Medical device and method for generating plasma activated fluid

Abstract

The present invention relates to a medical device for generating plasma activated liquid, a system for generating plasma activated liquid comprising the device, and a method for generating plasma activated liquid. The present invention also relates to a method for preventing and treating postoperative adhesion.

Description

Technical Field

[0001] The present invention relates to a medical device for generating plasma activated liquid, a generating system comprising the plasma activated liquid, and a generating method of the plasma activated liquid. The present invention also relates to a method for preventing and treating postoperative adhesion. Background Art

[0002] In physics, plasma refers to a mixture of particles at the atomic and molecular level. Plasma was named in the 1920s by chemist Irving Langmuir. It consists of a mixture of particles with partially charged components, ions and electrons. Plasma can be artificially produced, for example by heating a neutral gas or exposing it to strong electromagnetic fields until the ionized gaseous material becomes increasingly conductive.

[0003] Non-thermal or low temperature plasma can be generated at atmospheric pressure by using an electrode system called dielectric barrier discharge. This is an AC gas discharge in which at least one electrode is electrically isolated from the gas space using a current barrier of a dielectric. When the AC voltage between the electrodes generates a sufficient field strength in the gas space, the space filled with gas or air between the insulating encapsulated electrodes can be ionized, or enter a plasma state. The AC voltage required to generate plasma is several kilovolts, that is, a very high voltage is required to generate plasma. Pulsed excitation is also beneficial for the generation of plasma, in which case voltage pulses with amplitudes in the kilovolt range and pulse durations from a few microseconds to tens of nanoseconds are applied to the electrode arrangement.

[0004] Many studies have demonstrated that low-temperature plasma has significant selective effects on biological systems. For example, low-temperature plasma has an effective bactericidal effect and positive effects on chronic and acute wounds. In addition, low-temperature plasma treatment of tumors can lead to the inactivation of tumor cell apoptosis initiation.

[0005] Species called "bioactive plasma factors" are responsible for the observable effects of plasma on biological systems. The observable effects of plasma on biological systems are attributed to "bioactive plasma factors". These are reactive species in nature, such as reactive nitrogen species (RNS), reactive oxygen species (ROS), free radicals, ionic compounds such as NO 2- 、NO 3- 、ONOO - , electromagnetic radiation, etc., and possibly other species that have not yet been characterized in detail.

[0006] Plasma activated liquids (PALs) or plasma activated media (PAMs) are increasingly being used. The antiproliferative, antitumor and anti-inflammatory effects of PALs have recently been demonstrated in various studies. PALs also have potent bactericidal effects and have a positive effect on chronic and acute wounds. PALs can significantly improve wound healing and reduce pain sensitivity. The use of PALs allows for better application of dosage and control of bioactive plasma factors compared to direct application of physical plasma.

[0007] For example, the following publications describe devices for producing plasma-activated fluids: Adachi et al. (2015), Plasma-activated mediators induce A549 cell damage via a spiral apoptotic cascade involving the mitochondrial nuclear network, Free Radical Biology and Medicine, 79, pp. 28-44; Kajiyama et al. (2017), Future prospects of non-thermal plasma cancer treatment strategies, J. Clin. Bio-chem. Nutr., 60, pp. 33-38; Nakamura et al. (2017), Novel intraperitoneal treatment using non-thermal plasma-activated mediators inhibits the metastatic potential of ovarian cancer cells, Nature Scientific Reports, 7:6085, pp. 1-14; Azzariti et al. (2019), Plasma-activated mediators trigger cell death and presentation of immune activation danger signals in melanoma and pancreatic cancer cells, Nature Scientific Reports, 9:4099, pp. 1-13.

[0008] Known devices activate liquids by treating them with plasma. Known devices use an external plasma generator. They are therefore difficult to operate and are not suitable for direct clinical use by an operator. Therefore, devices for generating plasma-activated liquids have hitherto only been used in experimental systems.

