Device for removing noxious substances from blood, extracorporeal perfusion system comprising such a device, and method for producing such a device

Description

[0001] The invention relates to a device for removing noxious substances, in particular negatively charged ones, from blood containing plasma and cellular components in an extracorporeal perfusion system, comprising a housing and a plurality of hollow fibers provided within the housing, which are configured to be perfused by the blood, wherein the hollow fibers each have a plurality of pores designed such that the plasma of the blood can flow through the pores from an inner side of the hollow fibers to an outer side of the hollow fibers, wherein the hollow fibers are modified or pretreated, in particular chemically, such that they have a functionalized surface that binds the noxious substances to themselves and removes them from the blood. Furthermore, the invention relates to an extracorporeal perfusion system comprising such a device and a method for producing such a device. State of the art

[0002] Sepsis, or blood poisoning, is a complex systemic inflammatory reaction of the human body resulting from an infection by bacteria, their toxins, or fungi. Even today, despite all therapeutic measures, severe sepsis or septic shock is fatal for many patients. Causes of sepsis include the use of catheters and endoscopes, the implantation of prostheses, surgical procedures, the use of immunosuppressive drugs, the increasing number of elderly patients, and the growing resistance of bacteria to antibiotics. Patient infections today are often caused by (multi-)resistant bacteria.

[0003] State-of-the-art procedures such as plasmapheresis, also known as plasma exchange therapy, or antibody therapy have not been able to significantly improve the prognosis for septic patients. In particular, plasmapheresis has proven to be unselective and inefficient, as it deprives the patient of not only toxins and pro-inflammatory cytokines, but also protective, anti-inflammatory mediators. Furthermore, a single therapy cycle requires an exchange volume of approximately 12 liters of plasma (approximately 50 donors), which carries an additional risk of infections or allergic reactions. Antibody therapy procedures are very expensive due to the technically complex extraction, purification, and characterization of the respective antibodies, and their use carries the risk, among other things, of an allergic reaction by the body to the antibodies.

[0004] Furthermore, treatments of blood or plasma in an extracorporeal perfusion system for the neutralization or elimination of pathogenic blood components such as lipopolysaccharides, lipoteichoic acids, etc., using suitable adsorbent materials are also known from the prior art.

[0005] For example, porous carrier materials with immobilized polymyxin B are described in US 4,576,928 or DE 39 32 971, but these have proven to be unsuitable for clinical use because the ligand polymyxin B causes severe nephrotoxic and neurotoxic damage when released into the bloodstream.

[0006] DE 41 13 602 A1 discloses polyethyleneimine-modified percelluloses as adsorbers, which, however, have a low binding capacity for lipopolysaccharides, so that when they are used in an extracorporeal perfusion system, the medically tolerable extracorporeal dead volume is exceeded.

[0007] DE 44 35 612 A1 further describes a plasma perfusion procedure suitable for the elimination of lipopolysaccharides and TNF-α (tumor necrosis factor-α). However, this procedure is very complex and hemodynamically disadvantageous, as it requires a very large extracorporeal dead volume. Furthermore, it eliminates not only lipopolysaccharides and TNF-α but also fibrinogen, which is essential for plasma coagulation. Therefore, depending on the initial fibrinogen concentration, the application of this procedure is limited to only two to three consecutive treatments, which is usually insufficient for effective patient treatment.

[0008] A particularly effective removal of negatively charged pollutants from blood plasma is disclosed in EP 1 602 387 A1. The device disclosed in this publication contains hollow fibers which are chemically modified in such a way that the charged lipopolysaccharides (LPS) and lymphotoxin-α (LTA) bind particularly well to them and can thus be removed from the plasma. The hollow fibers are chemically modified on the surface, preferably by graft polymerization. During graft polymerization, compounds, for example anion exchangers (groups) with good binding capacity for LPS and LTA, are grafted onto the hollow fiber material. Longer chains designed as tentacles with a large number of cationic groups are provided as anion exchangers. Such tentacle-like extensions on the hollow fiber base material are capable of binding several LPS orLTA molecules can be bound, thereby increasing the efficiency of the hollow fibers. Synthetic, semi-synthetic, or natural polycation chains, which can be linear or branched, are preferably used for the modification of the hollow fibers. The hollow fibers are preferably modified with (poly)cation chains containing tertiary or quaternary amines.

