Periodic Reporting for period 1 - AORTYX (Revolutionary vascular repair patch to treat aortic dissections)
Berichtszeitraum: 2022-05-01 bis 2023-04-30
Aortic dissection (AD) is a life-threatening condition with a global incidence of 1/10,000 patients/year and up to 50% mortality. Current treatments have high mortality (30%) and mid-term complication (60%) rates due to invasiveness and poor mechanical compliance with the damaged tissue. Aortyx has developed a bioresorbable adhesive patch (AX-GEN01) that mimics the mechanical properties of the aorta for its endogenous regeneration. Shortly, the patch is tied to a deployer, using soluble polymeric stitches, to be navigated through the aorta until its damaged section, using a minimally invasive catheter. Then, it is bent at the entry tear, deployed and adhered against the aortic wall to plug the leak, empty the false lumen and integrate in the native tissue. The use of this patch will reduce mortality and morbidity, improving patient lifespan, quality, and surgeon confidence.
This project aims to advance AX-GEN01 through crucial clinical trials for commercialization in the EU and USA. Key steps include design transfer, safety and efficacy validation, Quality Management System implementation, and First in Human Assay. Simultaneously, we will develop AX-GEN02 to expand our product portfolio, attract investors, and establish ourselves as a reference in aortic devices. AX-GEN02 offers a safe approach to halt aneurysm progression, appealing to conservative physicians.
This project aims to advance AX-GEN01 through crucial clinical trials for commercialization in the EU and USA. Key steps include design transfer, safety and efficacy validation, Quality Management System implementation, and First in Human Assay. Simultaneously, we will develop AX-GEN02 to expand our product portfolio, attract investors, and establish ourselves as a reference in aortic devices. AX-GEN02 offers a safe approach to halt aneurysm progression, appealing to conservative physicians.
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.
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.
We have made significant advancements with profound impact that have been showcased at various prestigious congresses, including the Veith Symposium, SITE, and LINC. There, our team presented our device for the treatment of AD, captivating several KOLs. The response has been that AX-GEN01 could be a game-changer soon. Additionally, we presented at the Mobile World Congress (2022 and 2023) and participated in the EIT Health Goldtrack Program. We have garnered attention from influential commercial players in the industry. In parallel, we have initiated market access studies in Germany, the USA, UK, and Spain, which revealed the significant potential impact of our first device within these healthcare systems. By leveraging the advantages of AX-GEN01, we aim to reduce the costs associated with aortic dissection, offering substantial economic benefits to the patients and the surgeons.
To ensure the success of our devices, we have identified several key needs:
1. Clinical demonstration and validation of our device's capabilities.
2. Collaboration with KOLs, professional societies, and patient associations.
3. IP rights support is crucial to protect our technology.
4. Collaborations with regulatory bodies, clinicians, and industry partners worldwide will facilitate regulatory approvals, certifications, and compliance with international standards.
To ensure the success of our devices, we have identified several key needs:
1. Clinical demonstration and validation of our device's capabilities.
2. Collaboration with KOLs, professional societies, and patient associations.
3. IP rights support is crucial to protect our technology.
4. Collaborations with regulatory bodies, clinicians, and industry partners worldwide will facilitate regulatory approvals, certifications, and compliance with international standards.