ARRANGEMENT FOR IMPROVING THE EXCHANGE OF GASES VIA SEMIPERMEABLE MEMBRANES IN AN AQUEOUS MEDIUM

Abstract

Provided are methods and arrangements wherein gases are removed via semipermeable membranes from aqueous, optionally complex biological substance mixtures, by dialysis in an aqueous medium. Special carrier molecules for gases are included in the dialysate that are regenerated in the dialysate circuit so that they can be used for further gas exchange cycles on the membrane.

Claims

1. A method for influencing the concentration of gases in a composition, wherein the gases comprise oxygen and/or carbon dioxide, which comprises: guiding the composition one-sidedly along an asymmetric, semipermeable membrane, guiding a dialysate on a second side of the membrane, wherein the dialysate is oxygenated in a closed circuit comprising an oxygenator, wherein the composition comprises corpuscular gas carriers, wherein the dialysate comprises a gas carrier for at least one of the gases, wherein the gas is placed as closely as possible to the composition, wherein the membrane comprises a greater amount of open pores on the dialysate side than on the second side, wherein the gas carrier does not pass through the membrane, and wherein the dialysate is regenerated by input of oxygen (O2) and/or by withdrawal of carbon dioxide (CO2).

2. The method of claim 1, wherein the gas carrier is molecular hemoglobin.

3. The method of claim 1, wherein the pores on the dialysate side are less than 50 μm in diameter, and wherein the gas carrier passes through the membrane to an extent of not more than 10%.

4. The method of claim 1, wherein the composition is blood, wherein the blood comprises hemoglobin, and wherein, on the dialysate side, the concentration of the gas carrier is higher than the concentration of hemoglobin.

5. The method of claim 1, wherein the gas carrier is regenerated in a closed recirculation circuit in a secondary manner via a device by loading and/or unloading of gas.

6. The method of claim 5, wherein the device is an oxygenator that regenerates the carrier-bearing dialysate by withdrawal of carbon dioxide (CO2) and/or input of oxygen (O2).

7. The method of claim 1, wherein the membrane is an asymmetric high-flux dialysis membrane comprising a molecular weight cut-off of between 120 and 1 kDa.

8. The method of claim 2, wherein the dialysate comprises molecular hemoglobin having a molecular weight of less than 1 megadalton.

9. The method of claim 2, wherein the composition is blood, comprising electrolytes, buffer, sugar, molecular monomeric or multimeric hemoglobin, and/or albumin, wherein the hemoglobin is present at a concentration of between 0 g/l to its solubility limit, and wherein albumin is present at a concentration of between 0 g/l to its solubility limit.

10. The method of claim 1, wherein the dialysate comprises carbonic anhydrase present as a monomer or functionally cross-linked as a dimer or multimer.

11. An arrangement for influencing the concentration of gases in a composition, wherein the gases comprise oxygen and/or carbon dioxide, wherein the arrangement is: connectable to a pool and comprises two circuits, wherein a first circuit supplies the composition one-sidedly along a narrow-pore side of an asymmetric, semipermeable membrane from the pool via hoses and pumps, wherein the composition is conducted back into the pool via hoses, and a second circuit supplies a dialysate on a second side along an open-pore side of the asymmetric, semipermeable membrane via hoses and pumps, wherein the dialysate comprises a gas carrier in the form of proteins, and wherein the membrane comprises a greater number of open pores on the dialysate side than on the second side wherein the dialysate is conducted back via hoses into a recirculation circuit over a device for regeneration by loading and/or unloading of gases, wherein the dialysate is regenerated in the device for regeneration by input of oxygen (O2) and/or by withdrawal of carbon dioxide (CO2).

12. The arrangement of claim 11, wherein the pumps are roller pumps, impeller pumps, or membrane pumps, and wherein the asymmetric, semipermeable membrane is a flat or hollow-fiber membrane.

13. The arrangement of claim 11, wherein the membrane pores have a diameter of less than 50 μm.

14. The arrangement of claim 11, wherein the device for regeneration is an oxygenator.

15. The arrangement of claim 12, wherein the composition is blood or plasma, and further comprising a dialyzer that allows diffusive transfer of pore-crossing molecules from the blood or plasma into a dialysate through a semipermeable membrane.

