EP0486625A1 - A method for producing a biocompatible surface - Google Patents
A method for producing a biocompatible surfaceInfo
- Publication number
- EP0486625A1 EP0486625A1 EP90917894A EP90917894A EP0486625A1 EP 0486625 A1 EP0486625 A1 EP 0486625A1 EP 90917894 A EP90917894 A EP 90917894A EP 90917894 A EP90917894 A EP 90917894A EP 0486625 A1 EP0486625 A1 EP 0486625A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- phospholipid
- coated
- blood
- solvent
- bath
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000000576 coating method Methods 0.000 claims abstract description 12
- 239000011248 coating agent Substances 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 4
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 2
- 239000007900 aqueous suspension Substances 0.000 claims description 2
- 229940067606 lecithin Drugs 0.000 claims description 2
- 235000010445 lecithin Nutrition 0.000 claims description 2
- 239000000787 lecithin Substances 0.000 claims description 2
- 238000003466 welding Methods 0.000 abstract 1
- 239000008280 blood Substances 0.000 description 12
- 210000004369 blood Anatomy 0.000 description 12
- -1 Phosphoglycerides phosphatidic acids Chemical class 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000000151 deposition Methods 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 4
- 206010053567 Coagulopathies Diseases 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 4
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 4
- 229940106189 ceramide Drugs 0.000 description 4
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 4
- 230000035602 clotting Effects 0.000 description 4
- GNGACRATGGDKBX-UHFFFAOYSA-N dihydroxyacetone phosphate Chemical compound OCC(=O)COP(O)(O)=O GNGACRATGGDKBX-UHFFFAOYSA-N 0.000 description 4
- 229920000669 heparin Polymers 0.000 description 4
- 229960002897 heparin Drugs 0.000 description 4
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 4
- 230000001453 nonthrombogenic effect Effects 0.000 description 4
- 238000002525 ultrasonication Methods 0.000 description 4
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229960000367 inositol Drugs 0.000 description 3
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- SUHOOTKUPISOBE-UHFFFAOYSA-N O-phosphoethanolamine Chemical compound NCCOP(O)(O)=O SUHOOTKUPISOBE-UHFFFAOYSA-N 0.000 description 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- 239000008344 egg yolk phospholipid Substances 0.000 description 2
- 150000002327 glycerophospholipids Chemical class 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- PUPFBTIOIIGQNH-OHUGJFQKSA-N C(C(O)CO)P(=O)=C([C@@H]1[C@H]([C@@H]([C@H](C(O1)C(C(C(O)C1[C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)O)O)O)O)O)O Chemical compound C(C(O)CO)P(=O)=C([C@@H]1[C@H]([C@@H]([C@H](C(O1)C(C(C(O)C1[C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)O)O)O)O)O)O PUPFBTIOIIGQNH-OHUGJFQKSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000005875 antibody response Effects 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- FRKBLBQTSTUKOV-UHFFFAOYSA-N diphosphatidyl glycerol Natural products OP(O)(=O)OCC(OP(O)(O)=O)COP(O)(O)=O FRKBLBQTSTUKOV-UHFFFAOYSA-N 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002759 monoacylglycerols Chemical class 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N monoethanolamine hydrochloride Natural products NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 229940042880 natural phospholipid Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 1
- 229950004354 phosphorylcholine Drugs 0.000 description 1
- 150000003019 phosphosphingolipids Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- 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
- A61L33/0005—Use of materials characterised by their function or physical properties
- A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
- A61L33/0041—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate characterised by the choice of an antithrombatic agent other than heparin
-
- 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
Definitions
- the present invention relates to methods for producing biocompatible surfaces by coating them with phospholipid and binding the phospholipid to the surface by means of ultrasonication.
- the formation of blood clots on the surfaces of these instruments is dangerous and may prove fatal if the clots are washed off by the blood flow into the vascular system.
- US Patent 4 426 330 discloses a chemically modified phospholipid for more stable coatings.
- US Patent 4 438 329 discloses a phospholipid chemically bonded to a polymer for coating surfaces.
- the introduction of new, chemically modified phospholipids into a human body or blood stream may have unforseen - 2 -
- the present invention concerns a method for producing a biocompatible surface, by coating the surface with phospholipid characterised by immersing the surface to be coated in a bath containing a suspension of phospholipid in a liquid in which it is sparingly soluble, and then ultrasonicating the bath to coat the surface with phospholipid.
- Another aspect of the invention concerns pre-treating the surface to be coated.
- the surface is firstly immersed in a phospholipid solution.
