PL247103B1 - Device for blood oxygenation with a membrane made of organic material with pore-forming, anti-inflammatory and anticoagulant properties - Google Patents

Abstract

The subject of the invention is a device for blood oxygenation (oxygenator for blood oxygenation) with a membrane made of an organic material with pore-forming, anti-inflammatory and anticoagulant properties, used to supplement oxygen deficiency in hypoxic blood, especially in cases of acute respiratory distress syndrome. The device comprises a gas exchange chamber (1) of elongated shape in the form of a straight cylinder or an elliptical cylinder, in the bases (2 and 2') of which there are through holes, wherein on one side the chamber (1) is connected gas-tightly to a surge tank (4) supplying a gas mixture containing oxygen to the chamber (1), having an inlet opening for the gas mixture from the installation supplying this mixture, and on the other side the chamber (1) is connected gas-tightly to a tank (6) discharging the gas mixture from the chamber, having an outlet opening (7) for the gas mixture, and inside the chamber (1) there is placed a membrane in the form of a bundle of capillaries (8) made of a semi-permeable material, i.e. permeable for the molecules of the gas mixture and impermeable for blood particles, the ends of which are anchored on both sides in the through holes in the bases (2, 2') of the chamber (1), the capillaries (8) are tensioned a tensioning force of 1 to 100 N, and are parallel to the longitudinal axis of the chamber (1) and to each other, or in a more advantageous variant are spirally shaped, i.e. they are twisted along the longitudinal axis of the chamber (1) by an equal angle in the range of 15 to 720 degrees, furthermore, in the side wall of the chamber (1) near each base (2, 2') of the chamber, at least one inlet/outlet opening (10) for the blood stream is made, wherein the capillaries forming the membrane are in the form of tubes with an external diameter of 30 to 600 µm and are made of an organic material with pore-forming, anti-inflammatory and anti-coagulant properties, consisting of: - a base in the form of polypropylene (PP) or polyurethane (PU) or polyethylene terephthalate (PET) or polycarbonate (PC) or polyoxymethylene (POM) or polysulfone (PSU) or silicone or a fluoropolymer, preferably poly(tetrafluoroethylene) (PTFE) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP), - an admixture of 4-(diphenylamino)benzaldehyde, in a base-admixture proportion from 50 ÷ 1 to 5000 ÷ 1, and - an admixture of 1,3-indandione in a base-admixture amount of 50 ÷ 1 to 5000 ÷ 1, - an admixture of bivaluridine built into the microstructure of the base material, in a base-admixture proportion from 80 ÷ 1 to 1200 ÷ 1.

Description

The subject of the invention is a device for extracorporeal blood oxygenation (oxygenator for blood oxygenation) with a membrane made of organic material with pore-forming, anti-inflammatory and anticoagulant properties. Extracorporeal blood oxygenation is used in conditions in which there is a potentially reversible deep impairment of lung function to a degree that prevents effective gas exchange using mechanical ventilation.

The oxygenator acts as a lung and is an integral part of the heart-lung machine. Similar to physiological conditions in the lungs, a gas exchange process occurs here, in which oxygen supplied to the oxygenator chamber takes the place of carbon dioxide in the blood. The oxygenator is a device made of a large number of thin tubes, between which blood flows. The walls of the tubes are a semipermeable membrane, through which gases can penetrate - oxygen and carbon dioxide, but blood particles cannot. Inside the tubes (so-called capillaries) there is a space filled with a gas mixture, the concentration of which can be adjusted depending on the needs. Blood, flowing between the capillaries, gives off carbon dioxide and takes oxygen molecules - this is a process that normally takes place in the lungs.

From the current state of the art, devices for blood oxygenation and materials used in them are known.

For example, two oxygenators using a blood flow perpendicular to the gas mixture flow are described in a comparative analysis by Wang et al. (2016), which showed that the Quadrox-i Adult oxygenator has low resistance and high biocompatibility with lower pressure drop and lower hemodynamic energy consumption. In contrast, the Capiox RX25 oxygenator in clinical conditions had a lower risk of gaseous microemboli (GME). This shows that design optimization is necessary to improve the safety of therapy. Thousands of GME are delivered to the circulatory system during ECMO therapy despite the use of a membrane oxygenator and arterial filtration. GME causes tissue ischemia, damage to the vascular endothelium in the brain and other end organs, leading to vasodilation, increased permeability, platelet activation, coagulation cascade, and activation of complement and cellular mediators of inflammation. Current technologies only partially remove GME. It is desirable to develop systems that eliminate the formation of GME while maintaining good gas exchange parameters [Wang S, Kunselman AR, ^dar A. Evaluation of Capiox RX25 and Quadrox-i Adult Hollow Fiber Membrane Oxygenators in a Simulated Cardiopulmonary Bypass Circuit. Artif Organs. 2016;40(5):E69-E78. doi:10.1111/aor.12633].

In the experience of Formica et al. (2008), the Quadrox D oxygenator showed optimal performance without plasma leakage and the need for ECMO exchange for more than four days in adult patients with cardiogenic shock. The ECMO used in the study consisted of a membrane oxygenator with a blood flow perpendicular to the gas mixture flow, the material of which was modified with polymethylpentene and a magnetic centrifugal pump. Initial observations indicate that such a device with a modified membrane could work properly for up to two weeks. Further modifications of the membranes in the oxygenators could extend the life of these devices [Formica F, Avalli L, Martino A, et al. Extracorporeal membrane oxygenation with a polymethylpentene oxygenator (Quadrox D). The experience of a single Italian center in adult patients with refractory cardiogenic shock. ASAIO J. 2008; 54(1): 89-94. doi:

10.1097/MAT.0b013e31815ff27e].

Clingan et al (2016) continued the work initiated by Gipson et al (2014). They used hypobaric oxygenation to achieve a mild hypoxic state in the Terumo® FX15 oxygenator. Hypobaric oxygenation may reduce the risks associated with GME generation during pulsatile flow perfusion, vacuum-assisted venous drainage, and rapid temperature changes. Similar observations were made by Ginther et al (2013) during clinical use of the Maquet Quadrox-i neonatal oxygenator. The benefits of a low transmembrane pressure drop were demonstrated [Clingan S, Schuldes M, Francis S, Hoerr H Jr, Riley J. In vitro elimination of gaseous microemboli utilizing hypobaric oxygenation in the Terumo® FX15 oxygenator. Perfusion. 2016;31(7):552-559. doi:10.1177/0267659116638148; Gipson KE, Rosinski DJ, Schonberger RB, et al. Elimination of gaseous microemboli from cardiopulmonary bypass using hypobaric oxygena tion. Ann Thorac Surg. 2014;97(3):879-886. doi:10.1016/j.athoracsur.2013.08.074; Ginther RM Jr, Gorney R, Cruz R. A clinical evaluation of the Maquet Quadrox-i Neonatal oxygenator with integrated arterial filter. Perfusion. 2013;28(3):194-199. doi:1201177/0267659113475694].

From the patent description US4008047 a solution is known, which consists in subjecting ethylcellulose to fluoroacylation, which in turn results in good gas permeability and blood compatibility of polymer layers made of the resulting fluorinated esters. Fluoroacylated ethylcellulose has good hydrolytic stability at blood pH and sterilization conditions (e.g. 100°C). It is used in blood oxygenation devices, implantable biomedical devices, blood collection or analysis or purification devices, etc. The use of this material for the construction of membranes allows to eliminate problems with clotting and resistance to sterilization, but only until the surface layer is worn out. After its abrasion, the positive properties are lost, which is one of the weaknesses of this solution.

Membranes consisting of hollow fibers (capillaries, tubes) are also known. From patent description No. WO9534373 such semipermeable membranes with hollow fibers are known characterized in that they have monofilament spacer members, spirally arranged or formed on their outer surface. This invention also describes extracorporeal blood treatment devices containing such improved membranes.

Organic fluid oxygenators are also known, which can be used in particular for oxygenating blood flowing in an extracorporeal circuit, without creating zones in which the flow of fluid slows down and stops causing aggregates, clots and a significant reduction in the oxidation capacity. From the patent description No. US2020016312 a solution is known in that the oxygenator consists of a container body having a longitudinal axis; a first inlet opening for oxygen and a second outlet opening for exhaust gases obtained in the container body; a third inlet opening for the oxygenated organic fluid and a fourth outlet opening for the oxygenated organic fluid obtained in the container body; an oxygenation chamber for the fluid to be oxygenated, which is defined inside the container body; a preliminary distribution chamber for the fluid to be oxygenated, mounted between the third inlet opening and the oxygenation chamber; hollow fibers impermeable to fluids and porous to gases, designed to allow contact with the organic fluid and arranged within the oxygenation chamber in accordance with a common parallel direction of dynamic distribution means operated in the pre-distribution chamber by means of support means. The advantages of the invention are: a favorable ratio between the overall size and the oxygenation capacity; it prevents the slowing down of the flow of organic fluids and the consequent formation of accumulations and clots; it prevents the crushing of the hollow fiber skeins, keeping the useful transition sections intact and keeping all surfaces of each individual hollow fiber perfectly permeable and useful, even in the case of a large number of hollow fibers used in relation to one unit of volume.

