Device for improving gas exchange across a semipermeable membrane in an aqueous environment - Patent Application 20070122997

Abstract

To easily and rapidly remove gases through a semipermeable membrane in a bilateral aqueous environment. A method for influencing the concentration of gases such as oxygen and / or carbon dioxide in a substance mixture or solution of a biological or complex chemical liquid is described. The substance mixture or solution is conducted along an asymmetric semipermeable membrane on one side, while on the other side of the same membrane, an oxygenated dialysate is conducted in a closed circuit including an oxygenator. The substance mixture or solution to be influenced contains a particulate gas carrier, and the dialysate contains a gas carrier for at least one of the gases to be influenced in the closed circuit, so that the gas to be influenced is transported as close as possible to the substance mixture or solution. For regeneration, the dialysate is regenerated by introducing fresh oxygen and / or removing carbon dioxide.

Description

[Technical Field]

[0001] The present invention relates to a method and apparatus for improving gas exchange across a semipermeable membrane in an aqueous environment. [Background technology]

[0002] The introduction of oxygen into complex and / or biological fluids and the removal of carbon dioxide from said fluids take place, for example, during the treatment of blood.

[0003] The prior art is based on so-called oxygenators (or artificial lungs) which consist of a semipermeable membrane made of a hydrophobic porous material. The pores of the oxygenator are generally impermeable to blood cells. Blood is introduced along one side, while a gas, such as air, oxygen, or another gas mixture, is introduced along the other side. Gas exchange primarily occurs at the interface between the blood water and the gas phase, where the gas is primarily present in a physically dissolved state in the blood water and is ready to exchange with the red blood cells.

[0004] Because the material is hydrophobic, the intrusion (passage) of blood water from the blood side is initially prevented. However, over time, the blood becomes more hydrophilic, for example, due to the deposition of amphiphilic proteins on the surface (external surface) and internal surface of the membrane. Thus, the path along which the gas must travel while physically dissolved in the liquid phase is expanded. Therefore, in the case of the hollow fiber membranes used in most cases, the blood is also guided on the external surface of the hollow fiber, rather than on the internal surface, as is the case with dialysis in commercially available artificial kidneys. This is because the pressure drop on the blood side of the oxygenator is therefore smaller due to the larger fluid cross-section. Thus, compared to hemodialysis, greater turbulence occurs in the blood, which accelerates the coagulation process.

[0005] The poor hemocompatibility and anticoagulation requirements of existing ECMO (extracorporeal membrane oxygenation) membranes still result in serious and potentially life-threatening complications today.

[0006] This method is currently the most frequently used method for oxygen delivery and CO2 removal. When oxygen introduction is required, a high blood flow (up to 5 l / min) is often required for sufficient efficiency, but CO2 can be efficiently removed even at slower blood flows if oxygen delivery via the lungs is sufficient but CO2 exhalation is excessively small. This makes the use of extracorporeal circuits for dialysis therapy, which are typically less than 500 ml / min, attractive for parallel CO2 removal.

[0007] Between 10 and 30% of mechanically ventilated patients also undergo dialysis, because secondary renal failure during pulmonary failure due to infection and sepsis is a very frequent complication in intensive care units.

[0008] Mechanical ventilation requires the creation of non-physiological lung overpressures to not only deliver oxygen to the bloodstream but also to allow for efficient removal of CO2, resulting in relatively rapid ventilator-induced alveolar damage, which delays weaning (the process of weaning from the ventilator and returning to spontaneous breathing) and prolongs the duration of convalescence. This leads to increased costly ventilator-assisted hospital days, morbidity, and even mortality. CO2 removal with traditional oxygenators has been shown to be possible even with relatively small blood flows, such as those used in continuous dialysis. In this method, blood is sequentially routed through a dialyzer and an oxygenator, which removes CO2. This technology is expensive and requires extensive contact between the blood and polymeric plastic surfaces. This technology is promoted and used internationally by market leader Baxter under the trademark PrismaLung.

[0009] The idea of ​​using a dialyzer for simultaneous CO2 removal was first proposed by the company Hepawash. However, the Hepawash technology is based on increasing the pH of the dialysate, which supposedly increases the solubility of CO2 and allows for the equilibration (compensation) of respiratory acidosis in the blood. Furthermore, the risk of sodium hydroxide alkalosis limits its scope of use. This method has not yet been proven as a means of CO2 removal in controlled clinical trials.

[0010] Another problem is that when CO2 removal is performed in parallel with dialysis, sodium bicarbonate is typically used as a dialysate buffer during dialysis to balance (compensate for) the metabolic acidosis of renal failure. In this case, sodium bicarbonate is in solution equilibrium with CO2 and sodium hydroxide, thus increasing the CO2 load. Furthermore, in continuous dialysis, sodium citrate is increasingly used as a local anticoagulant, but its metabolism generates even more sodium bicarbonate. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] DE 102017216689 A1 [Patent Document 2] DE 2607706 C3 [Patent Document 3] US 2019 / 0030232 A1 [Patent Document 4] US 2006 / 0019385 A1 [Patent Document 5] US 3212498 A [Patent Document 6] DE 102015107269 A1 Summary of the Invention [Problem to be solved by the invention]

[0012] DE 102017216689 A1 describes a dialyzer and a further blood treatment element for extracorporeal blood therapy, such as a gas exchanger, which are arranged in series in a common extracorporeal blood circuit.

[0013] DE 2607706 C3 describes water-soluble polymer-crosslinked hemoglobins, a process for their preparation and their use.

[0014] US 2019 / 0030232 A1 generally relates to a method suitable for extracorporeal pulmonary support. The method involves contacting blood with a dialysate solution separated by a semipermeable membrane. Oxygen is introduced into the blood and / or the dialysate solution prior to contacting the blood with the dialysate solution, so that the oxygen arrives at the dialysate side of the dialyzer physically dissolved in the dialysate solution. CO2 and O2 exchange occurs across the membrane solely through physical dissolution in an aqueous solution. US 2019 / 0030232 A1 utilizes the Haldan effect in the extracorporeal contacting step.