[0009] However, the device disclosed in EP 1 602 387 A1 has the disadvantage that the chemically modified, coated, or grafted surface is incompatible with blood cells / the cellular components of the blood, so that prior to treatment, the blood cells must be separated from the blood plasma by plasma separation. Commercially available plasma separators consist of hollow fiber capillaries with a pore size of 0.1 to 0.5 µm. They are used for a maximum period of 4 to 6 hours. Since a patient suffering from sepsis is treated for a period of at least 74 hours, the plasma separator must be changed very frequently during this period.

[0010] EP 1 776 175 B1 discloses a continuous process for producing a regioselective, porous hollow-fiber membrane, whereby the resulting hollow-fiber membrane enables blood separation and blood purification in a single step. The hollow-fiber membrane is essentially made of a blood-compatible polymer and thus does not damage the cellular components of the blood. A special plasma treatment is used to equip only the outer surface of the hollow-fiber membrane and the pores with functional groups. When blood is then passed through the hollow fibers at high pressure, only (blood) plasma penetrates the fine pores. The cellular blood components are too large and remain in the blood-compatible main channel. Finally, binding molecules grafted onto the fine pores and the outer wall of the hollow fibers remove the toxins from the fluid via a wet-chemical treatment.

[0011] However, the method disclosed in EP 1 776 175 B1 has the disadvantage that it requires a complex vacuum system with a large number of vacuum chambers for the plasma pretreatment of the hollow fiber membrane(s), and thus the production of the hollow fiber membrane disclosed therein is very complex.

[0012] WO 2011 / 015197 A1 discloses a device for removing contaminants from blood. In WO 2011 / 015197 A1, it is undesirable for blood components to migrate from the blood side to the gas side of the hollow fibers. Either the inner or outer sides of the hollow fibers are coated simultaneously with contaminant-binding substances and heparin. Brief description of the invention

[0013] Against this background, the object of the present invention is to avoid or at least mitigate the disadvantages of the prior art and, in particular, to provide blood separation and blood purification in a single step (without prior plasma separation) using porous hollow fibers that are manufactured more easily than the prior art / using a device for removing contaminants from blood that is manufactured more easily than the prior art. In particular, the aim is to provide a simple treatment system with a long application period.

[0014] This object is achieved by a device for removing noxious substances from blood having the features of claim 1, an extracorporeal perfusion system having the features of claim 8, and a method for producing a device for removing noxious substances from blood having the features of claim 9. Advantageous embodiments and further developments are claimed in the subclaims and / or explained below.

[0015] The invention relates firstly to a device for removing negatively charged noxae from blood which comprises plasma and cellular components, in / for / for use in an extracorporeal perfusion system, having a housing and a plurality of hollow fibers / hollow fiber capillaries provided within the housing, which are configured to be perfused with the blood, wherein the hollow fibers each have a plurality of pores which are designed such that the plasma of the blood can flow through the pores from an inside of the hollow fibers to an outside of the hollow fibers, wherein the hollow fibers are chemically modified orare pretreated in such a way that they have a functionalized, positively charged surface that binds the negatively charged noxious substances to themselves and removes them from the blood, whereby only one inner surface of the hollow fibers is further provided (completely / the entire inner surface) with a hemocompatible and anticoagulant cover / coating to avoid / prevent damage to the cellular components of the blood when the blood flows through the hollow fibers, so that only the pores and one outer surface of the hollow fibers have the functionalized surface and there is no longer any functionalized surface on the inner surface of the hollow fibers.

[0016] In the context of this application, a noxious agent is understood to mean a substance or material that is undesirably present in the blood of a living being, for example, a human, and that exerts a damaging, pathogenic, and / or hazardous effect on the organism or a body organ. Noxious agents can include, for example, lipopolysaccharides (LPS, endotoxins), lipoteichoic acids (LTA), viruses, DNA, etc. An extracorporeal perfusion system is understood to mean a blood circulation system outside the body of the living being. When blood is mentioned in the context of this application, this generally refers to a suspension of plasma and cellular components such as erythrocytes, leukocytes, platelets, etc.

