Before this project, we performed hundreds of experiments that allowed us to select the final patch features. During this project we added radiopaque markers to the patch to assure visualization under X-ray during implantation. Besides, we developed a cleaning protocol to prepare the markers before placing them in the patch. Besides, we decided to use laser to cut our patches, as we have observed, that this prevents patch delamination. Moreover, we created a new device to quickly place the markers during the patch manufacturing process. Finally, we have scaled-up the manufacturing process of the patch.
For the stitches, we built an extrusion machine to produce polymeric filaments. We iterated the manufacturing parameters and we performed solubility, tensile strength, and storage characterization tests of the produced batches to decide the optimal manufacturing conditions. Besides, we performed a biocompatibility analysis in which the stitches proved to be non-cytotoxic.
Moreover, we worked on the adhesive distribution. Originally, we used to apply the adhesive on the patch using a micropipette. However, this was not reproducible. Thus, we decided to develop a new application method using a pulverizer. The optimal conditions to pulverize the adhesive have been tuned using different ex vivo tests, and tested in an in vivo experiment. Besides, we have performed storage stability tests that have showed that the adhesive is able to keep its adhesion strength after being stored.
The delivery system has become the primary focus of the R&D team at Aortyx. Before this project began, we were still facing significant challenges to develop the catheter. After several design iterations, experiments in cadavers and ex-vivo tests, we have developed a unique catheter (guider) that can be steered in two opposite directions at the same time, achieving angles never seen. Its goal is to face the entry tear perpendicular AD and generate enough free space to safely deploy the patch. Besides, the second catheter (carrier) will integrate a hypotube which provides enough flexibility to navigate inside the guider but is stiff enough to not compress the patch and deployer. Besides, the sealing valve of the distal tip of the carrier has been replaced by a sealing cap that is sutured to the carrier shaft.
After testing distinct deployer geometries, a final version was chosen and transferred to its outsourced manufacturing. We have designed a fixture that is used for the shape-setting of the deployers. We have iterated the design of the filler material to fill the entirety of the carrier ID, minimizing the air inside the shaft and stabilizing the deployer during implantation.
Moreover, we have used an open approach to perform another chronic implantation in rams subjected to an AD model using a micropipette to distribute the adhesive. The conclusion of this experiment was that all implanted patches resisted in place despite the tear. Complete neointima formation and maturation on top of the patch was confirmed 90 days post-implantation. The patch promoted the tissue ingrowth, with minimal signs of inflammation and no signs of thrombosis at the injury site. Besides, we used the same open approach to test the pulverizer methodology to distribute the adhesive over the patch. In short, we have realized that pulverizing the adhesive has significant advantages over micropipette, including ease of use and accelerated neointima formation.