16. The arrangement of claim 15, wherein the dialysate is regenerated both by switching on the device for regeneration and by additional adsorption, dialysis, and/or filtration for material removal or input.

17. The arrangement of claim 11, wherein the device further comprises an assimilative biological system that can converts carbon dioxide and water into glucose and oxygen on the basis of photosynthesis under the influence of light.

18. The arrangement of claim 11, wherein the device for regeneration comprises electrochemical processes for oxygen production.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0045] The methods and arrangements provided herein will now be described with reference to the drawings wherein:

[0046] FIG. 1 shows the structure of a closed circuit, wherein the circuit comprises an oxygenator for input of oxygen and for removal of CO2;

[0047] FIG. 2 shows a graphical representation of CO2 clearance;

[0048] FIG. 3 shows a graphical representation of oxygen saturation of the blood;

[0049] FIG. 4 shows a control experiment;

[0050] FIG. 5 shows a graphical representation of classic Nemo-oxygenation on CO2 clearance via the entire system; and,

[0051] FIG. 6 shows a graphical representation of oxygen saturation of the blood.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Example 1:

[0052] CO2-enriched blood is pumped at a rate of 200 ml/min through the hollow fibers of a dialyzer (ideally having an asymmetric membrane, for example polysulfone in a Fresenius FX1000 CORDIAX™), along the dialysate side of which a dialysis fluid containing approx. 30 g/l hemoglobin is conducted, which dialysis fluid likewise recirculates at 200 ml/min in a closed circuit, the circuit containing an oxygenator for input of oxygen and for removal of CO2. The structure is depicted in FIG. 1. Initially, the oxygenator is without an influx of oxygen. Despite a circling solution of hemoglobin dialysate, CO2 clearance decreases over time, since the dialysate hemoglobin is enriched with CO2. After 2.5 minutes, the supply of O2 to the oxygenator is adjusted to 600 ml/min. The effect on CO2 clearance is depicted in FIG. 2.

[0053] FIG. 1 shows a blood circuit (hematocrit approx. 40%) which is driven by a peristaltic pump 1 and flows through a dialyzer on the inside of the hollow fibers. The dialyzer is a commercially available asymmetric polysulfone high-flux dialyzer (sieving coefficient for albumin <10%, or <1%), though alternative materials can also be used, such as polyamide, polyethersulfone, et cetera. The membrane need not be a hollow-fiber membrane but in some instances is a flat membrane. Upstream and downstream of the dialyzer, the blood gases are measured at the sampling points SH1 and SH2. In order to simulate endogenous CO2 poisoning, CO2 is “blown in” downstream of the sensor SH2 and immediately upstream of the pool 3 for a composition or a solution, blood in the embodiment, via a gas exchanger (for example, oxygenator). The dialysate is a hemoglobin solution which comprises approx. 30 g/l hemoglobin and which is likewise driven by a pump 2, for example a peristaltic pump. In an alternative embodiment, optionally carbonic anhydrase can be used in the dialysate, which in some instances increases the effect. Owing to the asymmetric membrane, the molecules of the hemoglobin solution penetrate into the membrane structure from the dialysate side in order to get relatively close to the erythrocytes of the blood. On the dialysate side as well, blood gas analysis is performed upstream of SH4 and downstream of SH3. At the same time, O2 is blown in and exchanged for CO2, similar to a simple oxygenator, upstream of the sensor SH4 in the direction of flow. The dialysate can be operated in cocurrent or countercurrent, preference being given to countercurrent. The effect of “oxy-carbo-dialysis” with O2-enriched and CO2-depleted hemoglobin dialysate on the CO2 clearance of the dialyzer is demonstrated in FIG. 2. The effect on the oxygen saturation of the blood is shown in FIG. 3.