[0017] The device according to the invention is designed to be perfused by both the cellular components and the plasma of the blood, so that no separation of the plasma from the cellular components is necessary before the blood flows through the device. Thus, according to the invention, no plasma separation and thus no frequent replacement of a plasma separator is required. The device of the present invention is used for the treatment of patients with diseases caused by an invasion of gram-negative and / or gram-positive bacteria or other negatively charged noxious agents such as Shiga toxin.

[0018] With regard to the material of the porous / porous hollow fibers and the modification / pretreatment of the hollow fibers, reference is made in full to EP 1 602 387 A1. However, the most important aspects are also briefly outlined below in the present application.

[0019] In principle, hollow fiber materials made from polyamide, polysulfone, polyether, polyethylene, polypropylene, polyester, or derivatives and / or mixtures of such polymers can be used. Particularly preferably, the hollow fibers are made from nylon (polyamide 66). These membrane base materials can be modified by conventional methods, preferably by graft polymerization, to provide them with a functionalized surface that binds the noxious substances to itself and removes them from the blood. In the context of the present application, a functionalized surface is characterized by having a large surface area and functional groups that attract the noxious substances, thus promoting both mechanical and specific adhesion of the noxious substances to the hollow fibers.The hollow fibers used in the device according to the invention are chemically modified in such a way that negatively charged noxious substances such as LPS or LTA molecules can bind particularly well to the hollow fiber material and are thus removed from the blood (hollow fibers with a positive charge).

[0020] Chemical modification of the hollow fiber material is therefore preferably carried out by graft polymerization, in which compounds are grafted onto the hollow fiber material which show good binding ability for LPS and / or LTA in particular.

[0021] It has proven particularly advantageous to graft anion exchange groups onto the substrate. Such anion exchange groups are preferably designed as longer chains with a large number of cationic groups, known as tentacles. Such tentacle-like extensions on the base material are capable of binding multiple LPS or LTA molecules. Synthetic and / or semi-synthetic and / or natural polycation chains are preferably used to modify the hollow fiber material using tentacles, whereby these chains can be in linear or branched form. The hollow fiber materials according to the invention are particularly preferably modified by cation or polycation chains containing tertiary and / or quaternary amines.

[0022] Preferred anion exchange groups on the hollow fiber materials include di- or trialkylaminoalkyl, di- or trialkylaminoaryl, di- or triarylaminoalkyl, di- or triarylaminoaryl, di- or trialkylammoniumalkyl, di- or triarylammoniumalkyl, di- or triarylammoniumaryl, and di- or trialkylammoniumaryl residues. Furthermore, polymers of positively charged amino acids or amino acids containing tertiary or quaternary amino groups, such as polylysine, polyarginine, or polyhistidine, or copolymers or derivatives thereof, are suitable as anion exchange materials within the scope of the invention, as is polyethyleneimine. The device particularly preferably contains a polyamide hollow fiber material modified with diethylaminoalkyl or diethylaminoaryl residues, in particular diethylaminoethyl polyamide.

[0023] The multitude of hollow fibers / hollow fiber capillaries forms a hollow fiber membrane.

[0024] The housing of the device according to the invention can be viewed as a membrane module, which has a hollow fiber membrane / a plurality of porous hollow fibers inside. The device according to the invention is thus constructed similarly to a dialyzer with blood caps and a side port. The pores of the hollow fibers have a size of approximately 0.1 to 0.5 µm, so that only the plasma of the blood can flow through the pores, but not the cellular components / blood cells. The hollow fibers / the hollow fiber membrane have / have a large internal surface area.

[0025] The core of the present invention is that only the inner surfaces of the modified hollow fibers, which come into contact with the cellular components of the blood when blood flows through the hollow fibers, are coated or covered with a coating / covering that does not damage the cellular components of the blood. Thus, according to the invention, the inner surfaces of the hollow fibers no longer have a functionalized surface that binds the noxious substances to themselves and removes them from the blood. Only the pores and outer surfaces of the hollow fibers thus have the functionalized surface that binds the noxious substances to themselves and removes them from the blood. This allows the cellular components to flow through the hollow fibers without being damaged. The noxious substances are removed from the plasma when the plasma flows through the pores or along the outer surfaces of the hollow fibers.The device of the present invention thus provides a regioselective membrane adsorber.

