Brain aneurysms are a high risk condition in which bulging blood vessels in the brain are at risk of rupture. The mortality rate after rupture is 30-60% if no treatment is administered. Current treatment for both ruptured and unruptured aneurysms includes surgical clipping (exovascular therapy) and catheter based intervention (endovascular therapy). The latter, which is the focus of this work, places platinum coils into the aneurysm to induce clotting and sequestration of the aneurysm. The primary challenge associated with endovascular aneurysm therapy is the risk of aneurysm recurrence due to mechanical compaction and enzymatic digestion of the clot in the aneurysm sac. This proposal will produce a novel, cost-effective, clinically translatable strategy to improve the outcome of endovascular coiling of intracranial aneurysms. We posit that sustained release of naturally-occurring crosslinking agents delivered from coated endovascular coils will increase the mechanical stiffness of the clots and reduce fibrinolysis. Stabilized clots will be resistant to failure modes associated with coil compaction and enzymatic degradation. This approach will be validated in vitro during this project. Research activities will focus on characterizing the dosing and release of bioactive crosslinking agent from polymeric coatings. In vitro efficacy will be demonstrated using a model aneurysm sac under flow of whole blood. The results from this project will be used to define specific formulations and dosing ranges for use in prospective in vivo experiments using a canine pouch model for intracranial aneurysms. Pre-clinical studies will establish safety and efficacy of drug eluting embolization coils. This technology has the potential to dramatically improve outcomes related to coil embolization of intracranial aneurysms.
Public Health Relevance Statement:
Public Health Relevance: The purpose of this proposal is to design and fabricate drug-eluting coatings for medical devices used in the endovascular treatment of brain aneurysms. These devices will improve the outcome of endovascular coiling by delivering small naturally-occurring molecules that crosslink and stabilize nascent clots in the aneurysm sac. Clots with increased mechanical stiffness and thrombolytic resistance will increase the likelihood of positive clinical outcomes by rendering the clot resistant to mechanical compaction and subsequent recurrence.
Project Terms:
3D Print; Adverse event; Amines; Aneurysm; Animals; arm; base; Biological Assay; Blood Circulation; Blood flow; Blood Pressure; Blood Vessels; Brain; Brain Aneurysms; Businesses; Canis familiaris; Catheters; Cerebral Aneurysm; chemical stability; Clinical; clinically relevant; Coagulation Process; Code; controlled release; cost effective; Coupling; crosslink; design; Devices; Digestion; Dimensions; Dose; drug efficacy; Drug Formulations; Endothelial Cells; Exclusion; Exhibits; Failure (biologic function); Fibrin; Fibrinolysis; Gel; genipin; Geometry; high risk; improved; In Vitro; in vivo; Incidence; innovation; insight; Intervention; Intracranial Aneurysm; Kinetics; Lactate Dehydrogenase; Left; Marketing; Measures; Mechanics; Medical; Medical Device; Metabolism; Modeling; Monitor; Morphology; Mortality Vital Statistics; Neck; Nitric Oxide; novel; Outcome; Pharmaceutical Preparations; Phase; Platinum; Population; Positioning Attribute; preclinical study; Procedures; Production; Property; prospective; protein crosslink; Proteins; public health relevance; Recurrence; Research Activity; research study; Resistance; Rest; Risk; Rupture; Safety; small molecule; Surgical Clips; Techniques; Technology; Therapeutic; Therapeutic Embolization; thrombolysis; Toxic effect; Whole Blood; Workplace
