Arteriovenous fistulas (AVFs) are the preferred vascular access mode for hemodialysis patients, but ~60% of AVFs fail to mature and only ~60% of mature AVFs are patent after 1 year. Vascular access failure, including AVFs, results from neointimal hyperplasia and contributes to >$1 billion USD annual costs from vascular access failure including 20% of hemodialysis patient hospitalizations. Systemic statin treatment is known to help prevent neointimal hyperplasia in arterial bypass grafting, and recent study of ~10,000 patients showed a 21% reduction in AVF failure that was strongly tied to statin identity and dose. Recent evidence from Dr. Sanjay Misras lab shows that systemic statins were able to significantly reduce neointimal hyperplasia in a mouse chronic kidney disease AVF model. Affinity aims to create statin-loaded microparticles that can be injected into the adventitia of the venous outflow tract of the AVF to prevent neointimal hyperplasia by locally delivering statins over the course of weeks thereby eliminating potential side effects and increasing efficacy of statin action. Our long-term goal is to develop injectable microparticles capable of preventing neointimal hyperplasia. The objective of this proposal is to produce statin-loaded, injectable microparticles to prevent AVF failure due to neointimal hyperplasia. The central hypothesis is that localized delivery of statins over the course of several weeks will increase the lumen area of the venous outflow tract by preventing fibroblast conversion to myofibroblasts and preventing proliferation of smooth muscle cells thereby decreasing neointimal area in the venous outflow tract. This work will be accomplished in three aims: 1) Validate statin loading and delivery in vitro; 2) Validate statin delivery on a model of myofibroblast differentiation using hypoxic fibroblasts in vitro; and 3) Minimize venous neointimal hyperplasia following AVF creation in vivo. Our proposed work is innovative using injectable microparticles to deliver statins directly to the venous outflow tract tissue to prevent neointimal hyperplasia. We use a novel approach to achieve high loading and long-term, sustained delivery of statins in a mode that eliminates any potential systemic side effects. The expected outcomes include injectable microparticles capable of release statin for >28 days in vitro and preventing neointimal hyperplasia for at least 28 days in vivo. These results will positively impact the field of vascular access by decreasing failure rates for both AVFs and AV grafts due to neointimal hyperplasia. Future work in Phase II will translate these statin-loaded, injectable microparticles from this Phase I proof-of-concept work into a statistically powerful study in pigs where the vasculature and hemodynamics are most similar to those in humans.
Public Health Relevance Statement: Project Narrative This proposal is critically concerned with the issue of public health in that its long term goal is to prevent primary failure of vascular access in hemodialysis patients due to neointimal hyperplasia. Specifically we hope to accomplish this goal using an affinity-based drug delivery system to deliver drug over a period of weeks. The short-term goals are to develop a microparticle formulation from affinity-based polymers and to assess the efficacy of simvastatin delivery in a murine arteriovenous fistula in vivo model.
Project Terms: abstracting; Adverse effects; Affinity; American; Angioplasty; Anti-inflammatory; Anti-Inflammatory Agents; Area; Arteriovenous fistula; base; Blood Vessels; Bypass; Caliber; Cell Line; Cell Proliferation; Cholesterol; Chronic; Chronic Kidney Failure; Clinic; clinical development; Clinical Research; cost; Data; dosage; Dose; Drug Delivery Systems; Encapsulated; End stage renal failure; Endothelial Cells; Failure; Family suidae; Fibroblasts; Fistula; flexibility; Formulation; Funding; Future; Generations; Goals; heme oxygenase-1; Hemodialysis; hemodynamics; Histology; Hospitalization; Human; Hyperplasia; Hypoxia; In Vitro; in vivo; in vivo Model; Incubators; Infiltration; Injectable; innovation; Investigation; Kidney; Killings; Legal patent; Liver; macrophage; Measures; migration; Modeling; mouse model; Mus; Myofibroblast; novel strategies; Operative Surgical Procedures; Oral; Outcome; Patients; Pharmaceutical Preparations; Phase; Polymers; prevent; Prevention; Primary Prevention; Property; Public Health; Reactive Oxygen Species; Simvastatin; Small Business Innovation Research Grant; Smooth Muscle Myocytes; Staging; success; Surface; Therapeutic; Time; Tissues; Translating; Tunica Adventitia; United States National Institutes of Health; Validation; Vascular Diseases; Venous; Work
