Ciencias Exactas y Ciencias de la Salud

Human tissues exhibit a balance between aggregation and segregation, but achieving such microscale organization is challenging for most extrusion-based bioprinting techniques. Conventional strategies often require smaller nozzles to generate microscopic features. However, smaller nozzles decrease production yields, and increase cellular damage due to a higher shear stress. Recently, our research group introduced the concept of chaotic bioprinting for the high-throughput fabrication of tissue models exhibiting microscale organization. The focus of this PhD thesis was the development of spatially-organized cancer models using chaotic bioprinting. This document is organized into four (4) chapters. The first chapter introduces the concept of chaos-assisted production of architected spheres (CAPAS). This system allows to modulate the sphere diameter (0.6 to 3.5 mm) and production yield (up to ~2,000 droplets per minute) by adjusting simple process parameters: flow rate, printhead outlet diameter, polymer concentration (sodium alginate or GelMA), and crosslinking bath composition. CAPAS was used to create a breast cancer model where malignant cells were surrounded by healthy stromal cells. This multicellular cancer model exhibited a higher susceptibility to paclitaxel doses than monocultures of breast cancer cells. The second chapter presents an expanded portfolio of chaotic printheads by the incorporation of superior and lateral inlets. The number and type of biomaterials extruded through a printhead can be adjusted to meet different requirements. For example, chaotic printheads were used to produce fibers exhibiting axial microgradients, structured emulsions, micro-channeled hydrogel filaments, and a tumor niche containing breast cancer microtumors. Cells from embedded spheroids migrated through the micropatterns created by the lateral inlets of the printhead. The third chapter outlines a strategy to fabricate a pre-vascularized breast cancer model using a multimaterial chaotic printhead. In this model, breast cancer microtumors were surrounded by inner channels that served as corridors for cell migration. The length of the migratory fronts was higher in multichannel filaments (~1,400 μm in length) than in solid scaffolds (~400 μm in length). Genes involved in cell migration (N-cadherin, vimentin) were highly upregulated in multichannel filaments. The fourth chapter introduces a novel set of static mixers designed to mimic the architecture of some human tissues. Each mixer generates a specific inner structure in the printed filament that resembles, for example, the intestinal villi, the human breast tissue, or marbled meat. I fabricated a colon cancer model that exhibited a high post-printing viability (~75% viable cells) over an extended cultivation period (14 days). I also adapted these novel printheads to a cartesian bioprinter to produce three-dimensional scaffolds exhibiting inner microarchitecture. In conclusion, I envision that the work derived from my PhD thesis will help to fabricate disease models that better recapitulate the spatial organization of human tissues. One limitation of the current work is that the effective generation of microstructure by chaotic printing is strongly dependent on the rheology of the biomaterials used. This limitation may be addressed by optimizing biomaterial formulations for chaotic printing.

Ciencias Exactas y Ciencias de la Salud

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