[0026] Preferably, the coating is thus arranged or formed on the inner surface of the hollow fibers in such a way that the inner peripheral sides of the pores are not or incompletely covered by the coating.

[0027] Advantageously, the coating on the inner surface of the hollow fibers is both hemocompatible and anticoagulant, as well as compatible with the functionalized surface of the hollow fibers, to which the coating is applied on the inner side of the hollow fibers. This coating binds the noxious substances and removes them from the blood. In particular, the coating / cover is compatible with the cellular components of the blood, so that they are not damaged as they flow through the device. Furthermore, the coating, or the substance formed by the coating, is compatible with the functionalized original (inner) surface of the hollow fibers, which binds the noxious substances and removes them from the blood, so that the coating adheres well to it.In other words, the hemoincompatible surface of the hollow fibers / hollow fiber membrane is covered on the blood side with a hemocompatible substance / coating that is both compatible with the hemoincompatible surface and very well tolerated by blood.

[0028] A preferred embodiment is characterized in that the coating is applied to the inner surface of the hollow fibers by flowing a solution through the hollow fibers. In other words, the solution / substance is flowed through the hollow fiber membrane / the hollow fibers on the blood side. Preferably, the functionalized surface of the hollow fibers on the inner side of the hollow fibers is defunctionalized, i.e., saturated or bound by the solution. Preferably, the solution is / contains an anticoagulant substance that binds to the inner surface of the hollow fibers.

[0029] More preferably, the solution is a negatively charged anionic solution, in particular an anticoagulant polyanion, preferably heparin. This can ensure that the generally positively charged, functionalized surface of the hollow fibers is saturated / neutralized / discharged by the negatively charged solution. In other words, damage to the blood cells is avoided / prevented in the present invention precisely by binding / saturating the functional groups on the inner surface of the hollow fibers by the solution, and simultaneously by binding an anticoagulant substance such as heparin to the inner surface of the hollow fibers.

[0030] In a preferred embodiment of the present invention, the coating is thus an anionic coating. However, other coatings, such as cationic or hydrophilic coatings, are also conceivable according to the invention.

[0031] Preferably, by adjusting a quantity, a flow rate and preferably an anion concentration of the (anionic) solution, a coating of only the inner surfaces of the hollow fibers and a saturation of the inner surfaces of the hollow fibers with the (anionic) solution can be achieved and a thickness of the coating can be varied.

[0032] It has been found that, in particular, the parameters of the quantity / liquid quantity / volume of the (anionic) solution added to the device, as well as the flow rate of the (anionic) solution at which the solution flows through the device / hollow fibers, must be appropriately adjusted. If an anionic solution is used, the anion concentration parameter also has a significant influence and must be adjusted appropriately. The quantity / liquid quantity / volume of the solution particularly affects the saturation of the inner surfaces with the solution and the achievable thickness or layer thickness of the coating / covering on the inner surface. In other words, the thickness of the covering / coating can be controlled / adjusted (quantity control) by the quantity of solution / substance flowing through the hollow fibers.The thickness of the coating is preferably adjusted such that only a small portion of the existing surface area, and thus of the available capacity, is lost. The flow rate and the anion concentration have a particular effect on ensuring that only the inner surfaces of the hollow fibers are coated, but not the pores and outer surfaces of the hollow fibers. It should be noted at this point that the active surface for the removal of the pollutants is essentially located in the pores / membrane. The effective surface in the pores is preferably over 1500 times larger (for example, approximately 1600 times larger) than the inner surface or the outer surface of the hollow fiber. Against this background, the inactivation of the inner surface of the hollow fiber results in only a negligible loss of capacity.

[0033] Preferably, the housing is closed on the outlet side, in particular via a valve, when the solution is introduced into the hollow fibers. When blood flows through the device, the housing is open on the outlet side, so that the device is generally not operated in the so-called dead-end mode during patient treatment.

