Biomaterial processing for organ-on-a-chip engineering

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Tissue engineering may provide microhpysiological on-a-chip platforms for studies of paracrine signaling, tissue function and compound discovery. Recent advances in stem cell biology enable procurement of virtually all human cell types by differentiation of pluripotent stem cells (PSC) into specialized lineages e.g. cardiomyocytes (CM), hepatocytes, etc. However, the entire field is faced with two critical limitations: 1) Complexities related to integrating several cell types into high-fidelity tissue-on-a-chip models still remain. 2) Lack of understanding of structure-function relationships and design rules for building functional organs in vitro. Using approaches from biomaterial and polymer sciences, materials processing, microfabrication and chemical engineering this research program will overcome both limitations. Most current on-a-chip devices utilize poly(dimethylsiloxane), PDMS, which is notorious for absorption and leaching of small molecules. The on-a-chip devices have a closed configuration, usually with the tissue sealed between the PDMS layer and a glass substrate, requiring a pump driven flow. This makes direct access to the tissue difficult and integration of various compartments exponentially complex, requiring bulky external equipment. In vivo, metabolites are delivered by convection through the vasculature connecting different organs, passing through the endothelium into the parenchymal space. In Project 1, to engineer a robust tissue then organ-on-a-chip platform, we will first build a generic and functional vascular bed to support and then connect different tissues. For this purpose, we will develop a new 3D micro-stamping technique to create polyester-based perfusable branching vasculature that accommodates two opposing criteria: mechanically stable walls yet permeable to small molecules, proteins and ultimately migrating cells. The vascular bed will be seeded with parenchymal cells in a PDMS-free bioreactor, with a footprint of a well plate and open access for liquid dispensing. We aim to integrate cardiac, liver and breast tumor tissue onto a single platform. In Project 2 we hypothesize that a functional heart left ventricle (LV) can be engineered by bioprinting a multilayer 3D construct that recapitulates complex fiber orientation of the native LV, by specifying adhesive and non-adhesive regions for CM attachment in a hydrogel sheet using a microfluidic bioprinter. We expect the LV with appropriate fiber orientation to be capable of synchronously twisting and contracting as the native ventricle, while isotropic or circumferentially aligned fibers will not. Project 1 and 2 are interconnected as branching vasculature from Project 1  could be used in scale-up studies for Project 2. Both Projects will use cells differentiated from human induced PSC. Three PhD, 2 MASc and 5 undergraduate students will be trained through the proposed studies.