WO1991000745A1 - A method for producing a biocompatible surface - Google Patents

A method for producing a biocompatible surface Download PDF

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Publication number
WO1991000745A1
WO1991000745A1 PCT/AU1990/000292 AU9000292W WO9100745A1 WO 1991000745 A1 WO1991000745 A1 WO 1991000745A1 AU 9000292 W AU9000292 W AU 9000292W WO 9100745 A1 WO9100745 A1 WO 9100745A1
Authority
WO
WIPO (PCT)
Prior art keywords
phospholipid
coated
blood
solvent
bath
Prior art date
Application number
PCT/AU1990/000292
Other languages
French (fr)
Inventor
Brian Andrew Hills
Original Assignee
Macnaught Pty Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Macnaught Pty Limited filed Critical Macnaught Pty Limited
Priority claimed from AU59502/90A external-priority patent/AU631903B2/en
Publication of WO1991000745A1 publication Critical patent/WO1991000745A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L33/00Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005Use of materials characterised by their function or physical properties
    • A61L33/0011Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • A61L33/0041Anticoagulant, 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L33/00Antithrombogenic 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.

Abstract

The invention relates to methods for producing biocompatible surfaces by coating them with phospholipid and binding the phospholipid to the surface by means of ultrasonication.

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

- 8 -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.
PCT/AU1990/000292 1989-07-07 1990-07-06 A method for producing a biocompatible surface WO1991000745A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
AUPJ5139 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 (1)

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WO1991000745A1 true WO1991000745A1 (en) 1991-01-24

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WO (1) WO1991000745A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992006719A1 (en) * 1990-10-22 1992-04-30 Biocompatibles Limited Non-thrombogenic surfaces
WO1992021386A1 (en) * 1991-06-07 1992-12-10 Biocompatibles Limited Polymeric coating
EP0554869A1 (en) * 1992-02-07 1993-08-11 Paradigm Biotechnologies Partnership Biomaterials of enhanced compatibility
WO1993021970A1 (en) * 1992-04-24 1993-11-11 Biocompatibles Limited Method of reducing microorganism adhesion
EP0746266A1 (en) * 1992-07-27 1996-12-11 Smith & Nephew, Inc. Artificial heart components with improved biocompatible coating
US5798117A (en) * 1992-04-24 1998-08-25 Biocompatibles Limited Method of reducing microorganism adhesion
WO1999000153A1 (en) * 1997-06-30 1999-01-07 Becton Dickinson And Company Medical device lubricant containing lecithin
WO2001015752A1 (en) * 1999-08-31 2001-03-08 Destiny Pharma Limited Phospholipid-coated implants

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4348329A (en) * 1979-12-20 1982-09-07 Dennis Chapman Biocompatible surfaces
US4426330A (en) * 1981-07-20 1984-01-17 Lipid Specialties, Inc. Synthetic phospholipid compounds
WO1987002684A1 (en) * 1985-11-04 1987-05-07 Biocompatibles Limited Lipid containing plastics
US4725442A (en) * 1983-06-17 1988-02-16 Haynes Duncan H Microdroplets of water-insoluble drugs and injectable formulations containing same
US4803075A (en) * 1986-06-25 1989-02-07 Collagen Corporation Injectable implant composition having improved intrudability

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4348329A (en) * 1979-12-20 1982-09-07 Dennis Chapman Biocompatible surfaces
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
WO1987002684A1 (en) * 1985-11-04 1987-05-07 Biocompatibles Limited Lipid containing plastics
US4803075A (en) * 1986-06-25 1989-02-07 Collagen Corporation Injectable implant composition having improved intrudability

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Biochem. Soc. Trans., Vol. 17, No. 6, published 1989, D. CHAPMAN and P.I. HARIS "Biomembrane structures. Fourier transform infrared spectroscopy and biomembrane technology", pages 951-3. *
Prog. Clin. Biol. Res,. Vol. 292, published 1989, D. CHAPMAN et al. "Biomembranes: basic science and future technology" pages 3-12. *
See also references of EP0486625A4 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992006719A1 (en) * 1990-10-22 1992-04-30 Biocompatibles Limited Non-thrombogenic surfaces
US6521283B1 (en) 1990-10-22 2003-02-18 Biocompatibles Limited Non-thrombogenic surfaces
WO1992021386A1 (en) * 1991-06-07 1992-12-10 Biocompatibles Limited Polymeric coating
US5496581A (en) * 1991-06-07 1996-03-05 Biocompatibles Limited Polymeric coating
EP0554869A1 (en) * 1992-02-07 1993-08-11 Paradigm Biotechnologies Partnership Biomaterials of enhanced compatibility
AU675063B2 (en) * 1992-04-24 1997-01-23 Biocompatibles Uk Limited Method of reducing microorganism adhesion
US5798117A (en) * 1992-04-24 1998-08-25 Biocompatibles Limited Method of reducing microorganism adhesion
WO1993021970A1 (en) * 1992-04-24 1993-11-11 Biocompatibles Limited Method of reducing microorganism adhesion
EP0746266A1 (en) * 1992-07-27 1996-12-11 Smith & Nephew, Inc. Artificial heart components with improved biocompatible coating
EP0746266A4 (en) * 1992-07-27 1999-08-18 Smith & Nephew Richards Inc Artificial heart components with improved biocompatible coating
WO1999000153A1 (en) * 1997-06-30 1999-01-07 Becton Dickinson And Company Medical device lubricant containing lecithin
WO2001015752A1 (en) * 1999-08-31 2001-03-08 Destiny Pharma Limited Phospholipid-coated implants
US6863693B2 (en) 1999-08-31 2005-03-08 Destiny Pharma Limited Phospholipid-coated implants

Also Published As

Publication number Publication date
EP0486625A4 (en) 1992-04-01
EP0486625A1 (en) 1992-05-27

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