[0034] In other words, to achieve hemocompatibility with (whole) blood, the hollow fiber outlet is first closed, and a negatively charged solution is flowed through the inside of the hollow fibers. This ensures that the positively charged groups on the inside of the hollow fibers are saturated with the negatively charged solution, but the pores of the hollow fibers are not. This can be adjusted by adjusting the amount / flow rate / concentration of the flowing solution. During a patient treatment, the ends of the hollow fibers / hollow fiber capillaries are open, and blood flows through the hollow fibers. The bound functional groups and the bound anticoagulant substance on the inside of the hollow fibers prevent damage to the blood cells.

[0035] Preferably, the coating can be re-dosed during treatment of a patient.

[0036] More preferably, the device is designed in a tangential filter design so that both ends of the housing are open.

[0037] Furthermore, the device can preferably also be used as a plasma filter for long-term application.

[0038] Furthermore, the invention relates to an extracorporeal perfusion system with a device for removing contaminants from blood as described above. In particular, the extracorporeal perfusion system further comprises a pump that conveys at least part of the blood plasma out of the hollow fibers through the pores and, downstream of the device, returns it to the blood that has flowed through the device.

[0039] Since the device is configured to be perfused by both the cellular components and the plasma of the blood, so that no separation of the plasma from the cellular components is necessary before the blood flows through the hollow fibers, no plasma separation / plasma separator is required in the extracorporeal perfusion system of the present invention.

[0040] The invention further relates to a method for producing a device for removing negatively charged noxae from blood, in particular a device as described above, comprising the steps of: a) producing a plurality of porous hollow fibers, preferably made of plastic, more preferably of polyamide, polysulfone, polyether, polypropylene, polyester or derivatives and / or mixtures of such polymers; b) modifying orPretreating the hollow fibers chemically, preferably by graft polymerization, such that they have a functionalized, positively charged surface that binds the negatively charged noxious substances to themselves and removes them from the blood; c) inserting the plurality of porous hollow fibers into a housing; and d) flowing the plurality of porous hollow fibers located in the housing with a negatively charged anionic solution, in particular an anticoagulant polyanion, preferably heparin (before the start of treatment), such that only pores and an outer surface of the hollow fibers have the functionalized surface and no functionalized surface is present on the inner surface of the hollow fibers; wherein the process steps a) to d) are carried out in chronological order, i.e. first a), then b), then c) and finally d).

[0041] The method according to the invention is particularly suitable for modifying an internal coating of hollow fibers / hollow fiber capillaries.

[0042] Preferably, the method further comprises the step: e) adjusting a quantity and a flow rate of the solution; wherein method step e) is carried out before method step d).

[0043] More preferably, the method further comprises the step: f) closing the housing on the outlet side, in particular via a valve, before the solution is introduced into the hollow fibers.

[0044] It should be noted that with regard to the features of the method according to the invention, reference is also made in full to the above statements concerning the device according to the invention and the extracorporeal perfusion system according to the invention. Furthermore, with regard to method steps a) and b), reference is made in full to EP 1 602 387 A1. Short description of the characters

[0045] The invention is further explained below with the aid of figures. They show: Fig. 1 is a schematic view of an extracorporeal perfusion system according to the invention; Fig. 2 is a perspective view of a device according to the invention for removing noxae from blood; Fig. 3 is a perspective side view of the device according to the invention; Fig. 4 is a schematic sectional view of the device according to the invention; Fig. 5 is a perspective view of a hollow fiber provided in the device; Fig. 6 is a schematic view of the hollow fiber; Fig. 7 is a schematic sectional view of the hollow fiber, illustrating a blood treatment known from the prior art; Fig. 8 is a schematic sectional view of the hollow fiber, illustrating a blood treatment according to the invention; and Fig. 9 is a flow chart of the method according to the invention. Character description

[0046] The figures are merely schematic and serve solely to clarify the invention. Identical elements are designated by the same reference numerals.

