Implantable medical device having a negatively-charged and antimicrobial surface

Abstract

A completely or partially implantable medical device, the surface of which has attached to it a substance having a permanent negative charge excess, to which is in turn attached an antimicrobial substance. This imparts antimicrobial properties and at the same time repels the cellular constituents of killed bacteria.

Claims

1. An implantable medical device comprising a surface-attached substance having a permanent negative charge excess, wherein the negative charges are borne by one of carbonic acid groups, sulfonic acid groups, phosphonic acid groups and combinations thereof and this substance additionally has at least two molecular groups that are one of carboxyl groups, amino groups and a combination thereof, and by an antimicrobial substance that is linked to the substance having a negative charge excess.

2. The medical device as claimed in claim 1, wherein the surface-attached substance additionally has at least three molecular groups that are one of carboxyl groups, amino groups and a combination thereof

3. The medical device as claimed in claim 1, wherein the employed substance having a permanent negative charge excess is mellitic acid.

4. The medical device as claimed in claim 1, wherein the employed substance having a permanent negative charge excess is heparin.

5. The medical device as claimed in claim 1, wherein the substance having the permanent negative charge excess is applied with comprehensive coverage, but that the antimicrobial substance is applied to the surface with only partial coverage.

6. The medical device as claimed in claim 1, wherein the employed antimicrobial substance is an antimicrobial peptide.

7. The medical device as claimed in claim 6, wherein the employed antimicrobial substance is an antimicrobial peptide having the sequence kwivwrwrfkr-NH2.

8. The medical device as claimed in claim 1, wherein the employed antimicrobial substance is an antibiotic.

9. The medical device as claimed in claim 8, wherein the employed antibiotic is one of an aminopenicillin and a tetracycline.

10. The medical device as claimed in claim 1, wherein the substances are attached to the surface of the medical device by means of peptide bonds.

11. The medical device as claimed in claim 1, wherein the medical device is completely implantable.

12. The medical device as claimed in claim 1, wherein the medical device is partially implantable.

Description

DESCRIPTION OF PREFERRED EMBODIMENTS

[0015] The invention is elucidated in more detail hereinbelow with reference to following various exemplary embodiments:

Example ICovalent Coating Process with Mellitic Acid and Antimicrobial Peptide on a Medical Implant Having a Polyurethane Surface

[0016] 1) The polyurethane surface is immersed in an ether solution of hexamethylene diisocyanate for 12 h to prepare it for attachment of mellitic acid, after which it is rinsed in deionized water. [0017] 2) The thus prepared polyurethane surface is then immersed in an aqueous solution of sodium hydrogen carbonate for 12 h for hydrolysis, after which it is rinsed in deionized water. [0018] 3) The thus prepared polyurethane surface is immersed in an aqueous solution of mellitic acid and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide for 12 h to attach the mellitic acid via a peptide bond, after which it is rinsed in deionized water. [0019] 4) The thus prepared polyurethane surface is immersed in an aqueous solution of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide for 1 h to prepare it for the attachment of the peptide. [0020] 5) To attach the antimicrobial peptide, the thus prepared polyurethane surface is immersed in an aqueous solution containing the peptide having the sequence kwivwrwrfkr-NH2 for 12 h, after which it is rinsed in deionized water.

Example IICovalent Coating Process with Heparin and Doxycycline on a Medical Implant Having a Silicone Surface

[0021] 1) The silicone surface is immersed in an aqueous solution of 3-aminopropyltriethoxysilane for 12 h to prepare it for the attachment of heparin, after which it is rinsed in deionized water. [0022] 2) The thus prepared silicone surface is immersed in an aqueous solution of adipic acid and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide for 12 h to attach the heparin via a peptide bond, after which it is rinsed in deionized water. [0023] 3) The thus prepared silicone surface is immersed in an aqueous solution of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide for 1 h to prepare it for the attachment of the heparin. [0024] 4) To attach the heparin via a peptide bond, the thus prepared silicone surface is immersed in an aqueous solution containing heparin for 12 h, after which it is rinsed in deionized water. [0025] 5) The thus prepared silicone surface is immersed in an aqueous solution of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide for 1 h to prepare it for the attachment of the doxycycline. [0026] As a variant, it is possible to only partially activate the carboxyl groups of heparin, thereby achieving non-comprehensive coverage by the doxycycline. This is the case when there are fewer carbodiimide molecules in the solution than carboxyl groups on the surface or when the immersion time is reduced or when both measures are combined. [0027] 6) To attach the doxycycline via a peptide bond, the thus prepared silicone surface is immersed in an aqueous solution containing doxycycline for 12 h, after which it is rinsed in deionized water.

[0028] Accordingly furnished silicone samples have proved very successful in microbiological tests. Compared to uncoated silicone samples, the number of living bacteria on the surface was markedly reduced after immersion in bacterial suspensions for 24 hours. Compared to samples furnished exclusively with antimicrobial substances, the number of killed bacteria on the surface was drastically reduced, which is crucial to the maintenance of effectiveness when exposed to bacteria for long periods.