Development and validation of second-generation anti-infective, anti-biofilm and pro-regenerative envelopes for sheathing medical devices

The aim of this research proposal is to combine the expertise of Amynas and KU Leuven for development and validation of a second generation of anti-infective and pro-regenerative envelopes for coating medical devices (NanoPocket) in which a molecule with anti-biofilm characteristics is incorporated next to an antimicrobial agent. It is expected that these new Nanopocket prototypes will fight acute infections to the same extent but additionally can fight chronic infections by adding anti-biofilm molecules. The new envelope will be compared to the first generation NanoPocket envelopes and the antibiotic-releasing envelope already on the market today (TYRX), but does not contain pro-regenerative or long-term anti-biofilm properties. The following specific goals are envisioned: 1) In a first phase, the anti-biofilm molecules (a series of thirty 5-aryl-2-aminoimidazole (2-AI)) recently developed at KU Leuven will be extensively tested in vitro for their anti-biofilm activity against common pathogens after implantation of medical devices. This includes looking at the toxicity of the 2-AI molecules (2-AIs) as well as the stability of these 2-AIs in the presence of CaO2 - the antimicrobial agent in the first generation Nanopocket envelopes. Only molecules with good activity and stability combined with low toxicity will advance to the further research phase. 2) Three selected 2-AIs will be incorporated into the pro-regenerative nanofibers. In addition to studying the kinetics of release from the nanofibers of CaO2 and the selected 2-AI molecules (2-AIs), they will be extensively tested for their antimicrobial and anti-biofilm activity in vitro. The possible emergence of resistance to this combination treatment is also investigated. 3) Finally, an in vivo validation of the in vitro generated data will follow. For this purpose, a previously optimized rabbit model for the evaluation of the first generation Nanopocket prototypes will be implemented in the lab. The use of the same model allows for easy comparison of the first and second generation prototypes. 4) In steps 2) and 3), the comparison is also made in each case with i) the first generation NanoPocket envelope and ii) a biodegradable antibiotic-releasing envelope already on the market today (TYRX), but lacking pro-regenerative and long-term anti-biofilm properties. The next generation NanoPocket prototypes should be at least equivalent, and preferably superior, to both the first generation NanoPocket envelope and the TYRX envelope already available.