UC Irvine

This dissertation marks a significant advancement in the realm of in vitro disease modeling and drug screening, addressing the critical gap in existing methodologies that fail to replicate the refined microenvironment of human tissues with high fidelity. By addressing the critical limitations of traditional two-dimensional cultures and simpler 3D constructs, our work introduces novel, physiologically accurate models that replicate the complex microenvironments of organ tissues. The focus on developing organ-specific 3D bioprinted models for colorectal and lung cancer reflects a targeted approach to tackling two of the most challenging forms of cancer, highlighting the urgent need for more sophisticated and accurate disease models.Chapter 2 reveals a pioneering functional, three-dimensional colon model, utilizing the cutting-edge Freeform Reversible Embedding of Suspended Hydrogels (FRESH) 3D bioprinting technology. This innovation represents magnificent improvements in simulating the colon's mechanical, physical, and biological complexities. Our dual-layered construct not only matches the 3D luminal curvature and macrostructures of native colon tissue but also replicates the subepithelial and epithelial interaction through co-culture of 3T3 fibroblast cells with Caco-2 epithelial cells in 3D tissue geometry. Our in-vivo-mimicking colon model facilitates the formation of mini-colonic crypt structures, increasing the surface area, and therefore improving the absorption functionality. This mirrors the colon's natural architecture and enhances functionality in vitro. This model serves as a highly physiologically relevant platform, enabling an in-depth exploration of colorectal cancer mechanisms and the evaluation of therapeutic responses. Through comprehensive and novel drug efficacy analyses focusing on colorectal cancer treatments, we have demonstrated the model's unprecedented performance, showcasing its significant superiority in drug response assessments over traditional 2D cultures and other existing 3D constructs. Chapter 3 introduces the in-vivo mimicking 3D-lung-cancer-on-a-chip (IVM3DLCOC) model, developed and characterized to more precisely represent lung pathogenesis in vitro. The model innovatively co-cultures A549 lung cancer cells with human lung fibroblasts within 3D hydrogels, engineered to mirror the lung's extracellular matrix. This setup replicates essential mechanical and biological cues for cell adhesion, proliferation, and an accurate study of disease progression, particularly lung cancer metastasis. The inclusion of fluidic channels intersecting air channels via a porous membrane atop the lung epithelial cells establishes an air-liquid interface, simulating the lung's inhalation and exhalation cycles and reproducing the dynamic physiological microenvironment. The efficacy of this model was underscored through studies examining the impact of cigarette smoke extract (CSE), preserving metastatic characteristics and revealing translational properties crucial for understanding disease progression and the validation of drug efficacy. Both models showcase a transformative shift in the landscape of in vitro disease modeling and drug screening, offering a more accurate and physiologically relevant lens through which to view the complexities of cancer mechanisms and the development of effective therapies. This work not only challenges the limitations of traditional methodologies but also significantly contributes to the fields of biomedical engineering and personalized medicine. It lays the groundwork for future innovations in cancer research, with the potential to dramatically enhance the precision and effectiveness of cancer treatments.