An Image-Guided Microrobotic Drug Delivery Method for Preventive Vascular Interventions - PROJECT SUMMARY/ ABSTRACT End-stage kidney disease (ESKD) affects over 800,000 Americans and 4 million people worldwide, with 60% of patients relying on hemodialysis via arteriovenous fistulas (AVF). Despite diligent monitoring, over 30% of AVFs develop neointimal hyperplasia (IH), leading to venous stenosis (VS) and thrombosis, causing loss of patency as early as six weeks post-creation. The first-line treatment for restoring AVF patency after VS is percutaneous transluminal angioplasty (PTA). However, the efficacy of PTA diminishes with each procedure, as repeated injury to the AVF vessel initiates an injury-healing cycle that exacerbates IH and accelerates VS. These repeated interventions cost Medicare approximately $3 billion annually. Therefore, it is crucial to focus research on new methods to prevent VS and reduce the reliance on PTA. Recent studies have identified AZD8797 as a potent inhibitor of the CX3CR1 chemokine ligand, which is implicated in VS development in failed human AVFs and murine models. However, no medically approved method exists for the local inhibition of CX3CR1-mediated vessel wall inflammation at the AVF outflow vein using AZD8797 without injuring the venous wall or creating a systemic toxicity risk. To address this unmet need, this project aims to develop an endoluminal AZD8797 delivery system using soft microrobots. Our ultimate goal is to establish a preventive intervention capability where AZD8797 can be locally delivered to the AVF outflow vein as early as the surgical AVF formation, inhibiting the local inflammation, preventing IH and VS, and improving venous access for hemodialysis. The key innovation of our microrobotic delivery approach is that it can perform the drug delivery process in an entirely atraumatic way, thus avoiding injury to the endothelial cells and subsequent inflammation, as observed in current state-of-the-art drug-coated balloon technologies. Our specific aims in this study are: 1. Refine the microrobotic technology for safer and more effective endoluminal control 2. Identify the maximum deliverable non-toxic dose of AZD8797 at the venous wall 3. Assess the central hypothesis of locally inhibiting CX3CR1-mediated inflammation in a rat AVF model with chronic kidney disease This innovative microrobot technology for entirely atraumatic endoluminal drug delivery can pave the way for applications in various vascular injuries, e.g., bypass grafts used for coronary and peripheral arterial disease, and post-angioplasty treatment of stenosis in arterial, venous, and hemodialysis contexts. Our ultimate goal of this research and development is to develop a therapy that can be delivered at the time of AVF creation and reduce IH/VS for patients with ESKD.