- the solution comprises phospholipid substantially dissolved in a solvent in which it is soluble, such as ethanol or chloroform.
- the surface is then removed from the solution and the solvent allowed to evaporate off.
- the dry surface is then subjected to the ultrasonication process described above.
- Any suitable surface may be coated, such as metal, glass, plastics or ceramics. Any phospholipid may be used and some examples are described in Table 1. TABLE 1
- Phosphoglycerides phosphatidic acids cytidylic phosphoglycerides (CDP diglyceride) choline phosphoglycerides ethanolamine phosphoglycerides
- Phosphoglycolipids diacyl glycerylphosphoryldiglucosyl
- Phosphodiol lipids acyl dihydroxyacetone phosphate alkyl dihydroxyacetone phosphate
- the preferred phospholipid is phosphatidylcholine, (lecithin) .
- the ultrasonic treatment is conducted in the normal manner using commercially available ultrasonic equipment. - 4 - '
- the suspension of phospholipid used in the bath comprises preferably finely divided phospholipid suspended in a liquid in which it is only sparingly soluble.
- the suspension is preferably an aqueous suspension.
- Phospholipid is added to the suspension in solid form and is suspended by an initial ultrasonication to form liposomes.
- the phospholipid is preferably suspended at a concentration of 0.1 to 10% w/v, most preferably 1 to 2% w/v.
- the liquids that may be used to suspend the phospholipid in accordance with the present invention include water and physiological saline solutions.
- Any ultrasound device can be used in accordance with the present invention, such as the Model G112SPIT (serial No. 11254) produced by Laboratory Supplies Co. Inc., New York.
- the method of coating a surface with phospholipid may also comprise a pre-treatment step, which involves dissolving phospholipid in a solvent; placing the surface to be coated into the phospholipid/solvent solution to allow initial gross deposition of phospholipid onto the surface; removing the coated surface from the phospholipid solvent solution; evaporating off residual solvent on the coated surface; placing the coated surface into the suspension; and ultrasonicating the coated surface as described previously.
- a pre-treatment step which involves dissolving phospholipid in a solvent; placing the surface to be coated into the phospholipid/solvent solution to allow initial gross deposition of phospholipid onto the surface; removing the coated surface from the phospholipid solvent solution; evaporating off residual solvent on the coated surface; placing the coated surface into the suspension; and ultrasonicating the coated surface as described previously.
- the phospholipid is suspended in the solvent by stirring. Any solvent that dissolves phospholipid may be used in accordance with the present invention, such as chloroform or methanol.
- the pre-treatment by immersion in the dissolved phospholipid may involve the gross deposition of phospholipid from a solution with a low degree of supersaturation.
- the ultrasonication of the coated surface orientates and consolidates the phospholipid that was deposited on the surface to be coated from the solution.
- the slow deposition of the phospholipid from the solution with a low degree of supersaturation onto the surface to be coated enables the phospholipid to be deposited with a better orientation and thus gives an effective coating.
- the methods of the present invention enable the rapid and successful coating of surfaces with phospholipid.
- the methods may be used to coat the surfaces of medical instruments, thereby making the surfaces non-thrombogenic.
- the present invention is particularly applicable for the production of coated catheters for which the surfactant properties of lubrication and release are ideal. It may also be used to produce pacemakers and prosthetic devices which are less likely to be rejected by the body's immune system. The invention may also be applied to ceramic prosthesis to reduce their permeability.
- the present invention has found that surfaces having phospholipid adhered to them seem to be less likely to generate an antibody response than uncoated materials. Similarly, the formation of blood clots is greatly reduced on such coated surfaces.
- heparin which can now be grafted to certain surfaces to render then non-thrombogenic.
- One of the features of grafted heparin is the number of negative charges which they impart, indicating that they might function by providing a site most conducive to the adsorption of the endogenous surfactants, such as phospholipids, which are then the true interface with blood or other body fluids.
- the experiment was performed by solvent depositing soya lecithin in chloroform. Whilst these rods showed less clotting than the uncoated control rod, they were found to be less effective than the rods of comparative example 1 and markedly less effective than the rods coated using ultrasound..
- Example 2 The Experiments 2 and 3 were repeated, but the surfaces were allowed to dry before being placed in the bath and ultrasonicated as described in Example 1. The glass rods resulting were placed in blood as described in Example 1. The rods thus treated were clean of blood, amd the incidence of clotting was less than in Example 2 or 3.