[0009] Current equipment also does not allow the plasma-activated liquid to be applied immediately to the tissue. Rather, it is produced at an initial time and applied to the tissue at a later time. It can be said that in the prior art, the plasma-activated liquid is prepared for "stockpiling". However, the biologically active plasma factors are "volatile", that is, they are only stable for a limited time. Therefore, the plasma-activated liquids currently produced often have little therapeutic value, because storage often leaves only low concentrations of the biologically active plasma factors.

[0010] US 2008 / 0292497 discloses a large device for plasma impact disinfection of liquid. A first gas chamber is separated from a second gas chamber by a phase separator. The phase separator can be a porous or non-porous membrane having holes that allow gas to be transferred from the first compartment to the second compartment. Gas is pumped into the second compartment by applying a positive pressure to the first compartment. This causes gas bubbles to form in the form of large bubbles in the liquid in the second compartment. The device is not only unsuitable for medical applications because of its large size. Due to the accumulation of bubbles, there is a possibility that they will be flushed into the blood system, causing embolism. It is also impossible to use it in endoscopic procedures such as hysteroscopy because the bubbles formed make visibility difficult.

[0011] DE 102014 105720 discloses an active layer for surface inactivation of bacteria or biomedical applications. In this process, species generated by the plasma are transferred from the discharge space to the active medium located in the adjacent space. The discharge space and the space containing the active medium are separated by a non-characteristic membrane. The device is also not suitable for the prevention and treatment of postoperative adhesions. Summary of the invention

[0012] Based on the above technical background, the problem to be solved by the present invention is to provide a medical device for producing plasma activated liquid, which can avoid or at least reduce the disadvantages of current devices in the prior art. Specifically, the present invention aims to provide such a medical device, which can be easily operated by a treating physician and can be industrially produced; preferably, the device allows the plasma activated liquid to be used immediately after production without the need for long-term storage.

[0013] In order to solve the above technical problems, the present invention provides a medical device for generating plasma activated liquid, which includes an interface formed by a plasma discharge space and an adjacent liquid carrying space, wherein the interface includes a semipermeable membrane, which can permeate the bioactive plasma factors from the plasma discharge space but cannot permeate the liquid from the liquid carrying space.

[0014] Separating the plasma discharge space from the liquid-carrying space by means of a semipermeable membrane creates in a favorable manner the design requirements of a medical device that is easy for treating physicians to operate and can be mass-produced.

[0015] The plasma discharge space is configured to receive a medium suitable for generating a physical plasma, such as a gas, such as argon, helium, O2, N2, room air, or other suitable gas.

[0016] The liquid carrying space is configured to receive a liquid, such as water, saline solution, biological buffer, etc.

[0017] The semipermeable membrane can be realized by, for example, a conventional dialysis membrane, which allows the plasma discharge and liquid carrying spaces to be defined and separated from each other, while ensuring that the bioactive plasma factors accumulate in the liquid and can migrate from the plasma through the semipermeable membrane into the liquid.

[0018] According to one embodiment of the present invention, the semipermeable membrane is configured in such a way that the formation of gas bubbles in the liquid-carrying space is prevented; preferably large bubbles; further preferably large bubbles visible to the naked eye, i.e. bubbles with a diameter in the range of centimeters or millimeters. According to this embodiment, the technician will adjust the pore diameter by appropriately selecting the material of the semipermeable membrane so that essentially only the bioactive plasma factors are transferred from the plasma discharge space to the liquid-carrying space. This is the way to use conventional dialysis membranes or conventional biosymmetric dialysis membranes, such as copper-formed membranes, hemoformed membranes or cellulose triacetate, and other membranes based on natural polymer cellulose. The average pore radius of conventional dialysis membranes is 1.72 nm, and the corresponding permeability is 1000 Daltons, preferably 500 Daltons, i.e., macromolecules cannot penetrate the membrane; see Nowack et al. (2019), Dialysis and Nephrology for Professionals, 3rd edition, Chapter 7, Structure of the Dialyzer, pages 89-103. According to the present invention, the use of conventional dialysis membranes prevents (gas) bubbles from forming in the liquid in the liquid-carrying compartment.