[0015] US 2006 / 0019385 A1 describes an apparatus and method for growing (expanding) cells to high densities, products thereof, and uses thereof. In certain preferred embodiments, further oxygen supply means are included. Alternatively or additionally, the oxygen supply means can include the introduction of oxygen and / or an oxygen source or oxygen carrier into the cell culture medium, alone or in combination with one or more other gases and / or gas sources or gas carriers.

[0016] US 3,212,498 A describes a cell culture device in which cells are separately oxygenated and dialyzed by two distinct (separated) membranes.

[0017] DE 102015107269 A1 describes a dialysis machine with a blood circuit suitable for removing hydrophilic and hydrophobic substances from blood with a simple and compact structure. The dialysis machine includes a double pump unit with only one drive unit, the first pump unit of which is a dialysate pump, equipped with one or more sensors for detecting toxins contained in the dialysate of the dialysate circuit, and a display unit for displaying operation data of the dialysis machine and / or data on toxins contained in the dialysate of the dialysate circuit detected by the sensors. The dialysate is (contains) albumin, which allows for the removal of both hydrophilic and hydrophobic substances from blood.

[0018] The object of the present invention is to remove gases such as CO2 or oxygen through a semipermeable membrane in a bi-aqueous environment with ease and at a greater rate. [Means for solving the problem]

[0019] According to a first aspect of the present invention, there is provided a method of operating an apparatus for affecting the concentration of oxygen and / or carbon dioxide as gases in a biological or complex chemical liquid mixture of substances or solutions. The device includes an asymmetric semipermeable membrane, a first circulation circuit with a first pump, a second circulation circuit with a second pump, and a regeneration device. The method of operation comprises the following steps: the first pump directing the substance mixture or the solution supplied from the pool along the narrow-pore side of the asymmetric semipermeable membrane in the first circulation circuit; the second pump directing dialysis fluid oxygenated in a closed circuit including an oxygenator along the open pore side of the asymmetric semipermeable membrane in the second circulation circuit; and The regeneration device regenerates the dialysate by introducing fresh oxygen and / or removing carbon dioxide. containing, The substance mixture or solution to be affected contains a particulate gas carrier, and the dialysate contains, in the closed circuit, a particulate gas carrier for at least one of the gases to be affected. moleculara gas carrier, so that the gas to be affected is brought as close as possible to the substance mixture or the solution; The aforementioned molecular The gas carrier reaches the vicinity of the substance mixture or the solution through the asymmetric pore structure of the membrane, which has open pores on the dialysate side, so that oxygen diffuses into the substance mixture or the solution over the shortest possible distance, and at the same time, carbon dioxide is removed from the substance mixture or the solution into the dialysate by diffusion over the shortest possible distance, but the particulate gas carrier itself does not pass through the membrane. (Form 1). According to a second aspect of the present invention, there is provided an apparatus for influencing the concentration of oxygen and / or carbon dioxide as gases in a biological or complex chemical liquid mixture of substances or solutions. The device is connectable to a pool and includes two circulation circuits; a first circulation circuit is used on the one hand to supply the substance mixture or the solution from the pool along the narrow-pore side of the asymmetric semipermeable membrane via a tube and a pump, with the substance mixture or the solution then being guided back to the pool via a tube; The second circuit is used to supply the dialysate via a tube and a pump along the open-pore side of the asymmetric semipermeable membrane, the dialysate containing the gas to be affected in the form of molecular hemoglobin or other similar proteins. molecular containing a gas carrier, molecular the gas carrier can pass through the membrane through the asymmetric pore structure of the membrane with open pores on the dialysate side, and before its passage is hindered by the narrower pores of the asymmetric semipermeable membrane, it reaches the vicinity of the substance mixture or the solution, where the exchange of dissolved gases takes place, after which the dialysate is led back through a tube to the recirculation circuit and through a regeneration device which accepts and / or releases gases; In the regeneration device, the dialysate is regenerated by newly introducing oxygen and / or removing carbon dioxide (Mode 12). DETAILED DESCRIPTION OF THE INVENTION

