PL247990B1 - 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 oxygenating blood (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 (3), wherein on one side the chamber (1) is gas-tightly connected to a compensation 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 gas-tightly connected 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 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 the blood particles, the ends of which are anchored on both sides in the through holes (3) in the bases (2, 2') of the capillary chamber (1). (8) are tensioned with 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 they are spirally shaped, i.e. they are twisted along the longitudinal axis of the chamber (1) by the same 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 of 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 a fluoropolymer, preferably poly(tetrafluoroethylene) (PTFE, Teflon) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP), and - argatroban admixture incorporated into the microstructure of the base material, in a base-admixture ratio from 80 ÷ 1 to 1200 ÷ 1.

Description

Description of the invention

The invention concerns a device for extracorporeal blood oxygenation (blood oxygenator) with a membrane made of an organic material with pore-forming, anti-inflammatory, and anticoagulant properties. Extracorporeal blood oxygenation is used in conditions where potentially reversible, profound pulmonary dysfunction occurs to a degree that prevents effective gas exchange through mechanical ventilation.

The oxygenator functions 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, with oxygen supplied to the oxygenator chamber replacing carbon dioxide in the blood.

An oxygenator is a device constructed of a large number of thin tubes between which blood flows. The tube walls are a semipermeable membrane, allowing gases—oxygen and carbon dioxide—to pass through, but not blood molecules. Inside the tubes (called capillaries) is a space filled with a gas mixture, the concentration of which can be adjusted depending on needs. As blood flows between the capillaries, it releases carbon dioxide and absorbs oxygen molecules—a process that normally occurs in the lungs.

Blood oxygenation devices and the materials used in them are known from the state of the art.

For example, two oxygenators using a perpendicular blood flow to the gas mixture flow are described in a comparative analysis by Wang et al. (2016), which concluded that the Quadrox-i Adult oxygenator is characterized by low resistance and high biocompatibility, with lower pressure drop and lower hemodynamic energy consumption. In contrast, the Capiox RX25 oxygenator demonstrated a lower risk of gaseous microemboli (GME) in clinical settings. This demonstrates the need for design optimization to improve therapy safety. Thousands of GME are delivered to the circulatory system during ECMO (ExtraCorporeal Membrane Oxygenation) therapy despite the use of a membrane oxygenator and arterial filtration. GME causes tissue ischemia and damage to the vascular endothelium in the brain and other end organs, leading to vasodilation, increased permeability, platelet activation, the coagulation cascade, and activation of complement and cellular inflammatory mediators. Current technologies only partially eliminate GME. It is desirable to develop systems that eliminate GME formation while maintaining good gas exchange parameters [Wang S, Kunselman AR, ϋndar 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 demonstrated optimal performance without plasma leakage or the need for ECMO replacement for more than four days in adult patients with cardiogenic shock. The study used ECMO consisting of a membrane oxygenator with blood flow perpendicular to the gas mixture flow, the material of which was modified with polymethylpentene, and a magnetic centrifugal pump. Preliminary observations indicate that such a device with a modified membrane could function properly for up to two weeks. Further modifications to the oxygenator membranes could extend the life of these devices [Formica F, Avalli L, Martino A, et al. Extracorporeal membrane oxygenation with a poly-methylpentene oxygenator (Quadrox D). The experience of a single Italian center in adult patients with refractory cardiogenic shock. ASAIO J. 2008;54(l):89-94. doi: 10.1097/MAT. 0b013e31815ff27e].

Clingan et al. (2016) continued the study pioneered by Gipson et al. (2014). They used hypobaric oxygenation to achieve a mild hypoxic state in Terumo® FX15 oxygenators. Hypobaric oxygenation may reduce the risks associated with GME production 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 have been 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 oxygenation. 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. doklO.l 177/0267659113475694].

Patent description US4008047 describes a solution in which ethylcellulose is subjected to fluoroacylation, which 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, analysis, and purification devices, and so on. Using this material in membrane construction helps mitigate problems with clotting and sterilization resistance, but only until the surface layer wears out. Once the surface layer is abraded, its beneficial properties are lost, which is one of the drawbacks of this solution.

Membranes composed of hollow fibers (capillaries, tubes) are also known. Patent No. WO9534373 describes such semipermeable hollow fiber membranes characterized by having monofilament spacer members spirally arranged or formed on their outer surface. This invention also describes extracorporeal blood treatment devices incorporating such improved membranes.

Oxygenators for organic fluids are also known that can be used, in particular, to oxygenate blood flowing in an extracorporeal circuit, without creating zones in which the fluid flow slows down and stops, causing aggregates, clots and a significant reduction in the oxygenation capacity. From patent description No. US2020016312, a solution is known in that the oxygenator comprises 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; Fluid-impermeable and gas-porous hollow fibers designed to allow contact with the organic fluid and positioned within the oxygenation chamber in a common parallel direction of dynamic distribution means supported in the pre-distribution chamber by supporting means. Advantages of the invention include: a favorable ratio between overall size and oxygenation capacity; it prevents slowing of the flow of organic fluids and the consequent formation of accumulations and clots; it prevents crushing of the hollow fiber skeins by maintaining intact usable transition sections and keeping all surfaces of each individual hollow fiber perfectly permeable and usable, even when a large number of hollow fibers are used per unit volume.

Patent No. US2020129687 also discloses an oxygenator comprising a housing and a membrane assembly disposed within 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 arranged concentrically about the central axis. The membrane assembly is disposed within 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 arranged concentrically about the first zone, and the zones are fluidly open to each other along the body of the plurality of gas exchange elements and fluidly separated from each other along the distal end. The first zone is configured to fluidly communicate with an oxygen source, and the second zone is configured to fluidly communicate with a vacuum source. The blood flow path comprises a substantially radial flow through the first zone to add oxygen to the blood and the second zone to separate gas microemboli from the blood through the plurality of gas exchange elements.