[0019] According to another embodiment of the present invention, the average pore radius of the semipermeable membrane is < 5 nm, preferably ≤ 2 nm. This ensures that in the liquid, the formation of not only large bubbles but even microbubbles is completely impossible.

[0020] According to the present invention, the plasma discharge space can be realized by a continuous cavity, especially when the device of the present invention is constructed in a tubular or hose-like shape, the plasma discharge space forms an outer tubular or hose body, and the liquid-carrying space forms an inner tubular or hose body, or they are alternately arranged in reverse; a spacer can be used, and the spacer can ensure the spacing between the plasma discharge space and the liquid-carrying space. Alternatively, the plasma discharge space can be created by or include a gas-permeable material, such as glass fiber fabric or plastic. The advantage of this is that the arrangement of the plasma discharge and the liquid-carrying space can be realized in a flexible manner in a layered structure, and no spacer is required.

[0021] The objects of the invention are fully achieved here.

[0022] The inventors have for the first time provided a device for generating plasma-activated liquids which is easy to operate and produce and by means of which inflammations, chronic inflammations, tumors and tumorous diseases can be treated in vivo in an advantageous manner. The plasma-activated liquid can be used immediately after it has been generated on the tissue, which ensures a high degree of effectiveness.

[0023] The device of the present invention is also very suitable for the prevention and treatment of postoperative, iatrogenic or inflammatory adhesions. These pose a major challenge to the medical care system during surgical or endoscopic / laparoscopic surgery. Due to the anti-proliferative, anti-inflammatory and wound healing properties of the plasma activated fluid, the device of the present invention is suitable for routine treatment procedures at the completion of surgery to prevent postoperative adhesions.

[0024] Its non-invasiveness and non-toxicity determine that the device of the present invention can be used in vivo. Compared with the local application of physical plasma, the medical device of the present invention can achieve large-area, uniform body cavity treatment, such as the abdominal cavity or vaginal cavity, oral cavity and pharyngeal cavity, chest cavity, gastrointestinal cavity, joint space, etc.

[0025] In one embodiment, the pressure conditions in the plasma discharge gap can be selectively controlled by providing or connecting suitable devices. For example, low pressure or even vacuum or "near vacuum" may prevail in the plasma discharge gap. The advantage of this method is that the energy and voltage required for plasma generation will be greatly reduced, and a more uniform plasma can be produced.

[0026] According to one embodiment of the medical device of the present invention, the positive electrode insulated from the dielectric is adjacent to the plasma discharge space on a side opposite to the interface.

[0027] This measure creates favorable conditions for generating plasma by dielectric barrier discharge.

[0028] The structure of the positive electrode can be ring-shaped, grid-shaped, spindle-shaped, zigzag-shaped or honeycomb-shaped. In these embodiments, the electrode structure is evenly distributed, ensuring very uniform plasma generation in the plasma discharge space. They also allow the electrode structure to have favorable flexibility or shape adaptability.

[0029] The dielectric can be glass, ceramic or plastic, such as silicone. In particular, if the dielectric is formed by soft plastic (such as silicone), it may be flexible, that is, easy to bend, which is advantageous in applications.

[0030] In an alternative embodiment, the electrode structure is not insulated from the dielectric facing the plasma discharge space, so that the discharge can be carried out in a form similar to corona discharge.

[0031] According to a further embodiment of the medical device according to the present invention, a ground electrode is arranged on the interface and / or in the plasma discharge space near the interface. In this regard, the ground electrode can be integrated into the interface.

[0032] In the present embodiment, the ground electrode constitutes a counter electrode to the positive electrode, thereby creating structural conditions for generating plasma by dielectric barrier discharge.

