John Nicosia

PhD Proposal Presentation

Date: Tuesday August 16, 2016         

Time: 1:00 PM

Location:  EBB, Children’s Healthcare of Atlanta (CHOA) Seminar Room         

Co-Advisors: 

Thomas Barker, PhD (BME, University of Virginia)

Wilbur Lam, MD, PhD (BME, Georgia Institute of Technology/Emory University)

Thesis Committee Members:

Ashley Brown, PhD (BME, North Carolina State University/UNC Chapel Hill)

Philip Santangelo, PhD (BME, Georgia Institute of Technology/Emory University)

Gabriel Kwong, PhD (BME, Georgia Institute of Technology/Emory University)

Alberto Fernandez-Nieves, PhD (Physics, Georgia Institute of Technology)

Development and Characterization of a Platelet-like Particle for Treatment of Chemotherapy- and Radiation-induced Thrombocytopenia

Excessive bleeding is a common complication of cancer patients. Often, chemotherapy or radiation treatment leads to ablation of bone marrow resulting in low platelet count, a condition known as thrombocytopenia. Platelets are a critical component of hemostasis. In addition to forming a platelet plug within seconds of vascular injury, they secrete soluble factors to bolster the coagulation process. Additionally, platelets bind and contract the polymerized fibrin fibers that comprise the nascent blood clot, reinforcing its mechanical integrity. Annually, about 2.2 million platelet doses are transfused in the United States. However, due to bacterial contamination (about 1 in every 1000 doses) and immunogenicity concerns, transfusion of donor platelets entails considerable risk to the recipient. The Barker lab has recently reported on the development of a platelet substitute consisting of an ultra-low crosslinked (ULC), highly deformable poly(N-isopropylacrylamide-co-acrylic acid) (pNIPAm-AAc) microgel core functionalized with a fibrin-specific single-domain antibody fragment. These platelet-like particles (PLPs) were shown to augment clot formation in vitro and slow bleeding in a rat femoral vein injury model. However, little is known about the ability of PLPs to effectively marginate to the vessel wall, a crucial behavior of native platelets that might offer a means of augmenting PLP efficacy. Furthermore, there exists a significant gap in knowledge regarding the biodistribution and circulation time of PLPs. This proposal aims to explore the effect of increasing crosslinking density on PLP margination in an endothelialized microfluidic device and investigate biodistribution using positron emission tomography-computed tomography (PET/CT) in a mouse model of radiation-induced thrombocytopenia.