[0020] Preferred embodiments of the present invention are described below. (Mode 1) See the first aspect of the present invention above. (Mode 2) In the method of mode 1, The molecular nature Preferably, the molecule hemoglobin or other similar proteins is used as the gas carrier. (Mode 3) In the method of mode 1 or mode 2, The aforementioned molecular The gas carrier reaches the vicinity of the substance mixture or the solution through the asymmetric pore structure of the membrane, which has open pores on the dialysate side of less than 50 μm, or less than 1 μm, or less than 100 nm, molecular Preferably, no more than 10%, or less than 0.1%, or less than 0.01% of the gas carriers pass through the membrane, so that oxygen diffuses into the substance mixture or solution over as short a distance as possible, and at the same time, carbon dioxide is removed from the substance mixture or solution into the dialysis fluid by diffusion over as short a distance as possible, but the particulate gas carriers themselves do not pass through the membrane. (Mode 4) In any of the methods of modes 1 to 3, On the dialysate side, molecular The concentration of the gas carrier is preferably adjusted to be greater than the concentration of hemoglobin in the blood, thus providing additional mass transport enhancement of CO2 and oxygen. (Mode 5) In any of the methods of modes 1 to 4, Preferably, the received or discharged gas carrier is secondarily regenerated in a closed recirculation circuit by a device using the received and / or discharged gas. (Mode 6) In the method of mode 5, in the dialysis solution molecular The regeneration of the gas carrier is preferably performed by the oxygenator, which regenerates the carrier-carrying dialysate by removing carbon dioxide and / or introducing fresh oxygen. (Mode 7) In any of the methods of modes 1 to 6, As the membrane, it is preferred to use an asymmetric high-flux dialysis membrane having a cutoff between 120 and 1 KD, between 60 and 10 KD, or between 20 and 50 KD. (Embodiment 8) In the method of embodiment 2, The dialysate preferably contains molecular hemoglobin with a molecular weight of less than 1 megadalton, or less than 500 kD (kilodalton), or less than 60 kD. (Mode 9) In the method of mode 2 or mode 8, The dialysate is used for extracorporeal treatment of blood containing electrolytes, buffers, sugars, and monomeric or polymeric hemoglobin and / or albumin as components; the electrolytes, buffers and glucose vary within the range of concentrations of commercially available concentrates; Preferably, the hemoglobin molecule is concentrated to a concentration between above 0 g / l and the technical limit of solubility, or above 30 g / l, or above 70 g / l, and the albumin is concentrated to a concentration between above 0 g / l and the technical limit of solubility, or above 50 g / l, or above 200 g / l. (Mode 10) In the method of mode 1, The dialysate preferably contains carbonic anhydrase present as a monomer or as a functionally cross-linked dimer or multimer to allow passage through the open-pore dialysate side of the membrane, while preventing passage of at least 80%, or 95%, or more than 99% of the substance mixture or solution to be affected through the narrow-pore side of the membrane. (Mode 11) In any of the methods of modes 1 to 10, Preferably, the membrane is simultaneously used for the purification of blood according to the prior art by dialysis or for the removal of harmful substances by dialysis or filtration according to apheresis. (Mode 12) See the second aspect of the present invention above. (Mode 13) In the method of mode 12, The pump is preferably a roller pump, an impeller pump, or a membrane pump, and the asymmetric semipermeable membrane is preferably a flat membrane or a hollow fiber membrane. (Mode 14) In the method of mode 12, The aforementioned molecular The gas carrier reaches the vicinity of the substance mixture or the solution through the asymmetric pore structure of the membrane, which has open pores on the dialysate side of less than 50 μm, or less than 1 μm, or less than 100 nm, molecular the gas carrier passes through the membrane at no more than 10%, or less than 0.1%, or less than 0.01%; Therefore, it is preferred that oxygen diffuses into the substance mixture or solution over as short a distance as possible, and at the same time carbon dioxide is removed by diffusion from the substance mixture or solution into the dialysis fluid over as short a distance as possible, while the particulate gas carriers themselves contained in the substance mixture or solution do not pass through the membrane. (Mode 15) In the method of mode 12, The regeneration device is preferably a commercially available oxygenation device. (Mode 16) In any of the methods of modes 12 to 15, The substance mixture or the solution is blood or plasma; and Preferably, a dialyzer is included that allows for pore-permeable diffusional transport of molecules from the blood or plasma through a semipermeable membrane into the dialysate. (Mode 17) In the method of mode 16, For extracorporeal treatment of blood or plasma in a closed circuit, the dialysate is preferably regenerated both by operation of the regeneration device and by additional adsorption and / or dialysis and / or filtration for the removal or introduction of substances. (Mode 18) In any of the methods of modes 12 to 17, The regenerator preferably comprises a biological assimilation system based on photosynthesis, capable of converting carbon dioxide and water into glucose and oxygen under the action of light. (Mode 19) In any of the methods of modes 12 to 17, The regenerator preferably uses an electrochemical method for oxygen production.

[0021] The present invention is based on the surprising observation that oxygen can be transported from aqueous dialysate through commercially available dialyzers through a semipermeable membrane into the blood with high efficiency if a soluble oxygen carrier capable of transporting oxygen in the aqueous dialysate as close as possible to the blood side is present on the dialysate side. Surprisingly, even in the case of hydrophobic dialysis membranes, it has been observed that inherently hydrophobic gases reach the blood at high rates, even though the membrane is practically (substantially) impermeable to dissolved hemoglobin. The presence of hemoglobin in the internal porous structure accelerates this transport.

[0022] The invention under examination is characterized in that the substance mixture or solution to be affected contains a particulate (>1 μm diameter) gas carrier, such as red blood cells, and that a molecular gas carrier (such as hemoglobin or related proteins) that does not itself pass through the membrane is used as the gas carrier in the dialysis solution.

[0023] Upon reaching the bloodstream, oxygen enters the red blood cells, where it actively expels CO2 stored in the hemoglobin of the red blood cells. It is then forced into the aqueous phase of the blood, where it reacts with water to form carbonic acid, which is then converted back into hydrogen and bicarbonate ions. This reaction can additionally be accelerated by carbonic anhydrase. In either case, both carbonate and bicarbonate ions can be easily removed into the dialysate by dialysis. If hemoglobin itself is the oxygen carrier in the dialysate, the transport effect is enhanced. This is because CO2 is now accepted by hemoglobin in the dialysate, while the release of oxygen from hemoglobin in the dialysate is accelerated by "extrusion." Therefore, the exchange of O2 and CO2 can occur quite easily across the dialysis membrane in an aqueous environment. The uptake and release of oxygen and CO2 by and from dialysate hemoglobin can then occur through various methods, such as electrolysis or photosynthesis, that would not be readily possible in complex biological fluids such as blood. In any case, the use of a traditional oxygenator in hemoglobin dialysate allows for more efficient exchange than blood oxygenation, because the much smaller hemoglobin (10–20 nm diameter) can reach closer to the gas phase of the oxygenator than red blood cells (approximately 7 μm diameter and ellipsoidal). Additionally, the hemoglobin concentration on the dialysate side can be adjusted to be greater than that of blood hemoglobin, thereby further enhancing mass transfer of CO2 and oxygen. This innovation, of course, is not limited to the exchange of CO2 for O2 and vice versa, nor is it limited to hemoglobin. A similar effect of membrane transfer from one transport molecule to another would be expected, for example, in the case of carbon monoxide removal, which should be possible with high concentrations of hemoglobin. Oxygen could also be transported and exchanged by related proteins, such as leghemoglobin.The conditions for function (according to the present invention) are a separation layer as thin as possible between the blood and the dialysate proteins (for example, in the case of asymmetric dialysis membranes, in some cases a few nanometers, where it is to be noted that in this case the smaller the carrier proteins in the dialysate, the greater the proximity, but it would be desirable for them to be essentially unable to pass through the membrane) and reversible binding of the gas to one or more carrier proteins. Furthermore, the present invention is not limited to the gassing or degassing of blood, but extends in general to the gassing or degassing of biological or complex chemical liquids (fluids).