[0033] The structure of the ground electrode may correspond to that of the positive electrode.

[0034] In this embodiment, the bioactive plasma factors diffuse passively from the plasma through the membrane into the liquid by Brownian motion. This ensures membrane-retained migration of the bioactive plasma factors. Therefore, the enrichment of the liquid with active plasma factors can be adjusted by the volume of liquid flowing through each time or the energy input of the plasma to adapt to clinical conditions.

[0035] The spacing between the positive electrode and the ground electrode is selected to avoid heat generation on the one hand and to form sufficient physical plasma between the positive electrode and the ground electrode on the other hand. This can be achieved by designing the plasma discharge space with the above-mentioned spacer and / or using a gas permeable material with sufficient thickness.

[0036] According to another embodiment of the device according to the invention, a ground electrode is arranged in the liquid carrying space.

[0037] According to the present invention, the ground electrode is arranged "inside" the liquid-carrying space, which means that the ground electrode can be in contact with the liquid on at least one side, preferably on both sides or as a whole. In this embodiment, the bioactive plasma factors can be driven not only by Brownian motion but also by electric charge, and migrate from the plasma through the membrane into the liquid in an accelerated manner. This arrangement ensures rapid and strong enrichment of the liquid with bioactive plasma factors. The enrichment of the liquid with active plasma factors can be adjusted and adapted to clinical conditions not only by the volume of the liquid flowing each time, but also by the applied voltage.

[0038] Also in this embodiment, the spacing between the positive electrode and the ground electrode is selected to avoid heat generation on the one hand and to form a sufficient physical plasma between the positive electrode and the ground electrode on the other hand. As mentioned above, this can be achieved by designing the plasma discharge space with the spacer discussed above and / or using a gas permeable material with sufficient thickness.

[0039] In another embodiment, the medical device of the present invention is in the shape of a tube and / or a hose.

[0040] The advantage of this method is that the tubular and / or hose-shaped shape makes it possible to separate individual spaces and structures in a simple way, and to electrically insulate the electrode structure. In addition, the tubular and / or hose-shaped shape of the device according to the present invention simplifies the flexible and bendable design. Similarly, the tubular and / or hose-shaped shape of the device according to the present invention simplifies the entry into the body cavity by minimally invasive methods, as well as the application to body cavities and / or openings, which also generally have a tubular and / or hose shape. According to the present invention, "tubular and / or hose-shaped" means that various spaces and structures are arranged in the form of nested tubes or hoses. This embodiment can be particularly well integrated into existing modules, such as endoscopic equipment, high-pressure atomization and / or spraying units, etc.

[0041] Therefore, in the first embodiment in which the device is tubular or hose-shaped, the liquid-carrying space is located in the innermost layer of the device, surrounded by a semipermeable membrane, and a ground electrode is arranged outside the semipermeable membrane, and the outside of the ground electrode is surrounded by the plasma discharge space via a spacer. A dielectric and a positive electrode adjacent to it are arranged outside the plasma discharge space. The outside of the positive electrode may have external insulation. The outermost layer may be formed by a supporting material, which gives the device structure and the required flexibility.

[0042] In another embodiment in which the device is tubular and / or hose-shaped, the ground electrode is located in the innermost part of the device and is surrounded by a liquid-carrying space. The liquid-carrying space is surrounded on the outside by a semipermeable membrane, which in turn is surrounded on the outside by a plasma discharge space. A dielectric and a positive electrode adjacent thereto are arranged outside the plasma discharge space. The outside of the positive electrode may have an external insulation. The outermost layer may be formed by a supporting material, which gives the device structure and the required flexibility.

[0043] In a further embodiment of the present invention, the positive electrode is located in the innermost part of the device. In turn, the plasma discharge space surrounds the outside of the positive electrode, and outside the plasma discharge space is the liquid carrying space. In this embodiment, the further structure is consistent with the further construction in the above-mentioned embodiment.

