DE2508416A1 - Membrane for medical-biological uses - comprising copolymer of vinyl sulphonic acid and acrylonitrile - Google Patents

Abstract

A membrane consisting of a copolymer of vinyl sulphonic acid and acrylonitrile in a molar propn. of 1:20 to 1:1, in medical-biological appts. in contact with bloo, cells or body tissue, or as artificial organs or as a component of an artificial organ. In partic. the membrane can be used for haemodialysis or haemoperfusion, or for perfusion cell cultures as artificial skin. The copolymerise. of vinylsulphonic acid with acrylonitrile is simplified by avoiding use of emulsifiers and the resulting polymer is water insoluble without cross-linking but soluble in organic solvents. The partic. combination of monomers in the copolymers produces the excellent, bio-compatibility of the materials, the required variable selectivity w.r.t. metabolites, nutrients or toxins and brings about the flexibility, resistance to decomposition, or mechanical damage, the sterilisability as well as the simple and reproducible processing to extremely thin film. (1 mu m) or capillaries.

Description

Use of a membrane for medical-biological purposes The invention refers to a novel use of a particular membrane.

In the field of medical technology, including both medical-biological Devices, for example for hemqdialysis, hemoperfusion, etc., as well as artificial ones Organs and components artificial organs, artificial skin and Artificial pancreas are counted, different plastics are called today Membranes used (see summaries in: hemodialysis and peritoneal dialysis, E. Wetzels, Springer-Verlag 1970, So 70 and Handbook of Biomedical Plastics, He Lee, K. Neville, Pasadena Technology Press, 1971, So 13/2-13/5) Membranes, the consist mainly of regenerated cellulose (DT-OS 2 116 067), are due to their tested dialysance of urinary substances in clinics for operation in artificial ones Kidneys (hemodialysis).

Due to the fluctuating properties of the natural raw materials However, the clinics will achieve better reproducibility, including with regard to mechanical Strength or the avoidance of submicroscopic defects is required. Above all but the hitherto unsolved problem of blood tolerance is in the foreground, that also with new hemodialysis membranes made of polyacrylonitrile (Proc. E, D, T, A ,, June 1972, 9, 55-66) remains open, other membranes, for example those from Collagen (DT-OS 2 009 515) with partially improved blood compatibility again only a low tensile strength or, in the case of membranes, are based from poly - # - amino acids (Proc. 6th Annual Contractors' Conference of the Artificåal Kidney Program, U.S. Department of Health, Bethesda, Maryland, February 19739 pp. 217-226) on expensive raw materials, also for blood detoxification With the help of hemoperfusion, membranes are used, e.g. as a coating of granulated Adsorbents The membranes that are permeable to toxic substances, such as hydrogels (Lancet 1 (1974) 1301-1307) show poor mechanical properties, especially when used in flat, non-granular membrane shapes. On the other hand own more stable columbium or nylon membranes (Artificial Cells, TeMoSo Chang, C.C, Thomas Publisher, Springfield 1972) only inadequate blood tolerance, which is only due to expensive subsequent surface treatment with heparin or serum albumin Can be improved, even the coverage of large wounds and burns With an artificial skin, attempts are now being made with membranes, for example with Membranes made of collagen (ASAIO Conference, Chicago, April 1974, Sun 60/64) or silicone (Trans. Amer. Soc. Artif. Int. Organs XVIII (1972) 39-43).

Due to poor tissue compatibility, mechanical stimulation or lack of fibroblast proliferation, however, must still be natural materials such as pig skin or split skin flaps are used, with the disadvantages of difficult availability or antigenicity.

Finally, membrane compartments also gain for the continuous Cultivation of cells in differentiated state as perfusion culture systems increasing Interest, e.g. for the cultivation of insulin-producing cells as an artificial pancreas (Battelle-Information 19 (1974) 60) This involves hormone-producing cell cultures continuously supplied with nutrient solution in compartments via permeable membranes and the resulting metabolites are removed and thus a natural steady state maintained, However, the known flat membranes used for this prove to be or membrane capillaries as insufficient, especially for the cultivation of three-dimensional, doh.

layered cultures, the reasons for this are either in the not selective supply and disposal of the cells or in the low cell tolerance the plastics used, for example cellulose-based membranes.

The object of the present invention is therefore to provide a medical-technical Range of widely usable, easy to manufacture and sterilizable membrane found that are both highly compatible with blood, cells or body tissues excels as well as in their selectivity, for example with respect to different ones Metabolites are suitably modifiable, Surprisingly it has it has now been shown that these very diverse, - partly still unsolved tasks can be met by a single type of membrane consisting of a copolymer of Vinyl sulfonic acid built up with acrylonitrile in molar proportions of 1:20 to 1: 1 is, depending on the proportion of vinyl sulfonic acid, the blood, cell and tissue compatibility promoted, but at the same time also the high permselectivity achieved. Due to the specific proportion of acrylonitrile, on the other hand, caused the high mechanical strength and the film-forming properties.

The copolymerization of vinyl sulfonic acid is effected by acrylonitrile in The polymer makes it easier to use aqueous solution by avoiding emulsifiers already insoluble in water without crosslinking? but still readily soluble in organic ones solvents, for example in N-methylpyrrolidone, dimethylformamide, dimethylacetamide or dimethyl sulfoxide. Just the specific combination of these two monomers in proportions from 1:20 to 1: 1, the surprisingly wide range of applications is called for and the unexpectedly high variability of the material Biocompatibility of the material, the different selectivity required endogenous metabolites, nutrients or toxins and causes the flexibility, Resistance to degradation or mechanical damage, the sterilizability as well as the simple and reproducible processing even into extremely thin films (<1 / um) or capillaries Further features, advantages and details of the invention, especially the functionally essential membrane, is based on the following explanation based on some exemplary embodiments of the invention.