Patent description No. US2020108194 discloses an oxygenator with an integrated air removal system, the bubbles of which could lead to embolism. The oxygenator comprises 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 comprises a gas exchange portion disposed along the blood flow path; a heat exchange portion disposed along the blood flow path upstream of the gas exchange portion; and one or more porous hollow fibers arranged perpendicular to the blood flow path upstream of the heat exchange portion.

Patent US4722829A discloses a blood oxygenation device, dialyzer, heat exchanger, or 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 positioned between them. A plurality of parallel tubes pass through the central chamber, connecting the inlet and outlet chambers, creating passageways for the flow of the working medium between them. The outer surface of each tube is shaped like a series of rounded petals connected end-to-end. Furthermore, adjacent tubes are offset relative to each other to allow for tight and orderly packing of their petals. The treatment medium, such as oxygen, flows through the tubes, while the treatment medium, such as 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.

CN208893292 describes an integrated membrane oxygenator with a spiral flow path, consisting of a lower cover, an oxygenation section, and an upper cover. The oxygenation section is located on the lower cover and consists of a stem structure, an oxygenation shell, and a membrane structure with an oxygenation tube. The oxygenation shell is equipped with a blood outlet tube, and the blood outlet tube is located near the lower cover. The upper cover is located on the oxygenation section and is equipped with a blood inlet tube and an oxygen inlet tube. This is a multi-layer design, where the capillaries are arranged in a ring along the longitudinal axis and at 45 degrees to their own axes, every other band on the ring.

The flow concept disclosed in CN107638601 is similar to that contained in CN208893292. The invention CN107638601 relates to a membrane structure and a membrane-type oxygenator. The membrane structure comprises 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, each first layer of hollow fibers and each second layer of hollow fibers being provided with a plurality of tubular hollow fibers arranged omnidirectionally.

The membrane structure can effectively reduce the pre-charge volume of blood and lower blood pressure to avoid blood damage. Blood transfusion can be achieved by forming a thin blood film, increasing the contact area between blood and oxygen, and improving the efficiency of blood and oxygenation.

Patent specification WO2015095334A1 discloses a partial radial heat exchanger and oxygenator. This design incorporates a plurality of capillary tubes, each terminating at opposite first and second ends, each extending around a core along an arc angle of less than 360 degrees. The oxygenation bundle is formed as part of the core assembly and includes a plurality of gas-exchange fibers. The core assembly is housed in a housing having a blood inlet and outlet. In WO2015095334A1, a kind of rope-like braiding of capillaries is used around the core.

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

Many known blood oxygenation systems are constructed using capillary membranes arranged parallel to each other but perpendicular to the direction of blood flow, or intersecting at a 90° angle but arranged in a plane perpendicular to the direction of blood flow in the device, creating a capillary layer. A gas mixture with oxygen flows through the capillaries. The capillaries are separated and stabilized using spacers in the form of a fiber or mesh arrangement, most often made of polyolefin, layered between the membrane (capillary) systems. Additionally, each capillary layer can be separated from adjacent capillary layers by a spacer layer composed of fibers in a dense mesh. Blood is passed through such a system perpendicular to the longitudinal axis of the capillaries (membranes), i.e., perpendicular to the direction of flow of the gas-oxygen mixture in the capillaries. This system has numerous disadvantages, the most important of which are:

- to effectively transfer oxygen to blood particles, a relatively high pressure of the gas mixture containing up to 100% oxygen is required, 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 reduces the efficiency of gas exchange.

The weaknesses of existing solutions include the fact that the shape and positioning of the tubular (capillary) membranes used in them can affect clotting in certain components and can also cause hemolysis of blood cells. Membrane designs sometimes incorporate spacers between capillaries, which maintain the capillaries in their initial positions. However, these spacers disrupt the laminarity of blood flow and create turbulent flow, thus promoting the formation of clots and microemboli. Clotting can lead to infections and organ failure, particularly kidney failure.

Patients with acute respiratory distress syndrome (ARDS) are typically aggressively mechanically ventilated prior to the initiation of ECMO, requiring high-pressure ventilation. Despite the use of a lung-conserving ventilation protocol, the airway pressure required to maintain lung ventilation can damage unaffected alveolar areas. This leads to barotrauma, which is responsible for further secondary lung damage. Furthermore, severe respiratory distress also requires the use of high oxygen concentrations for adequate tissue oxygenation. The degree of respiratory distress is associated with the need to administer high oxygen concentrations, even close to 100%, during mechanical ventilation. Such high oxygen concentrations, through reflex action and increased nitrogen reabsorption from the lungs, exacerbate existing atelectasis and further impair gas exchange. High oxygen concentrations in the respiratory mixture also lead to direct damage to type II pneumocytes in the alveoli. This results in a progressive deficiency of surfactant, a substance that coats the inner surface of the alveoli and prevents their collapse. In states of surfactant deficiency, the areas of the lung affected by atelectasis expand and gas exchange disorders deepen. Furthermore, a factor that exacerbates gas exchange problems, clinically significant in diseases affecting the majority of the interstitial lung tissue, is physiological hypoxemic constriction of the pulmonary vasculature and bronchioles. This is beneficial in processes that damage the lungs locally, but in cases of generalized hypoxemia, it exacerbates the symptoms of hypoxia.

