MEDICAL DEVICE AND METHOD FOR GENERATING A PLASMA-ACTIVATED LIQUID

Abstract

The present invention relates to a medical device for generating a plasma-activated liquid, a system for generating plasma-activated liquids comprising said device, and a method for generating a plasma-activated liquid. It also relates to a method for prophylaxis and treatment of postoperative adhesions.

Claims

1. A medical device for generating a plasma-activated liquid, comprising a plasma discharge space and a liquid-carrying space adjacent thereto to form an interface, characterized in that the interface comprises a semipermeable membrane permeable to biologically reactive plasma factors from the plasma discharge space and impermeable to the liquid from the liquid-carrying space.

2. The medical device according to claim 1, wherein the semipermeable membrane is configured in such a way that in the liquid-carrying space in the liquid the formation of gas bubbles is prevented.

3. The medical device according to claim 2, wherein the gas bubbles are macrobubbles.

4. The medical device according to claim 1, wherein the semipermeable membrane has an average pore radius of about <5 nm.

5. The medical device of claim 4, wherein the semipermeable membrane has an average pore radius of about ≤2 nm.

6. The medical device according to claim 1, wherein the semipermeable membrane has an exclusion limit of about 1000 Daltons.

7. The medical device according to claim 1, wherein the semipermeable membrane has an exclusion limit of about 500 Daltons.

8. The medical device according to claim 1, wherein a positive electrode insulated with a dielectric is adjacent to the plasma discharge space on a side opposite the interface.

9. The medical device according to claim 1, wherein a ground electrode is arranged in the plasma discharge space on and/or near the interface.

10. The medical device according to claim 1, wherein a ground electrode is disposed within the liquid carrying space.

11. The medical device according to claim 1, which is tubular and/or hose-shaped.

12. The medical device according to claim 1, which is box-shaped.

13. The medical device according to claim 1, which comprises an enclosing support structure.

14. The medical device according to claim 1, which comprises a gas connection via which a carrier gas can be introduced into plasma discharge space.

15. The medical device according to claim 14, which comprises the gas connection via which the carrier gas can be released from the plasma discharge space.

16. The medical device according to claim 1, which comprises a connection for a high-pressure nebulization or spraying unit.

17. The medical device according to claim 1, which comprises a connector for connection to an endoscopic device.

18. The medical device according to claim 1, which is configured for intermittent or continuous generation of a plasma-activating liquid.

19. A system for generating plasma activated liquids, comprising the medical device according to claim 8, and a high voltage source connectable to the medical device for applying high voltage to the electrode.

20. A method for generating a plasma activated liquid comprising the steps of: 1. Providing a device having a plasma discharge space and a liquid-carrying space adjacent thereto to form an interface, the interface comprising a semipermeable membrane permeable to biologically reactive plasma factors from the plasma discharge space and impermeable to the liquid from the liquid-carrying space; 2. Flowing a gas through the plasma discharge space, 3. Flowing a liquid through the liquid-carrying space, 4. Generating a physical plasma containing biologically reactive plasma factors from the gas in the plasma discharge space, 5. Allowing the biologically reactive plasma factors to migrate through the semi-permeable membrane into the liquid.

21. The method according to claim 20, wherein the device provided is the device according to claim 1.

22. A plasma-activated liquid for use in the prophylaxis and/or treatment of postoperative adhesions.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0074] FIG. 1 shows a first (A) and second (B) embodiment of the device according to the invention in longitudinal section;

[0075] FIG. 2 shows a first embodiment of the device according to the invention (A) in broken-up plan view and (B) in cross-section;

[0076] FIG. 3 shows a second embodiment of the device according to the invention (A) in broken-up plan view and (B) in cross section;

[0077] FIG. 4 shows a third embodiment of the device according to the invention in broken-up plan view;

[0078] FIG. 5 schematically shows the use of the device according to the invention during a gynecological operation; and

[0079] FIG. 6 Selective PAL effects on mesothelial cells and fibroblasts. a) PAL dose-de-pendent proliferation of human fibroblasts and mesothelial cells. PAL doses of 1:2 result in specific inhibition of fibroblasts, with continued proliferation of mesothelial cells. b) Bright field microscopy of fibroblasts (upper panel) and mesothelial cells (lower panel). c) Hydroxyproline assay (left) and Sircol assay (right) for quantification of extracellular insoluble collagen and procollagen. PAL treatment results in a decreased amount of insoluble collagen with an increased amount of soluble procollagen. d) Flow cytometry after PI staining. A PAL dose of 1:2 results in fibroblast-specific G1 cell cycle arrest. e) Cell viability assay. A PAL dose of 1:2 results in a fibroblast-specific reduction in cellular metabolism inducing various cellular mechanisms and an increase in cellular metabolism in mesothelial cells.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0080] 1. Details of the Device according to the Invention.

[0081] FIG. 1A shows an enlarged longitudinal section through a medical device for generating a plasma-activated liquid, designated by the general reference sign 10. The device 10 is suitable for intracorporeal treatment of inflammatory, chronic inflammatory, neoplastic, and oncological diseases, as well as for postoperative adhesion prophylaxis. The medical device 10 has a plasma discharge space 12 and a liquid-carrying space 14 adjacent thereto at the bottom in the embodiment. Physical plasma 16, particularly low or room temperature plasma under normal atmospheric pressure or even under 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 intermittently or continuously through the liquid-carrying space 14.

