Engineering polymer biomaterial interfaces for promoting cellular morphogenesis

Abstract

Three-dimensional in vitro tissue and organ cultures have immense promise as models of human pathophysiology and stand to make a significant impact on the process of drug discovery and development. Many existing model systems do not capture the relevant complexity of the native tissue environment, relying on poorly characterized natural extracellular matrices (ECMs) for growth and development. These models are notably limited by the lack of vasculature, a key functional component of most human tissues, enabling oxygen and nutrient exchange, as well as facilitating paracrine signaling with surrounding epithelial cells. Fully-defined and tunable synthetic ECMs that support the generation of vascular network structures in dense tissue environments represent a path towards overcoming the limitations of existing model systems.

This thesis focuses on the development and characterization of polymeric biomaterials that can be used to enhance in vitro tissue models through engineering the cell-material interface to guide a particular biological response. A major application focus of this research is to engineer biomaterial tools that would enable vascularization of dense epithelial tissue in vitro. We developed and characterized a poly(ethylene glycol)-based microbead angiogenesis scaffold with tunable physical and biochemical properties, identifying a critical ligand concentration regime on the microbead surface that promotes integrin-mediated endothelial cell attachment and invasion into both a synthetic ECM as well as a tissue aggregate of hepatocarcinoma cells.

Furthermore, we investigated a novel hybrid PEG-polypeptide polymer, poly([gamma]-propargyl- L-glutamate) (PPLG) as a hydrogel substrate that can enhance endothelial cell attachment and spreading through modulation of the macromer structure and hydrophobicity properties. This work demonstrates how rational biomaterial design through chemical and structural modifications to polymer scaffolds can control cell fate within an in vitro tissue culture system.