Landscapes
- Health & Medical Sciences (AREA)
- Hematology (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Materials For Medical Uses (AREA)
Abstract
Les procédés décrits, qui permettent de produire des surfaces biocompatibles, consistent à recouvrir ces surfaces d'un phospholipide et à faire adhérer le phospholipide sur la surface au moyen d'une technique de soudage aux ultrasons.The methods described, which make it possible to produce biocompatible surfaces, consist in coating these surfaces with a phospholipid and in adhering the phospholipid to the surface by means of an ultrasonic welding technique.
Description
A METHOD FOR PRODUCING A BIOCOMPATIBLE SURFACE
TECHNICAL FIELD
The present invention relates to methods for producing biocompatible surfaces by coating them with phospholipid and binding the phospholipid to the surface by means of ultrasonication.
BACKGROUND ART
A major problem experienced with medical equipment and devices that comes into contact with the blood flow, such as cannulae, in dwelling electrodes and catheters, is that blood clots may form on their surfaces. The formation of blood clots on the surfaces of these instruments is dangerous and may prove fatal if the clots are washed off by the blood flow into the vascular system.
It has been reasoned that the best non-thrombogenic surface model is provided by the lining of blood vessels themselves - the endothelial lining. Some blood vessels, such as the aorta and cerebral vessels, have extremely hydrophobic inner surfaces. Electron microscopic studies of the inner surface of these vessels has revealed that they are lined with an oligolamellar lining of phospholipid. It is thought that mimicking the lining of the blood vessels on artificial surfaces should substantially overcome the abovementioned problems.
Early attempts at coating surfaces with phospholipid proved unsuccessful. Surfaces were left in contact with phospholipid or phospholipid/hyaluronic acid suspensions and then tested in blood stirred by a magnetic stirrer to mimic flowing blood. However, blood clots still developed on these surfaces.
US Patent 4 426 330 (Sears) discloses a chemically modified phospholipid for more stable coatings. US Patent 4 438 329 (Chapman) discloses a phospholipid chemically bonded to a polymer for coating surfaces. However, the introduction of new, chemically modified phospholipids into a human body or blood stream may have unforseen
- 2 -
results. Also, the expense and difficulty of preparing these modified phospholipid substances is a disadvantage for their use.
There is therefore an advantage in finding a way to coat surfaces with natural phospholipids on which flowing blood does not coagulate or form clots. A method of coating with phospholipids to produce non-thrombogenic surfaces has therefore been developed.
DISCLOSURE OF INVENTION
It is therefore an object of the present invention to provide a method for producing a biocompatible surface by coating it with phospholipid.
The present invention concerns a method for producing a biocompatible surface, by coating the surface with phospholipid characterised by immersing the surface to be coated in a bath containing a suspension of phospholipid in a liquid in which it is sparingly soluble, and then ultrasonicating the bath to coat the surface with phospholipid. "
Another aspect of the invention concerns pre-treating the surface to be coated. The surface is firstly immersed in a phospholipid solution. The solution comprises phospholipid substantially dissolved in a solvent in which it is soluble, such as ethanol or chloroform. The surface is then removed from the solution and the solvent allowed to evaporate off. The dry surface is then subjected to the ultrasonication process described above.
Any suitable surface may be coated, such as metal, glass, plastics or ceramics. Any phospholipid may be used and some examples are described in Table 1.
TABLE 1
Phosphoglycerides phosphatidic acids cytidylic phosphoglycerides (CDP diglyceride) choline phosphoglycerides ethanolamine phosphoglycerides
N-methylethanolamine phosphoglycerides
N,N-dimethylethanolamine phosphoglycerides
N-acylethanolamine phosphoglyceride serine phosphoglycerides
N-2-(hydroxyethyl)alanine phosphoglyceride glycerol phosphoglycerides glycerophosphate phosphoglycerides phosphatidylglycerol phosphoglyceride
(diphosphatidylglycerol) mono and diacylglycerol phosphoglycerides
(lysobisphosphatidic acids) glucosaminylglycerol phosphoglyceride
O-amino acid esters of glycerol phosphoglycerides inositol phosphoglyceride inositol monophosphate phosphoglyceride inositol diphosphate phosphoglyceride monomannosyl-hexamannosyl inositol phosphoglycerides glucose phosphoglyceride
O-diglucosylglycerol phosphoglyceride
Phosphoglycolipids diacyl (glycerylphosphoryldiglucosyl) glycerol
Phosphodiol lipids acyl dihydroxyacetone phosphate alkyl dihydroxyacetone phosphate
Phosphosphingolipids sphingomyelin (ceramide phosphorylcholine) cera ide phosphorylethanolamine ceramide phosphorylglycerol ceramide phosphorylglycerophosphate ceramide phosphorylinositol-containing lipids
The preferred phospholipid is phosphatidylcholine, (lecithin) .