[0024] For the method according to the invention for influencing (changing) the concentration of a gas, such as oxygen (O2) and / or carbon dioxide (CO2), in a substance mixture or solution, the substance mixture or solution is guided on one side along an asymmetric semipermeable membrane. Dialysate is guided on the other side of the same membrane in a closed circuit, where the dialysate contains a gas carrier for at least one gas to be influenced. An oxygenator is included in the closed circuit.

[0025] The substance mixture or solution to be affected contains particulate gas carriers, for example red blood cells, and the gas carrier for at least one gas to be affected is the molecule hemoglobin or other related (similar) proteins.

[0026] The gas carrier reaches the vicinity of the substance mixture or solution through the asymmetric pore structure of the membrane, which has open pores on the dialysate side of less than 50 μm, preferably less than 1 μm, most preferably less than 100 nm, with 10% or less, preferably less than 0.1%, most preferably less than 0.01% of the gas carrier passing through the membrane. Therefore, oxygen (O2) diffuses into the substance mixture or solution over the shortest possible distance, and at the same time, carbon dioxide (CO2) is removed from the substance mixture or solution into the dialysate by diffusion over the shortest possible distance, but the gas carrier itself does not pass through the membrane.

[0027] The received or released gas carrier is subsequently regenerated in a closed recirculation circuit by a device using the received and / or released gas. The regeneration of the gas carrier in the dialysate is carried out by an oxygenator, which regenerates the carrier-carrying (containing) dialysate by removing carbon dioxide (CO2) and / or introducing oxygen (O2).

[0028] For one embodiment, as the membrane, an asymmetric high-flux dialysis membrane is used, having a cutoff between 120 and 1 KD, preferably between 60 and 10 KD, particularly preferably between 20 and 50 KD.

[0029] In one embodiment, the dialysate contains molecular hemoglobin having a molecular weight of less than 1 megadalton (approximately 20 hemoglobin tetramers, cross-linked), preferably less than 500 kD (kilodaltons) (approximately 10 hemoglobin tetramers, cross-linked), and most preferably less than 60 kD (1 tetramer).

[0030] In one embodiment of the method, a dialysate is used for the extracorporeal treatment of blood containing electrolytes, buffers, sugars, monomeric or polymeric hemoglobin and / or albumin as components. In this case, albumin serves as a hemoglobin stabilizer and ionic buffer. The electrolytes, buffers, and glucose are varied within the concentrations of commercially available (standard) concentrates, with molecular hemoglobin concentrated to a concentration between 0 g / L and the technical limit of solubility, preferably above 30 g / L, particularly preferably above 70 g / L, and albumin concentrated to a concentration between 0 g / L and the technical limit of solubility, preferably above 50 g / L, particularly preferably above 200 g / L.

[0031] In a further embodiment, the dialysate contains carbonic anhydrase present as a monomer or as a functionally crosslinked dimer or multimer to prevent passage of at least 80%, preferably 95%, and ideally more than 99% of the substance mixture or solution to be affected on the narrow-pore side of the membrane, while allowing passage to the open-pore dialysate side of the membrane.

[0032] The membrane is simultaneously used for the purification of blood according to conventional techniques by dialysis or for the removal of harmful substances by dialysis or filtration according to the apheresis method (detoxification or detoxification).

[0033] The device for influencing (changing) the concentration of gases such as oxygen (O2) and / or carbon dioxide (CO2) in a substance mixture or solution comprises two circulation circuits (hereinafter also referred to as "circuits"); the first circuit is used on the one hand to feed the substance mixture or solution from a pool via tubing and a pump along the narrow-pore side of an asymmetric semipermeable membrane. The substance mixture or solution is then led back to the pool via tubing; the second circuit is used on the other hand to feed the dialysate via tubing and a pump along the open-pore side of the asymmetric semipermeable membrane. The dialysate contains a gas carrier in the form of a molecule of hemoglobin or other related (similar) protein for at least one of the gases to be influenced and is then led back via tubing to the recirculation circuit, via a regeneration device that accepts and / or releases the gas.

[0034] The pump is a roller pump (peristaltic pump), an impeller pump or a membrane pump, and the asymmetric semipermeable membrane is a flat membrane or a hollow fiber membrane.

[0035] The regenerator is a commercially available oxygenator.

[0036] The dialysate in the closed circuit is doped with a gas carrier such as molecular hemoglobin, and the dialysate is regenerated in the regeneration device by newly introducing oxygen (O2) and / or removing carbon dioxide (CO2).

[0037] The substance mixture or solution is blood or plasma. The device includes a dialyzer that allows for pore-permeable diffusional transport of molecules from the blood or plasma through a semipermeable membrane into a dialysate.

[0038] For one embodiment, for extracorporeal treatment of blood or plasma in a closed circuit, the dialysate is regenerated both by activating (switching on) the regeneration device and by additional adsorption and / or dialysis and / or filtration for substance removal or introduction.

[0039] The regenerator comprises a biological assimilation system, such as an isolated chloroplast, capable of converting carbon dioxide and water into glucose and oxygen under the action of light based on photosynthesis.

[0040] For a further embodiment, the regenerator uses an electrochemical method for oxygen production, such as electrolysis.

[0041] The removal of CO2 is achieved by physical-chemical reactions, such as dialysis against a basic dialysate or precipitation in calcium hydroxide.

