column (4) from the plasma line (8B) to the waste line (13), (E) stopping the supply of the regeneration solution and proceeding to the supply of the washing solution of at least one regeneration line (14) to the plasma line (8A) or directly to the apheresis column (4), (F) blocking the waste line (13) and directing the flow of fluid flowing from the apheresis column (4) into the venous line (6), (G) stop the flushing solution and stop redirecting the separated plasma from the plasma line (8A) to the bypass line (12) while directing the separated plasma from the plasma line (8A) to the apheresis column (4). 11. The method of claim 9, wherein the regeneration solution(s) is selected from the group consisting of or consisting of a citrate solution, a tris-glycine solution, a NaCl solution, a saturated electrolyte solution, and an EDTA (ethylene diamine tetraacetic acid) solution. ) and, mainly, citrate solution. 12. The method of claim 9, wherein the wash solution is saline NaCl and/or the regeneration solution is a citrate solution. 13. The method according to claim 12, in which step (C) is started after a full volume X of the regeneration solution(s) has been supplied to the plasma line (8A) or directly to the apheresis column (4), while X corresponds to at least 75% of the volume of the device between the point at which the regeneration line (14) is connected to the extracorporeal circulation system (2), in the direction of flow after the branch of the bypass line (12), and the point at which the line (13) waste begins from the system (2) extracorporeal circulation. 14. A method for regenerating an apheresis column (4') to remove C-reactive protein (CRP) by affinity chromatography during operation of the second apheresis column (4'') in the apheresis device (II) according to claim 8, including the following steps: (A) Starting with the blood plasma flowing through the apheresis column (4''), start feeding the separated plasma from the plasma manifold (8A) into the apheresis column (4') and direct the CRP-poor plasma to the venous manifold (6) and stop at this feeds the separated plasma through the bypass section (12') in the bypass line (12) into the apheresis column (4''), (B) start supplying the regeneration solution of at least one regeneration line (14) to the bypass section (12') in the bypass line (12) or directly to the apheresis column (4''), (C) start redirecting the flow of fluid flowing from the apheresis column (4'') from the bypass section (12'') in the bypass line (12) to the waste line (13''), (D) start feeding the separated plasma through the bypass section (12') in the bypass line (12) into the apheresis column (4'') and direct the CRP-depleted blood plasma into the venous line (6) while stopping the separated plasma supply through lines (8A) of plasma into the apheresis column (4'), (E) shut off the waste line (13'') and start redirecting the flow of fluid flowing from the apheresis column (4') from the plasma line (8B) into the waste line (13').

Images