WO1994017904A1 - Modified membrane for medical purposes - Google Patents
Modified membrane for medical purposes Download PDFInfo
- Publication number
- WO1994017904A1 WO1994017904A1 PCT/EP1994/000355 EP9400355W WO9417904A1 WO 1994017904 A1 WO1994017904 A1 WO 1994017904A1 EP 9400355 W EP9400355 W EP 9400355W WO 9417904 A1 WO9417904 A1 WO 9417904A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- membrane
- treatment
- plasma
- dialysis
- modified
- Prior art date
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
- B01D67/0081—After-treatment of organic or inorganic membranes
- B01D67/009—After-treatment of organic or inorganic membranes with wave-energy, particle-radiation or plasma
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/0094—Physical treatment, e.g. plasma treatment
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C59/00—Surface shaping of articles, e.g. embossing; Apparatus therefor
- B29C59/14—Surface shaping of articles, e.g. embossing; Apparatus therefor by plasma treatment
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29L—INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES
- B29L2031/00—Other particular articles
- B29L2031/755—Membranes, diaphragms
Definitions
- the invention relates to a membrane modified by treatment with a low-pressure plasma for medical purposes, which thereby has a reduction in complement activation and thrombogenicity compared to the unmodified membrane.
- Membranes for medical purposes in the form of flat membranes, tubular membranes or hollow fiber membranes have been known for a long time, with very high demands being placed on these membranes (for example those for dialysis, hemodialysis, He ofiltration, oxygenation and others) with regard to the so-called “biocompatibility" so that the blood flowing past the membranes is affected as little as possible.
- biocompatibility A large number of different properties and parameters are summarized under the term biocompatibility, which essentially determine the blood tolerance of dialyzers,
- the biocompatibility data of the individual components of the system determine the biocompatibility of the entire system.
- the biocompatibility of the membrane material or the membrane itself is assessed.
- Essential aspects of biocompatibility are, for example, thrombogenicity, complement activation, leucopenia and the sieving coefficients for ß2-microglobulin, albumin and other substances.
- a number of methods have been proposed to influence the properties of such a membrane with a view to improving the biocompatibility.
- the membrane material can be chemically modified in order to obtain a less or more active surface of the membrane, which then has an effect on certain of the above-mentioned factors.
- these membranes show a strong reduction in C5a complement activation compared to unmodified membranes, but in contrast to classic dialysis membranes, such as cuprophan, in some cases show increased thrombogenicity, so that problems are encountered in the treatment of patients may occur.
- plasma is a gas in Plasma state (according to LANGMUIR) understood. It is a highly ionized gas with special properties, which is based on the interactions of the ions, electrons, excited atoms and radiation quanta present in the plasma.
- gases or gas mixtures are electrically excited by means of a gas discharge in such a way that the plasma state just mentioned is reached.
- a mixture of neutral gas, electron gas, excited atoms, ions and light quanta is created. This mixture can then be used, for example, for surface activation of membranes and other bodies.
- DD 0 272 340 describes a planar, coarse-pore membrane made of an acrylonitrile polymer and a process for its production, whereby by successive or simultaneous layering of a casting solution containing the acrylonitrile polymer and an incompatible solution of a second polymer and subsequent solution Coagulation are deformed into a 2-layer molded body, characterized in that before or after the separation of the 2-layer body, the surface layer of the membrane formed from the acrylonitrile polymer is subjected to a low-temperature plasma treatment in an inert medium with an energy of 330 to 3300 Wsc transferred to the membrane .
- the membranes produced in this way are distinguished by the approximately uniform size of the pores present in the separating layer on the top of the membrane. These membranes are suitable for microfiltration or as supports for the production of composite membranes.
- DE-OS 35 09 068 describes pore membranes which are obtained by the action of plasma or corona discharge in the presence of gaseous substances on pore membranes and, if necessary, chemical modification. These pore membranes are produced by subjecting a pore membrane to a plasma or corona discharge in the presence of gaseous substances and then modifying them chemically if necessary. The pore membranes are then used for the desalination or concentration of aqueous or liquid systems, which may contain dyes, for example.
- DE-OS 37 12 491 describes a hydrophobic, microporous microfiltration membrane with a permanently hydrophilic surface and a pore size of about 0.1 ⁇ m or less for separating particles from aqueous solutions, containing a hydrophobic, microporous microfiltration substrate with a permanently hydrophilic surface , which has received its permanently hydrophilic surface through treatment with a non-polymerizable plasma gas, the body of the substrate largely having the same properties as pore size, hydrophobicity, mechanical strength and chemical resistance as the original substrate before the treatment. These membranes are then used for use in bioreactors.