[0042] The method and device are preferably used outside of therapy, e.g., for research, donation (organ transplantation or transfusion), or production purposes, e.g., in the case of high-density cell cultures (e.g., ELAD cartridges) or life support of isolated or interconnected organs. These are typically provided with blood or blood-like biological fluids, which often require secondary dialysis and / or oxygenation. Briefly, the problem is the regeneration of the dialysate, which can be performed in a laboratory. The pool in the device is the bioreactor or organ(s).

[0043] The advantages of the present invention are, inter alia, that during gas intake and release of biological fluids, especially blood, there is no liquid / gas interface during gas exchange, which has advantages in terms of biocompatibility or hemocompatibility. Proteins can be denatured when in contact with air or gas, which, in particular in blood, can lead to, for example, coagulation and complement activation.

[0044] In this way, the hollow fiber system does not need to be perfused on the outside for gas exchange with the blood (as in various prior art techniques, which would result in turbulence with additional coagulation and complement activation), but blood perfusion inside the hollow fiber system allows for better rheology and less coagulation induction.

[0045] A major advantage of this method is that several processes can be carried out simultaneously (e.g., detoxification or removal of water-soluble and / or lipid-soluble toxins, such as by additional albumin dialysis, can be carried out through the same membrane as the "gas exchange"; additionally, nutrients can be introduced from the dialysate side, and electrolytes and their pH value can be balanced). Thus, the exposure of biological materials is reduced and the stress on biological fluids or blood is less. Prior art devices often involve the sequential introduction of several biological materials into one circulation circuit or have several parallel circulation circuits.

[0046] Since oxygen supply and CO2 removal from the inert protein mixture (Hb / albumin / dialysate) can be performed exogenously (indirectly), alternative gas exchange techniques such as electrolysis, precipitation in calcium hydroxide, or dialysis against a basic dialysate or anabolic organelles (e.g., chloroplasts) are practical. This method can be used under extreme conditions, and in some cases, where gas is unavailable but electrical current or light is, such as in outer space.

[0047] Several examples will be described below. It should be noted that the reference numerals in the drawings used in the claims are intended solely to aid in understanding the invention and are not intended to limit the present invention to the illustrated embodiments. [Brief explanation of the drawings]

[0048] [Figure 1] 1 shows the structure of an example of a closed circulation circuit according to the present invention, which is equipped with an oxygenator for introducing oxygen and removing CO2. [Figure 2] Graph showing an example of CO2 clearance. [Figure 3] 1 is a graph showing an example of blood oxygen saturation. [Figure 4] An example of a control experiment. [Figure 5] An example graph of traditional blood oxygenation versus CO2 clearance for the entire system. [Figure 6] Graph of an example of blood oxygen saturation. Example 1

[0049] In a first embodiment, CO2-rich blood is pumped at a rate of 200 ml / min through hollow fibers in a dialyzer (ideally with an asymmetric membrane, such as Fresenius FX1000 Cordiax™ polysulfone), with a dialysate containing approximately 30 g / L hemoglobin along the dialysate side, which is also recirculated at 200 ml / min in a closed circuit. This circuit (circulation circuit) is equipped with an oxygenator for oxygen introduction and CO2 removal. Its structure is shown in Figure 1. Initially, no oxygen flows into the oxygenator. Despite the circulation of hemoglobin dialysate, CO2 clearance decreases over time as the dialysate hemoglobin enriches (accepts) CO2. After 2.5 minutes, oxygen is supplied to the oxygenator at 600 ml / min. The effect on CO2 clearance is shown in Figure 2.

[0050] FIG. 1 shows a blood circuit (hematocrit, approximately 40%) driven by a peristaltic pump 1 and flowing through a dialyzer inside a hollow fiber. The dialyzer is a commercially available asymmetric polysulfone high-flux dialyzer (sieving coefficient for albumin <10%, preferably <1%), although other materials such as polyamide, polyethersulfone, etc. can also be used. The membrane does not have to be a hollow fiber membrane; flat membrane dialyzers can also be used. Blood gases are measured at test points (sensors) SH1 and SH2 before and after the dialyzer (upstream and downstream). To simulate endogenous CO2 contamination or poisoning, CO2 is "infused" into the substance mixture or solution downstream of sensor SH2 (just before pool 3, which in this example is for blood) via a gas exchanger (e.g., oxygenator). A hemoglobin solution is used as the dialysate. This hemoglobin solution contains approximately 30 g / L hemoglobin and is also driven by pump 2, e.g., a peristaltic pump. Additionally, carbonic anhydrase can be added to the dialysate. This is not essential, but it can enhance its effectiveness. Due to the use of an asymmetric membrane, hemoglobin solution molecules can penetrate the membrane structure from the dialysate side and reach closer to the red blood cells of the blood. Furthermore, on the dialysate side, blood gas analysis is performed on the dialyzer before SH4 and after SH3. In this case, O2 is blown in before (upstream of) sensor SH4 in the flow direction and exchanged with CO2, as in a simple oxygenator. The dialysate can be driven in cocurrent (parallel flow) or countercurrent (countercurrent), although countercurrent flow may be advantageous. The effect of "Oxy-Carbo-Dialyse" with O2-enriched and CO2-depleted hemoglobin dialysate on the CO2 clearance of the dialyzer is shown in Figure 2. The effect on blood oxygen saturation is shown in Figure 3.

[0051] Figure 2 shows the CO2 clearance (black dots) through the dialyzer calculated for the decrease in CO2 concentration through the dialyzer between sensors SH1 and SH2 in Figure 1, the progression of blood flow (200 ml / min), and the oxygen partial pressure of the inflowing dialysate. In this case, it is clear that the hemoglobin-containing dialysate (200 ml / min) itself does not enhance CO2 clearance (CO2 introduction at 200 ml / min in the gas exchanger (GE)), but rather that CO2 clearance in the dialyzer increases rapidly only when oxygen is introduced into the hemoglobin-containing dialysate in the oxygenator 2, practically reaching nearly 100% of the blood flow.