[0047] Fig. 1 shows a schematic view of an extracorporeal perfusion system 2 according to the invention with a device 4 for removing noxious substances from blood. In this case, blood is taken from a person 6, which is pumped to the device 4 via a first line 8 by means of a first pump 10. The device 4 has, as shown for example in Fig. 2shown, a housing 12 and a plurality of hollow fibers 14 located within the housing 12. The blood is essentially supplied to the hollow fibers 14. The hollow fibers 14 are porous, so that the plasma of the blood (blood plasma) can be at least partially sucked / pumped out of the device 4 into a second line 18 by means of a second pump 16. At least the cellular components of the blood, such as erythrocytes, leukocytes, or thrombocytes, leave the device 4 via a third line 20. Downstream of the device 4, the second line 18 and the third line 20 converge again, and the blood is supplied back to the person 6 via a fourth line 22. In the extracorporeal perfusion system 2 according to the invention, the blood with all its components, i.e., in particular, both plasma and blood cells, is supplied to the device 4. There is no need for a separate plasma separator to separate the plasma from the blood cells.The device 4 is designed to purify the blood or remove contaminants from the blood. A shut-off valve 24 is provided on the outlet side of the device 4 / at the beginning of the third line 20.

[0048] Fig. 2 shows a perspective view of the device 4 according to the invention, which comprises a housing 12 and a plurality of hollow fibers 14 located within the housing 12. The housing 12 has a substantially tubular / cylindrical shape. On the outer circumferential surface of the housing 12, a first connection 26 is provided near an inlet side of the housing 12, and a second connection 28 is provided near an outlet side of the housing 12. The Fig. 1 The second line 18 shown can be connected to the first connection 26 and / or to the second connection 28 in order to pump the plasma of the blood out of the device 4 by means of the second pump 16.

[0049] Fig. 3shows a perspective side view of the device 4 according to the invention. In the Fig. 3 In the view shown, the device 4 is covered on the inlet side by a first cover cap 30 and on the outlet side by a second cover cap 32. The cover caps 30, 32 are identical in design and are adapted in shape and size to the round / circular inlet and outlet of the housing 12, respectively.

[0050] Fig. 4 shows a schematic sectional view of the device 4 according to the invention, cut at the Fig. 3 shown section line AA. In the Fig. 4 In the view shown, the hollow fibers 14 are shown somewhat enlarged in order to better show the arrangement of the hollow fibers 14 within the housing 12 than in Fig. 2The case is to be clarified. The plurality of hollow fibers 14 extend in a longitudinal / axial direction of the substantially tubular / cylindrical housing 12 and substantially fill an entire interior space defined by the housing 12 (see also Fig. 2 ). The totality of the hollow fibers 14 forms a hollow fiber membrane.

[0051] Fig. 5 shows an enlarged perspective view of a single hollow fiber 14 provided in the device 4. The base material of the hollow fiber 14 is preferably polyamide, onto which diethylaminoalkyl or diethylaminoaryl is grafted in a tentacle-like manner (not shown). As in Fig. 5 As indicated, the hollow fibers 14 are porous.

[0052] In Fig. 6 a schematic view of the hollow fiber 14 is shown, in which the porous structure is shown by means of a plurality of enlarged pores 34. In Fig. 7 and Fig. 8 are sectional views of the Fig. 6 hollow fiber 14 shown, cut at the Fig. 6 shown section line BB.

[0053] The core aspects of the present invention are explained with reference to Fig. 7 and Fig. 8 explained. Fig. 7 a blood treatment known from the prior art of EP 1 602 387 A1 and Fig. 8 a blood treatment according to the invention.

[0054] The Fig. 7The hollow fiber 14 shown has a functionalized surface 36. The functionalized surface 36 is positively charged and configured to bind to itself or remove contaminants 38 present in blood 44 from the blood 44. The functionalized surface 36 is provided both on an inner surface 40 of the hollow fiber 14 and on an outer surface 42 of the hollow fiber 14, as well as in the region of the pores 34. The functionalized surface 36 is produced by chemical modification, in particular by graft polymerization.