Also known from patent description no. US2020129687 is an oxygenator comprising a housing and a membrane assembly disposed in the housing. The housing has a blood inlet, a blood outlet, and a blood flow path from the blood inlet to the blood outlet. The housing defines a central axis and a plurality of zones concentrically disposed about the central axis. The membrane assembly is disposed in the housing. The membrane assembly includes a first plurality of gas exchange elements disposed in a first zone of the housing and a second plurality of gas exchange elements disposed in a second zone of the housing. The second zone is disposed concentrically about the first zone, and the zones are fluidly open to one another along a body of the plurality of gas exchange elements and fluidly separated from one another along a distal end. The first zone is configured to fluidly communicate with a source of oxygen, and the second zone is configured to fluidly communicate with a source of negative pressure. The blood flow path includes a substantially radial flow through the first zone to add oxygen to the blood and the second zone to separate gas micro-emboli from the blood by the plurality of gas exchange elements.

From the patent description no. US2020108194 a solution is known in that the oxygenator has an integrated system for removing air, the bubbles of which could lead to embolism. The oxygenator includes a blood inlet and a blood outlet. The blood flow path extends from the blood inlet to the blood outlet. The blood oxygenation apparatus also includes a gas exchange part disposed along the blood flow path; a heat exchange part disposed along the blood flow path upstream of the gas exchange part; and one or more porous hollow fibers disposed perpendicularly to the blood flow path upstream of the heat exchange part.

From the patent description US4722829A there is known a blood oxygenation device, dialyzer, heat exchanger and the like, comprising a rectangular or cylindrical, elongated housing. The interior of the housing is divided into three chambers, including an inlet chamber located at one axial end, an outlet chamber located at the opposite axial end and a central mass/heat exchange chamber located between them. A plurality of parallel tubes pass through the central chamber, which connect the inlet and outlet chambers, creating passages for the flow of the working medium therebetween. The outer surface of each tube is in the form of a series of rounded petals, connected end to end. In addition, adjacent tubes are offset with respect to each other to allow for tight and orderly packing of their petals. The therapeutic medium, e.g. oxygen, flows through the tubes, while the medium to be treated, e.g. blood, flows through the interstitial spaces between the tubes. The gas exchange system is based on the flow of blood between a system of heterogeneous capillaries in the form of a bubble cooler.

From the description CN208893292 is known an integrated membrane oxygenator with spiral flow guidance, which consists of a lower cover, an oxygenating part and an upper cover. The oxygenating part is placed on the lower cover and consists of a stem structure, an oxygenating coating and a membrane structure of an oxygenating wire, the oxygenating coating is equipped with a blood outlet tube, and the blood outlet tube is located close to the lower cover. The upper cover is placed on the oxygenating part and is equipped with a blood inlet tube and an oxygen inlet tube. This is a multi-layer solution, where the capillaries are arranged in the form of a wreath along the longitudinal axis and 45 degrees to their own axes every second strip on the wreath.

The flow idea disclosed in the description of CN107638601 is similar to that contained in the description of CN208893292. The invention of CN107638601 relates to a membrane structure and a membrane type oxygenator. The membrane structure includes a plurality of first layers of hollow fibers and a plurality of second layers of hollow fibers arranged with the first layers of hollow fibers in a staggered arrangement, and each first layer of hollow fibers and each second layer of hollow fibers are equipped with a plurality of tubular hollow fibers arranged omnidirectionally. The membrane structure can effectively reduce the pre-charging volume of blood and lower the blood pressure to avoid damaging the blood. Blood transfusion can be achieved to make the blood form a thin blood film, increase the contact area between blood and oxygen, and improve the oxygenation efficiency of blood and oxygen.

From the patent description WO2015095334A1 a partial radial heat exchanger and oxygenator is known. The solution is provided with a plurality of capillary tubes, each terminating at opposite first and second ends, and each extending around the core along an arc angle of less than 360 degrees. The oxygenating bundle is formed as part of the core assembly and includes a plurality of gas-exchanging fibers. The core assembly is placed in a housing having a blood inlet and outlet. In the solution WO2015095334A1 a kind of rope braiding of capillaries around the core is used.

The described solutions US4722829A, CN208893292, CN107638601 and WO2015095334A1 are characterized by a completely different main feature related to the time of contact of the blood molecule with the oxygen molecule than in the case of the reported solution, in which there is something like a surface effect and a reduction in flow turbulence, which is impossible to achieve with blood flow perpendicular to the longitudinal axis of the capillaries.

Many of the previously known blood oxygenation systems are constructed in such a way that they consist of membranes in the form of capillaries arranged parallel to each other but perpendicular to the direction of blood flow or intersecting at an angle of 90°, but arranged in a plane perpendicular to the direction of blood flow in the device, creating a layer of capillaries. A gas mixture with oxygen flows through the capillaries. The capillaries are separated from each other and stabilized using spacer elements in the form of a system of fibers or meshes, most often made of polyolefins, arranged in layers between the membrane (capillary) systems. Additionally, each capillary layer can be separated from neighboring capillary layers by a spacer layer made of fibers in the form of a dense mesh. Blood is passed through such a system perpendicularly to the longitudinal axis of the capillaries (membrane), i.e. perpendicularly to the direction of flow in the capillaries of the gas mixture with oxygen. Such a system is characterized by numerous disadvantages, the most important of which are:

- effective transfer of oxygen to blood particles requires a relatively high pressure of the gas mixture containing up to 100% oxygen, which increases the risk of oxidative stress for cells,

- risk of gas bubbles in the blood, which necessitates the use of degassing systems,

- lack of self-regulation - despite achieving the absorption capacity of the blood, the saturated particle is still exposed to oxygen, which increases the risk of oxidative stress (after saturation, gas is released in the form of bubbles into the blood),

- short contact time of blood particles with oxygen molecules, which causes reduced efficiency of gas exchange.

The weaknesses of known solutions include the fact that the shape and location of the membranes used in them in the form of tubes (capillaries) can affect clotting on some elements and can also cause hemolysis of blood cells. Membrane structures sometimes contain spacers between capillaries, which maintain the capillaries in their initial positions, but which disrupt the laminarity of blood flow and cause the formation of turbulent flows, and as a result can promote the formation of clots and microemboli. As a consequence of clotting, infections, organ failure, mainly kidney failure, can occur.

Patients with acute respiratory distress syndrome (ARDS) in the period preceding the introduction of ECMO are usually aggressively mechanically ventilated with the need to use ventilation using high pressure of the respiratory mixture. Despite the use of a lung-sparing ventilation protocol, the airway pressure necessary to maintain lung ventilation may damage areas of the lung alveoli not affected by the disease. This leads to the development of barotrauma, which is responsible for further secondary lung damage. In addition, severe respiratory failure is also associated with the need to use high concentrations of oxygen for proper tissue oxygenation. The degree of respiratory failure is associated with the need to supply oxygen with a high, even close to 100% concentration of oxygen in the gas mixture during mechanical ventilation of the lungs using a ventilator. Such a high concentration of oxygen, through reflex and increased nitrogen reabsorption from the lung alveoli, intensifies the already existing atelectasis and further impairs gas exchange. High concentrations of oxygen in the respiratory mixture also lead to direct damage to type II pneumocytes in the pulmonary alveoli. This results in increasing surfactant deficiency, a substance that coats the inner surface of the pulmonary alveoli and prevents their collapse. In conditions of surfactant deficiency, the areas of the lungs affected by atelectasis increase and gas exchange disorders in the lungs become more severe. In addition, a factor that increases problems with gas exchange, clinically significant in diseases affecting most of the interstitial tissue of the lungs, is physiological hypoxemic constriction of the pulmonary vessels and bronchioles, which is a beneficial phenomenon in the case of processes that locally damage the lungs, but in the case of generalized hypoxemia - it increases the symptoms of hypoxia.

These adverse phenomena associated with a high, almost 100% oxygen content in the gas mixture may also occur in the case of extracorporeal oxygenation - ECMO. The need to use a gas mixture with almost 100% oxygen content supplied to the oxygenator results from the technological limitations of the membrane in which gas exchange takes place, which is the main component of the device. The gas exchange surface of the membrane is much smaller than the exchange surface of the lungs. The surface of the alveolar capillaries in the lungs is about 70-100 m ² , which is a much larger surface than in the membranes currently used in ECMO. Oxygen exchange through the membrane depends to some extent on the partial pressure of oxygen on both sides of the membrane. To ensure maximum membrane efficiency, a gas mixture with almost 100% oxygen content supplied to the oxygenator is used. Almost pure oxygen, often used in treatment using veno-venous or veno-arterial ECMO, contacting morphological elements of blood leads to oxidative stress, damage to the cell membranes of circulating red blood cells. This leads to the disintegration of blood cells with the release of heme compounds into the blood. Hemolysis leads to anemia in treated patients.

Other morphological elements of the blood are also subjected to similar effects of harmful, high oxygen concentration. Damage to the cell membranes of leukocytes and thrombocytes will result in impaired cellular immunity and a worsening of the body's ability to defend itself against bacterial and fungal infections, as well as induction of a generalized inflammatory response and secretion of prothrombotic factors. Impaired cellular immunity and impaired immune function affect the effectiveness of treatment of severe pneumonia and sepsis, which are the main indications for venovenous ECMO. In addition, impaired patient immunity leads to infections associated with hospitalization: infections of the vascular bed, blood-borne pneumonia, skin infections at the site of drain insertion. Infections during therapy are the second most common complication during ECMO therapy. The occurrence of infections thus affects the final outcome of treatment. There is a need for more frequent and long-term use of broad-spectrum antibiotic therapy, and thus the generation of strains of bacteria resistant to antibiotics.

The increasing resistance of bacterial strains to antibiotics is a factor in increasing patient mortality. In turn, damage to platelets will result in the development of hypercoagulability (the third most common complication), often responsible for thromboembolic complications and the need for intensified anticoagulation.

