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Light-Assisted Biopatterning of Hydrogels for Investigating Cell Interactions within their Microenvironment

  • Author(s): Hribar, Kolin C.
  • et al.
Abstract

Our bodies are composed of complex tissues and organs, and each tissue is governed by the careful coordination of cells, solutes, and extracellular matrix components. As such, the tissue engineering field has sought to develop tools to study tissue physiology at the molecular and cellular level. Biomaterials play a critical role in mimicking the extracellular matrix in design and function, acting as the scaffolding from which cells can attach, proliferate, and differentiate to form complex tissues. This dissertation focuses on light-assisted patterning of these materials for investigating cellular interactions within the tissue microenvironment. The stiffness of the extracellular matrix has been implicated in governing cell fate (e.g. proliferation, migration, and differentiation) in vivo, thus we developed digital plasmonic patterning (DPP) -- a laser-based patterning system -- to control stiffness on a two-dimensional (2D) hydrogel substrate in vitro. Cells exhibited durotaxis, or migration to the stiffer patterns, as well as alignment onto the patterns. We built on this research by studying cellular migration in a three-dimensional (3D) collagen hydrogel. We used ultrafast laser-induced degradation (ULID) to spatially pattern channels (void spaces) in the collagen gel. Endothelial cells responded to the void spaces by migrating, aligning, and eventually forming tube-like structures similar to early blood vessel formation. To enable the fabrication of more complex hydrogel structures, we turned to UV light-based 3D printing. First, we printed hydrogels with precise concave architectures and seeded breast cancer cells. Cells aggregated into spheroids over several days and developed hypoxic and necrotic cores by day 10, hallmarks of the tumor microenvironment. These results suggest a new way to study tumor progression. We furthered our study of cancer progression by developing a co-culture 3D printed in vitro model of glioblastoma (GBM) and its blood vessels. Results showed GBM proliferating, invading, and ultimately coopting the vasculature, and moreover demonstrated a similar response to FDA approved drugs as the clinical outcome. In summary, we demonstrated the vast utility of light-assisted biopatterning for understanding cellular interactions in their microenvironment and later applied these methods to develop in vitro models for drug screening

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