Non-pathogenic biofilms and uses thereof
In an embodiment, the present disclosure pertains to a method and compositions for modification of medical devices, such as indwelling medical devices, implantable catheters, in particular, urinary catheters, to enhance formation of a high density and stable biofilm comprising non-pathogenic organisms for the treatment and prevention of colonization of pathogens leading to device-associated infections, such as urinary tract infections. In some embodiments the present disclosure also relates to a method and compositions for storage and use of the catheters coated with a non-pathogenic biofilm. In some embodiments the present disclosure also pertains to a method and compositions for modification of implantable medical devices with bacterial resistant polymers, and/or antimicrobial agents.
1. A method of making a modified silicone surface comprising:
activating the silicone surface;
mixing a plurality of cross-linking dendrimers with a plurality of ligand derivatives to allow binding of dendrimers to ligand derivatives, wherein the plurality of cross-linking dendrimers comprise an alkynylated generation 5 poly(amido amine) dendrimer and the plurality of ligand derivatives comprise azido-poly-N-acetyl-glucosamine; and
functionalizing the silicone surface by immobilizing the plurality of the cross-linked dendrimers bound to the plurality of ligand derivatives on the activated silicone surface; and
adhering a non-pathogenic biolfilm to the modified silicone surface, wherein the functionalizing provides a ligand-presenting modified silicone surface conducive for the formation and accumulation of a non-pathogenic biofilm.
2. The method of claim 1 , wherein the modified silicone surface interferes with pathogen colonization.
3. The method of claim 1 , wherein the activating comprises oxidizing of the silicone surface.
4. The method of claim 3 , wherein the oxidizing comprises treatment with CO 2 plasma.
5. The method of claim 4 , wherein the treatment with CO 2 plasma is for about 30 s to about 60 s.
6. The method of claim 4 , wherein the treatment with CO 2 plasma is at a low power setting.
7. The method of claim 6 , wherein the power setting ranges from about 1 W to about 10 W.
8. The method of claim 1 , wherein the activated silicone surface comprises poly(dimethylsiloxane).
9. The method of claim 1 , wherein the plurality of ligand derivatives are mixed with an activating agent prior to mixing with the plurality of the cross-linking derivatives.
10. The method of claim 9 , wherein the activating agent comprises 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide.
11. The method of claim 1 , wherein the mixing of the plurality of ligand derivatives with the plurality of cross-linked dendrimers is in the ratio ranging from about 2:1 to about 60:1.
12. The method of claim 1 , wherein the non-pathogenic biofilm comprises a plurality of bacteria.
13. The method of claim 12 , wherein the bacteria comprise E. coli 83972.
14. The method of claim 12 , wherein the bacteria comprise fim+ E. coli mutant strain HU2425.
15. A method of making a modified silicone surface comprising:
activating the silicone surface;
immobilizing a plurality of cross-linking dendrimers on the activated silicone surface; and
binding a plurality of ligand derivatives to the immobilized plurality of cross-linking dendrimers in the presence of an activating agent, wherein the the plurality of ligand derivatives comprise a bacterial adhesion molecule;
co-depositing oligo(ethylene)glycol linker, wherein the oligo(ethylene)glycol linker is end-capped with a carboxyl group, and wherein the co-deposition of the oligo(ethylene)glycol linker controls the density of the ligand-derivatives on the modified silicone surface; and
adhering a non-pathogenic biofilm to the modified silicone surface.
16. The method of claim 15 , wherein the modified silicone surface interferes with pathogen colonization.
17. The method of claim 15 , wherein the plurality of cross-linking dendrimer comprise a dendrimeric moiety selected from the group consisting of poly (amido amine)polylysine, poly(amino acid), polyallylamine, polyamines, poly(proplyl imine), and combinations thereof.
18. The method of claim 15 , wherein the plurality of cross-linking dendrimers comprise a generation 5 poly(amido amine) dendrimer.
19. The method of claim 15 , wherein the plurality of ligand derivatives comprise mannose derivatives.
20. The method of claim 19 , wherein the mannose derivatives are selected from BiPh-Man, PhP-Man, TA-C3T-Man, Man, TACIT-Man, BiPh-F-Man.
21. The method of claim 15 , wherein the plurality of ligand derivatives comprise poly-3-(1-6)-N-acetyl-D-glucosamine (PNAG).