In connection with the above, it has become clinically important to develop such a device design that will enable more effective oxygenation and elimination of carbon dioxide at less than 100% concentrations of oxygen used at the point where oxygenation of circulating blood occurs in the oxygenator. The basis for introducing design changes to previously known devices are physiological phenomena and observed adaptive mechanisms of healthy lungs.

Physiologically, in conditions of basic metabolism, blood flows through the pulmonary bed at a rate of about 6 L/min. In conditions of increased oxygen demand, such as physical exertion or hypermetabolism occurring, for example, during sepsis, the demand for oxygen increases significantly, which is a factor that increases cardiac output and lung ventilation. This allows for a 2-3-fold increase in blood flow through the pulmonary bed, shortening the time the erythrocyte stays in the pulmonary capillaries by about 70%, which, thanks to the expansion of the pulmonary capillaries and increased cardiac output, occurs without affecting blood oxygenation (saturation of hemoglobin with oxygen) and pressure in the pulmonary bed (in physiological conditions, hemoglobin is fully oxygenated after the erythrocyte has passed 1/3 of the length of the pulmonary capillary).

Based on the adaptive mechanisms known from the physiology of respiration and gas exchange in the lungs, it is desirable to maximize the contact time of the erythrocyte with the capillary filled with the gas mixture in order to enable effective oxygenation of hemoglobin using the lowest possible concentration of oxygen in the gas mixture used in the oxygenator.

However, simply extending the length of the capillaries to extend the time of contact between the erythrocyte and the capillary filled with a gas mixture is not a good solution. It may encounter technical complications in production and then during use of the device, especially related to maintaining the desired parallelism between the capillaries and the distance between them, and may increase the likelihood of clotting of the flowing blood. Therefore, taking into account the fact that the capillaries cannot be excessively extended, and their length may still be insufficient for effective gas exchange of the gas mixture flowing in them with the blood flowing around them, it became desirable to continue searching for ideas to increase the efficiency of this exchange.

Such a solution was proposed by the creators of this invention, in which they used a mechanism ensuring the transport of the blood stream in parallel to the transport of the gas mixture in the capillaries, in the same direction as the blood or, more preferably, in the opposite direction, which will allow for more effective gas exchange, because the ease of gas exchange will increase, and the resulting oxygen gradient will allow for gradual oxygenation of erythrocytes. The combination of mechanisms in the countercurrent advantageous variant, i.e. the extension of the real path of active gas exchange and the countercurrent mechanism, will allow for a significant reduction in the required pressure of the gas mixture, which, based on pathophysiological and cellular mechanisms, should reduce the risk of numerous complications and improve the effects of treatment of patients.

An additional problem that needs to be solved is the selection of appropriate materials from which individual elements of oxygenators are made, especially their most important element, i.e. the membrane used for gas exchange with blood. Such materials should be characterized primarily by so-called semi-permeability, i.e. they must be permeable to molecules of the gas mixture and impermeable to blood particles, but their additional parameters improving their functional properties are desirable.

From the prior art, materials with pore-forming properties are known for producing selective membranes, i.e. those that only allow particles of a specific size to pass through. Such materials are used to produce, among others, membranes for use in the production of tents, jackets, filters, osmotic membranes, including oxygenators for blood oxygenation.

The most popular, highly technologically advanced - in non-medical applications - pore-forming material (used, for example, for the production of jackets) from which the membranes were made is poly(tetrafluoroethylene).

However, in medical applications, i.e. for the construction of medical equipment, the prior art includes membranes, including porous membranes used in equipment having direct contact with body fluids, made of various materials.

For example, from the patent description PL225257 a membrane system for local immobilization of eukaryotic cells is known, having a support and at least one bilayer, formed successively from one polyelectrolyte layer comprising polysaccharide hydrogels, especially sodium alginate containing incorporated fullerenol and protein A in its structure, characterized in that the first layer is applied directly to a group of isolated cells then placed on a support made of the same material in terms of composition and the second polymer layer of aliphatic secondary or tertiary amines - containing ethyl or methyl groups with incorporated fullerenol. In this system, one layer is applied directly to a group of isolated eukaryotic cells, and it allows for isolation of eukaryotic cells from the external environment, in particular microorganisms, while not limiting the transport of nutrients through the membrane, allowing for their directed growth.

Patent description PL212620 describes a specially modified polyolefin membrane (PP, PE) and a method of modifying microporous polyolefin membranes intended for the isolation of Gram (+) bacteria, consisting in introducing into the structure of a polyolefin membrane with high porosity in a known manner a solution of a polycation selected from the group consisting of aliphatic amino acids, especially proteinaceous, preferably polar and dissolved in a NaCl solution, and then introducing into the membrane structure in a known manner, preferably by soaking, a solution of a polyanion selected from the group consisting of a polymer of a secondary or tertiary amine, especially methylamine and ethylamine, preferably containing 100% of methyl or ethyl groups, dissolved in a NaCl solution.

Patent description PL 197199 also describes a polymeric proton-conducting membrane based on hydrated poly(perfluorosulfonic acid), characterized in that it is a product of the radiation grafting reaction of poly(perfluorosulfonic acid) with vinylphosphonic acid used in an amount of 1 to 40% by weight or 2-acrylamido-2-methylpropanesulfonic acid used in an amount of 1 to 40% by weight.

Patent description PL165872 describes a method for manufacturing a multilayer porous polytetrafluoroethylene membrane containing at least two layers having pores of different average diameters, which comprises the steps of: filling the extruder barrel with at least two different types of fine-grained polytetrafluoroethylene powders, with each of them being mixed with a liquid lubricant.

From the patent description EP0409496 a process for obtaining microporous membranes containing at least partially crystalline aromatic polymer containing ether or thioether and ketone bonds in the chain is known. The process allows for the production of membranes from certain aromatic polymers with a high melting point, for example PEDK.

The type of materials from which the membranes known from the above-mentioned solutions were made allows - for steric reasons - their use for blood oxygenation, however their significant biochemical limitations significantly limit this use. Moreover, due to their structure, they are characterized by a developed surface topography on a micrometric scale, which was the cause of their negative impact on living organisms. At the cellular level, these membranes cause steric damage to cell membranes, which results in cell destabilization. Moreover, the membranes cannot inhibit the formation of clots and do not protect against the formation of bacterial biofilm.

So far, in medical applications, polypropylene (PP) and polyurethane (PU) have been used primarily as pore-forming materials. For example, in devices used in the process of blood oxygenation, polyurethane was used as a porous material for the construction of membranes, and polypropylene was used for the construction of elements for separating membrane layers (spacers). Despite the high efficiency of such membranes in terms of gas exchange, they have weaknesses related primarily to the formation of inflammation resulting from the low bioinertia of these materials, which affected the formation of clots on the membrane surface, which gradually grew. In such a case, in order to maintain the effectiveness of blood oxygenation, the oxygen concentration must be increased, which again causes oxidative stress and intensifies the clotting process, causing an unfavorable cascade, i.e. a gradual drive of unfavorable factors, because the oxygen concentration must be constantly increased to maintain the level of blood saturation, and this increases oxidative stress and intensifies clotting. After exceeding a certain threshold, the number of clots is so large that the device is no longer suitable for further operation (it does not fulfill its function) and the entire oxygenator system must be replaced.

Therefore, there was a need to select membranes made of previously unknown materials for use in oxygenators, which would allow for achieving a high level of pore-forming properties, while ensuring biocompatibility and bioinertia (inertness), and which would limit the risk of inducing inflammation in the oxygenator, and consequently slow down the clotting process on the membrane and extend the life of the device.

Various compounds with antithrombotic activity are known from the state of the art. Among others, bivalirin is known - an antithrombotic drug from the group of direct specific thrombin inhibitors (DTI). DTIs block the active site, responsible for the main action of thrombin and/or the external site, where the substrate is recognized and properly oriented. The action of these inhibitors is direct and does not depend on the presence of antithrombin. Unlike indirect DTI inhibitors, they can inhibit thrombin bound to fibrin, which prevents thrombin from cleaving fibrinogen to fibrin monomers, activating factors XIII, V, VIII and stimulating thrombocytes to aggregate.

So far, however, there are no known oxygenators with membranes made of materials with pore-forming, anti-inflammatory and anticoagulant properties, containing immobilized bivaliridin in their composition and semi-permeable to gases, and their development has become an additional additional goal of the inventors of the present invention.