These unfavorable phenomena associated with a high, nearly 100% oxygen content in the gas mixture can also occur during extracorporeal membrane oxygenation (ECMO). The need to use a gas mixture with nearly 100% oxygen content delivered to the oxygenator stems 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 area of the membrane is much smaller than that of the lungs. The surface area of the alveolar capillaries in the lungs is approximately 70-100 ^m² , which is much larger than that of the membranes currently used in ECMO. Oxygen exchange across 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 nearly 100% oxygen content is delivered to the oxygenator. Nearly pure oxygen, often used in venovenous or venoarterial ECMO therapy, comes into contact with blood cells, leading to oxidative stress and damage to the cell membranes of circulating red blood cells. This leads to the breakdown of red blood cells, releasing heme compounds into the bloodstream. Hemolysis leads to anemia in treated patients.

Other blood cells are also subjected to similar harmful effects of high oxygen concentrations. Damage to the cell membranes of leukocytes and platelets will result in impaired cellular immunity and a decline in the body's ability to defend against bacterial and fungal infections, as well as the induction of a generalized inflammatory response and the secretion of prothrombotic factors. This deterioration of cellular immunity and impaired immune function impacts the effectiveness of treatment for severe pneumonia and sepsis, which are the main indications for venovenous ECMO. Furthermore, a patient's immune impairment leads to infections associated with hospitalization: infections of the vascular bed, hematogenous pneumonia, and skin infections at the site of drain insertion. Infections during therapy are the second most common complication of ECMO therapy. The occurrence of infections therefore impacts the final outcome of treatment. This necessitates more frequent and prolonged use of broad-spectrum antibiotic therapy, leading to the development of antibiotic-resistant bacterial strains.

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

Therefore, it has become clinically important to develop a device design that allows for more effective oxygenation and carbon dioxide elimination at less than 100% oxygen concentrations at the point where circulating blood is oxygenated in the oxygenator. The basis for introducing design changes to previously known devices is based on physiological phenomena and the observed adaptive mechanisms of healthy lungs.

Physiologically, under conditions of basal metabolism, blood flows through the pulmonary bed at a rate of approximately 6 L/min. Under conditions of increased oxygen demand, such as physical exertion or hypermetabolism, such as that occurring during sepsis, oxygen demand increases significantly, which increases cardiac output and pulmonary ventilation. This allows for a two- to three-fold increase in blood flow through the pulmonary bed, shortening the time spent by red blood cells in the pulmonary capillaries by approximately 70%. This, thanks to pulmonary capillary dilation and increased cardiac output, occurs without affecting blood oxygenation (hemoglobin oxygen saturation) and pulmonary bed pressure (under physiological conditions, hemoglobin is fully oxygenated after the red blood cell has passed one-third 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 oxygen concentration in the gas mixture used in the oxygenator.

Merely extending the capillary length to increase the contact time of the erythrocyte with the capillary filled with the gas mixture is not a good solution, however. This may lead to technical complications during production and later during device use, particularly those related to maintaining the desired parallelism and spacing between the capillaries. It may also increase the likelihood of clotting of the flowing blood. Therefore, given that capillaries cannot be excessively extended and their length may still be insufficient for effective gas exchange between the gas mixture flowing through them and the blood surrounding them, further exploration of ideas for increasing the efficiency of this exchange has become desirable.

The authors of this invention proposed such a solution. They employed a mechanism that ensures the transport of blood flow parallel to the transport of the gas mixture in the capillaries, either in the same direction as the blood or, more preferably, in the opposite direction. This mechanism allows for more efficient gas exchange, as the ease of gas exchange increases, and the resulting oxygen gradient allows for gradual red blood cell oxygenation. Combining the mechanisms in the countercurrent variant, which is advantageous, i.e., extending the actual active gas exchange pathway, and the countercurrent mechanism will significantly reduce the required pressure of the gas mixture. Based on pathophysiological and cellular mechanisms, this should reduce the risk of numerous complications and improve treatment outcomes.

An additional challenge that needed to be addressed was the selection of appropriate materials for the individual oxygenator components, especially their most important element, the membrane used for gas exchange with blood. Such materials should be characterized primarily by semipermeability—that is, they must be permeable to gaseous molecules but impermeable to blood particles. However, additional parameters are desirable to improve their performance.

The state of the art includes materials with pore-forming properties used to produce selective membranes, meaning they only allow particles of a specific size to pass through. Such materials are used to produce membranes for use in the production of tents, jackets, filters, and osmotic membranes, including oxygenators for blood oxygenation.

The most popular, technologically advanced - in non-medical applications - pore-forming material (used, for example, in 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, membranes are known from the prior art, including porous membranes used in equipment in direct contact with body fluids, made of various materials.

For example, patent description PL225257 describes a membrane system for local immobilization of eukaryotic cells, comprising a support and at least one bilayer composed of a polyelectrolyte layer comprising polysaccharide hydrogels, particularly sodium alginate containing incorporated fullerenol and protein A. 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 a second polymer layer composed 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, allowing for isolation of eukaryotic cells from the external environment, particularly microorganisms, while not restricting 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 for modifying microporous polyolefin membranes intended for the isolation of Gram (+) bacteria, which consists in introducing a solution of a polycation selected from the group consisting of aliphatic amino acids, especially proteinaceous ones, preferably polar and dissolved in a NaCl solution, into the structure of a polyolefin membrane with high porosity in a known manner, and then introducing 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 into the structure of the membrane in a known manner, preferably by soaking.

Patent description PL197199 also describes a polymeric proton-conducting membrane based on hydrated poly(perfluorosulfonic acid), characterized in that it is a product of a 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 producing a multi-layer 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, each of which is mixed with a liquid lubricant.

Patent EP0409496 describes a process for obtaining microporous membranes containing at least partially crystalline aromatic polymers containing ether or thioether and ketone bonds in the chain. The process allows for the production of membranes from certain high-melting aromatic polymers, for example PEDK.