22. A modified silicone surface comprising:
a plurality of the cross-linked dendrimers bound to a plurality of ligand derivatives immobilized on the silicone surface to form a functionalized ligand-presenting silicone surface, wherein the plurality of ligand derivatives comprise a bacterial adhesion molecule; and
a non-pathogenic biolfilm adhered to the functionalized ligand-presenting silicone surface, wherein the modified silicone surface interferes with pathogen colonization.
23. The modified silicone surface of claim 22 , wherein the plurality of cross-linked dendrimers bound to the plurality of ligand derivatives are immobilized on the silicone surface via activation of the silicone surface.
24. The modified silicone surface of claim 23 , wherein the activation of the silicone surface comprises oxidizing of the silicone surface.
25. The modified silicone surface of claim 22 , wherein the modified silicone surface comprises poly(dimethylsiloxane).
26. The modified silicone surface of claim 22 , wherein the plurality of the cross-linked dendrimers are bound to the plurality of ligand derivatives in presence of an activating agent.
27. The modified silicone surface of claim 22 , the plurality of cross-linking dendrimers comprise a generation 5 poly(amido amine) dendrimer.
28. The modified silicone surface of claim 22 , wherein the plurality of ligand derivatives comprise mannose derivatives.
29. The modified silicone surface of claim 28 , wherein the mannose derivatives are selected from BiPh-Man, PhP-Man, TA-C3T-Man, Man, TACIT-Man, BiPh-F-Man.
30. The method of claim 22 , wherein the plurality of ligand derivatives comprise poly-β-(1-6)-N-acetyl-D-glucosamine (PNAG).
31. The modified silicone surface of claim 22 , wherein the ratio of the plurality of ligand derivatives to the plurality of cross-linked dendrimers ranges from about 2:1 to about 60:1.
32. The modified silicone surface of claim 22 , wherein the non-pathogenic biofilm comprises a plurality of bacteria.
33. The modified silicone surface of claim 32 , wherein the bacteria comprise E. coli 83972.
34. The modified silicone surface of claim 32 , wherein the bacteria comprise fim+ E. coli mutant strain HU2425.
35. The modified silicone surface of claim 22 , wherein the surface is that of an implantable medical device.
36. A medical device comprising a modified silicone surface, the modified silicone surface comprising:
an activated silicone layer;
a plurality of activated dendrimers absorbed on to the activated silicone layer;
a plurality of ligand derivatives, each bound to at least one of the plurality of cross-linked dendrimers, wherein the plurality of ligand derivatives comprise a bacterial adhesion molecule; and
a non-pathogenic biofilm adhered to the plurality of ligand derivatives.
37. The medical device of claim 36 , wherein the modified silicone surface contributes to the inhibition of pathogen colonization and growth.
38. The medical device of claim 36 , wherein the cross-linked dendrimers each comprise an amidation product of the amino-terminus of an amino-terminated cross-linking dendrimer.
39. The medical device of claim 38 , wherein the amino-terminated dendritic polymer is the G5 PAMAM.
40. The medical device of claim 36 , wherein the bacterial adhesion molecule is a mannose derivative.
41. The medical device of claim 36 , wherein the bacterial adhesion molecule is PNAG.
42. The medical device of claim 36 , wherein the non-pathogenic biofilm comprises a plurality of bacteria.
43. The medical device of claim 42 , the bacteria comprise Escherichia Coli.
44. The medical device of claim 43 , wherein the Escherichia Coli lack fimbriae.
45. The medical device of claim 43 , wherein the bacteria is Escherichia Coli 83972.
46. A modified silicone surface comprising:
a plurality of the cross-linked dendrimers bound to a plurality of ligand derivatives immobilized on the silicone surface to form a functionalized ligand-presenting silicone surface, wherein the plurality of cross-linking dendrimers comprise an alkynylated generation 5 poly(amido amine) dendrimer and the plurality of ligand derivatives comprise azido-poly-N-acetyl-glucosamine; and
a non-pathogenic biofilm adhered to the functionalized ligand-presenting silicone surface, wherein the modified silicone surface interferes with pathogen colonization.
47. A method of making a modified silicone surface comprising:
activating the silicone surface;
mixing a plurality of cross-linking dendrimers with a plurality of ligand derivatives to allow binding of dendrimers to ligand derivatives, wherein the plurality of ligand derivatives comprise a bacterial adhesion molecule; and
functionalizing the silicone surface by immobilizing the plurality of the cross-linked dendrimers bound to the plurality of ligand derivatives on the activated silicone surface; and
adhering a non-pathogenic biolfilm to the modified silicone surface, wherein the functionalizing provides a ligand-presenting modified silicone surface conducive for the formation and accumulation of a non-pathogenic biofilm.