[0054] FIG. 2 shows CO2 clearance via the dialyzer (black points), calculated via the drop in CO2 concentration over the dialyzer between the sensors SH1 and SH2 in FIG. 2 and the blood flow (200 ml/min), plotted with the partial pressure of oxygen of the incoming dialysate. It is clear that it is not the dialysis (200 ml/min) with hemoglobin itself which increases CO2 clearance (CO2 input of 200 ml/min at the gas exchanger (GE)); instead, it is only with the input of oxygen into the hemoglobin-containing dialysate in the oxygenator 2 that the CO2 clearance at the dialyzer rises rapidly and reaches practically almost 100% of the blood flow.

[0055] FIG. 3 shows the oxygen saturation downstream of the dialyzer SH2 in the embodiment according to FIG. 1. The first 8 minutes correspond to the first 8 minutes of FIG. 2. Here too, it is clear that solely the circulation with hemoglobin does not have a substantial effect on oxygen saturation and that the oxygenation (1 l O2 via oxygenator 2) of the hemoglobin-containing dialysate, which starts after 4 min, is however associated with a very rapid saturation of the blood with oxygen. To illustrate the effect, the oxygen stream and the dialysate is stopped again, which results in an immediate drop at the SH2 sampling point to the SH1 values, which are greatly reduced by the input of 200 ml/min CO2 at the gas exchanger GE in the blood (<20%). The oxygen is reinitiated after 15 min at (600 ml/min) and the dialysate is switched back on to 200 ml/min, which leads to rapid improvement in the O2 saturation at SH2, despite 200 ml CO2/min “poisoning” via the gas exchanger GE in the blood. After 20 min, this “poisoning” is switched off and the pool 3 for the composition or the solution, for example for blood, as a whole also steadily improves with oxygen saturation.

Example 2: Control

[0056] FIG. 4 shows a blood circuit (hematocrit approx. 40%) that is driven by a peristaltic pump 1 and flows through a dialyzer on the inside of the hollow fibers.

[0057] As in FIG. 1, the dialyzer is a commercially available asymmetric polysulfone high-flux dialyzer (sieving coefficient for albumin <10%, or <1%), though alternative materials can also be used, such as polyamide, polyethersulfone, et cetera. The membrane is a hollow-fiber membrane or a flat membrane. Upstream and downstream of the dialyzer, the blood gases are measured at the sampling points SH1 and SH2. In order to simulate endogenous CO2 poisoning, CO2 is “blown in” downstream of the sensor SH2 immediately upstream of the pool 3 for blood via a gas exchanger (for example, oxygenator).

[0058] After the sensor SH1 in the direction of flow, classic oxygenation and CO2 elimination is performed by an

[0059] Nemo-oxygenator (O2 blown in and exchanged for CO2, similar to a simple oxygenator). The combined effect of oxygenator and dialysis is measured downstream of the dialyzer at SH2. In such embodiments, the dialysate is commercially available dialysate that is likewise driven by a pump 2, for example a peristaltic pump. On the dialysate side as well, blood gas analysis is performed upstream SH4 and downstream SH3 of the dialyzer.

[0060] The dialysate can be operated in cocurrent or countercurrent, preference being given to countercurrent. The effect of this classic hemo-oxygenation on the CO2 clearance via the entire system is demonstrated in FIG. 5. The effect on the oxygen saturation of the blood is shown in FIG. 6.

[0061] The significance of the oxygen/S02 carrier in the blood is additionally demonstrated by, as an additional control experiment, sequential connection of the option of oxygenation of the hemoglobin-free dialysate from a dialysate pool, and this is why an identical synergy oxygenator is also installed in the dialysate. This comes into operation only in the second part of the experiment.

[0062] FIG. 5 shows the CO2 clearance via the oxygenator and dialyzer (black points), calculated via the drop in CO2 concentration over the oxygenator and dialyzer between the sensors SH1 and SH2 in FIG. 4 and the blood flow (200 ml/min), plotted with the partial pressure of oxygen at the exiting dialysate SH3—corresponds to the partial pressure of O2 prevailing in the system. The combined oxygenation and dialysis at 200 ml achieves good oxygenation, the synergy dialyzer being a highly effective dialyzer that is actually customary for full oxygenation at approx. 5 l/min.

