EP0683690A1

EP0683690A1 - Modified membrane for medical purposes

Info

Publication number: EP0683690A1
Application number: EP94906922A
Authority: EP
Inventors: Thomas Flottmann; Karl Kopp; Horst-Dieter Lemke
Original assignee: Kopp Karl; Akzo Nobel NV
Current assignee: Kopp Karl
Priority date: 1993-02-10
Filing date: 1994-02-08
Publication date: 1995-11-29
Also published as: WO1994017904A1; JPH08506741A

Abstract

A membrane for medical purposes treated with a low pressure plasma is modified so that its complement activation capacity and thrombogenicity are reduced with respect to non-modified dialysis membranes. The membrane is characterized in that complement activation is reduced by at least 50 % and thrombogenicity by at least 5 %. Also disclosed is a process for manufacturing this plasma-modified membrane.

Description

Modified membrane for medical purposes

Description:

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. A large number of different properties and parameters are summarized under the term biocompatibility, which essentially determine the blood tolerance of dialyzers,

Determine and influence membranes and other components.

In the area of medical treatment of dialysis patients, the so-called zero definition has generally prevailed for the definition of blood tolerance, i.e. that the components of such a system and the system itself should meet as many of the following requirements as possible:

- no thrombogenic, toxic, allergic or inflammatory reactions

- no destruction of biological cells

- no changes in plasma proteins and enzymes

- no carcinogenic effects

- no changes in the surrounding tissue.

The biocompatibility data of the individual components of the system, such as the degree and type of sterilization (sterility), the housing design, the embedding material of the actual membrane and some other factors, determine the biocompatibility of the entire system. In the context of the present invention, above all 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. For example, 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.

Chemically modified membranes, especially dialysis membranes, which have improved biocompatibility, are described, for example, in DE-OS 39 01 945, DE-OS 39 01 946, DE-OS 39 01 947, DE-OS 38 14 326, DE-OS 35 24 596, DE-PS 33 41 113 and EP-A-0 459 293.

In dialysis and also in other applications, 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.

In general, however, the processes for chemically modifying membranes have proven to be complicated and uneconomical. In addition, often only one of the parameters influencing the biocompatibility is improved, while one or more others - in particular the thrombogenicity - deteriorate.

It has therefore already been proposed to influence the membrane material by physical action, for example by treatment with a plasma. For the purposes of the invention, 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.

For this purpose, 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.

For example, 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 μm 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. In addition to the fact that these are highly questionable substances in terms of environmental protection, there is also the disadvantage that 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.

In hemodialysis using membranes made from regenerated cellulose, among other phenomena, a clear complement activation has also been found. 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.

At the same time, 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.

In this context, reference is made to the following work: D.E. Chenoweth et al, Kidney International Vol. 24, pages 764 ff, 1983, and D.E. Chenoweth, Asaio-Journal Vol. 7, pages 44 ff, 1984.

In the context of the present invention, the complement activation was assessed using the fragment C5a. For this purpose, in the case of hollow fibers, 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.

Although the clinical significance of complement activation has not yet been clarified, efforts are being made to exclude it as much as possible during hemodialysis.

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.

In principle, 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. In addition, the injury to the vascular endothelium via the so-called exogenous system has a clotting effect. In the end, 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.

The inhibition of thrombin by antithrombin III leads to the TAT (thrombin-antithrombin III complex), which was used in the context of the present invention to assess thrombogenicity. As the platelet coagulation is promoted by platelets, the number of platelets (platelet count) is particularly useful as a thrombogenicity parameter.

During the dialysis treatment of a kidney patient with dialyzers that contain membranes made from regenerated cellulose, a temporary drop in the number of leukocytes occurs in the dialysis treatment. This effect is known as leukopenia. 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.

Cellulose membranes cause pronounced leukopenia. Even if the clinical significance of leukopenia has not been scientifically clarified, there is still a desire for a dialysis membrane for hemodialysis which does not show the effect of leukopenia without impairing the other very desirable positive properties of dialysis membranes made from regenerated cellulose.

The substances that also influence the biocompatibility of a membrane include albumin and the ß2-microglobulin. ß2-microglobulin (molecular weight approx. 11,800) is loosely bound to the surface of all nucleated cells as part of the main histocompatibility antigen complex. 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.

This increase in the β2-microglobulin level in long-term dialysis patients is observed in particular after the use of membranes made from regenerated cellulose and is attributed to the fact that these membranes are less permeable in the molecular range of 1000 to 20,000 and the microglobulins are therefore not sufficient in dialysis the dimensions are removed. It is therefore of great interest that the β2-microglobulin is effectively removed during the treatment.

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.

In the case of the various membranes which are suitable for medical purposes and which have long been used for dialysis and ultrafiltration, there is a desire to have membranes which have as little complement activation as possible. All other important parameters which are characteristic of such a membrane should be retained or at least not deteriorated.

So far, however, it has not been possible or only possible using complex methods to treat membranes for medical purposes in such a way that that later you get a well-functioning membrane, but only with a low complement activation. In addition, the thrombogenicity parameters should not be deteriorated in such a membrane.

It was therefore an object of the invention to provide a membrane for medical purposes, in which the outer surface can be influenced in a targeted manner so that its biocompatibility, in particular with regard to C5a complement activation, is increased.