[0044] As a further embodiment, the device of the present invention is box-shaped.

[0045] This optional embodiment can conveniently utilize sandwich construction methods by virtue of the horizontal arrangement and spatial structural order that is substantially consistent with the tubular and / or hose-shaped embodiments. This embodiment can also be well integrated with existing modules.

[0046] In another embodiment of the present invention, the medical device comprises a support structure surrounding the medical device.

[0047] The advantage of this approach is that the support structure gives the device structure and, if desired, flexibility or even rigidity. In addition, the carrier provides an additional barrier to ensure that the generated plasma can be applied to the tissue to be treated in a targeted manner and that other parts of the body cannot come into contact with the plasma. For example, the carrier can be made of metal or plastic.

[0048] In one embodiment, the medical device according to the invention has a gas connection, via which a carrier gas can be introduced into the plasma discharge space and released again if necessary.

[0049] In this way, a gas, for example argon, can be introduced into the plasma discharge space, which is very suitable for generating a plasma, for example by means of a dielectric barrier discharge.

[0050] In one embodiment, the medical device of the present invention comprises a connection for a high pressure atomization and / or spraying unit.

[0051] In this way, the device according to the invention is integrated into a device that allows targeted application of the plasma-activated liquid and, if necessary, regional application. Thus, the connection of the device according to the invention with a high-pressure atomization and / or spraying unit enables targeted treatment of tumor tissue. It is also possible to reduce or avoid postoperative adhesions, for example, by atomizing and / or spraying surgically treated tissue with plasma-activated liquid. The above process can be carried out during or directly after the operation, which can better avoid postoperative follow-up treatment.

[0052] In another embodiment of the present invention, the medical device has a connector for connecting to an endoscopic apparatus.

[0053] An advantage of this approach is that the devices of the present invention can be integrated into endoscopic surgery and existing endoscopic systems or trocars, allowing them to be used during or immediately after surgical treatment.

[0054] According to one embodiment, the medical device according to the invention is configured for intermittent and / or continuous generation of a plasma-activated liquid.

[0055] For example, this embodiment can be implemented by connecting a pump or similar device for conveying liquid, which can selectively convey liquid intermittently and / or continuously through the liquid conducting space. Alternatively, the plasma discharge can also be controlled by applying intermittent and / or continuous voltage. This embodiment allows setting an appropriate treatment mode according to the respective purpose of use.

[0056] Another object of the present invention relates to a system for producing a plasma-activated liquid, the liquid having a medical device according to the present invention, and a high-voltage power supply connected to the medical device for applying a high voltage to electrodes.

[0057] The features, implementation modes and advantageous effects of the device described in the present invention are correspondingly applicable to the system described in the present invention.

[0058] Another object of the present invention relates to a method for producing a plasma activated solution, comprising the following steps:

[0059] 1. Provided is a device, comprising an interface formed by a plasma discharge space and an adjacent liquid-carrying space, wherein the interface comprises a semipermeable membrane, wherein the semipermeable membrane is permeable to bioactive plasma factors from the plasma discharge space but impermeable to liquid from the liquid-carrying space;

[0060] 2. allowing gas to flow in the plasma discharge space;

[0061] 3. Allowing the liquid to flow in the liquid-carrying space;

[0062] 4. generating a physical plasma containing biologically active plasma factors from the gas in the plasma discharge space;

[0063] 5. Allow bioactive plasma factors to migrate through the semipermeable membrane into the liquid.

[0064] The features, implementation modes and advantageous effects of the device described in the present invention are correspondingly applicable to the method described in the present invention.

[0065] The gas is preferably argon, helium, O2, N2, room air or other suitable gas.

[0066] The term "migration of bioactive plasma factors" generally refers to the movement of bioactive plasma factors through a semipermeable membrane, including passive diffusion of bioactive plasma factors through the semipermeable membrane by Brownian motion, and charge-driven diffusion of bioactive plasma factors through the semipermeable membrane.