The essence of the invention is a device for blood oxygenation, with a membrane made of an organic material with pore-forming, anti-inflammatory and anti-coagulant properties, containing a gas exchange chamber of an elongated shape in the form of a straight cylinder or an elliptical cylinder, in the gas inlet base and the gas outlet base of which there are through holes, wherein on the one hand the gas exchange chamber is gas-tightly connected to a surge tank supplying a gas mixture containing oxygen to the chamber, having an inlet opening for the gas mixture from the installation supplying this mixture, and on the other hand the gas exchange chamber is gas-tightly connected to a tank discharging the gas mixture from the chamber, having an outlet opening for the gas mixture, and inside the gas exchange chamber there is a membrane in the form of a bundle of capillaries, the ends of which are anchored on both sides in the through holes in the outlet and inlet bases of the chamber, characterized in that the capillaries are tensioned by a force a tensioning force of 1 to 100 N, preferably 10 N, and are parallel to the longitudinal axis of the chamber and to each other, furthermore, at least one blood stream inlet opening is made in the side wall of the chamber near the outlet base of the chamber, and at least one blood stream outlet opening is made in the side wall of the chamber near the inlet base of the chamber, additionally the device is equipped with a blood stream cooler - heating module system, built in such a way that a blood stream cooler with parameters enabling its cooling by 0.5-3.5°C, preferably by 2°C, is connected to the blood stream inlet opening(s) to the gas exchange chamber, and a blood stream heating module with parameters enabling its heating to the physiological blood temperature is connected to the blood stream outlet opening(s) from the gas exchange chamber, while the capillaries forming the membrane have the form of tubes with an outer diameter of 30 to 600 μm, preferably 100 μm, and are made of an organic material with pore-forming, anti-inflammatory and anti-coagulant properties, semi-permeable, i.e. permeable to gas mixture molecules but impermeable to blood particles, consisting of:

- a base in the form of polypropylene (PP) or polyurethane (PU) or polyethylene terephthalate (PET) or polycarbonate (PC) or polyoxymethylene (POM) or polysulfone (PSU) or silicone or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP) or a fluoropolymer, most preferably poly(tetrafluoroethylene) (PTFE),

- 4-(diphenylamino)benzaldehyde admixture, in a base-admixture ratio of 50:1 to 5000:1, preferably 100:1,

- a 1,3-indandione admixture in a base-admixture amount of 50:1 to 5000:1, preferably 100:1, and - a bivalirudin admixture incorporated into the microstructure of the base material, in a base-admixture ratio of 80:1 to 1200:1, preferably 150:1, wherein the membrane contains pores, of which 40 to 60% are open pores (unfilled), and the remaining are closed pores, i.e. they are filled with an active substance in the form of bivalirudin. As the membrane is used, bivalirudin is gradually released, and consequently consumed, and the total amount of bivalirudin decreases and the number of open pores increases, which results in a larger gas exchange surface, i.e. better oxygenation. New pores also form, which take over the gas exchange function from open pores that may have been blocked by gradually forming clots or the formation of a biofilm on the membrane surface.

The essence of the invention is also a device for blood oxygenation, with a membrane made of an organic material with pore-forming, anti-inflammatory and anticoagulant properties, containing a gas exchange chamber of an elongated shape in the form of a straight cylinder or an elliptical cylinder, in the gas inlet base and the gas outlet base of which there are through holes, wherein on the one hand the gas exchange chamber is connected gas-tightly to a surge tank supplying a gas mixture containing oxygen to the chamber, having an inlet opening for the gas mixture from the installation supplying this mixture, and on the other hand the gas exchange chamber is connected gas-tightly to a tank discharging the gas mixture from the chamber, having an outlet opening for the gas mixture, and inside the gas exchange chamber there is a membrane in the form of a bundle of capillaries, the ends of which are anchored on both sides in the through holes in the outlet and inlet bases of the chamber, characterized in that the capillaries are tensioned by a force a tensioning force of 1 to 100 N, preferably 10 N, and are spirally shaped, i.e. they are twisted along the longitudinal axis of the chamber by a uniform angle in the range of 15 to 720 degrees, preferably by an angle of 90 to 360 degrees, furthermore, at least one blood stream inlet opening is made in the side wall of the chamber near the outlet base of the chamber, and at least one blood stream outflow opening is made in the side wall of the chamber near the inlet base of the chamber, additionally the device is equipped with a blood stream cooler - heating module system, built in such a way that a blood stream cooler with parameters enabling its cooling by 0.5-3.5°C, preferably by 2°C, is connected to the blood stream inlet opening(s) to the gas exchange chamber, and a blood stream heating module with parameters enabling its heating to the physiological blood temperature is connected to the blood stream outflow opening(s) from the gas exchange chamber, while the capillaries forming the membrane have the form of tubes with an external diameter of 30 to 600 µm, preferably 100 µm, and are made of an organic material with pore-forming, anti-inflammatory and anticoagulant properties, semi-permeable, i.e. permeable to molecules of the gas mixture but impermeable to blood particles, consisting of:

- a base in the form of polypropylene (PP) or polyurethane (PU) or polyethylene terephthalate (PET) or polycarbonate (PC) or polyoxymethylene (POM) or polysulfone (PSU) or silicone or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP) or a fluoropolymer, most preferably poly(tetrafluoroethylene) (PTFE),

- 4-(diphenylamino)benzaldehyde admixture, in a base-admixture ratio of 50:1 to 5000:1, preferably 100:1,

- an admixture of 1,3-indandione in a base-admixture amount of 50:1 to 5000:1, preferably 100:1, and

- an admixture of bivalirudin incorporated into the microstructure of the base material, in a base-admixture ratio of 80:1 to 1200:1, preferably 150:1, wherein the membrane contains pores, of which 40 to 60% are open pores (unfilled), and the remaining are closed pores, i.e. they are filled with the active substance in the form of bivalirudin. As the membrane is used, bivalirudin is gradually released, and consequently it is consumed, and the total amount of bivalirudin decreases and at the same time the number of open pores increases, which results in a larger gas exchange surface, i.e. better oxygenation. New pores are also formed, which take over the gas exchange function from open pores, which could have been blocked by gradually forming clots or the formation of a biofilm on the membrane surface.

The method of making spirally shaped capillaries is optional; preferably, the capillaries are attached to bases in the form of straight and parallel tubes, then stretched to achieve the appropriate tension and the bases are twisted in opposite directions, thereby causing the capillaries to twist by a planned angle, while ensuring that the capillary tension remains at a planned level that does not damage the capillaries.

Preferably, Peltier cells are used as a blood flow cooler.

Preferably, Peltier cells are used as the blood flow heating module. The heating module allows to obtain the physiological temperature of the blood.

Advantageously, the opening/openings located near the base of the chamber on the side of the tank discharging the gas mixture constitute the blood stream inlet opening, while the opening/openings located near the base of the chamber on the side of the equalizing tank supplying the gas mixture constitute the blood stream outlet opening. The indicated advantageous arrangement of the blood stream inlet and outlet openings ensures blood flow in a countercurrent to the direction of the gas mixture flow, and thanks to this, an optimal way of using the technical possibilities of the solution, i.e. maximum blood oxygen saturation with minimum external pressure of the gas mixture.

By applying the appropriate tension force to the capillaries, there is no need to use spacers (spacers) between them to ensure their stability. Such spacers would disrupt the laminarity of blood flow and limit the active surface of gas exchange. Appropriate tension of the capillaries will ensure the stability of the position of each of them, which will prevent the viscoelastic effect of the capillaries (their trembling) during blood flow. Capillary trembling is unfavorable because it disrupts the laminarity of the blood flow.

The expansion tank allows to maintain a constant pressure of the gas mixture at the inlet to each capillary, and if one of the capillaries becomes clogged, the tank will automatically force to increase the pressure at the inlet of the remaining capillaries, but within a limited range limited by the flow.

Gas exchange takes place in the chamber, i.e. oxygen molecules are taken into the blood from the capillaries in which the gas mixture flows, and carbon dioxide is released into the capillaries.

Advantageously, the holes in the bases of the outlet and inlet chambers are made at equal distances from each other and symmetrically to each other, and at the same time the capillaries anchored in these holes are also at equal distances from each other. Such a capillary layout ensures almost ideal laminarity of blood flow. This is an advantage over solutions in which it was necessary to use spacers maintaining a constant distance of hollow fiber tubes (capillaries) from each other.

Advantageously, a HEPA filter is installed at the outlet of the gas mixture discharge tank, thanks to which any factors that may constitute a biological hazard are removed from the gas mixture escaping from the device.

Preferably, the blood flow inlet opening and the blood flow outlet opening are formed at a distance of no more than 5 mm from a given base of the chamber.

Advantageously, the blood flow inlet opening is made on the opposite side than the blood flow outlet opening, symmetrically with respect to the center of symmetry of the chamber.

Advantageously, in the variant with straight capillaries, on the internal surface of the chamber, along its entire length, at least two blood flow guides are mounted symmetrically with respect to the axis of symmetry of the chamber, in the form of longitudinal notches, most advantageously with a triangular or close to a triangle cross-section, which are parallel to the longitudinal axis of the chamber.

Preferably, in the variant with spirally shaped capillaries, on the internal surface of the chamber, along its entire length, at least two blood flow guides are mounted symmetrically with respect to the axis of symmetry of the chamber, most preferably with a triangular or similarly triangular cross-section, which are arranged spirally, i.e. twisted along the longitudinal axis of the chamber by an equal angle in the range from 15 to 720 degrees, preferably by an angle equal to the angle of twist of the capillaries. Such a guide arrangement forces the desired direction - in the preferred variant swirl - of the blood flow, and at the same time does not disturb the laminarity of its flow.

Advantageously, a densely woven fiber mesh, preferably made of a material identical to the material of the capillaries, is attached to the blood flow outflow opening, so that the mesh openings are 15 to 100 μm, preferably 38 μm, parallel to the plane of the opening on which it is attached.

Advantageously, a densely woven fiber mesh, preferably made of a material identical to the material of the capillaries, is attached to the blood flow inlet opening, so that the mesh openings are 15 to 100 μm, preferably 38 μm, parallel to the plane of the opening on which it is attached.

Such a mesh constitutes a filter that allows for significantly increased protection against the penetration of potential clots, and the anticoagulant factor contained in the mesh may advantageously lead to spontaneous dissolution of clots on the mesh surface. This will constitute a kind of automatic mechanism for cleaning the clot filter, which will prevent the device from being clogged with clots and the penetration of clots into the systems behind the device in the long term.

Preferably, at least one clot filter module, preferably two parallel clot filter modules with a bypass (splitter) for smooth switching, i.e. directing the blood flow alternately through one or the other clot filter module, is installed on the outlet channel from the blood outlet opening of the gas exchange chamber, wherein in the present variant with the clot filter module/modules the blood flow heating module is installed before or more preferably after the clot filter module/modules. The bypass (splitter) enables the blood flow to be directed exclusively through one clot filter module, which is the working module at a given moment, while the other is the passive module at that time and can be replaced with a new one without having to stop the blood flow.