- Membranes treated with low pressure plasma show a reduced complement activation (F. Poncin-Epaillard et al., Journal of Applied Polymer Science, Vol. 44, 1513-1522 (1992)), the treating plasma gas consisting of tetrafluorocarbon or sulfur hexafluoride.
- the treated membranes have a significantly increased thrombogenicity. The treatment time is a few minutes, so that the modified membrane cannot be produced economically.
- Membranes that are supposed to be suitable for medical purposes must have the highest possible biocompatibility, as has already been described in the beginning.
- the complement system within the blood plasma is a complex plasma enzyme system consisting of many components, which serves in various ways to ward off damage caused by invading foreign cells (bacteria, etc.). If antibodies against the penetrating organism are present, the complement system can be activated by the complex of the antibodies with antigenic structures of the foreign cells, otherwise the complement activation takes place in an alternative way through special surface features of the foreign cells. After activation, these proteins react specifically with one another in a certain order and, at the end, a cell-damaging complex is formed, which destroys the foreign cell.
- peptides such as C5a and C3a are released from individual components, which trigger inflammation symptoms and can occasionally also cause undesirable allergic reactions of the organism. It is assumed that the activation in hemodialysis membranes regenerated cellulose via the alternative route. Complement activation is determined objectively by determining the complement fragments C3a or C5a.
- the complement activation was assessed using the fragment C5a.
- 250 ml of heparinized blood were recirculated over a period of 4 hours with a plasma flow of 100 ml / min through a dialyzer with an effective exchange surface of 1 m.
- the C5a fragments were determined in the plasma using ELISA (enzyme-linked immunosorbent assay) from Behring.
- the relative complement activation for the respective time of measurement was calculated by forming the ratio of the concentration at the time of sampling and the initial value in percent. The measured value after 4 hours of recirculation was used for the evaluation.
- Flat membranes are incubated with 8 ml heparinized blood for 3 hours and then the C5a concentration is determined.
- Dialysis membranes can very easily cause blood to clot when used therapeutically in the artificial kidney. This is usually prevented by medication using heparin. However, the heparin will underdosed, the thrombogenicity of a dialysis membrane can have an adverse effect on the patient.
- Plasma coagulation is a complex, enzymatically controlled process. Similar to the complement system, about 20 plasma proteins work together, both promoting and inhibiting and thus controlling the coagulation process.
- plasma coagulation can be triggered by two different biological mechanisms.
- the so-called endogenous system plays a major role in the activation of foreign surfaces.
- the injury to the vascular endothelium via the so-called exogenous system has a clotting effect.
- both ways lead to the formation of the central enzyme for coagulation, thrombin.
- the main inhibitor of thrombin and blood coagulation as a whole is antithrombin III.
- TAT thrombin-antithrombin III complex
- platelet count is particularly useful as a thrombogenicity parameter.
- leukopenia is a decrease in the number of leukocytes (white blood cells) in the bloodstream.
- the number of white blood cells in humans is approximately 4,000 to 12,000 cells / mm 3 .
- Dialysis leukopenia is most pronounced 15 to 20 minutes after the start of treatment, although the neutrophils (those that can be stained with neutral or simultaneously stained with acid and basic dyes) can almost completely disappear. After that, the number of leukocytes recovers to almost the original value or exceeds it within about an hour. If a new dialyzer is connected after the leukocytes have recovered, leukopenia occurs again to the same extent.
- the substances that also influence the biocompatibility of a membrane include albumin and the ß2-microglobulin.
- ß2-microglobulin molecular weight approx. 11,800
- This complex is responsible for the compatibility of foreign tissue with the body's own tissue.
- ß2-microglobulin is only broken down in the kidney, the daily production rate in healthy people is about 150 mg. However, dialysis patients and uraemics have much higher ß2-microglobulin plasma levels than healthy people.
- the albumins also belong to the group of serum proteins, and represent the largest group in them.
- the albumins maintain the colloid osmotic pressure and transport the body's own and foreign non-molecular substances. They also form the body's protein reservoir. Since the number of albumins is generally reduced in dialysis patients, care must be taken during treatment that the albumin loss remains as small as possible.
- the degree of reduction in C5a complement activation is preferably even greater and is more than 85%, in particular more than 90%.
- the membrane according to the invention is further characterized in that it has an improved thrombogenicity compared to the unmodified membrane.
- polyacrylonitrile, polysulfone, polyether sulfone, sulfonated polysulfone, sulfonated polyether sulfone, polyvinylidene fluoride, polycarbonates, polypropylene, polyamide, polystyrene and / or polyurethanes are used as synthetic polymers.