[0067] According to one embodiment of the method of the present invention, the provided device is the medical device of the present invention.

[0068] Another object of the present invention relates to the use of a plasma-activated fluid in the prevention and / or treatment of postoperative adhesions.

[0069] Preferably, the plasma-activated liquid is a liquid produced using the medical device of the present invention and / or according to the method of the present invention.

[0070] The features, embodiments and beneficial effects of the device described in the present invention are correspondingly applicable to the use described in the present invention.

[0071] Further advantages and features will become apparent from the following description of preferred embodiments and the accompanying drawings.

[0072] It is understood that the above-mentioned features (which will be explained below) can be used not only in the combination indicated in each case but also in other combinations or alone, without departing from the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Figure 1 A longitudinal cross-sectional view of a first embodiment A) and a second embodiment B) according to the present invention is shown;

[0074] Figure 2 Shows a fracture diagram A) and a cross-sectional diagram B) according to a first embodiment of the present invention;

[0075] Figure 3 Shows a fracture diagram A) and a cross-sectional diagram B) according to a second embodiment of the present invention;

[0076] Figure 4 shows a fracture diagram according to a third embodiment of the present invention;

[0077] Figure 5 is a schematic diagram of the device of the present invention being used in gynecological surgery;

[0078] Figure 6 Selective effects of PAL on mesothelial and fibroblasts. A) PAL dose dependence of proliferation of human fibroblasts and mesothelial cells. At a PAL dose of 1:2, fibroblasts were specifically inhibited, while mesothelial cells continued to proliferate. B) Bright field microscopy of fibroblasts (top) and mesothelial cells (bottom). C) Quantitative detection of extracellular insoluble collagen and procollagen by hydroxyproline assay (left) and Sircol assay (right). PAL treatment resulted in a decrease in insoluble collagen and an increase in soluble procollagen. D) Flow cytometry after PI staining. A 1:2 PAL dose resulted in a fibroblast-specific G1 cell cycle arrest. E) Cell viability assay. A 1:2 PAL dose resulted in a fibroblast-specific decrease in cell metabolism, induction of various cellular mechanisms, and an increase in cell metabolism in mesothelial cells. DETAILED DESCRIPTION

[0079] 1. Detailed description of the device of the present invention

[0080] Figure 1A) shows an enlarged longitudinal section through a medical device for generating a plasma-activated liquid, which is indicated by reference symbol 10. The medical device 10 is suitable for in vivo treatment of inflammation, chronic inflammation, tumors, tumor diseases, and prevention of postoperative adhesions. In this embodiment, the medical device 10 has a plasma discharge space 12 and a liquid-carrying space 14 located adjacent to it at the bottom. A physical plasma 16, in particular a low-temperature or room-temperature plasma under normal or even low-pressure conditions, can be generated in the plasma discharge space 12. A liquid 18, such as water, a buffer solution or a physiological saline solution, flows through the liquid-carrying space 14 intermittently or continuously.

[0081] The plasma discharge space 12 and the liquid carrying space 14 adjacent thereto form an interface 20, which includes a semipermeable membrane 22. The semipermeable membrane 22 is permeable to the bioactive plasma factors from the plasma 16 generated in the plasma discharge space 12, but is impermeable to the liquid 18 from the liquid carrying space 14.

[0082] As shown in this embodiment, the positive electrode 26 is insulated from the plasma discharge space 12 with the dielectric 24 and is adjacent to the top surface of the plasma discharge space 12. The dissipative ground electrode 28 is adjacent to the semi-permeable membrane 22 in the direction toward the plasma discharge space 12. The electrodes 26 and 28 may be formed of a single wire, or may be in a lattice shape, a spindle shape, a meander shape, or a honeycomb shape.