The materials used to construct the membranes known from the solutions mentioned above allow for steric reasons to be used for blood oxygenation. However, their significant biochemical limitations significantly limit this application. Furthermore, due to their structure, they are characterized by a developed surface topography on a micrometric scale, which led to their negative impact on living organisms. At the cellular level, these membranes cause steric damage to cell membranes, resulting in cell destabilization. Furthermore, the membranes cannot inhibit clot formation and do not protect against bacterial biofilm formation.

To date, polypropylene (PP) and polyurethane (PU) have been primarily used as pore-forming materials in medical applications. For example, in devices used in the blood oxygenation process, polyurethane was used as the porous material for membrane construction, and polypropylene was used for the elements separating membrane layers (spacers). Despite the high efficiency of such membranes in terms of gas exchange, they have weaknesses primarily related to inflammation resulting from the low bioinertia of these materials, which led to the formation of clots on the membrane surface, which gradually grew. In this case, to maintain blood oxygenation efficiency, the oxygen concentration must be increased, which in turn causes oxidative stress and intensifies the clotting process, triggering an unfavorable cascade, i.e., a gradual increase in unfavorable factors, as the oxygen concentration must be continually increased to maintain blood saturation levels, which increases oxidative stress and intensifies clotting. After exceeding a certain threshold, the amount of clots is so great 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 reduce 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 in the art. Among them is argatroban, a synthetic analogue of hirudin, which is a small-molecule direct thrombin inhibitor (DTI) used for antithrombotic treatment in patients with heparin-induced thrombocytopenia type II who require parenteral anticoagulant therapy. The primary mechanism of action of DTIs involves blocking the active site of thrombin, while the secondary mechanism involves inhibiting the fibrin binding site, where the substrate is recognized and properly oriented. The action of these inhibitors is direct and independent of the presence of antithrombin. Unlike indirect DTIs, they can inhibit thrombin bound to fibrin.

So far, however, there are no known oxygenators with membranes made of materials with pore-forming, anti-inflammatory and anticoagulant properties, containing immobilized argatroban in their composition, semi-permeable to gases, and their development has become an additional goal of the authors 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 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 stressed 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, in the side wall of the chamber near the outlet base of the chamber there is at least one blood stream inlet opening, and in the side wall of the chamber near the inlet base of the chamber there is at least one blood stream outflow opening, additionally the device is equipped with a cooler - blood stream heating module system, built in such a way that to the blood stream inlet opening/openings to the gas exchange chamber there is connected a blood stream cooler with parameters enabling its cooling by 0.5-3.5°C, preferably by 2°C, and to the blood stream outflow opening/openings from the gas exchange chamber there is connected a blood stream heating module with parameters enabling its heating to the physiological blood temperature, while the capillaries forming the membrane are in 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 molecules of the gas mixture and impermeable to blood particles, consisting of:

- a base in the form of a fluoropolymer, most preferably poly(tetrafluoroethylene) (PTFE, Teflon), or polyvinylidene fluoride (PVDF), or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP), and

- an argatroban admixture incorporated into the microstructure of the base material, in a base-to-admixture ratio of 80+1 to 1200+1, preferably 150+1. The membrane contains pores, of which 40% to 60% are open (unfilled), and the remaining pores are closed, meaning they are filled with the active substance argatroban. As the membrane is used, argatroban is gradually released, which leads to its wear and tear. The total amount of argatroban decreases while the number of open pores increases, resulting in a larger gas exchange surface, i.e., better oxygenation. New pores also form, taking over the gas exchange function from open pores that may have been blocked by gradually forming clots or biofilm formation 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 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 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 stressed 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, in the side wall of the chamber near the outlet base of the chamber there is at least one blood stream inlet opening, and in the side wall of the chamber near the inlet base of the chamber there is at least one blood stream outflow opening, additionally the device is equipped with a cooler - blood stream 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 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 molecules of the gas mixture and impermeable to blood particles, consisting of:

- a base in the form of a fluoropolymer, most preferably poly(tetrafluoroethylene) (PTFE, Teflon), or polyvinylidene fluoride (PVDF), or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP), and

- an argatroban admixture incorporated into the microstructure of the base material, in a base-to-admixture ratio of 80+1 to 1200+1, preferably 150+1. The membrane contains pores, of which 40% to 60% are open (unfilled), and the remaining pores are closed, meaning they are filled with the active substance argatroban. As the membrane is used, argatroban is gradually released, which leads to its wear and tear. The total amount of argatroban decreases while the number of open pores increases, resulting in a larger gas exchange surface, i.e., better oxygenation. New pores also form, taking over the gas exchange function from open pores that may have been blocked by gradually forming clots or biofilm formation 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, thus causing the capillaries to twist by the planned angle, while ensuring that the capillary tension remains at the planned level that does not cause damage to 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 the blood to reach physiological temperature.

Preferably, the opening(s) located near the base of the chamber on the side of the tank discharging the gas mixture constitutes the blood stream inlet, while the opening(s) located near the base of the chamber on the side of the equalizing tank supplying the gas mixture constitutes the blood stream outlet. This advantageous arrangement of the blood stream inlet and outlet openings ensures blood flow in a countercurrent direction to the flow of the gas mixture, and thus optimally utilizes the technical capabilities of the solution, i.e., maximum blood oxygen saturation with minimal external pressure of the gas mixture.

By applying the appropriate tension force to the capillaries, there is no need for spacers (spacers) between them to ensure their stability. Such spacers would disrupt the laminarity of blood flow and limit the active surface area for gas exchange. Appropriate capillary tension ensures the stability of each capillary position, preventing the viscoelastic effect of the capillaries (their tremors) during blood flow. Capillary tremors are unfavorable because they disrupt the laminarity of the blood flow.