- regenerated cellulose and cellulose derivatives are used as natural polymers.
- the membrane according to the invention can be designed in various ways, for example as a tubular membrane, as a hollow fiber membrane or as a flat membrane.
- both surfaces of the membrane are modified by treatment with a low-pressure plasma.
- the object is also achieved by a method for producing a membrane for medical purposes by treatment with a low-pressure plasma, characterized in that an untreated dialysis membrane at a speed of more than 2 m / min, based on a plasma treatment line of 10 to 30 cm is passed through a room in which a low-pressure plasma is present.
- the speed is preferably more than 50 m / min. It is also possible not to carry out the process continuously, with cut membrane films (in the case of flat membranes) or generally membrane sections being treated individually with a low-pressure plasma. On the other hand, transport speeds of 2 to 200 m / min for the membrane are possible in continuous processes.
- the non-continuous mode of operation can take place in such a way that a continuous belt is led batchwise through the plasma treatment section and is moved on after the corresponding treatment time.
- the non-continuous treatment is preferably carried out with defined membrane pieces.
- the treatment can be carried out on one or two sides.
- the energy density of the plasma generated during the treatment is approximately S
- the duration of treatment or dwell time in the plasma section is generally between 0.1 and 10 seconds.
- the treatment of the invention advantageously changes the surface of the membrane.
- the changes in the surface generally cover a range of about 1 to 2 nm.
- the treatment is preferably carried out with sulfur dioxide, water, air, oxygen, nitrogen, a mixture of methane and oxygen, individually or in a mixture with noble gases, preferably argon.
- a 12 x 32 cm Cuprophan flat membrane was plasma-treated in a vacuum chamber.
- the flat membrane was stretched onto the inside of a copper cylinder, which was then mounted on a test plate in the vacuum chamber.
- the copper cylinder and the chamber wall formed the electrodes for the high frequency (13.56 MHz), with an intense and homogeneous plasma burning inside the copper cylinder.
- the flat membrane was therefore only treated on one side.
- the treatment lasted 24 seconds.
- the plasma-treated flat membrane showed a 88% reduction in C5a complement activation compared to the untreated flat membrane.
- Example 1 instead of the Cuprophan flat membrane, an SPES flat membrane (Vitrex 5200 G) was treated with the gas mixture of Example 1 for 28 seconds. All other test conditions corresponded to those of Example 1.
- the plasma treated SPES membrane showed a 86% reduction in C5a complement activation.
- a 25 cm wide Cuprophan flat membrane wound on a roll was drawn through a 50 x 30 cm plasma treatment room at a speed of 2 m / min.
- the plasma (13.56 MHz HF) was coupled in via a hollow cathode, whereby spatial concentration of the plasma space is achieved.
- a water / argon mixture (30% argon) was used as the plasma gas.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP94906922A EP0683690A1 (en) | 1993-02-10 | 1994-02-08 | Modified membrane for medical purposes |
JP6517658A JPH08506741A (en) | 1993-02-10 | 1994-02-08 | Modified membrane for medical purposes |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4303870 | 1993-02-10 | ||
DEP4303870.0 | 1993-02-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1994017904A1 true WO1994017904A1 (en) | 1994-08-18 |
WO1994017904A9 WO1994017904A9 (en) | 1994-09-29 |
Family
ID=6480069
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1994/000355 WO1994017904A1 (en) | 1993-02-10 | 1994-02-08 | Modified membrane for medical purposes |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0683690A1 (en) |
JP (1) | JPH08506741A (en) |
WO (1) | WO1994017904A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0873756A2 (en) * | 1997-04-21 | 1998-10-28 | Hüls Aktiengesellschaft | Antibacterial blood compatible modified surfaces |
WO2003045461A1 (en) * | 2001-11-23 | 2003-06-05 | Feg Textiltechnik Forschungs- Und Entwicklungsgesellschaft Mbh | Surface-modified textile product and a corresponding method for surface modification |