[0083] When a high voltage is applied to the electrodes 26 and 28, a physical plasma 16 is generated in the plasma discharge space 12. The bioactive plasma factors therein migrate through the semipermeable membrane 22 into the liquid 18 of the liquid carrying space 14 by Brownian motion, as indicated by the snake-shaped arrows.

[0084] Figure 1 B) shows a second embodiment, in which Figure 1 Corresponding structures and features in A) are shown with the same reference symbols. Figure 1 B) The embodiment shown and Figure 1 A) The difference of the embodiment shown is that the ground electrode 28 is no longer against the upper side of the semipermeable membrane 22 facing the plasma discharge space 12, but is arranged in the liquid-carrying space 14. When a high voltage is applied to the electrodes 26 and 28, the bioactive plasma factors no longer migrate to the liquid-carrying space 14 through the semipermeable membrane simply due to Brownian motion, but are "injected" into the liquid-carrying space 14 in a charge-driven manner.

[0085] exist Figure 2 In the figure, a first embodiment of the medical device 10 of the present invention is shown (corresponding to Figure 1 A) Arrangement shown). Figure 2A) is a fracture diagram of the device 10, and B) is a cross-sectional diagram of the device 10. Figure 1 A) and Figure 1 B) are shown with the same reference symbols. In addition, in this embodiment, the device 10 of the present invention has a high voltage source 30 for applying a high voltage to the electrodes 26 and 28, an outer insulation 32 for insulating the positive electrode 26 from the outside, and a carrier 34 surrounding the outer insulation.

[0086] exist Figure 3 In the figure, a second embodiment of the medical device 10 of the present invention is shown (corresponding to Figure 1 B) Arrangement shown). Figure 3 A) is a fracture diagram of the device 10, and B) is a cross-sectional diagram of the device 10. Figure 2 Corresponding structures and features in FIG. 5 are shown with the same reference symbols.

[0087] exist Figure 4 , a third embodiment of the medical device 10 of the present invention is shown, wherein the structure and space are arranged in a horizontally layered manner like a sandwich in a carrier 34 having a box-like design. Figure 1 , Figure 2 , Figure 3 Corresponding structures and features in FIG. 5 are shown with the same reference symbols.

[0088] Figure 5 The use of the device 10 according to the invention in gynecological surgery is schematically shown. Also shown are a pump 36 connected to the device according to the invention for supplying liquid through a hose 38, a high-voltage source or generator 30 for applying high voltage to the electrodes through a cable 40, and a gas connection with a gas source 42 and a gas line 44, through which a carrier gas can be introduced into the plasma discharge space 12 and, if necessary, discharged again.

[0089] 2. Example Plasma activation solution can specifically inhibit connective tissue cells that produce ECM to prevent postoperative adhesion

[0090] Gynecologic and general surgical procedures below the transverse colon are at particularly high risk for postoperative adhesions (PA) and associated serious morbidity. Clinically, PAs are often characterized by a chronic severe pain syndrome in the abdomen, flank, or back and are often misdiagnosed for many years. PAs also account for 15-20% of secondary infertility and 50-70% of mechanical intestinal obstructions. PAs are estimated to impose significant costs on healthcare systems. The etiology of PA is due to excessive extracellular matrix (ECM) formation due to activation of peritoneal mesothelial cells, fibroblasts, and immune cells. Plasma activated liquid (PAL) prevents PA through inhibition and excessive proliferation of fibrin and ECM-producing connective tissue cells.

[0091] Using the device described herein, dose-dependent PAL treatment of primary human mesothelial cells and fibroblasts showed a clear and reproducible therapeutic window (here represented as 1:2) ( Figure 1 A), 1B). Using this PAL concentration, the excessive proliferation of ECM- and fibrin-producing fibroblasts was significantly inhibited, while the physiological cell proliferation of mesothelial cells was not significantly affected. After PAL treatment, the extracellular soluble procollagen (less cross-linked) content increased significantly, while the insoluble collagen (highly cross-linked) content decreased significantly. The selective antiproliferative effect on primary fibroblasts was associated with a significant G2 cell cycle arrest and a significant decrease in cell viability. Interestingly, the same PAL dose showed a significant increase in mesothelial cell viability.