[0082] The plasma discharge space 12 and the liquid-carrying space 14 adjacent to the underside thereof form an interface 20 that includes a semipermeable membrane 22. The semipermeable membrane 22 is permeable to biologically reactive plasma factors from the plasma 16 formed in the plasma discharge space 12 and impermeable to the liquid 18 from the liquid-carrying space 14.

[0083] A positive electrode 26, insulated from the plasma discharge space 12 with a dielectric 24, is adjacent to the top surface of the plasma discharge space 12 as shown in the embodiment. A dissipative ground electrode 28 is adjacent to the semipermeable membrane 22 with orientation toward the plasma discharge space 12. The electrodes 26 and 28 may be formed by a single wire or may be lattice-, spindle-, meander-, or honeycomb-shaped.

[0084] When high voltage is applied to the electrodes 26 and 28, a physical plasma 16 is generated in the plasma discharge space 12. The biologically reactive plasma factors therein can migrate through the semipermeable membrane 22 into the liquid 18 in the liquid carrying space 14 due to Brownian motion, as indicated by the serpentine arrows.

[0085] FIG. 1B shows a second embodiment in which the structures and features corresponding to those of FIG. 1A are shown with the same reference signs. The embodiment shown in FIG. 1B differs from the embodiment shown in FIG. 1A in that now the ground electrode 28 no longer rests against the upper side of the semipermeable membrane 22 with orientation towards the plasma discharge space 12, but is arranged inside the liquid-carrying space 14. When high voltage is applied to the electrodes 26 and 28, the biologically reactive plasma factors now no longer migrate through the semipermeable membrane 22 into the liquid-carrying space 14 solely due to Brownian motion, but are “shot into” it in a charge-driven manner.

[0086] In FIG. 2, the medical device 10 according to the invention is shown according to a first embodiment (corresponding to the arrangement shown in FIG. 1A). Sub-figure A shows the device 10 in a broken-up plan view, and sub-figure B shows a cross-section through the device 10. Structures and features corresponding to those shown in FIGS. 1A and 1B are shown with the same reference signs. In addition, in this embodiment, the device 10 according to the invention has a high-voltage source 30 for applying high voltage to the electrodes 26 and 28, an outer insulation 32 insulating the positive electrode 26 from the outside, and a carrier 34 surrounding this outer insulation.

[0087] In FIG. 3, the medical device 10 according to the invention is shown according to the second embodiment (corresponding to the arrangement shown in FIG. 1B). Sub-figure A shows the device 10 in a broken-up plan view, sub-figure B shows a cross-section through the device 10. Structures and features corresponding to those of FIG. 2 are shown with the same reference signs.

[0088] In FIG. 4, the medical device 10 according to the invention is shown in a third embodiment, in which the structures and spaces are arranged in a sandwich-like manner in horizontal layering in a carrier 34 with a box-like design. Structures and features corresponding to those of FIGS. 1, 2 and 3 are shown with the same reference signs.

[0089] FIG. 5 schematically shows the use of the device 10 according to the invention during a gynecological operation. Also shown are a pump 36 connected to the device according to the invention for supplying liquid via a hose 38, a high-voltage source or high-voltage generator 30 for applying high voltage to the electrodes via a cable 40, and a gas connection with a gas source 42 and a gas line 44, via which a carrier gas can be introduced into the plasma discharge space 12 and, if necessary, discharged again.

2. Plasma-Activated Liquid Enables Specific Inhibition of ECM-Producing Connective Tissue Cells for Prophylaxis of Postoperative Adhesions—Experiments

[0090] Gynecologic and general surgery below the transverse colon carries a particularly high risk for postoperative adhesions (PA) and associated severe disease. Clinically, PAs are often characterized by chronic severe pain syndromes in the abdomen, flanks, or back that are often misdiagnosed for years. PAs also account for 15-20% of all cases of secondary infertility and 50-70% of all mechanical ileus. PAs are estimated to cause enormous costs to health care systems. The cause of PA is excessive extracellular matrix (ECM) formation due to activation of peritoneal mesothelial cells, fibroblasts and immune cells. Plasma activated liquid (PAL) could prevent PA by inhibiting the dysregulation and overproliferation of fibrin and ECM-producing connective tissue cells.

[0091] Dose-dependent PAL treatment of primary human mesothelial cells and fibroblasts with the device of the invention showed a defined and reproducible therapeutic window (denoted here as 1:2) (FIG. 1a,b). With this PAL concentration, the excessive cellular proliferation of ECM- and fibrin-producing fibroblasts could be significantly inhibited, whereas the physiological cell proliferation of mesothelial cells did not change significantly. Extracellular amounts of soluble procollagen (less cross-linked) were significantly increased after PAL treatment, whereas insoluble (highly cross-linked) collagen significantly decreased. The selective antiproliferative effect on primary fibroblasts was associated with significant G2 cell cycle arrest and a significant decrease in cellular viability. Interestingly, the same PAL dose showed a significant increase in mesothelial cell viability.

[0092] Accordingly, peritoneal PAL treatment using the device of the invention offers a hopeful medical application to selectively reduce postoperative (over)proliferation of ECM and fibrin-producing fibroblasts, as well as synthesis and cross-linking of functional ECM components such as collagen.