Example 1: A solution of 25 g of sodium vinyl sulfonic acid and 21 g of acrylonitrile in 100 ml of water is adjusted to pH 1 with hydrochloric acid, excess Hydrochloric acid is expelled with nitrogen and the solution with 0.01 NaHSO3 and 24 g K2S208 offset. After about 50 hours of polymerization at OOC, methanol is used precipitated and washed, washed with water and dissolved in cold N-methylpyrrolidone. A solution of 15% by weight of the polymer is polished with a 200 μm doctor blade The glass plate was pulled out at room temperature, the film was precipitated in water and stored Membrane thickness (moist) 75 μm swelling in water 6% by volume tear strength 360 kg / cm2 (damp, 200C, withdrawal 30 mm / min).

In the nitrogen, sulfur analysis the polymer shows a molar ratio Vinyl sulfonic acid to acrylonitrile of 1: 16.1.

Example 2: There is a copolymer according to Example 1 with a molar Ratio of vinyl sulfonic acid to acrylonitrile of 1: 2.9. A solution of 15% by weight of the polymer is applied to a polished glass plate with a 200 μm doctor blade pulled out at room temperature, dried in vacuo for 16 hours and stored in water Membrane thickness (moist) 15 μm swelling in water 23% by volume tear strength 220 kg / cm2 (moist, 200 ° C., withdrawal 30 mm / min) O Example 3: 23 g of extruded activated carbon of the particle size 37-74 µm (American Norit Co., Inc.) is placed in a 1% sodium chloride solution and degassed in vacuo for 2-3 hours. After washing and filtering particles several times 10 / um (metal mesh, mesh size 20 - 30 / um) the activated carbon in 100 ml of an aqueous solution of 15% by weight copolymer of vinyl sulfonic acid with Acrylonitrile was stirred in in a molar ratio of 1: 2.9. After 2 hours, the mixture was homogeneous Suspension formed, which was drawn out on a polished glass plate with a doctor blade and dried in vacuo for 16 hours. 600 cm2 of the filled with adsorbent Membrane are placed in a glass cylinder in 14 300 ml of an aqueous solution of 100 Milligrams of 14C paracetamol incubated. It is stirred for 4 hours at 370C and the The membrane is then rinsed several times with distilled water. The one remaining in the solution Amount of paracetamol is determined in the scintillation counter with 27 milligrams, what corresponds to an amount of adsorbate of 73 milligrams.

Example 4: Three glass tubes each (inner diameter 10 mm, length 75 mm) are drawn out with copolymers according to Examples 1 and 2.

Appropriate tubes with silicone rubber (Dow Chemical, medical grade), polyacrylonitrile and visking cellophane lined, three further tubes are left unlined, with a siliconized needle equal amounts of human blood are placed in the tubes and the clotting times according to Lee-White determined: Glass: 3 minutes Cellophane: 7 minutes Polyacrylonitrile: 13 minutes silicone rubber: 19 minutes copolymer 1: 22 minutes Copolymer 2: 27 minutes Example 5: To test the tissue compatibility Membrane pieces (20 x 10 mm) with molar ratios of vinyl sulfonic acid to acrylonitrile : 1: 16.1 / 1: 7.2 / 1: 2.9 sterilized in 70% ethanol for 16 hours, 3 times Rinsed in sterile, double-distilled water for 30 minutes and in nutrient medium for 16 hours incubated for sterility control, in 4 Petri dishes each with nutrient medium (minimum Essential Medium Dulbecco's Modification) 0.2 ml cell suspension (106 cells / ml) Cells (mouse fibroblasts # connective tissue cells) or BHK cells (baby hamster kidney cells) inoculated. A piece of membrane was placed in each of 3 Petri dishes before the nutrient medium was added inserted. After 4 days there is a confluent cell layer in all Petri dishes, which appears denser on the membrane pieces; the polymers show no cytotoxicity.

Example 60 In a cylindrical dialysis cell, stirred on both sides A membrane according to the example is made from Plexiglas with a membrane area of 13.8 cm 2 1 and a membrane made of Cuprophan PT-150 (Bemberg) clamped as a reference. the Cells are in 4 test series with 100 ml of an aqueous solution each with 0.1 wt .-% urea, creatinine, vitamin B12 and human serum albumin charged. on 3 liters of distilled water are given to the dialysate side. In regular At intervals, 2 ml samples are taken from the cells and the decrease in concentration determined colorimetrically or photometrically. Converted to the same membrane thickness the following half-lives are measured during dialysis: Copolymer cuprophane urea 75 min. 78 min.

Creatinine 123 min. 149 min.

Vit.B12 310 min. 1380 min.

Serum albumin no decrease no decrease

Claims (3)

Claims Use of a membrane made from vinyl sulfonic acid and acrylonitrile in molar proportions from 1:20 to 1: 1, in medical-biological proportions Devices in contact with blood, cells or body tissues or as an artificial organ or as part of an artificial organ. 2. Use of the membrane according to claim 1 for hemodialysis or for haemoperfusion, 3. Use of the membrane according to claim 1 for perfusion cell cultures, than artificial skin.