Advantageously, at least one module with a clot filter, preferably two parallel modules with clot filters with a bypass (splitter) for smooth switching, i.e. directing the blood flow alternately through one or the other module with a clot filter, is installed in front of the cooler of the blood flow, which is then introduced through the blood flow inlet opening to the gas exchange chamber. Such a solution enables directing the blood flow exclusively through one module with a clot filter, which is the working module at a given moment, while the other one is a passive module at that time and it is possible to replace it with a new one, without having to stop the flow of the blood flow.

In the variant of the invention with spirally shaped capillaries, the gas exchange chamber is a vortex chamber, which results from the twisting of the capillaries by an appropriate angle and the advantageous spiral shape of the blood flow guides located on the internal walls of the chamber. Ensuring a vortex flow of the blood stream extends the active path and the time the blood stays in the chamber, which in turn extends the time and efficiency of gas exchange while maintaining minimized parameters of the size of the entire device and minimizes the volume of blood that is outside the body during the oxygenation process. Due to the centrifugal force, gas exchanges are separated. Heavy particles are pushed outwards, i.e. towards the walls of the chamber, and light ones are located in the middle of the blood stream, which increases the efficiency of gas exchange by minimizing multidirectional exchange.

It is proposed to use fibers arranged longitudinally in the plane of blood flow, intertwined with each other so as to maximize the active surface of the blood-fiber contact, which makes the blood flow more laminar, and the spiral arrangement of fibers will result in better diffusion and more effective exchange of oxygen and carbon dioxide, according to the concentration gradient. During the implementation, it is recommended to arrange the fibers parallel to each other along the longitudinal axis of the flow, then immobilize them in the bases and twist the bases relative to each other by an angle between 90 and 360 degrees; such twisting will create a vortex channel, which is beneficial in terms of flow laminarness and exchange efficiency. Such a system will allow the use of lower oxygen pressure, or even the use of a system with reduced oxygen concentration, thanks to which oxidative stress will also be reduced, which as a result causes, among other things, less blood clotting on the membrane fibers.

In the proposed solution, a blood stream cooler is installed before the gas exchange chamber, where the patient's blood is oxygenated in the ECMO extracorporeal circulation, i.e. on the blood inlet channel to the gas exchange chamber, allowing it to be cooled by 0.3-3.5°C, preferably by 2°C. Such conditions will be maintained throughout the oxygenation process. Lowering the temperature of the blood stream before the oxygenation process will have a beneficial effect on the saturation of hemoglobin with oxygen, because the solubility of gases in the aqueous environment will increase. The use of such a solution will allow the hemoglobin dissociation curve to be shifted to the left and will therefore allow for a colder FiO2 in the gas mixture fed to the oxygenator. Thanks to this, it will not be necessary to use a high, sometimes even close to 100% oxygen content in the oxygenating gas mixture. The oxygen content in the mixture can be reduced to as little as 21%. This will minimize the risk of negative effects related to oxidative stress and damage to the cell membranes of blood morphological elements. After the oxygenation process, the patient's blood will be warmed up to physiological temperature again. The proposed solution will therefore not affect the patient's body temperature, the patient will be maintained in a state of normothermia at all times. The solution with a blood cooling system before the oxygenator additionally protects against an increase in blood pressure in the installation, resulting from increased flow resistance. The pressure will remain at a physiological level.

The materials used to construct the membrane do not release chemical compounds that are toxic to cells and do not cause pathogenic reactions in cells.

A membrane composed of the described materials protects against the formation of biofilm (no bacterial plaque forms on it), due to the internal structure of the material, i.e. the arrangement of macromolecules and pores in the material, which is not a protagonist of the development and adhesion of bacterial plaque.

All materials used to make the membrane provided for in the solution according to the invention allow to achieve the expected technical effect. The most advantageous is the use of poly(tetrafluoroethylene) (PTFE), which is characterized by many advantages as a material for the production of gas exchange membranes, related to its safety in contact with blood and tissues, including:

- Biocompatibility: PTFE is a biocompatible material, meaning it does not cause immunological or toxic reactions that could lead to tissue or organ damage. Therefore, PTFE is a safe choice for membranes that come into contact with blood and tissue.

- Chemical resistance: PTFE is resistant to many chemicals and enzymes, including those found in the human body. Therefore, membranes made of this material do not degrade or change their properties, which could be harmful to tissue or blood.

- Resistance to high and low temperatures while maintaining its dimensions (no thermal shrinkage): PTFE retains its physical and chemical properties over a wide temperature range, which allows its use in vitro and in vivo.

- Abrasion resistance: PTFE has a very low coefficient of friction, meaning it is resistant to abrasion and wear, which is important when in contact with tissue and blood.

- Hygroscopicity: PTFE is a material that does not have moisture in it, which means that it does not absorb water, which is beneficial in the case of contact with blood. Additionally, PTFE is characterized by low adhesion to viscoelastic bodies, which reduces the risk of clot sticking to the surface.

The chemical structure of the macromolecules of the materials used to create membranes in the device according to the invention affects their good pore-forming properties, and at the same time ensures their biocompatibility and bioinertia (inertness). In oxygenators, the risk of inducing cellular and humoral mediators of inflammation is limited, and as a result, the process of clotting on the membrane is slowed down. This reduces the risk of secondary multi-organ damage.

The studies on the ability to release the active agent (bivalirudin) from the membrane were conducted in a known flow vessel using a constant volume of a polar solvent in the form of ultrapure water 18.2 MQ. The membrane was immersed in the solvent for 30 minutes. Then the solvent was collected and injected into the flow vessel, observing the changes in the natural frequency of the disk in the form of a quartz resonator with an electrode applied, in accordance with the Sauerbrey relationship, i.e. the relationship linking the change in vibrations with the change in mass. The disk was placed so that any sedimentation of the analyte from the solvent would not cause a falsification of the result through gravitational settling on the disk. The location of the disk guaranteed that only the mass of the absorbed analyte would be measured. Based on the observed changes in the natural frequency of the disk (their decrease), the presence of the active agent in the solvent was found, which was deposited on the electrode. This means that during the immersion of the membrane in the solvent, the active agent was released from the membrane into the solvent. The experiment was repeated ten times on the same sample and the measurement results were similar each time (within the measurement error range). The constancy of changes over time indicates a controlled process of releasing the active agent from the membrane.

The use of immobilized bivalirudin allows for maintaining its constant concentration on the contact surface of the detail throughout the period of use of the materials (programmed product life). The possibility of excessive leaching of bivalirudin is minimized, and due to the diffusion-controlled process of bivalirudin release, its contact concentration on the product surface is constant.

The introduction of bivalirudin into the material from which the membrane is made also gives it the desired antithrombotic and anti-inflammatory properties. Bivalirudin, as already mentioned above, has a strong antithrombotic effect on blood and due to its effect on lipids by activating lipase, it is also used as an antithrombotic agent used for antithrombotic coatings. The admixture of bivalirudin is built into both the pores of the material and into the microcracks created as equilibrium defects at the stage of material creation. This significantly improves the surface continuity of the material structure, and thus protects against the retention of organic material in the pores and microcracks, and significantly reduces clotting.

The introduction of 4-(diphenylamino)benzaldehyde and 1,3-indandione admixtures reduces the internal stresses in the material, which results in better orientation of macromolecules during processing and pore formation, which is ultimately observed as a smooth external structure and thanks to which there are no mechanical steric foci of clot formation due to the uniformity of the material and the lack of sharp edges around pores and cracks.

The subject of the invention is explained in more detail in the following examples of embodiment and in the drawing, in which figures 1 to 11 show a more advantageous variant of the invention with spirally shaped capillaries, while figures 12 to 14 show a variant of the invention with capillaries parallel to the longitudinal axis of the chamber, wherein fig. 1 shows the blood oxygenation device in an axonometric projection, fig. 2 - the blood oxygenation device in a side view, from the side of the blood stream inlet opening, fig. 3 - the blood oxygenation device in a side view, from the side of the blood stream outlet opening, fig. 4 - the blood oxygenation device in an axonometric projection, in a view after connecting the blood heating module, fig. 5 - the blood oxygenation device in an axonometric projection, in a view after connecting the cooler, fig. 6 - the blood oxygenation device in an axonometric projection, in cross-section (after subtracting the reservoir 7 - the blood oxygenation device in an axonometric projection, in cross-section (after removing the equalization tank and removing the gas exchange chamber base from the gas mixture stream inlet side), with visible capillary inlet holes, fig. 8 - the blood oxygenation device in a top view, in a variant with a clot filter module installed, both on the inlet and outlet sides of the blood stream and with a cooler installed, fig. 9 - the blood oxygenation device in a top view, in a variant with a clot filter module installed, both on the inlet and outlet sides of the blood stream, and with a cooler and a blood heating module installed, fig. 10 - the blood oxygenation device in an axonometric projection, in a variant with a clot filter module installed, a clot filter, both on the inlet and outlet sides of the blood stream, and with a mounted cooler and a mounted blood heating module, while fig. 11 shows the blood oxygenation device in a side view, in a variant with a module with a clot filter installed in front of the blood inlet opening to the chamber, fig. 12 shows the blood oxygenation device in an axonometric projection, fig. 13 shows the blood oxygenation device in a side view, from the side of the blood stream inlet opening, while fig. 14 shows the blood oxygenation device in an axonometric projection, in cross-section (after subtracting the expansion tank), with the base of the gas exchange chamber shown from the side of the gas mixture stream inlet.