FR2842122A1 (en) * | 2002-07-10 | 2004-01-16 | Maco Pharma Sa | SELECTIVE DELEUCOCYTATION UNIT FOR A PLATELET PRODUCT |
WO2005097154A2 (en) * | 2004-04-06 | 2005-10-20 | Manfred Schmolz | Neurotransmitter mixture which promotes the healing of wounds |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59186604A (en) * | 1983-04-06 | 1984-10-23 | Fuji Photo Film Co Ltd | Membrane filter made hydrophilic by positive column plasma treatment |
DE3509068A1 (en) * | 1985-03-14 | 1986-09-18 | Bayer Ag, 5090 Leverkusen | Pore membranes |
DE3712491A1 (en) * | 1986-04-11 | 1987-10-15 | Applied Membrane Tech | Microfiltration membrane, process for the production thereof and use thereof |
EP0323341A2 (en) * | 1987-12-25 | 1989-07-05 | TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION | Medical instrument |
EP0513389A1 (en) * | 1990-11-29 | 1992-11-19 | Nitto Denko Corporation | Liquid-filtering film and filtering device using said film |
-
1994
- 1994-02-08 JP JP6517658A patent/JPH08506741A/en active Pending
- 1994-02-08 WO PCT/EP1994/000355 patent/WO1994017904A1/en not_active Application Discontinuation
- 1994-02-08 EP EP94906922A patent/EP0683690A1/en not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59186604A (en) * | 1983-04-06 | 1984-10-23 | Fuji Photo Film Co Ltd | Membrane filter made hydrophilic by positive column plasma treatment |
DE3509068A1 (en) * | 1985-03-14 | 1986-09-18 | Bayer Ag, 5090 Leverkusen | Pore membranes |
DE3712491A1 (en) * | 1986-04-11 | 1987-10-15 | Applied Membrane Tech | Microfiltration membrane, process for the production thereof and use thereof |
EP0323341A2 (en) * | 1987-12-25 | 1989-07-05 | TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION | Medical instrument |
EP0513389A1 (en) * | 1990-11-29 | 1992-11-19 | Nitto Denko Corporation | Liquid-filtering film and filtering device using said film |
Non-Patent Citations (6)
Title |
---|
CHEMICAL ABSTRACTS, vol. 102, no. 10, 11 March 1985, Columbus, Ohio, US; abstract no. 80997t * |
DATABASE WPI Section Ch Week 8448, Derwent World Patents Index; Class A11, AN 84-298548 * |
F. VIGO: "Poly(vinyl chloride) ultrafiltration membranes modified by high frequency discharge treatment", JOURNAL OF MEMBRANE SCIENCE, vol. 36, no. 1, March 1988 (1988-03-01), AMSTERDAM, NL, pages 187 - 199, XP000008334, DOI: doi:10.1016/0376-7388(88)80016-4 * |
P.W. KRAMER: "Low temperature plasma for thr preparation of separation membranes", JOURNAL OF MEMBRANE SCIENCE, vol. 46, no. 1, September 1989 (1989-09-01), AMSTERDAM, NL, pages 1 - 28, XP000114357, DOI: doi:10.1016/S0376-7388(00)81167-9 * |
PATENT ABSTRACTS OF JAPAN vol. 9, no. 41 (C - 267) 21 February 1985 (1985-02-21) * |
PONCIN-EPAILLARD: "Plasma Modification of Cellulose Derivatives as Biomaterials", JOURNAL OF APPLIED POLYMER SCIENCE, vol. 44, 1992, NEW-YORK, pages 1513 - 1522 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0873756A2 (en) * | 1997-04-21 | 1998-10-28 | Hüls Aktiengesellschaft | Antibacterial blood compatible modified surfaces |
US6022553A (en) * | 1997-04-21 | 2000-02-08 | Huels Aktiengesellschaft | Method of making a blood-compatible antimicrobial surface |
EP0873756A3 (en) * | 1997-04-21 | 2000-09-20 | Degussa-Hüls Aktiengesellschaft | Antibacterial blood compatible modified surfaces |
WO2003045461A1 (en) * | 2001-11-23 | 2003-06-05 | Feg Textiltechnik Forschungs- Und Entwicklungsgesellschaft Mbh | Surface-modified textile product and a corresponding method for surface modification |
FR2842122A1 (en) * | 2002-07-10 | 2004-01-16 | Maco Pharma Sa | SELECTIVE DELEUCOCYTATION UNIT FOR A PLATELET PRODUCT |
EP1382361A1 (en) * | 2002-07-10 | 2004-01-21 | Maco Pharma | Unit for the selective removal of leucocytes from a platelet product |
US7140497B2 (en) | 2002-07-10 | 2006-11-28 | Macopharma | Selective deleukocytation unit for a platelet product |
WO2005097154A2 (en) * | 2004-04-06 | 2005-10-20 | Manfred Schmolz | Neurotransmitter mixture which promotes the healing of wounds |
WO2005097154A3 (en) * | 2004-04-06 | 2007-08-09 | Manfred Schmolz | Neurotransmitter mixture which promotes the healing of wounds |
Also Published As
Publication number | Publication date |
---|---|
JPH08506741A (en) | 1996-07-23 |
EP0683690A1 (en) | 1995-11-29 |
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