[0092] Therefore, peritoneal PAL treatment using the device described in the present invention provides a promising medical application to selectively reduce postoperative (excessive) proliferation of ECM and fibrin-producing fibroblasts, as well as synthesize and cross-link functional ECM components, such as collagen.

Claims

1. A medical device (10) for generating plasma activated liquid, comprising an interface (20) formed by a plasma discharge space (12) and an adjacent liquid carrying space (14) carrying a liquid (18) without bubbles, characterized in that: The interface (20) includes a semipermeable membrane (22), which is permeable to the bioactive plasma factors from the plasma discharge space (12) but impermeable to the liquid (18) from the liquid carrying space (14). wherein a positive electrode (26) insulated from a dielectric (24) is adjacent to the plasma discharge space (12) on a side opposite to the interface (20), The ground electrode (28) is arranged in the liquid carrying space (14). The medical device (10) comprises a connector connected to an endoscopic device.

2. The medical device (10) according to claim 1, characterized in that The semipermeable membrane (22) is configured to prevent the formation of bubbles in the liquid in the liquid carrying space.

3. The medical device (10) according to claim 1 or 2, characterized in that: The average pore radius of the semipermeable membrane (22) is < 5 nm.

4. The medical device (10) according to claim 3, characterized in that The average pore radius of the semipermeable membrane (22) is ≤2 nm.

5. The medical device (10) according to claim 1 or 2, characterized in that: The exclusion limit of the semipermeable membrane (22) is 1000 Daltons.

6. The medical device (10) according to claim 5, characterized in that The exclusion limit of the semipermeable membrane (22) is 500 Daltons.

7. The medical device (10) according to claim 1 or 2, characterized in that: The medical device (10) is tubular.

8. The medical device (10) according to claim 1 or 2, characterized in that: The medical device (10) is in the shape of a hose.

9. The medical device (10) according to claim 1 or 2, characterized in that: The medical device (10) is box-shaped.

10. The medical device (10) according to claim 1 or 2, characterized in that: The medical device (10) includes a closed support structure (34).

11. The medical device (10) according to claim 1 or 2, characterized in that: The medical device (10) has a gas connection (42, 44) through which a carrier gas can be introduced into the plasma discharge space (12) and released if necessary.

12. The medical device (10) according to claim 1 or 2, characterized in that: The medical device (10) comprises a connection for a high-pressure atomization and / or spraying unit.

13. The medical device (10) according to claim 1 or 2, characterized in that: The medical device (10) is configured to generate plasma-activated liquid intermittently or continuously.

14. A system for generating a plasma activated liquid, characterized in that: The medical device (10) comprises any one of claims 1 and 7 to 13, and a high voltage power supply (30) connected to the medical device (10) for applying a high voltage to the electrodes (26, 28).

15. A method for producing a plasma activated solution, comprising the steps of: 1) A device is provided, wherein the device has an interface formed by a plasma discharge space and an adjacent liquid-carrying space, wherein the interface comprises a semipermeable membrane, wherein the semipermeable membrane is permeable to bioactive plasma factors from the plasma discharge space but impermeable to liquid from the liquid-carrying space, wherein a positive electrode insulated from a dielectric is adjacent to the plasma discharge space on a side opposite to the interface, wherein a ground electrode is disposed in the liquid-carrying space; 2) allowing gas to flow in the plasma discharge space; 3) allowing the liquid without bubbles to flow in the liquid-carrying space; 4) generating a physical plasma containing biologically active plasma factors from the gas in the plasma discharge space; 5) Allow bioactive plasma factors to migrate into the liquid through the semipermeable membrane.

16. The method according to claim 15, characterized in that The device is the device as described in any one of claims 1 to 10.

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