The ultrasonic treatment is conducted in the normal manner using commercially available ultrasonic equipment.
- 4 - '
The suspension of phospholipid used in the bath comprises preferably finely divided phospholipid suspended in a liquid in which it is only sparingly soluble. The suspension is preferably an aqueous suspension.
Phospholipid is added to the suspension in solid form and is suspended by an initial ultrasonication to form liposomes. The phospholipid is preferably suspended at a concentration of 0.1 to 10% w/v, most preferably 1 to 2% w/v. The liquids that may be used to suspend the phospholipid in accordance with the present invention include water and physiological saline solutions.
Any ultrasound device can be used in accordance with the present invention, such as the Model G112SPIT (serial No. 11254) produced by Laboratory Supplies Co. Inc., New York.
The method of coating a surface with phospholipid may also comprise a pre-treatment step, which involves dissolving phospholipid in a solvent; placing the surface to be coated into the phospholipid/solvent solution to allow initial gross deposition of phospholipid onto the surface; removing the coated surface from the phospholipid solvent solution; evaporating off residual solvent on the coated surface; placing the coated surface into the suspension; and ultrasonicating the coated surface as described previously.
Surfaces that may be coated and phospholipids that may be used in accordance with the present invention are as described above. The phospholipid is suspended in the solvent by stirring. Any solvent that dissolves phospholipid may be used in accordance with the present invention, such as chloroform or methanol. Alternatively the pre-treatment by immersion in the dissolved phospholipid may involve the gross deposition of phospholipid from a solution with a low degree of supersaturation. The ultrasonication of the coated surface orientates and consolidates the phospholipid that was deposited on the surface to be coated from the solution.
The slow deposition of the phospholipid from the solution with a low degree of supersaturation onto the surface to be coated enables the phospholipid to be deposited with a better orientation and thus gives an effective coating.
Surprisingly, the methods of the present invention enable the rapid and successful coating of surfaces with phospholipid. As such, in one application the methods may be used to coat the surfaces of medical instruments, thereby making the surfaces non-thrombogenic.
The present invention is particularly applicable for the production of coated catheters for which the surfactant properties of lubrication and release are ideal. It may also be used to produce pacemakers and prosthetic devices which are less likely to be rejected by the body's immune system. The invention may also be applied to ceramic prosthesis to reduce their permeability.
In addition to the anti-friction properties of the phospholipids the present invention has found that surfaces having phospholipid adhered to them seem to be less likely to generate an antibody response than uncoated materials. Similarly, the formation of blood clots is greatly reduced on such coated surfaces. In this respect it is to be noted that by far the most successful anti-coagulent is heparin which can now be grafted to certain surfaces to render then non-thrombogenic. One of the features of grafted heparin is the number of negative charges which they impart, indicating that they might function by providing a site most conducive to the adsorption of the endogenous surfactants, such as phospholipids, which are then the true interface with blood or other body fluids. When such surfaces are removed they are more hydrophobic than before implantation. Hence it would seem better to proceed directly to the phospholipid surface rather than risk desorption of heparin or adjuvant heparin which inhibits coagulation of the blood in general, causing problems to the surgeon.
MODES FOR CARRYING OUT THE INVENTION
The invention will now be described by way of various examples.
EXAMPLE 1
Clean glass rods were placed in a bath of water containing 2% egg lecithin and ultrasonicated in the
*_. apparatus for 75 minutes. The glass rods were then allowed to drain for 135 minutes and suspended in 125 ml of blood in a beaker. The blood was kept flowing past the rods by a magnetic stirrer. Uncoated, clean glass rods were used as controls in the same blood at the same speed. At intervals of 30 seconds both sets of rods were checked for build up of coagulated material. Within 30 minutes there was appreciable build up of clotted blood on the control rods whereas those rods coated with phospholipid were clean.
COMPARATIVE EXAMPLE 2
The experiment was repeated by solvent depositing the egg lecithin from a solution (2% in methanol) which was allowed to evaporate for two and a half hours. Although the coated rods initiated less clotting than the uncoated control rods, the incidence of clotting was still markedly more than seen for the rods coated in Example 1.