Example 1

A device for oxygenation of blood comprising a gas exchange chamber 1 of elongated shape in the form of a straight cylinder, in the bases of which outlet 2 and inlet 2' there are through holes 3, wherein on one side chamber 1 is connected gas-tightly to a surge tank 4 supplying a gas mixture containing oxygen to chamber 1, having an inlet opening 5 for the gas mixture from the installation supplying this mixture, and on the other side chamber 1 is connected gas-tightly to a tank 6 discharging the gas mixture from chamber 1, having an outlet opening 7 for the gas mixture. Inside chamber 1 there is placed a membrane in the form of a bundle of capillaries 8 (otherwise hollow fibers or tubes) in the form of tubes with an external diameter of 30 pm made of a porous semi-permeable material, i.e. permeable to molecules of the gas mixture and impermeable to blood particles. The material consists of a polycarbonate base and an admixture of 4-(diphenylamino)benzaldehyde in a base-admixture ratio of 1000:1 and an admixture of 1,3-indandione in a base-admixture ratio of 5000:1 and an admixture of bivalirudin incorporated into the microstructure of the base material in a base-admixture ratio of 150:1. The membrane contains pores, of which 40% are open pores, and the rest are closed pores filled with the active substance in the form of bivalirudin. The ends of the capillaries 8 are anchored (fixed) on both sides in the through holes 3 in the outlet bases 2 and inlet bases 2' of the chamber 1, and the capillaries 8 are spirally shaped, i.e. they are twisted along the longitudinal axis of the chamber 1 by an equal angle of 360 degrees and are tensioned with a tensioning force of 80 N. In the side wall 9 of the chamber 1, near the outlet base 2 of the chamber 1 from the side of the tank 6 discharging the gas mixture, an inlet hole 10' of the blood stream is made, while near the inlet base 2' of the chamber 1 from the side of the equalizing tank 4 supplying the gas mixture, an outlet hole 10" of the blood stream is made. The inlet hole 10' of the blood stream and the outlet hole 10" of the blood stream are made at a distance of 5 mm from the given base of the chamber 1, furthermore, the inlet hole 10' of the blood stream is made on the side opposite the 10” blood stream outflow tract, symmetrically to the center of symmetry of ventricle 1.

The openings 3 in the bases of the outlet 2 and inlet 2' of the chamber 1 are made at equal distances from each other and symmetrically with respect to each other, and at the same time the capillaries 8 anchored in these openings are also located at equal distances from each other and symmetrically with respect to each other.

A HEPA 11 filter is installed at the outlet of the tank draining the gas mixture.

On the internal surface of the chamber, along its entire length, two blood flow guides 12 are mounted symmetrically in relation to the axis of symmetry of the chamber 1, in the form of elongated notches with a triangular cross-section, arranged spirally, i.e. twisted along the longitudinal axis of the chamber 1 by an identical angle equal to the angle of twist of the capillaries 8.

A densely woven fiber mesh 13 made of a material identical to that of the capillaries 8 is attached to the 10” blood drainage opening, so that the mesh openings are 38 μm in side, perpendicular to the capillaries 8.

A blood stream cooler 16 in the form of Peltier cells with parameters enabling its cooling by 0.5-3.5°C, preferably by 2°C, is connected to the blood stream inlet opening 10' to the gas exchange chamber 1, while a blood stream heating module 17 in the form of Peltier cells with parameters enabling its heating to the physiological blood temperature is connected to the blood stream outlet opening 10" from the gas exchange chamber 1.

Example 2

A blood oxygenation device as in example no. 1, however, the capillary 8 twist angle is 720 degrees and the capillary tensioning force is 100 N, furthermore, in this variant the solution does not include a densely woven fiber mesh 13 mounted on the 10” blood outlet opening, but it includes two parallel modules 14 with clot filters with a bypass (splitter) installed on the outlet channel from the 10” blood outlet opening from the gas exchange chamber 1 enabling smooth switching, i.e. directing the blood flow interchangeably through one or the other module with a clot filter. The modules 14 with clot filters are installed between the 10” outlet opening and the blood flow heating module 17.

Furthermore, in front of the cooler 16 of the blood flow which is then introduced through the blood inlet opening 10' into the gas exchange chamber 1, two parallel modules 15 with clot filters with a bypass (splitter) are installed, enabling smooth switching, i.e. directing the blood flow interchangeably through one or the other module with a clot filter.

Example 3

A device for oxygenation of blood comprising a gas exchange chamber 1 of elongated shape in the form of an elliptical cylinder, in the bases of which outlet 2 and inlet 2' there are through holes 3, wherein on one side chamber 1 is connected gas-tightly to a surge tank 4 supplying a gas mixture containing oxygen to chamber 1, having an inlet opening 5 for the gas mixture from the installation supplying this mixture, and on the other side chamber 1 is connected gas-tightly to a tank 6 removing the gas mixture from chamber 1, having an outlet opening 7 for the gas mixture. Inside chamber 1 there is placed a membrane in the form of a bundle of capillaries 8 (also known as hollow fibers or tubes) in the form of tubes with an external diameter of 600 μm made of a porous semi-permeable material, i.e. permeable to molecules of the gas mixture and impermeable to blood particles. The material consists of a base in the form of polyurethane and an admixture of 4-(diphenylamino)benzaldehyde in a base-admixture ratio of 50:1 and an admixture of 1,3-indandione in a base-admixture ratio of 1250:1 and an admixture of bivalirudin incorporated into the microstructure of the base material in a base-admixture ratio of 80:1. The membrane contains pores, of which 40% are open pores, and the remaining are closed pores filled with an active substance in the form of bivalirudin. The ends of capillaries 8 are anchored (fixed) on both sides in through holes 3 in the bases of outlet 2 and inlet 2' of chamber 1, and capillaries 8 are spirally shaped, i.e. they are twisted along the longitudinal axis of chamber 1 by an equal angle of 90 degrees and are tensioned with a tensioning force of 10 N.

In the side wall 9 of chamber 1, near the outlet base 2 of chamber 1 from the side of the tank 6 discharging the gas mixture, a blood stream inlet opening 10' is made, while near the inlet base 2' of chamber 1 from the side of the equalizing tank 4 supplying the gas mixture, a blood stream outlet opening 10" is made. The blood stream inlet opening 10' and the blood stream outlet opening 10" are made at a distance of 5 mm from the given base of chamber 1, furthermore, the blood stream inlet opening 10' is made on the opposite side than the blood stream outlet opening 10", symmetrically with respect to the center of symmetry of chamber 1.

The openings 3 in the bases of the outlet 2 and inlet 2' of the chamber 1 are made at equal distances from each other and symmetrically with respect to each other, and at the same time the capillaries 8 anchored in these openings are also located at equal distances from each other and symmetrically with respect to each other.

A HEPA filter 11 is installed at the outlet of the gas mixture discharge tank 6.

On the internal surface of the chamber, along its entire length, two blood flow guides 12 are mounted symmetrically in relation to the axis of symmetry of the chamber 1, in the form of elongated notches with a triangular cross-section, arranged spirally, i.e. twisted along the longitudinal axis of the chamber 1 by an identical angle equal to the angle of twist of the capillaries 8.

A densely woven mesh 13 made of fibers of a material identical to that of the capillaries 8 is attached to the 10” blood outlet so that the mesh openings are 20 µm long, perpendicular to the capillaries 8.

A blood stream cooler 16 in the form of Peltier cells with parameters enabling its cooling by 0.5-3.5°C, preferably by 2°C, is connected to the blood stream inlet opening 10' to the gas exchange chamber 1, while a blood stream heating module 17 in the form of Peltier cells with parameters enabling its heating to the physiological blood temperature is connected to the blood stream outlet opening 10" from the gas exchange chamber 1.

Example 4

The blood oxygenation device as in example no. 3, however the capillary 8 twist angle is 15 degrees and the capillary tensioning force is 60 N, furthermore in this variant the solution does not contain a densely woven fiber mesh 13 mounted on the 10” blood outlet opening, but it contains two parallel modules 14 with clot filters with a bypass (splitter) installed on the outlet channel from the 10” blood outlet opening from the gas exchange chamber 1 enabling smooth switching, i.e. directing the blood flow interchangeably through one or the other module with a clot filter. The modules 14 with clot filters are installed between the 10” outlet opening and the blood flow heating module 17.

Furthermore, in front of the cooler 16 of the blood flow which is then introduced through the blood inlet opening 10' into the gas exchange chamber 1, two parallel modules 15 with clot filters with a bypass (splitter) are installed, which enables smooth switching, i.e. directing the blood flow interchangeably through one or the other module with a clot filter.

Example 5

Blood oxygenation device as in example no. 1, however capillaries 8, of which the membrane is composed, have the form of tubes with a diameter of 600 pm and are made of a semi-permeable material, i.e. permeable to molecules of a gas mixture and impermeable to blood particles. The material consists of a base in the form of polyurethane and an admixture of 4-(diphenylamino)benzaldehyde in a base-admixture ratio of 50:1 and an admixture of 1,3-indandione in a base-admixture ratio of 1250:1 and an admixture of bivalirudin built into the microstructure of the base material in a base-admixture ratio of 150:1. The membrane contains pores, of which 50% are open pores, and the rest are closed pores filled with an active substance in the form of bivalirudin.