[0052] Figure 3 shows the oxygen saturation at SH2, downstream of the dialyzer in the example of Figure 1. The first 8 minutes correspond to the first 8 minutes of Figure 2. Again, it becomes clear that circulation with hemoglobin alone does not have a substantial effect on oxygen saturation, but that oxygenation of the hemoglobin-containing dialysate (1 liter of O2 via oxygenator 2), which begins after 4 minutes, is associated with a very rapid blood oxygenation. To demonstrate this effect, the oxygen flow and dialysate are stopped, resulting in a rapid drop at the SH2 test point to the value at SH1, which has been significantly reduced in blood (<20%) by the introduction of 200 ml / min of CO2 in the gas exchanger (GE). When oxygen is resumed after 15 minutes (at 600 ml / min) and dialysate is reintroduced at 200 ml / min, the O2 saturation in SH2 improves rapidly, despite the blood being "poisoned" by 200 ml / min CO2 via the gas exchanger GE. After 20 minutes, this "poisoning" stops, and pool 3 for the substance mixture or solution, e.g., blood, also continues to improve overall, along with the oxygen saturation.

[0053] Control experiment Figure 4 shows an example of a blood circuit (hematocrit, approximately 40%) driven by a peristaltic pump 1 and flowing through a dialyzer inside a hollow fiber. The dialyzer, as in Figure 1, is a commercially available asymmetric polysulfone high-flux dialyzer (sieving coefficient for albumin <10%, preferably <1%), although other materials such as polyamide, polyethersulfone, etc. can also be used. The membrane does not have to be a hollow fiber membrane; flat membrane dialyzers can also be used. Blood gases are measured at test points SH1 and SH2 before and after the dialyzer (upstream and downstream). To simulate endogenous CO2 contamination or poisoning, CO2 is "bubbled" through a gas exchanger (e.g., oxygenator) downstream of sensor SH2, just before pool 3 for blood.

[0054] Downstream of the sensor SH1 in the flow direction, traditional oxygenation or CO2 removal is performed by a blood oxygenator (as in a simple oxygenator, O2 is blown in and exchanged for CO2). The combined effect of the oxygenator and dialysate (dialysis) is measured at SH2 downstream of the dialyzer.

[0055] The dialysate used is a commercially available dialysate, which is likewise driven by a pump 2, for example a peristaltic pump. Also on the dialysate side, before SH4 and after SH3, a blood gas analysis is carried out on the dialyzer.

[0056] The dialysate can be driven cocurrently (parallel flow) or countercurrently (countercurrent flow), although countercurrent flow may be advantageous. The effect of this traditional blood oxygenation on CO2 clearance for the entire system is shown in Figure 5. The effect on blood oxygen saturation is shown in Figure 6.

[0057] To further demonstrate the importance of oxygen / CO2 carriers in the blood, an additional control experiment was conducted in series with the possibility of oxygenating hemoglobin-free dialysate from the dialysate pool, using the same Synergy oxygenator for the dialysate. This was first performed in the second part of the experiment.

[0058] Figure 5 shows the calculated CO2 clearance (black dots) through the oxygenator and dialyzer for the drop in CO2 concentration through the oxygenator and dialyzer between sensors SH1 and SH2 in Figure 4, the progression of blood flow (200 ml / min), and the partial oxygen pressure of the outgoing dialysate at SH3, which corresponds to the partial pressure of O2 prevailing in the system. According to the prior art, good oxygenation is achieved by combined oxygenation and dialysis at 200 ml, but in this case the Synergy dialyzer is a high-efficiency dialyzer that is inherently used at 5 l / min for full oxygenation.

[0059] Figure 6 shows the oxygen saturation downstream of the dialyzer SH2 in a control experiment according to Figure 4. Full oxygenation with 1 liter of O2 by the oxygenator (Synergy), which begins after 4 minutes, is achieved according to the prior art. After the CO2 "toxicization flow" and oxygenation in the blood oxygenator are stopped, the oxygen saturation begins to drop slowly, and oxygenation introduced into the end of the hemoglobin-free dialysate is not able to rapidly increase the oxygen saturation in SH2 as in Figure 3.