[0063] FIG. 6 shows the oxygen saturation downstream of the dialyzer SH2 in the control experiment according to FIG. 4. In the case of full oxygenation with 1 liter O2 via the oxygenator (synergy) beginning after 4 minutes, full oxygenation is achieved in line with the prior art. After the CO2 “poisoning flow” and the oxygenation in the blood oxygenator are stopped, the oxygen saturation starts to fall slowly; even the oxygenation of the hemoglobin-free dialysate switched on at the end is not able to rapidly raise the oxygen saturation in SH2 as in FIG. 3.

Exemplary Further Embodiments

[0064] A further embodiment is a method for influencing the concentration of gases such as oxygen (O2) and/or carbon dioxide (CO2) in a composition or a solution of biological or complex chemical fluids, in which the composition or the solution is guided one-sidedly along an asymmetric, semipermeable membrane, and a dialysate is guided on the other side of the same membrane, which dialysate is oxygenated in a closed circuit containing an oxygenator, characterized in that the composition or solution to be influenced contains corpuscular gas carriers (erythrocytes) and the dialysate in the closed circuit contains a gas carrier for at least one of the gases to be influenced, via which the gas to be influenced is taken as closely as possible to the composition or the solution, wherein the gas carrier gets close to the composition or the solution owing to an asymmetric pore structure of the membrane with more-open pores on the dialysate side, such that oxygen (O2) diffuses into the composition or the solution over a shortest possible distance and, at the same time, carbon dioxide (CO2) is withdrawn from the composition or the solution into the dialysate by diffusion over a shortest possible distance without the gas carrier itself passing through the membrane, wherein, for regeneration, the dialysate is regenerated by fresh new input of oxygen (O2) and/or by withdrawal of carbon dioxide (CO2).

[0065] A further embodiment of the above method is characterized in that the gas carrier used is molecular hemoglobin or other related proteins.

[0066] According to a further embodiment of the above methods, the gas carrier gets close to the composition or the solution owing to an asymmetric pore structure of the membrane with more-open pores on the dialysate side of up to below 50 μm, preferably below 1 pm and most preferably below 100 nm, wherein the gas carrier, however, passes through the membrane to an extent of not more than 10%, preferably less than 0.1% and most preferably less than 0.01%, such that oxygen (O2) diffuses into the composition or the solution over a shortest possible distance and, at the same time, carbon dioxide (CO2) is withdrawn from the composition or the solution into the dialysate by diffusion over a shortest possible distance without the gas carrier itself passing through the membrane.

[0067] According to a further embodiment of the above methods, on the dialysate side, the concentration of the gas carrier is set higher than the concentration of the blood hemoglobin, thereby additionally increasing the mass transfer of CO2 and oxygen.

[0068] According to a further embodiment of the above methods, the loaded or unloaded gas carrier is regenerated in a closed recirculation circuit in a secondary manner via a device by loading and/or unloading of gas.

[0069] According to a further embodiment of the above methods, the regeneration of the gas carrier in the dialysate is done by the oxygenator, which regenerates the carrier-bearing dialysate by withdrawal of carbon dioxide (CO2) and/or fresh new input of oxygen (O2).

[0070] According to a further embodiment of the above methods, the membrane used is an asymmetric high-flux dialysis membrane having a cut-off between 120 and 1 KD, preferably between 60 and 10 KD and particularly preferably 20 and 50 KD.

[0071] According to a further embodiment of the above methods, the dialysate contains molecular hemoglobin having a molecular weight of less than 1 megadalton (approx. 20 hemoglobin tetramers, cross-linked), preferably of less than 500 kD (approx. 10 hemoglobin tetramers, cross-linked) and most preferably below 60 kD (one tetramer).