Example 6

Blood oxygenation device as in example no. 1, however capillaries 8, of which the membrane is composed, have the form of tubes with a diameter of 100 pm and are made of a semi-permeable material, i.e. permeable to molecules of the gas mixture and impermeable to blood particles. The material consists of a base in the form of polypropylene and an admixture of 4-(diphenylamino)benzaldehyde in a base-admixture ratio of 500:1, an admixture of 1,3-indandione in a base-admixture ratio of 4375:1 and an admixture of bivalirudin built into the microstructure of the base material in a base-admixture ratio of 80:1. The membrane contains pores, of which 60% are open pores, and the rest are closed pores filled with an active substance in the form of bivalirudin.

Example 7

Blood oxygenation device as in example no. 3, however capillaries 8, of which the membrane is composed, have the form of tubes with a diameter of 100 μm and are made of a semi-permeable material, i.e. permeable to molecules of the gas mixture and impermeable to blood particles. The material consists of a base in the form of polyoxymethylene and an admixture of 4-(diphenylamino)benzaldehyde in a base-admixture ratio of 200:1 and an admixture of 1,3-indandione in a base-admixture ratio of 1750:1 and an admixture of bivalirudin built into the microstructure of the base material in a base-admixture ratio of 200:1. The membrane contains pores, of which 60% are open pores, and the remaining are closed pores filled with an active substance in the form of bivalirudin.

Example 8

Blood oxygenation device as in example no. 3, however capillaries 8, of which the membrane is composed, have the form of tubes with a diameter of 200 μm and are made of a semi-permeable material, i.e. permeable to molecules of the gas mixture and impermeable to blood particles. The material consists of a base in the form of polysulfone and an admixture of 4-(diphenylamino)benzaldehyde in a proportion of 443:1 and an admixture of 1,3-indandione in a base-admixture proportion of 3875:1 and an admixture of bivalirudin built into the microstructure of the base material in a base-admixture proportion of 1000:1. The membrane contains pores, of which 50% are open pores, and the remaining are closed pores filled with an active substance in the form of bivalirudin.

Example 9

Blood oxygenation device as in example no. 1, however capillaries 8, of which the membrane is composed, have the form of tubes with a diameter of 150 μm and are made of a semi-permeable material, i.e. permeable to molecules of a gas mixture and impermeable to blood particles. The material consists of a base in the form of poly(tetrafluoroethylene) and an admixture of 4-(diphenylamino)benzaldehyde in a base-admixture ratio of 101:1, an admixture of 1,3-indandione in a base-admixture ratio of 888:1 and an admixture of bivalirudin built into the microstructure of the base material in a base-admixture ratio of 500:1. The membrane contains pores, of which 55% are open pores, and the remaining are closed pores filled with an active substance in the form of bivalirudin.

Example 10

Blood oxygenation device as in example no. 1, however capillaries 8, of which the membrane is composed, have the form of tubes with a diameter of 500 μm and are made of a semi-permeable material, i.e. permeable to molecules of the gas mixture and impermeable to blood particles. The material consists of a base in the form of polyvinylidene fluoride and an admixture of 4-(diphenylamino)benzaldehyde in a base-admixture ratio of 1033:1, an admixture of 1,3-indandione in a base-admixture ratio of 4805:1 and an admixture of bivalirudin built into the microstructure of the base material in a base-admixture ratio of 150:1. The membrane contains pores, of which 45% are open pores, and the remaining are closed pores filled with an active substance in the form of bivalirudin.

Example 11

Blood oxygenation device as in example no. 1, however capillaries 8, of which the membrane is composed, have the form of tubes with a diameter of 100 μm and are made of a semi-permeable material, i.e. permeable to molecules of a gas mixture and impermeable to blood particles. The material consists of a base in the form of a copolymer of tetrafluoroethylene and hexafluoropropylene and an admixture of 4-(diphenylamino)benzaldehyde in a base-admixture ratio of 250:1 and an admixture of 1,3-indandione in a base-admixture ratio of 862:1 and an admixture of bivalirudin built into the microstructure of the base material in a base-admixture ratio of 150:1. The membrane contains pores, of which 60% are open pores, and the remaining are closed pores filled with an active substance in the form of bivalirudin.

Example 12

Blood oxygenation device as in example no. 1, however capillaries 8, of which the membrane is composed, have the form of tubes with a diameter of 150 μm and are made of a semi-permeable material, i.e. permeable to molecules of the gas mixture and impermeable to blood particles. The material consists of a base in the form of silicone and an admixture of 4-(diphenylamino)benzaldehyde in a base-admixture ratio of 105:1 and an admixture of 1,3-indandione in a base-admixture ratio of 3500:1 and an admixture of bivalirudin built into the microstructure of the base material in a base-admixture ratio of 100:1. The membrane contains pores, of which 50% are open pores, and the rest are closed pores filled with an active substance in the form of bivalirudin.

Example 13

A device for oxygenating blood as in example No. 1, but instead of spiral capillaries in the membrane, straight capillaries are used, i.e. parallel to the longitudinal axis of the chamber and to each other.

Example 14

A device for oxygenating blood as in example No. 3, but instead of spiral capillaries in the membrane, straight capillaries are used, i.e. parallel to the longitudinal axis of the chamber and to each other.

The operation of the device consists in introducing the gas mixture from the installation supplying the mixture into the equalizing tank through the inlet opening, and from there the gas mixture is then introduced through the holes in the inlet base of the chamber into the capillaries, transported in the capillaries and discharged through the holes made in the opposite outlet base into the tank discharging the gas mixture and from there through the outlet opening to the outside of the device, while at the same time blood cooled in the cooler is introduced into the gas exchange chamber through the inlet opening, the blood stream is transported along the longitudinal axis of the chamber, countercurrently to the direction of transport of the gas mixture in the capillaries, after which the blood is discharged from the chamber through the blood stream outlet opening and then heated in the heating module to the physiological temperature. Thanks to the system ensuring the transport of blood in the chamber in parallel, but counter-current to the transport of the gas mixture in the capillaries, without losing the efficiency of oxygenation, it is possible to reduce the concentration of oxygen in the gas mixture, which will reduce the oxidative stress for cells, especially for haemoglobin, and this will prevent clotting and an increase in pressure, and will also reduce the risk of the effect of trapping (blocking) drugs possibly transported in the blood, especially antibiotics, on the membrane (clots may form on the membrane, and as a result, drug particles remain there).

Blood in the oxygenator is passed in countercurrent to the flow of the gas mixture, due to the higher efficiency of gas exchange while maintaining the lowest possible oxidative stress. This makes it possible to maintain a constant concentration of oxygen molecules in the blood (diffusion-controlled process).

In the co-current variant, the blood particle would move in the same direction as the oxygen particles, gas exchange would occur, but the efficiency would be limited (controlled) by diffusion. In the counter-current variant, however, due to the continuous change in the contact phase - resulting from the fact that the blood and oxygen particles pass each other - the process is not controlled by diffusion and there is no limitation of the process in the entire area of the oxygenator chamber due to diffusion control. The blood particle that is still not saturated, i.e. will still be able to receive another batch of fresh oxygen, will still be able to take it thanks to contact with the next oxygen particles passing it. In addition, the partial pressure at the contact boundary of the blood particles with the oxygen particles will be higher than in the case of the co-current variant, which will enable more effective gas exchange. With an appropriately fast flow of the gas mixture stream containing oxygen, the effect of gas exchange will be additionally reinforced by the Venturi effect. As the blood flows, it sucks oxygen molecules from the capillary, even at a relatively low pressure of the gas mixture stream (the oxygen pressure does not have to be high, as is necessary in an oxygenator with blood flow perpendicular to the direction of the oxygen flow).

In the known solution, i.e. in the perpendicular variant (blood stream perpendicular to the direction of oxygen flow), oxygen molecules that escaped through the micropores of the capillaries had short contact with the blood and higher energy was needed to detach the oxygen molecule from the tube surface (high energy expenditure or high oxygen concentration needed, which can cause oxidative stress and impairment of hemoglobin cells). As a result, blood oxygenation was uneven and burdened with high oxidative stress.

In the previously known solution, blood in the oxygenator was passed perpendicularly to the direction of oxygen transport in the capillaries, which caused changes in oxygen concentrations and oxygenation was not linear but sinusoidal, because the active exchange surface was relatively smaller (step by step from one capillary to the other), which forced the use of a high oxygen concentration to achieve the same blood oxygenation effect as in the solution according to the present invention.

Claims (24)