The equalizing tank allows for maintaining 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 the pressure at the inlet of the remaining capillaries to increase, 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 spaced equidistantly, and the capillaries anchored in these holes are also spaced equidistantly. This capillary arrangement ensures near-perfect laminarity of blood flow. This is an advantage over solutions that required spacers to maintain a constant distance between the hollow fiber tubes (capillaries).

Preferably, a HEPA filter is installed on the outlet opening 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 made at a distance of no more than 5 mm from the given base of the chamber.

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

Preferably, 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 preferably with a triangular or close to triangular cross-section, which are parallel to the longitudinal axis of the chamber.

Preferably, in the variant with spirally shaped capillaries, at least two blood flow guides in the form of elongated notches, preferably triangular or near-triangular in cross-section, are mounted on the internal surface of the chamber along its entire length, symmetrically relative to the chamber's axis of symmetry. These guides are arranged helically, meaning they are twisted along the chamber's longitudinal axis by a uniform angle ranging from 15 to 720 degrees, preferably by an angle equal to the capillary twist angle. This guide arrangement forces the desired direction—in the preferred variant, swirl—of the blood flow, while not disturbing the laminarity of its flow.

Preferably, a densely woven fiber mesh, preferably made of a material identical to the material of the capillaries, is mounted on the blood flow outflow opening, so that the mesh mesh has a side of 15 to 100, preferably 38 μm, parallel to the plane of the opening on which it is mounted.

Preferably, a densely woven fiber mesh is mounted on the blood flow inlet opening, preferably made of a material identical to the material of the capillaries, so that the mesh mesh has a side of 15 to 100, preferably 38 μm, parallel to the plane of the opening on which it is mounted.

This mesh acts as a filter that significantly increases protection against the ingress of potential clots. The anticoagulant contained in the mesh can, advantageously, lead to the spontaneous dissolution of clots on the mesh surface. This will act as an automatic mechanism for cleaning the clot filter, which will, in the long run, prevent clots from clogging the device and preventing clots from entering downstream systems.

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

Preferably, at least one clot filter module, preferably two parallel clot filter modules with a bypass (splitter), is installed upstream of the blood flow cooler, which is then introduced into the gas exchange chamber through the blood flow inlet. This solution allows the blood flow to be directed solely through one clot filter module, which is currently the working module, while the other is passive and can be replaced without having to stop the blood flow.

In the variant with spirally shaped capillaries, the gas exchange chamber is a vortex chamber, resulting from the capillaries being twisted at an appropriate angle and the advantageous spiral shape of the blood flow guides located on the chamber's internal walls. Ensuring a vortex flow of the blood stream extends the active path and the residence time of the blood in the chamber, which in turn extends the duration and efficiency of gas exchange while maintaining the minimized size of the entire device and minimizes the volume of blood that is extracorporeal during the oxygenation process. Centrifugal force separates the gas exchanges. Heavy particles are pushed outward, i.e., towards the chamber walls, while light particles are located in the center of the blood stream, thus increasing the efficiency of gas exchange by minimizing multidirectional exchange.

The proposed approach is to use fibers arranged longitudinally in the blood flow plane, interwoven to maximize the active surface area of the blood-fiber interface. This allows for more laminar blood flow, while the spiral fiber arrangement will result in improved diffusion and more efficient exchange of oxygen and carbon dioxide along the concentration gradient. During fabrication, it is recommended to arrange the fibers parallel to each other along the longitudinal axis of the flow, then immobilize them in bases and twist the bases relative to each other by an angle between 90 and 360 degrees. This twist will create a vortex channel, which is beneficial in terms of both laminar flow and exchange efficiency. This arrangement will enable the use of lower oxygen pressure, or even a system with reduced oxygen concentration, which will also reduce oxidative stress, which in turn leads to, among other things, less blood clotting on the membrane fibers.

In the proposed solution, a blood cooler is installed before the gas exchange chamber where the patient's blood is oxygenated in ECMO, i.e., on the blood inlet channel to the gas exchange chamber. This allows for cooling of the blood by 0.5-3.5°C, preferably by 2°C. These conditions will be maintained throughout the oxygenation process. Lowering the blood stream temperature before oxygenation will positively impact hemoglobin oxygen saturation by increasing the solubility of gases in the aqueous environment. This solution will shift the hemoglobin dissociation curve to the left, thus allowing for a colder FiO2 in the gas mixture fed to the oxygenator. This will eliminate the need for high oxygen concentrations, sometimes even close to 100%. The oxygen content in the mixture can be reduced to as low as 21%. This will minimize the risk of negative effects related to oxidative stress and damage to the cell membranes of blood cells. After the oxygenation process, the patient's blood will be warmed back to physiological temperature. 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 upstream of the oxygenator, additionally protects against increased blood pressure in the system 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 toxic to cells and do not cause pathogenic reactions in cells.

A membrane made of the described materials protects against the formation of biofilm (no bacterial plaque is formed 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 construct the membrane in the invention achieve the desired technical result. The most advantageous material is poly(tetrafluoroethylene) (PTFE), which has many advantages as a material for manufacturing 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 from this material do not degrade or change their properties, which could be harmful to tissues 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 moisture-free material, meaning it does not absorb water, which is beneficial in the event of contact with blood. Furthermore, PTFE has low adhesion to viscoelastic bodies, reducing the risk of clots sticking to the surface.

