A transcatheter manufacturing toolkit for minimally-invasive and patient-specific device-based stroke prevention - Project Summary: Atrial fibrillation (AF) is the most common arrhythmia, affecting ~9% of the US population >65 years old. AF patients have a 5-fold increased risk of stroke, a leading cause of death and disability that costs over $50 billion/year. Over 90% of stroke-causing blood clots in AF patients form in the left atrial appendage (LAA), and thus occlusion of the LAA (LAAO) represents a promising alternative to long-term blood-thinners. In theory, this one-time procedure will seal off the LAA to eliminate stroke risk associated with LAA thrombus and bleeding risk associated with indefinite systemic anticoagulation. In practice, LAAO is limited by the intrinsic disparity between prefabricated, one-size-fits-all medical devices and individual human patients. FDA-approved LAAO devices are metallic, round, and mass-produced in standard sizes, whereas human LAAs are composed of soft tissues in a limitless range of shapes and sizes. This inherent geometric and mechanical mismatch leads to incomplete LAA sealing, challenging deployment workflows, local tissue trauma, and failed stroke prevention. Ultimately, we do not expect these issues to be solved by iterative improvements to the same one- size-fits-all manufacturing paradigm. Instead, we propose to form fully-soft, personalized medical implants directly inside the patient’s body in a minimally-invasive approach. By delivering, forming, and stabilizing soft materials at the target tissue location, we provide atraumatic 3D implants that are custom made to fit each patient’s unique anatomy. This concept will simultaneously address the patient-device mismatch and device-anatomy alignment problems to achieve safer and more effective stroke prevention in a simplified clinical workflow. Our Catalyze project is focused on establishing a strong translational foundation while generating critical feasibility, safety, and efficacy data. In the R61 Phase, we develop design, regulatory and commercialization documentation, refine and verify the catheter and implant sub-systems, produce in-vitro and ex-vivo validation for the integrated prototype, and demonstrate feasibility of the full deployment workflow in a benchtop cardiovascular simulator. In the R33 Phase, we test and refine our prototype in iterative large animal pilot trials (terminal, conducted internally), formalize and characterize the prototype assembly process, and finally establish preclinical feasibility, safety, and efficacy in a large animal study at an independent test facility (non-GLP, conducted externally). Upon completion, we’ll have produced a functional product prototype that satisfies early-stage design constraints, fulfills key performance requirements, and enables safe and effective execution of our in-situ implant formation workflow in challenging preclinical models. This data will concretely establish the technical feasibility and clinical potential for our new technology, and the corresponding design documentation and regulatory plans will provide a solid foundation for product finalization, quality management, GMP manufacturing, GLP testing, and IDE submission. If realized, our approach for on-demand, in-situ formation of atraumatic and patient-specific cardiac implants would be a paradigm shift in device-based stroke prevention for the millions of patients living with atrial fibrillation.