1. A device for blood oxygenation, with a membrane made of an organic material with pore-forming, anti-inflammatory and anti-coagulant properties, containing a gas exchange chamber of elongated shape in the form of a straight cylinder or an elliptical cylinder, in the gas inlet base and the gas outlet base of which there are through holes, wherein on one side the gas exchange chamber is connected gas-tightly to a surge tank supplying a gas mixture containing oxygen to the chamber, having an inlet opening for the gas mixture from the installation supplying this mixture, and on the other side the gas exchange chamber is connected gas-tightly to a tank discharging the gas mixture from the chamber, having an outlet opening for the gas mixture, and inside the gas exchange chamber there is placed a membrane in the form of a bundle of capillaries, the ends of which are anchored on both sides in through holes in the outlet and inlet bases of the chamber, characterized in that the capillaries (8) are tensioned with a tensioning force of values from 1 to 100 N, preferably 10 N, and are parallel to the longitudinal axis of the chamber (1) and to each other, furthermore, in the side wall (9) of the chamber (1) near the outlet base (2) of the chamber (1), at least one blood stream inlet opening (10') is made, and in the side wall (9) of the chamber (1) near the inlet base (2') of the chamber (1), at least one blood stream outlet opening (10") is made, additionally, the device is equipped with a blood stream cooler - heating module system, built in such a way that a blood stream cooler (16) with parameters enabling its cooling by 0.5-3.5°C, preferably by 2°C, is connected to the blood stream inlet opening(s) (10') to the gas exchange chamber (1), and a blood stream heating module (17) is connected to the blood stream outlet opening(s) (10") from the gas exchange chamber (1) with parameters enabling it to be heated to the physiological temperature of blood, while the capillaries forming the membrane are in the form of tubes with an external diameter of 30 to 600 μm, preferably 100 μm, and are made of an organic material with pore-forming, anti-inflammatory and anticoagulant properties, semi-permeable, i.e. permeable to molecules of the gas mixture but impermeable to blood particles, consisting of: - a base in the form of polypropylene (PP) or polyurethane (PU) or polyethylene terephthalate (PET) or polycarbonate (PC) or polyoxymethylene (POM) or polysulfone (PSU) or silicone or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP) or a fluoropolymer, most preferably poly(tetrafluoroethylene) (PTFE), - 4-(diphenylamino)benzaldehyde admixture, in a base-admixture ratio of 50:1 to 5000:1, preferably 100:1, - a 1,3-indandione dopant in a base-dopant amount of 50:1 to 5000:1, preferably 100:1, and - a bivalirudin dopant incorporated into the microstructure of the base material, in a base-to-dopant ratio -admixture from 80:1 to 1200:1, preferably 150:1, - the membrane contains pores, of which 40 to 60% are open pores and the rest are closed pores, i.e. they are filled with the active substance in the form of bivalirudin. 2. A device for blood oxygenation, with a membrane made of an organic material with pore-forming, anti-inflammatory and anti-coagulant properties, containing a gas exchange chamber of elongated shape in the form of a straight cylinder or an elliptical cylinder, in the gas inlet base and the gas outlet base of which there are through holes, wherein on one side the gas exchange chamber is connected gas-tightly to a surge tank supplying a gas mixture containing oxygen to the chamber, having an inlet opening for the gas mixture from the installation supplying this mixture, and on the other side the gas exchange chamber is connected gas-tightly to a tank discharging the gas mixture from the chamber, having an outlet opening for the gas mixture, and inside the gas exchange chamber there is placed a membrane in the form of a bundle of capillaries, the ends of which are anchored on both sides in through holes in the outlet and inlet bases of the chamber, characterized in that the capillaries (8) are tensioned with a tensioning force of values from 1 to 100 N, preferably 10 N, and are spirally shaped, i.e. they are twisted along the longitudinal axis of the chamber (1) by a uniform angle in the range from 15 to 720 degrees, preferably by an angle from 90 to 360 degrees, furthermore, in the side wall (9) of the chamber (1) near the outlet base (2) of the chamber (1) there is made at least one blood stream inlet opening (10'), and in the side wall (9) of the chamber (1) near the inlet base (2') of the chamber (1) there is made at least one blood stream outflow opening (10"), additionally the device is equipped with a blood stream cooler - heating module system, built in such a way that a blood stream cooler (16) with parameters enabling its cooling by 0.5-3.5°C, preferably by 2°C, and a blood flow heating module (17) with parameters enabling its heating to the physiological temperature of blood is connected to the blood flow outlet opening(s) (10") from the gas exchange chamber (1), while the capillaries forming the membrane are in the form of tubes with an external diameter of 30 to 600 μm, preferably 100 μm, and are made of an organic material with pore-forming, anti-inflammatory and anti-coagulant properties, semi-permeable, i.e. permeable to the gas mixture molecules and impermeable to the blood particles, consisting of: - a base in the form of polypropylene (PP) or polyurethane (PU) or polyethylene terephthalate (PET) or polycarbonate (PC) or polyoxymethylene (POM) or polysulfone (PSU) or silicone or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP) or a fluoropolymer, most preferably poly(tetrafluoroethylene) (PTFE), - 4-(diphenylamino)benzaldehyde admixture, in a base-admixture ratio of 50:1 to 5000:1, preferably 100:1, - an admixture of 1,3-indandione in a base-dopant amount of 50:1 to 5000:1, preferably 100:1, and - an admixture of bivalirudin incorporated into the microstructure of the base material, in a base-dopant ratio of 80:1 to 1200:1, preferably 150:1, - the membrane contains pores, of which 40 to 60% are open pores and the rest are closed pores, i.e. they are filled with the active substance in the form of bivalirudin. 3. The device according to claim 1, characterized in that Peltier cells are used as a blood flow cooler. 4. The device according to claim 1, characterized in that Peltier cells are used as the blood flow heating module. 5. A device according to claim 1, characterized in that the holes (3) in the bases of the outlet (2) and inlet (2') chambers (1) are made at equal distances from each other, and at the same time the capillaries (8) anchored in these holes are also located at equal distances from each other. 6. A device according to claim 1, characterized in that a HEPA filter (11) is mounted on the outlet opening (7) from the tank (6) discharging the gas mixture. 7. A device according to claim 1, characterized in that the blood flow inlet opening (10') and the blood flow outlet opening (10") are made at a distance of no more than 5 mm from the given base of the chamber (1). 8. A device according to claim 1, characterized in that the blood flow inlet opening (10') is made on the opposite side of the chamber than the blood flow outlet opening (10"), symmetrically with respect to the centre of symmetry of the chamber (1). 9. The device according to claim 2, characterized in that Peltier cells are used as a blood flow cooler. 10. The device according to claim 2, characterized in that Peltier cells are used as the blood flow heating module. 11. A device according to claim 2, characterized in that the holes (3) in the bases of the outlet (2) and inlet (2') chambers (1) are made at equal distances from each other, and at the same time the capillaries (8) anchored in these holes are also located at equal distances from each other. 12. A device according to claim 2, characterized in that a HEPA filter (11) is mounted on the outlet opening (7) from the tank (6) discharging the gas mixture. 13. A device according to claim 2, characterized in that the blood flow inlet opening (10') and the blood flow outlet opening (10") are made at a distance of no more than 5 mm from the given base of the chamber (1). 14. A device according to claim 2, characterized in that the blood flow inlet opening (10') is made on the opposite side of the chamber than the blood flow outlet opening (10"), symmetrically with respect to the centre of symmetry of the chamber (1). 15. A device according to claim 1, characterized in that on the inner surface of the chamber (1), along its entire length, at least two blood flow guides (12) are mounted symmetrically with respect to the axis of symmetry of the chamber, in the form of elongated notches, most preferably with a triangular or nearly triangular cross-section, which are parallel to the longitudinal axis of the chamber (1). 16. A device according to claim 2, characterized in that on the inner surface of the chamber (1), along its entire length, at least two blood flow guides (12) are mounted symmetrically with respect to the axis of symmetry of the chamber, in the form of elongated notches, most preferably with a triangular or close to triangular cross-section, which are arranged in a spiral manner, i.e. they are twisted along the longitudinal axis of the chamber (1) by an identical angle in the range from 15 to 720 degrees, preferably by an angle equal to the angle of twist of the capillaries (8). 17. A device according to claim 1, characterized in that a densely woven mesh (13) made of fibres, preferably made of a material identical to the material of the capillaries (8), is attached to the blood flow drainage opening (10"), so that the mesh openings are 15 to 100 μm, preferably 38 μm, parallel to the plane of the opening on which it is attached. 18. A device according to claim 1, characterized in that a densely woven mesh (13) made of fibres, preferably made of a material identical to the material of the capillaries (8), is attached to the blood flow inlet opening (10'), so that the mesh openings are 15 to 100 μm, preferably 38 μm, parallel to the plane of the opening on which it is attached. 19. A device according to claim 1, characterized in that at least one clot filter module (14), preferably two parallel clot filter modules (14) with a bypass (splitter) for smooth switching, i.e. directing the blood flow alternately through one or the other clot filter module (14), is installed on the outlet channel from the blood outlet opening (10") of the gas exchange chamber (1), wherein in the present variant with the clot filter module/modules (14), the blood flow heating module (17) is installed before or, more preferably, after the clot filter module/modules (14). 20. A device according to claim 1, characterized in that at least one module (15) with a clot filter, preferably two parallel modules (15) with clot filters with a bypass (splitter) for smooth switching, i.e. directing the blood flow alternately through one or the other module with a clot filter, is installed in front of the cooler (16) of the blood flow which is then introduced through the blood flow inlet opening (10') into the gas exchange chamber (1). 21. A device according to claim 2, characterized in that a densely woven mesh (13) made of fibres, preferably made of a material identical to the material of the capillaries (8), is attached to the blood flow drainage opening (10"), so that the mesh openings are 15 to 100 μm, preferably 38 μm, parallel to the plane of the opening on which it is attached. 22. A device according to claim 2, characterized in that a densely woven mesh (13) made of fibres, preferably made of a material identical to the material of the capillaries (8), is attached to the blood flow inlet opening (10'), so that the mesh openings are 15 to 100 μm, preferably 38 μm, parallel to the plane of the opening on which it is attached. 23. A device according to claim 2, characterized in that at least one clot filter module (14), preferably two parallel clot filter modules (14) with a bypass (splitter) for smooth switching, i.e. directing the blood flow alternately through one or the other clot filter module (14), is installed on the outlet channel from the blood outlet opening (10") of the gas exchange chamber (1), wherein in the present variant with the clot filter module/modules (14), the blood flow heating module (17) is installed before or, more preferably, after the clot filter module/modules (14). 24. A device according to claim 2, characterized in that at least one module (15) with a clot filter, preferably two parallel modules (15) with clot filters with a bypass (splitter) for smooth switching, i.e. directing the blood flow alternately through one or the other module with a clot filter, is installed in front of the cooler (16) of the blood flow which is then introduced through the blood flow inlet opening (10') into the gas exchange chamber (1).