[0055] Now flows through blood 44, which contains blood plasma 46 and blood cells 48, which are Fig. 7The hollow fiber 14 shown, the negatively charged noxious substances 38 located in the blood 44 or in particular in the blood plasma 46 are bound to the positively charged (surface of the) hollow fiber 14 both on the inner surface 40 and on the outer surface 42 as well as in the area of the pores 34 and thus removed from the blood. The size or diameter of the pores 34 is designed such that the blood cells 48 cannot flow through the pores 34. If the Fig. 7 shown blood cells 48 in contact with the functionalized surface 36, the blood cells 48 are damaged / destroyed, as shown in Fig. 7 indicated by a flash. Therefore, in the prior art, the blood cells 48 must be separated from the blood plasma 46 so that the blood cells 48 do not enter the device 4 or the hollow fibers 14.

[0056] According to the present invention, the inner surface 40 of the hollow fibers 14 is further provided with a hemocompatible and anticoagulant coating 50 (see Fig. 8 ). The coating 50 is applied by flowing a negatively charged anionic solution (for example, an anticoagulant polyanion such as heparin) through the hollow fibers 14 (prior to the blood treatment shown). This achieves, on the one hand, that the functionalized, positively charged surface 36 on the inner surface 40 of the hollow fibers 14 is bound / discharged / neutralized by the negatively charged anionic solution, as shown in Fig. 8by the interconnected positive and negative, correspondingly neutralizing, charges on the inner surface 40 of the hollow fibers 14. On the other hand, a coating 50 binds to the (previously) functionalized surface 36. The coating 50 is hemocompatible and anticoagulant, so that the blood cells 48 flowing through the hollow fibers 14 are not damaged when they hit the inner surface 40 (in Fig. 8 indicated by a hook). The coating 50 is compatible with the functionalized surface 36 and adheres to it.

[0057] Now flows through blood 44, which contains blood plasma 46 and blood cells 48, which are Fig. 8In the hollow fiber 14 shown, the negatively charged pollutants 38 present in the blood 44 or, in particular, in the blood plasma 46 are bound only to the positively charged (surface of the) hollow fiber 14 on the outer surface 42 and in the region of the pores 34 and are thus removed from the blood. No pollutants 38 are bound to the inner surface 40 of the hollow fiber 14, and, as already explained, the blood cells 48 are not damaged. In the device 4 according to the invention, it is therefore not necessary to separate the blood cells 48 from the blood plasma 46 upstream of the device 4.

[0058] By adjusting a flow rate and an anion concentration of the anionic solution flowing through the hollow fibers 14 prior to the blood treatment described, it is possible to coat only the inner surfaces 40 of the hollow fibers 14, but not the pores 34 and the outer surfaces 42 of the hollow fibers 14. This is achieved in particular by setting the flow rate to a low value and the anion concentration to a high value (more viscous anionic solution). By adjusting the amount of anionic solution, the saturation of the inner surfaces 40 of the hollow fibers 14 and the thickness of the coating 50 can be adjusted. The larger the amount / quantity of liquid introduced into the hollow fibers 14, the thicker the coating 50 becomes.

[0059] The Fig. 1The shut-off valve 24 shown is closed when the anionic solution is added to the device 4 or to the plurality of hollow fibers 14.

[0060] Fig. 9illustrates a flow diagram of the method according to the invention. According to the method according to the invention, a plurality of porous hollow fibers 14 are first produced in step S1. Subsequently, in step S2, the hollow fibers 14 are modified / pretreated such that they have a functionalized surface 36 that binds the noxious substances to themselves and removes them from the blood 44. Then, in a step S3, the plurality of porous hollow fibers 14 are inserted into a housing 12. In a step S4, the housing 12 is closed on the outlet side via a valve (the shut-off valve 24), and in parallel, in a step S5, a quantity, a flow rate, and an anion concentration of an anionic solution are adjusted. Finally, in a step S6, the anionic solution flows through / through the hollow fibers 14 located in the housing 12. List of reference symbols

[0061] 2Extracorporeal perfusion system 4Device 6Human 8First line 10First pump 12Housing 14Hollow fiber 16Second pump 18Second line 20Third line 22Fourth line 24Shut-off valve 26First connection 28Second connection 30First cover cap 32Second cover cap 34Pores 36Functionalized surface 38Noxene 40Inner surface 42Outer surface 44Blood 46Blood plasma 48Blood cells 50(Hemocompatible and anticoagulant) coating