The chemical structure of the macromolecules of the membrane materials used in the device according to the invention influences their excellent pore-forming properties while also ensuring their biocompatibility and bioinertness. Oxygenators limit the risk of inducing cellular and humoral inflammatory mediators, which in turn slows down the clotting process on the membrane. This reduces the risk of secondary multi-organ damage.

The release capacity of the active agent (argatroban) from the membrane used in the device according to the invention was tested in a conventional flow-through vessel using a constant volume of a polar solvent in the form of 18.2 MΩ ultrapure water. The membrane was immersed in the solvent for 30 minutes. The solvent was then collected and injected into the flow-through vessel, observing changes in the natural frequency of a disk in the form of a quartz resonator with an electrode attached, according to the Sauerbrey relationship, which relates vibration change to mass change. The disk was positioned so that any sedimentation of the analyte from the solvent would not distort the results through gravitational settling on the disk. The disk's positioning ensured 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 determined, which was deposited on the electrode. This indicates that during the membrane's immersion 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 active agent release from the membrane.

The use of immobilized argatroban allows for maintaining a constant concentration of argatroban on the contact surface of the part throughout the entire life of the materials (programmed product life). The potential for excessive argatroban leaching is minimized, and due to the diffusion-controlled argatroban release process, its contact concentration on the product surface remains constant.

The incorporation of argatroban into the membrane material also imparts desirable antithrombotic and anti-inflammatory properties. As noted above, argatroban has a strong antithrombotic effect and, due to its effect on lipids through lipase activation, is also used as an antithrombotic agent in antithrombotic coatings. The argatroban admixture is incorporated into both the material's pores and the microcracks that arise as equilibrium defects during the material's formation. This significantly improves the surface integrity of the material's structure, thus preventing organic material from accumulating in the pores and microcracks, and significantly reduces clotting.

The subject of the invention is explained in more detail in the following examples of embodiments 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 a device for blood oxygenation in an axonometric projection, fig. 2 - a device for blood oxygenation in a side view, from the side of the blood stream inlet opening, fig. 3 - a device for blood oxygenation in a side view, from the side of the blood stream outlet opening, fig. 4 - a device for blood oxygenation in an axonometric projection, in a view after connecting the blood heating module, fig. 5 - a device for blood oxygenation in an axonometric projection, in a view after connecting the cooler, fig. 6 - a device for blood oxygenation in an axonometric projection, in a cross-section (after subtracting 7 - blood oxygenation device in an axonometric view, 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 - 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 - 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 - blood oxygenation device in an axonometric view, in a variant with a clot filter module installed, with a clot filter, both on the inlet and outlet side of the blood stream, and with a cooler and a blood heating module installed, while Fig. 11 - a blood oxygenation device in a side view, in a variant with a clot filter module installed in front of the blood inlet opening to the chamber, Fig. 12 shows the blood oxygenation device in an axonometric projection, Fig. 13 - a blood oxygenation device in a side view, from the side of the blood stream inlet opening, while Fig. 14 - a blood oxygenation device in an axonometric projection, in cross-section (after subtracting the equalizing tank), with the base of the gas exchange chamber shown from the side of the gas mixture stream inlet.

Example 1

A device for blood oxygenation comprising a gas exchange chamber 1 of elongated shape in the form of a straight cylinder, in the bases of which the outlet 2 and inlet 2' are provided with passage openings 3, wherein on one side the chamber 1 is gas-tightly connected to a compensation tank 4 supplying a gas mixture containing oxygen to the chamber 1, having an inlet opening 5 for the gas mixture from the installation supplying this mixture, and on the other side the chamber 1 is gas-tightly connected to a tank 6 discharging the gas mixture from the chamber 1, having an outlet opening 7 for the gas mixture. Inside the chamber 1 there is 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 outer diameter of 600 μm made of a porous semi-permeable material, i.e. permeable to molecules of the gas mixture but impermeable to blood particles. The material consists of a PTFE base and an argatroban admixture incorporated into the microstructure of the base material in a base-to-admixture ratio of 1200:1. The membrane contains pores, 40% of which are open pores, and the remaining are closed pores filled with the active substance argatroban. 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 the same 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, on 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, on 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 orifice, symmetrically to the center of symmetry of ventricle 1.

The holes 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 holes 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 tank discharging the gas mixture 6.

On the internal surface of the chamber, along its entire length, two blood flow guides 12 are mounted symmetrically with respect 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 equal 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 outflow opening, so that the mesh openings are 38 μm in diameter, 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

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

Moreover, in front of the cooler 16 of the blood stream 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 stream alternately through one or the other module with a clot filter.

Example 3

A device for blood oxygenation comprising a gas exchange chamber 1 of elongated shape in the form of an elliptical cylinder, in the bases of which the outlet 2 and inlet 2' are provided with passage openings 3, wherein on one side the chamber 1 is gas-tightly connected to a compensation tank 4 supplying a gas mixture containing oxygen to the chamber 1, having an inlet opening 5 for the gas mixture from the installation supplying this mixture, and on the other side the chamber 1 is gas-tightly connected to a tank 6 discharging the gas mixture from the chamber 1, having an outlet opening 7 for the gas mixture. Inside the chamber 1 there is 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 outer diameter of 30 μm made of a porous semi-permeable material, i.e. permeable to molecules of the gas mixture but impermeable to blood particles. The material consists of a PTFE base and an argatroban admixture incorporated into the microstructure of the base material in a base-to-admixture ratio of 80:1. The membrane contains pores, 40% of which are open pores, and the remaining are closed pores filled with the active substance in the form of argatroban. The ends of capillaries 8 are anchored (fixed) on both sides in through holes 3 in the bases of the outlet 2 and inlet 2' of chamber 1, and capillaries 8 are spirally shaped, i.e., twisted along the longitudinal axis of chamber 1 by a uniform angle of 90 degrees and tensioned with a tension force of 10 N.