COMPARATIVE EXAMPLE 3
The experiment was performed by solvent depositing soya lecithin in chloroform. Whilst these rods showed less clotting than the uncoated control rod, they were found to be less effective than the rods of comparative example 1 and markedly less effective than the rods coated using ultrasound..
EXAMPLE 4
The Experiments 2 and 3 were repeated, but the surfaces were allowed to dry before being placed in the bath and ultrasonicated as described in Example 1. The glass rods resulting were placed in blood as described in Example 1. The rods thus treated were clean of blood, amd the incidence of clotting was less than in Example 2 or 3.
It will be obvious to those skilled in the art that
numerous variations and modifications could be made to the method of the present invention as described, with reference to the examples, without departing from the overall scope or spirit of the invention.
Claims
1. A method for producing a biocompatible surface, by coating the surface with phospholipid, characterised by immersing the surface to be coated in a bath containing a suspension of phospholipid in a liquid in which it is sparingly soluble, and then ultrasonicating the bath to coat the surface with phospholipid.
2. The method according to claim 1 further characterised in that before "immersing the surface in the bath the surface is pre-treated by being immersed in a solution of phospholipid dissolved in a solvent, removed from the solution and allowed to dry.
3. The method according to claim 1 wherein the bath contains an aqueous suspension of phospholipid.
4. The method according to claim 1 wherein the phospholipid in lecithin.
5. The method according to claim 2 wherein the solvent is methanol or chloroform.
6. The method of claim 1 wherein the surface is that of a catheter, prosthetic device or a heart pacemaker.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU5139/89 | 1989-07-07 | ||
| AUPJ513989 | 1989-07-07 | ||
| AU59502/90A AU631903B2 (en) | 1989-07-07 | 1990-07-06 | A method for producing a biocompatible surface |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0486625A4 EP0486625A4 (en) | 1992-04-01 |
| EP0486625A1 true EP0486625A1 (en) | 1992-05-27 |
Family
ID=25632425
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP90917894A Withdrawn EP0486625A1 (en) | 1989-07-07 | 1990-07-06 | A method for producing a biocompatible surface |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP0486625A1 (en) |
| WO (1) | WO1991000745A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5282850A (en) * | 1989-07-25 | 1994-02-01 | Smith & Nephew Richards, Inc. | Artificial heart components with wear resistant coatings of reduced thrombogenicity |
| GB9022938D0 (en) | 1990-10-22 | 1990-12-05 | Biocompatibles Ltd | Non-thrombogenic surfaces |
| GB9112267D0 (en) * | 1991-06-07 | 1991-07-24 | Biocompatibles Ltd | Polymeric coating |
| US5217743A (en) * | 1992-02-07 | 1993-06-08 | Paradigm Biotechnologies Partnership | Biomaterials of enhanced biocompatibility |
| EP0637309B1 (en) * | 1992-04-24 | 1999-03-31 | Biocompatibles Limited | Metal coatings |
| US5798117A (en) * | 1992-04-24 | 1998-08-25 | Biocompatibles Limited | Method of reducing microorganism adhesion |
| US5824359A (en) * | 1997-06-30 | 1998-10-20 | Becton Dickinson And Company | Medical device lubricant containing lecithin |
| GB9920547D0 (en) * | 1999-08-31 | 1999-11-03 | Destiny Pharma Ltd | Coated implant |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0032622B1 (en) * | 1979-12-20 | 1985-08-14 | Dennis Chapman | Polymerisable phospholipids and polymers thereof, methods for their preparation, methods for their use in coating substrates and forming liposomes and the resulting coated substrates and liposome compositions |
| US4426330A (en) * | 1981-07-20 | 1984-01-17 | Lipid Specialties, Inc. | Synthetic phospholipid compounds |
| US4725442A (en) * | 1983-06-17 | 1988-02-16 | Haynes Duncan H | Microdroplets of water-insoluble drugs and injectable formulations containing same |
| GB8527071D0 (en) * | 1985-11-04 | 1985-12-11 | Biocompatibles Ltd | Plastics |
| US4803075A (en) * | 1986-06-25 | 1989-02-07 | Collagen Corporation | Injectable implant composition having improved intrudability |
-
1990
- 1990-07-06 EP EP90917894A patent/EP0486625A1/en not_active Withdrawn
- 1990-07-06 WO PCT/AU1990/000292 patent/WO1991000745A1/en not_active Application Discontinuation
Non-Patent Citations (2)
| Title |
|---|
| No further relevant documents have been disclosed. * |
| See also references of WO9100745A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1991000745A1 (en) | 1991-01-24 |
| EP0486625A4 (en) | 1992-04-01 |
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