[0060] Possible embodiments of the present invention are listed below. [Appendix 1] A method for influencing the concentration of gases such as oxygen and / or carbon dioxide in a mixture of substances or solutions of biological or complex chemical fluids, by conducting said mixture of substances or said solution along an asymmetric semipermeable membrane on one side and conducting a dialysate supplied with oxygen in a closed circuit including an oxygenator on the other side of the same membrane. The substance mixture or solution to be affected contains particulate gas carriers (red blood cells), and the dialysis fluid contains a gas carrier for at least one of the gases to be affected in the closed circuit, so that the gas to be affected is transported as close as possible to the substance mixture or solution. For regeneration, the dialysate is regenerated by the introduction of fresh oxygen and / or by the removal of carbon dioxide. [Appendix 2] In the above method, As a gas carrier, the molecule hemoglobin or other similar proteins is used. [Supplementary Note 3] In the above method, the gas carrier reaches the vicinity of the substance mixture or the solution through the asymmetric pore structure of the membrane, which has open pores on the dialysate side of less than 50 μm, preferably less than 1 μm, most preferably less than 100 nm, but 10% or less, preferably less than 0.1%, most preferably less than 0.01% of the gas carrier passes through the membrane, so that oxygen diffuses into the substance mixture or the solution over the shortest possible distance, and at the same time, carbon dioxide is removed from the substance mixture or the solution into the dialysate by diffusion over the shortest possible distance, but the gas carrier itself does not pass through the membrane. [Appendix 4] In the above method, On the dialysate side, the concentration of the gas carrier is adjusted to be greater than the concentration of hemoglobin in the blood, thus additionally enhancing the mass transport of CO2 and oxygen. [Appendix 5] In the above method, The received or discharged gas carrier is secondarily regenerated in a closed recirculation circuit by a device using the received and / or discharged gas. [Appendix 6] In the above method, Regeneration of the gas carrier in the dialysate is achieved by the oxygenator, which regenerates the carrier-carrying dialysate by removing carbon dioxide and / or introducing fresh oxygen. [Appendix 7] In the above method, As the membrane, an asymmetric high-flux dialysis membrane having a cutoff between 120 and 1 KD, preferably between 60 and 10 KD, particularly preferably between 20 and 50 KD, is used. [Appendix 8] In the above method, The dialysate contains molecular hemoglobin having a molecular weight of less than 1 megadalton (approximately 20 hemoglobin tetramers, cross-linked), preferably less than 500 kD (kilodaltons) (approximately 10 hemoglobin tetramers, cross-linked), and most preferably less than 60 kD (1 tetramer). [Appendix 9] In the above method, The dialysate is used for the extracorporeal treatment of blood, which contains as components electrolytes, buffers, sugars, molecular monomeric or polymeric hemoglobin and / or albumin; The electrolytes, buffers and glucose vary within the range of concentrations of commercially available concentrates; The hemoglobin molecule is concentrated to a concentration between above 0 g / l and the technical limit of solubility, preferably above 30 g / l, particularly preferably above 70 g / l, and the albumin is concentrated to a concentration between above 0 g / l and the technical limit of solubility, preferably above 50 g / l, particularly preferably above 200 g / l. [Appendix 10] In the above method, The dialysate contains carbonic anhydrase present as a monomer or as a functionally cross-linked dimer or multimer to allow passage to the open-pore dialysate side of the membrane on the one hand, and to prevent passage of at least 80%, preferably 95%, and ideally more than 99% of the substance mixture or solution to be affected on the narrow-pore side of the membrane on the other hand. [Appendix 11] In the above method, The membranes are simultaneously used for the purification of blood according to the prior art by dialysis or for the removal of harmful substances by dialysis or filtration according to the apheresis method. [Appendix 12] Devices that affect the concentration of gases such as oxygen and / or carbon dioxide in mixtures of substances or solutions of biological or complex chemical liquids. The device can be connected to a pool and includes two circulation circuits. The first circulation circuit is used on the one hand to supply the substance mixture or the solution from the pool via a tube and a pump along the narrow-pore side of the asymmetric semipermeable membrane, whereupon the substance mixture or the solution is led back to the pool via a tube. The second circulation circuit, on the other hand, is used to supply dialysate via tubing and a pump along the open-pore side of the asymmetric semipermeable membrane, the dialysate containing a gas carrier in the form of molecular hemoglobin or other similar proteins for the gas to be affected, which is then directed back via tubing to the recirculation circuit and through a regeneration device that accepts and / or releases the gas. In the regeneration device, the dialysate is regenerated by introducing new oxygen and / or removing carbon dioxide. [Appendix 13] In the above device, The pump may be a roller pump, an impeller pump or a membrane pump. The asymmetric semipermeable membrane is a flat membrane or a hollow fiber membrane. [Appendix 14] In the above device, the semipermeable membrane has an asymmetric pore structure on the dialysate side with open pores of less than 50 μm, preferably less than 1 μm, most preferably less than 100 nm, and the gas carriers pass through the membrane at a rate of not more than 10%, preferably less than 0.1%, most preferably less than 0.01%; Therefore, oxygen diffuses into the substance mixture or the solution over the shortest possible distance, and at the same time, carbon dioxide is removed by diffusion from the substance mixture or the solution into the dialysis solution over the shortest possible distance, while the gas carrier itself does not pass through the membrane. [Appendix 15] In the above device, The regenerator is a commercially available oxygenator. [Appendix 16] In the above device, The substance mixture or the solution is blood or plasma. A dialyzer is included that allows for pore-permeable diffusional transport of molecules from the blood or plasma through a semipermeable membrane into a dialysate. [Appendix 17] In the above device, For extracorporeal treatment of blood or plasma in a closed circuit, the dialysate is regenerated both by operation of the regeneration device and by additional adsorption and / or dialysis and / or filtration for the removal or introduction of substances. [Appendix 18] In the above device, The regenerator includes a biological assimilation system based on photosynthesis, capable of converting carbon dioxide and water into glucose and oxygen under the action of light. [Appendix 19] In the above device, The regenerator uses an electrochemical method for oxygen production.

Claims

1. 1. A method of operating an apparatus for influencing the concentration of oxygen (O2) and / or carbon dioxide (CO2) as gases in a biological or complex chemical liquid substance mixture or solution, comprising: the device includes an asymmetric semipermeable membrane, a first circulation circuit with a first pump, a second circulation circuit with a second pump, and a regeneration device; The method of operation comprises the following steps: the first pump directing the substance mixture or the solution supplied from a pool (3) along the narrow-pore side of the asymmetric semipermeable membrane in the first circulation circuit; the second pump directing dialysis fluid oxygenated in a closed circuit including an oxygenator along the open-pore side of the asymmetric semipermeable membrane in the second circulation circuit; and The regeneration device regenerates the dialysate by introducing oxygen (O2) and / or removing carbon dioxide (CO2). containing, the substance mixture or solution to be affected contains a particulate gas carrier, and the dialysis solution contains, in the closed circuit, a molecular gas carrier for at least one of the gases to be affected, so that the gas to be affected is transported as close as possible to the substance mixture or the solution; The molecular gas carriers reach the vicinity of the substance mixture or the solution through the asymmetric pore structure of the membrane, which has open pores on the dialysate side, so that oxygen (O2) diffuses into the substance mixture or the solution over the shortest possible distance, and at the same time, carbon dioxide (CO2) is removed from the substance mixture or the solution into the dialysate by diffusion over the shortest possible distance, but the particulate gas carriers themselves do not pass through the membrane. A method characterized by:

2. 10. The method of claim 1, The molecular gas carrier is hemoglobin or other similar proteins. A method characterized by:

3. 3. The method according to claim 1 or 2, The molecular gas carriers reach the vicinity of the substance mixture or the solution through an asymmetric pore structure of the membrane having open pores on the dialysate side of less than 50 μm, or less than 1 μm, or less than 100 nm, but 10% or less, or less than 0.1%, or less than 0.01% of the molecular gas carriers pass through the membrane, so that oxygen (O2) diffuses into the substance mixture or the solution over the shortest possible distance, and at the same time, carbon dioxide (CO2) is removed from the substance mixture or the solution into the dialysate by diffusion over the shortest possible distance, but the particulate gas carriers themselves do not pass through the membrane. A method characterized by:

4. The method according to any one of claims 1 to 3, On the dialysate side, the concentration of the molecular gas carrier is adjusted to be greater than the concentration of hemoglobin in the blood, thus enhancing the mass transport of CO2 and oxygen. A method characterized by:

5. The method according to any one of claims 1 to 4, The received or discharged gas carrier is secondarily regenerated in a closed recirculation circuit by a device using the received and / or discharged gas. A method characterized by:

6. 6. The method of claim 5, The regeneration of the molecular gas carrier in the dialysate is performed by the oxygenator, which regenerates the carrier-carrying dialysate by removing carbon dioxide (CO2) and / or introducing oxygen (O2). A method characterized by:

7. The method according to any one of claims 1 to 6, As the membrane, an asymmetric high-flux dialysis membrane having a cutoff between 120 and 1 KD, between 60 and 10 KD, or between 20 and 50 KD is used. A method characterized by:

8. 3. The method of claim 2, The dialysate contains hemoglobin molecules having a molecular weight of less than 1 megadalton, or less than 500 kD (kilodalton), or less than 60 kD. A method characterized by:

9. 9. The method of claim 2 or 8, The dialysate is used for extracorporeal treatment of blood containing electrolytes, buffers, sugars, and monomeric or polymeric hemoglobin and / or albumin as components; the electrolytes, buffers and glucose vary within the range of concentrations of commercially available concentrates; The hemoglobin molecule is concentrated to a concentration between 0 g / l and the technical limit of solubility, or greater than 30 g / l, or greater than 70 g / l, and the albumin is concentrated to a concentration between 0 g / l and the technical limit of solubility, or greater than 50 g / l, or greater than 200 g / l. A method characterized by:

10. 10. The method of claim 1, The dialysate contains carbonic anhydrase present as a monomer or as a functionally crosslinked dimer or multimer to allow passage to the open-pore dialysate side of the membrane, while preventing passage of at least 80%, 95%, or more than 99% of the substance mixture or solution to be affected on the narrow-pore side of the membrane. A method characterized by:

11. The method according to any one of claims 1 to 10, The membrane is simultaneously used for the purification of blood according to the prior art by dialysis or for the removal of harmful substances by dialysis or filtration according to the apheresis method. A method characterized by:

12. 1. A device for influencing the concentration of oxygen (O2) and / or carbon dioxide (CO2) as gases in a mixture of substances or solutions of biological or complex chemical liquids, comprising: The device is connectable to a pool (3) and comprises two circulation circuits; a first circulation circuit is used on the one hand to supply the substance mixture or the solution from the pool (3) along the narrow-pore side of the asymmetric semipermeable membrane via a tube and a pump, the substance mixture or the solution then being led back to the pool (3) via a tube; the second circulation circuit is used on the other hand to supply a dialysate via a tube and a pump along the open-pore side of the asymmetric semipermeable membrane, the dialysate containing a molecular gas carrier in the form of molecular hemoglobin or other similar proteins for the gas to be affected, the molecular gas carrier being able to pass through the membrane through the asymmetric pore structure of the membrane with open pores on the dialysate side, reaching the vicinity of the substance mixture or the solution before its passage is hindered by the narrower pores of the asymmetric semipermeable membrane, whereby an exchange of dissolved gases takes place, after which the dialysate is led back via a tube to the recirculation circuit, via a regeneration device which accepts and / or releases gases, In the regeneration device, the dialysis fluid is regenerated by newly introducing oxygen (O2) and / or removing carbon dioxide (CO2). An apparatus characterized by:

13. 13. The apparatus of claim 12, The pump is a roller pump, an impeller pump, or a membrane pump, and the asymmetric semipermeable membrane is a flat membrane or a hollow fiber membrane. An apparatus characterized by:

14. 13. The apparatus of claim 12, The molecular gas carriers reach the vicinity of the substance mixture or the solution through an asymmetric pore structure of a membrane having open pores on the dialysate side of less than 50 μm, or less than 1 μm, or less than 100 nm, but less than 10%, or less than 0.1%, or less than 0.01% of the molecular gas carriers pass through the membrane; Therefore, oxygen (O2) diffuses into the substance mixture or the solution over the shortest possible distance, and at the same time, carbon dioxide (CO2) is removed from the substance mixture or the solution to the dialysis solution by diffusion over the shortest possible distance, while the particulate gas carriers themselves contained in the substance mixture or the solution do not pass through the membrane. An apparatus characterized by:

15. 13. The apparatus of claim 12, The regeneration device is a commercially available oxygenation device. An apparatus characterized by:

16. The device according to any one of claims 12 to 15, The substance mixture or the solution is blood or plasma; and a dialyzer that allows for pore-permeable diffusional transport of molecules from the blood or plasma through a semipermeable membrane into a dialysate; An apparatus characterized by:

17. 17. The apparatus of claim 16, For extracorporeal treatment of blood or plasma in a closed circuit, the dialysate is regenerated both by operating the regeneration device and by additional adsorption and / or dialysis and / or filtration for the removal or introduction of substances. An apparatus characterized by:

18. The device according to any one of claims 12 to 17, The regenerator includes a biological assimilation system that is capable of converting carbon dioxide and water into glucose and oxygen under the action of light based on photosynthesis. An apparatus characterized by:

19. The device according to any one of claims 12 to 17, The regenerator uses an electrochemical method for oxygen generation. An apparatus characterized by:

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