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

The holes 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 holes 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 tank discharging the gas mixture 6.

On the internal surface of the chamber, along its entire length, two blood flow guides 12 are mounted symmetrically with respect 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 equal angle equal to the angle of twist of the capillaries 8.

A densely woven mesh 13 made of fibers made of a material identical to the material of the capillaries 8 is attached to the 10” blood outflow opening, so that the mesh openings are 20 pm 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 is as in example No. 1, however, the capillary rotation angle 8 is 15 degrees and the capillary tension force is 60 N. Furthermore, in this variant, the solution does not include a densely woven fiber mesh 13 mounted on the 10" blood outflow opening, but includes two parallel modules 14 with clot filters with a bypass (splitter) installed on the outlet channel from the 10" blood outflow opening from the gas exchange chamber 1 enabling smooth switching, i.e. directing the blood flow alternately through one or the other clot filter module. The modules 14 with clot filters are installed between the 10" outflow opening and the blood flow heating module 17.

Moreover, in front of the cooler 16 of the blood stream 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 stream alternately through one or the other module with a clot filter.

Example 5

The blood oxygenation device is similar to Example 1, but the capillaries 8 that comprise the membrane are 100 μm diameter tubes made of a semipermeable material, meaning they are permeable to gaseous mixture molecules but impermeable to blood particles. The material consists of a PVDF base and an argatroban admixture incorporated into the microstructure of the base material in a base-to-admixture ratio of 150:1. The membrane contains pores, 50% of which are open pores, and the remaining 50% are closed pores filled with the active substance argatroban.

Example 6

The blood oxygenation device is as in Example 1, but the capillaries 8 that comprise the membrane are 30 μm diameter tubes made of a semipermeable material, meaning they are permeable to gas mixture molecules but impermeable to blood particles. The material consists of a FEP base and an argatroban admixture incorporated into the microstructure of the base material in a base-to-admixture ratio of 180:1. The membrane contains pores, 60% of which are open pores, and the remaining are closed pores filled with the active substance argatroban.

Example 7

The blood oxygenation device is similar to Example 1, but the capillaries 8 that comprise the membrane are 100 μm diameter tubes made of a semipermeable material, meaning they are permeable to gaseous mixture molecules but impermeable to blood particles. The material consists of a PVDF base and an argatroban admixture incorporated into the microstructure of the base material in a base-to-admixture ratio of 200:1. The membrane contains pores, 60% of which are open pores, and the remaining pores are closed pores filled with the active substance argatroban.

Example 8

The blood oxygenation device is as in Example 1, but the capillaries 8 that comprise the membrane are 200 μm diameter tubes and are made of a semipermeable material, meaning they are permeable to gas mixture molecules but impermeable to blood particles. The material consists of a FEP base and an argatroban admixture incorporated into the microstructure of the base material in a base-to-admixture ratio of 1000:1. The membrane contains pores, 50% of which are open pores, and the remaining 50% are closed pores filled with the active substance argatroban.

Example 9

The blood oxygenation device is similar to Example 1, but the capillaries 8 that comprise the membrane are 150 μm diameter tubes made of a semipermeable material, meaning they are permeable to gaseous mixture molecules but impermeable to blood particles. The material consists of a PTFE base and an argatroban admixture incorporated into the microstructure of the base material in a base-to-admixture ratio of 500:1. The membrane contains pores, 55% of which are open pores, and the remaining pores are closed pores filled with the active substance argatroban.

Example 10

The blood oxygenation device is similar to Example 1, but the capillaries 8 that comprise the membrane are 500 μm diameter tubes made of a semipermeable material, meaning they are permeable to gaseous mixture molecules but impermeable to blood particles. The material consists of a PTFE base and an argatroban admixture incorporated into the microstructure of the base material in a base-to-admixture ratio of 150:1. The membrane contains pores, 45% of which are open pores, and the remaining are closed pores filled with the active substance argatroban.

Example 11

The blood oxygenation device is as in Example 1, but the capillaries 8 that comprise the membrane are 100 μm diameter tubes and are made of a semipermeable material, meaning it is permeable to gas mixture molecules but impermeable to blood particles. The material consists of a FEP base and an argatroban admixture incorporated into the microstructure of the base material in a base-to-admixture ratio of 150:1. The membrane contains pores, 60% of which are open pores, and the remaining are closed pores filled with the active substance argatroban.

Example 12

The blood oxygenation device is similar to Example 1, but the capillaries 8 that comprise the membrane are 150 μm diameter tubes made of a semipermeable material, meaning they are permeable to gaseous mixture molecules but impermeable to blood particles. The material consists of a PVDF base and an argatroban admixture incorporated into the microstructure of the base material in a base-to-admixture ratio of 100:1. The membrane contains pores, 50% of which are open pores, and the remaining 50% are closed pores filled with the active substance argatroban.

Example 13

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

Example 14

A device for oxygenation of 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 is based on the fact that through the inlet opening of the gas mixture from the installation supplying this mixture, it is introduced into the equalizing tank, and from there, the gas mixture is further introduced through holes in the inlet base of the chamber to the capillaries, it is transported in the capillaries and discharged through holes made in the opposite outlet base to 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, in counter-current 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 oxygen concentration in the gas mixture, which will reduce the oxidative stress for cells, especially for hemoglobin, and this will prevent clotting and an increase in pressure, and will also reduce the risk of the trapping (blocking) effect on the membrane of drugs possibly transported in the blood, especially antibiotics (clots may form on the membrane, and thus drug particles will also remain there).

