Vibroshear: A System for High-Throughput Drug Discovery of Agents Limiting Shear-Mediated Cell (Platelet) Activation

Project Goal: To design and build a system for high throughput drug screening of agents capable of limiting shear-mediated cell (platelet) activation. The heart of the system is a “multiwell plate unit,” with contained means for exposing fluid and cells within each well to defined shear stress. The shear mechanisms to be considered in design include: 1. magnetically activatable beads 2. focused ultrasound or 3. vibration/acoustics, all inducing defined, predictable shear stress to fluid contained in each well. The utility and value of this system will be to systematically, in large scale, uniformly shear-activate platelets placed in each well, either with or without test compounds. The system will be utilized for screening of new agents able to limit shear-mediated platelet activation. The multiwell plate unit, once shear studies are complete, will be “run” in a multiwell plate reader for readout. The system will interface with a multiwell dispenser for compound loading. The system wil have an output data collection and display module for recording and displaying +compound hits from the plate reader output.

Project Background/Scope: Thrombosis or “blood clot formation” is a major limitation of implantable cardiovascular therapeutic devices (CTDs) such as ventricular assist devices (VADs), prosthetic heart valves and stents. Thrombosis is also an issue and complication for patients having implanted shunts and fistulas as occurs in renal failure for those on dialysis. Central to blood clot formation is the platelet. Platelets become activated in passing through CTDs via exposure to excessive shear forces imparted to flowing blood through the fluid paths of these devices. To limit clot formation, currently patients are prescribed a range of anti-platelet drugs aimed at limiting platelet activation. In recent years the Slepian lab has been repeatedly demonstrated that no current anti-platelet drugs in routine clinical use block shear-mediated platelet activation! – these drugs were developed for biochemical activation means, not mechanical means as occurs with shear! As such a major gap in clinical therapy for patients implanted with CTDs are effective drugs able to limit the activation of platelets due to shear, rather than biochemical stimulation. Developing a system and tool as outlined here will jumpstart and accelerate new drug discovery via high-throughput screening.