[0072] According to a further embodiment of the above methods, the dialysate is used for extracorporeal treatment of blood, containing electrolytes, buffer, sugar, molecular monomeric or multimeric hemoglobin and/or albumin as components, wherein the electrolytes, buffer and glucose vary within the concentrations of commercially available concentrates, wherein the molecular hemoglobin is concentrated in the concentration between greater than 0 g/l up to the technical solubility limit, preferably above 30 g/l and particularly preferably above 70 g/l, and albumin is concentrated with a concentration between greater than 0 g/l up to the technical solubility limit, preferably above 50 g/l and particularly preferably above 200 g/l.

[0073] According to a further embodiment of the above methods, the dialysate contains carbonic anhydrase present as a monomer or functionally cross-linked as a dimer or multimer in order to allow passage into the open-pore dialysate side of the membrane, and to prevent passage into the composition or solution to be influenced on the narrow-pore side of the membrane to an extent of at least 80%, preferably 95% and ideally above 99%.

[0074] According to a further embodiment of the above methods, the membrane is simultaneously used for detoxification by dialysis or filtration in the context of blood purification methods with dialysis or apheresis methods.

[0075] A further embodiment is an arrangement for influencing the concentration of gases such as oxygen (O2) and/or carbon dioxide (CO2) in a composition or a solution of biological or complex chemical fluids, wherein the arrangement is connectable to a pool (3) and consists of two circuits, wherein a first circuit is used for supplying the composition or the solution one-sidedly along a narrow-pore side of an asymmetric, semipermeable membrane from the pool (3) via hoses and pumps, wherein the composition or the solution is then conducted back into the pool (3) via hoses, and a second circuit is used for supplying a dialysate other-sidedly along an open-pore side of the asymmetric, semipermeable membrane via hoses and pumps, wherein the dialysate contains a gas carrier in the form of molecular hemoglobin or other related proteins for the gas to be influenced, and wherein the gas carrier, owing to an asymmetric pore structure of the membrane with more-open pores on the dialysate side, can penetrate said membrane and thus get close to the composition or the solution before the decreasing pores of the asymmetric membrane prevent through-passage, the exchange of dissolved gas takes place, and the dialysate is then conducted back via hoses into a recirculation circuit over a device for regeneration by loading and/or unloading of gases, wherein the dialysate is regenerated in the device for regeneration by fresh new input of oxygen (O2) and/or by withdrawal of carbon dioxide (CO2).

[0076] A further embodiment of the above arrangement is characterized in that the pumps are roller pumps, impeller pumps or membrane pumps and the asymmetric, semipermeable membrane is a flat or hollow-fiber membrane.

[0077] According to a further embodiment of the above arrangements, the gas carrier gets close to the composition or the solution owing to an asymmetric pore structure of the membrane with more-open pores on the dialysate side of up to below 50 μm, preferably below 1 μm and most preferably below 100 nm, wherein the gas carrier, however, passes through the membrane to an extent of not more than 10%, preferably less than 0.1% and most preferably less than 0.01%, such that oxygen (O2) diffuses into the composition or the solution over a short distance and, at the same time, carbon dioxide (CO2) is withdrawn from the composition or the solution into the dialysate by diffusion over a short distance without the gas carrier itself passing through the membrane.

[0078] According to a further embodiment of the above arrangements, the device for regeneration is a commercially available oxygenator.

[0079] According to a further embodiment of the above arrangements, the composition or the solution is blood or plasma, and in that a dialyzer which allows diffusive transfer of pore-crossing molecules from the blood or plasma into a dialysate through a semipermeable membrane is comprised.

[0080] According to a further embodiment of the above arrangements, for extracorporeal treatment of blood or plasma in a closed circuit, the dialysate is regenerated both by switching on the device for regeneration and by additional adsorption and/or dialysis and/or filtration for material removal or input.

[0081] According to a further embodiment of the above arrangements, the device for regeneration contains assimilative biological systems which can convert carbon dioxide and water into glucose and oxygen on the basis of photosynthesis under the influence of light.

[0082] According to a further embodiment of the above arrangements, the device for regeneration uses electrochemical processes for oxygen production.

[0083] It is understood that the foregoing description is that of the preferred embodiments of the invention and that various changes and modifications may be made thereto without departing from the spirit and scope of the invention as defined in the appended claims.