Blood in the oxygenator is passed countercurrently to the gas mixture, resulting in higher gas exchange efficiency while maintaining the lowest possible oxidative stress. This allows for maintaining a constant concentration of oxygen molecules in the blood (a diffusion-controlled process).

In the co-current variant, the blood molecule would move in the same direction as the oxygen molecules, and gas exchange would occur, but the efficiency would be diffusion-limited (controlled). However, in the counter-current variant, due to the continuous change in the contact phase—resulting from the fact that blood and oxygen molecules pass each other—the process is not diffusion-controlled, and the process is not limited by diffusion control throughout the oxygenator chamber. A blood molecule that is still not saturated, meaning it is still capable of absorbing another batch of fresh oxygen, will still be able to absorb it thanks to contact with subsequent oxygen molecules passing it. Furthermore, the partial pressure at the contact point between the blood molecules and the oxygen molecules will be higher than in the co-current variant, enabling more effective gas exchange. With a sufficiently rapid flow of the oxygen-containing gas mixture, the gas exchange effect will be further enhanced by the Venturi effect. The flowing blood sucks oxygen molecules from the capillary, even at a relatively low pressure of the gas mixture stream (there does not have to be a high oxygen pressure, which is necessary in an oxygenator with blood flow perpendicular to the direction of oxygen flow).

In the known perpendicular design (blood flow perpendicular to the direction of oxygen flow), oxygen molecules escaping through the capillary micropores had brief contact with the blood, requiring higher energy to detach the oxygen molecule from the tube surface (requiring high energy expenditure or high oxygen concentration, which can cause oxidative stress and impairment of hemoglobin cells). Consequently, blood oxygenation was uneven and subject to 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 (stepwise 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)

Patent claims 1. A device for blood oxygenation, with a membrane made of an organic material with pore-forming, anti-inflammatory and anticoagulant properties, comprising 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 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 side 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 through holes in the outlet and inlet bases of the chamber, characterized in that the capillaries (8) are stressed with a tension force of the value 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) there is at least one inlet opening (10') of the blood stream, and in the side wall (9) of the chamber (1) near the inlet base (2') of the chamber (1) there is at least one outlet opening (10") of the blood stream, additionally the device is equipped with a cooler - blood stream 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 outlet opening(s) (10") of the blood stream from the gas exchange chamber (1), and a blood stream heating module (17) with parameters enabling its cooling by 0.5-3.5°C, preferably by 2°C is connected to the outlet opening(s) (10") of the blood stream from the gas exchange chamber (1) parameters enabling its heating 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 and impermeable to blood particles, consisting of: - a base in the form of a fluoropolymer, most preferably poly(tetrafluoroethylene) (PTFE, Teflon), or polyvinylidene fluoride (PVDF), or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP), and - an argatroban 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 and the remaining are closed pores, i.e. they are filled with the active substance in the form of argatroban. 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 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 side 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 through holes in the outlet and inlet bases of the chamber, characterized in that the capillaries (8) are stressed with a tension force of the value 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 inlet opening (10') of the blood stream, 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 outlet opening (10") of the blood stream, 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 stream heating module (17) with parameters enabling its heating to the physiological blood temperature is connected to the blood flow outlet(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 molecules of the gas mixture and impermeable to the blood particles, consisting of: - a base in the form of a fluoropolymer, most preferably poly(tetrafluoroethylene) (PTFE, Teflon), or polyvinylidene fluoride (PVDF), or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP), and - an argatroban 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 and the remaining are closed pores, i.e. they are filled with the active substance in the form of argatroban. 3. A device according to claim 1, characterized in that Peltier cells are used as a blood flow cooler. 4. A 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') chamber (1) are made at equal distances from each other, and at the same time the capillaries (8) anchored in these holes are also 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 gas mixture discharge tank (6). 7. A device according to claim 1, characterized in that the blood stream inlet opening (10') and the blood stream 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 center of symmetry of the chamber (1). 9. A 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 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 gas mixture discharge tank (6). 13. A device according to claim 2, characterized in that the blood stream inlet opening (10') and the blood stream 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 center 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 longitudinal notches, most preferably with a triangular or close to 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 longitudinal notches, most preferably with a triangular or close to triangular cross-section, which are arranged spirally, i.e. they are twisted along the longitudinal axis of the chamber (1) 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 (8). 17. A device according to claim 1, characterized in that a densely woven mesh (13) made of fibers, preferably made of a material identical to the material of the capillaries (8), is mounted on the blood flow outlet opening (10"), so that the mesh openings have a side of 15 to 100 μm, preferably 38 μm, parallel to the plane of the opening on which it is mounted. 18. A device according to claim 1, characterized in that a densely woven mesh (13) made of fibers, preferably made of a material identical to the material of the capillaries (8), is mounted on the blood flow inlet opening (10'), so that the mesh openings have a side of 15 to 100 μm, preferably 38 μm, parallel to the plane of the opening on which it is mounted. 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 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 outflow 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 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 fibers, preferably made of a material identical to the material of the capillaries (8), is mounted on the blood flow outlet opening (10"), so that the mesh openings have a side of 15 to 100 µm, preferably 38 µm, parallel to the plane of the opening on which it is mounted. 22. A device according to claim 2, characterized in that a densely woven mesh (13) made of fibers, preferably made of a material identical to the material of the capillaries (8), is mounted on the blood flow inlet opening (10'), so that the mesh openings have a side of 15 to 100 µm, preferably 38 µm, parallel to the plane of the opening on which it is mounted. 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 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 outflow opening (10") of the gas exchange chamber (1), wherein in the present variant with the clot filter module(s), the blood flow heating module (17) is installed before or, more preferably, after the clot filter module(s) (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 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).