Claims

1. A device (4) for removing negatively charged noxae (38) from blood (44), which comprises plasma (46) and cellular components (48), in an extracorporeal perfusion system (2), comprising: a housing (12) and a plurality of hollow fibers (14) provided inside the housing (12) and configured to be perfused by the blood (44), wherein the hollow fibers (14) each have a plurality of pores (34) configured such that the plasma (46) of the blood (44) can flow through the pores (34) from an inside of the hollow fibers (14) to an outside of the hollow fibers (14), and wherein the hollow fibers (14) are modified or pretreated chemically in such a way that they have a functionalized, positively charged surface (36) which binds the negatively charged noxae (38) to itself and removes them from the blood, wherein exclusively an inside surface (40) of the hollow fibers is further provided with a hemocompatible and anticoagulant coating (50) to prevent damage of the cellular components (48) of the blood (44) when the blood (44) flows through the hollow fibers (14), so that merely the pores (34) and an outside surface (42) of the hollow fibers (14) have the functionalized surface (36) and on an inside surface (40) of the hollow fibers (14), a functionalized surface (36) is no longer provided.

2. The device (4) according to claim 1, characterized in that the coating (50) is arranged or formed on the inside surface (40) of the hollow fibers (14) in such a way that the inner circumferential sides of the pores (34) are not covered or are incompletely covered by the coating (50).

3. The device (4) according to claim 1 or 2, characterized in that the coating (50) on the inside surface (40) of the hollow fibers (14) is both hemocompatible and anticoagulant as well as compatible with the functionalized surface (36) of the hollow fibers (14) which binds the noxae (38) to itself and removes them from the blood and to which the coating (50) is applied on the inside of the hollow fibers (14).

4. The device (4) according to any of claims 1 to 3, characterized in that the coating (50) is applied to the inside surface (40) of the hollow fibers (14) by causing a solution to flow through the hollow fibers (14).

5. The device (4) according to claim 4, characterized in that the solution is a negatively charged anionic solution, in particular an anticoagulant polyanion, preferably heparin.

6. The device (4) according to claim 4 or 5, characterized in that, by adjusting a quantity, a flow rate and preferably an anion concentration of the solution, a coating of only the inside surfaces (40) of the hollow fibers (14) and a saturation of the inside surfaces (40) of the hollow fibers (14) with the solution can be achieved and a thickness of the coating (50) can be varied.

7. The device (4) according to any of claims 4 to 6, characterized in that the housing (12) is closed on the outlet side, in particular via a valve (24), when the solution is introduced into the hollow fibers (14).

8. An extracorporeal perfusion system (2) comprising a device (4) for removing noxae (38) from blood (44) according to any of the preceding claims, and a pump (16) which conveys the plasma (46) of the blood (44) out of the hollow fibers (14) via the pores and feeds it back, downstream of the device (4), to the blood (44) which has flowed through the device (4).

9. A method for producing a device (4) for removing negatively charged noxae (38) from blood (44) according to any of preceding claims 1 to 7, comprising the steps of: a) producing a plurality of porous hollow fibers (14); b) modifying or pretreating the hollow fibers (14) chemically in such a way that they have a functionalized, positively charged surface (36) which binds the noxae (38) to itself and removes them from the blood (44); c) introducing said plurality of porous hollow fibers (14) into a housing (12); and d) causing a negatively charged anionic solution to flow through the plurality of porous hollow fibers (14) located in the housing (12) so that merely pores (34) and an outside surface (42) of the hollow fibers (14) have the functionalized surface (36), and on an inside surface (40) of the hollow fibers (14), a functionalized surface (36) is no longer provided; the method steps a) to d) being carried out in chronological order.

10. The method according to claim 9, further comprising the step of: e) adjusting a quantity and a flow rate of the solution; wherein method step e) is carried out before method step d).

11. The method according to claim 9 or 10, further comprising the step of: f) closing the housing (12) on the outlet side, in particular via a valve (24), before the solution is introduced into the hollow fibers (14).