This object is achieved with a membrane according to the preamble of claim 1, characterized in that the reduction in C5a complement activation is at least 50% and the reduction in thrombogenicity is at least 5%.

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.

Their essential transport and separation properties are preferred, at least with regard to the ultrafiltration rate, the dialysis performance for vitamin B12 and creatinine and the sieving coefficients for albumin and β2-microglobulin, compared to the unmodified membrane, the same or improved or at least not significantly deteriorated . Not significantly deteriorated means at most in the order of 10%, but preferably less than 10%. Synthetic or natural polymers or mixtures thereof are used as the material for the membrane.

In one embodiment of the invention, polyacrylonitrile, polysulfone, polyether sulfone, sulfonated polysulfone, sulfonated polyether sulfone, polyvinylidene fluoride, polycarbonates, polypropylene, polyamide, polystyrene and / or polyurethanes are used as synthetic polymers.

In a further advantageous embodiment of the invention, 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.

In one embodiment of the invention, 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. However, the non-continuous treatment is preferably carried out with defined membrane pieces. The treatment can be carried out on one or two sides.

It is expedient that the energy density of the plasma generated during the treatment is approximately S

0.00 to 1.2 - is. c

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.

It goes without saying that if plasma treatment sections other than 10 to 30 cm are present, the speed is adapted to the corresponding dimensions. 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.

The invention is illustrated by the following examples:

example 1

A 12 x 32 cm Cuprophan flat membrane was plasma-treated in a vacuum chamber. For this purpose, 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.

Treatment parameters:

Gas mixture: Sθ2 / argon (30%) Total gas flow: 150 ml / min. Total pressure: 1.8.10 mbar

The treatment lasted 24 seconds.

The plasma-treated flat membrane showed a 88% reduction in C5a complement activation compared to the untreated flat membrane.

The values for the ultrafiltration rate, the dialysis power for NaCl, vitamin B12 and urea were unchanged before and after the plasma treatment within the scope of the usual measurement accuracy. The values for the breaking strength and elongation at break of the membrane also remained unchanged. Example 2

In accordance with 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.

The other performance data of the membrane did not change significantly.

Example 3

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.

The reduction in C5a complement activation was 77.2% compared to the untreated membrane, while the other data showed no significant changes.

Example 4

The procedure was as in Example 3, the speed of the film being 25 m / min.

The reduction in C5a complement activation was 91.2%, while the other data showed no significant changes.

Claims

Modified membrane for medical purposes

1. By treatment with a low-pressure plasma modified dialysis membrane for medical purposes, which thereby has a reduction in complement activation and thrombogenicity compared to the unmodified dialysis membrane, characterized in that the reduction in complement activation is at least 50% and the reduction in thrombogenicity is at least 5 % is.

2. Membrane according to claim 1, characterized in that the reduction in complement activation is more than 85%.

3. Membrane according to claim 1, characterized in that the reduction in complement activation is more than 90%.

4. Membrane according to one or more of claims 1 to 3, characterized in that its essential transport and separation properties, at least with regard to the ultrafiltration rate, the dialysis performance for vitamin B12 and creatinine and the sieving coefficient for albumin and β2-microglobulin, compared to the non- modified membrane are the same or improved or at least not significantly deteriorated.

5. Membrane according to one or more of claims 1 to 4, characterized in that synthetic or natural polymers or mixtures thereof are used as the material for the membrane.

6. A membrane according to claim 5, characterized in that polyacrylonitrile, polysulfone, polyether sulfone, sulfonated polysulfone, sulfonated polyether sulfone, polyvinylidene fluoride, polycarbonates, polypropylene, polyamides, polystyrene and / or polyurethane are used as synthetic polymers.

7. Membrane according to claim 5, characterized in that regenerated cellulose and cellulose derivatives are used as natural polymers.

8. Membrane according to one or more of claims 1 to 7, characterized in that it is a tubular membrane, a hollow fiber membrane or a flat membrane.

9. Membrane according to one or more of claims 1 to 8, characterized in that only one surface of the membrane is modified by treatment with a low pressure plasma.

10. Membrane according to claim 9, characterized in that it is the surface which is later turned to the blood during dialysis.

11. Membrane according to one or more of claims 1 to 8, characterized in that both surfaces of the membrane are modified by treatment with a low pressure plasma.

12. A method for producing a membrane for medical purposes by treatment with a low-pressure plasma according to claim 1, characterized in that an untreated dialysis membrane with a speed of more than 2 m / min, based on a plasma treatment distance of 10 to 30 cm by a Space in which a low-pressure plasma is present is passed through.

13. The method according to claim 12, characterized in that the speed is more than 50 m / min.

14. The method according to one or more of claims 12 to 13, characterized in that the treatment with sulfur dioxide, water, air, oxygen, nitrogen, a mixture of methane and oxygen, individually or in a mixture with noble gases, preferably argon, takes place.

15. A method for producing a membrane for medical purposes by treatment with a low-pressure plasma according to claim 1, characterized in that the membrane for a time of 0.1 to 10 seconds with a plasma energy density of 0.04 to 1.2 Ws / cm treated.

16. The method according to claim 12, characterized in that the membrane for a time of 0.1 to 10 seconds with a plasma energy density of 0.04 to

•)

1.2 Ws / cm treated.