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Author ORCID Identifier
Campus-Only Access for Five (5) Years
Doctor of Philosophy (PhD)
Year Degree Awarded
Month Degree Awarded
Bioinformatics | Biomaterials | Molecular, Cellular, and Tissue Engineering
The lung extracellular matrix (ECM), besides maintaining the structural integrity of the tissue, regulates the phenotype and functions of resident fibroblasts in both healthy and diseased lungs, such as fibrotic and metastatic lungs. Bioengineers have aimed to design instructive ECM models that can tailor the protein composition and biomechanics of the lung in vitro to study cell-matrix interactions during healthy and diseased conditions. However, these mechanical and biochemical features cannot be independently controlled in protein-based hydrogels and tissue-derived scaffolds. Synthetic in vitro hydrogels, on the other hand, can independently tune these substrate characteristics. Independent control over these substrate properties enables study of effects of these individual properties on cell-matrix interactions. There is a lack of synthetic in vitro lung models that study fibroblast phenotype with precise control as a function of the ECM features. This dissertation sought to develop an in vitro model that would enable the study of fibroblast phenotype and functions in health and during breast-to-lung metastasis. Here we introduce a synthetic hydrogel that shows maintenance of quiescence of human lung fibroblasts (HLFs) and control over their activation based on metastatic and fibrotic cues. We first characterized the mechanics of the porcine lung and matched the lung modulus of 1.5 kPa using our synthetic lung hydrogel formulation. We then characterized the human lung ECM based on proteomics and bioinformatics data and incorporated the most abundant ECM peptide motifs responsible for integrin binding and MMP-mediated degradation into the fully synthetic hydrogel. We demonstrated control over fibroblast phenotype using this hydrogel, composed of PEG and peptides. While encapsulated HLFs maintained quiescence in lung ECM hydrogels, we achieved fibroblast activation via the pro-fibrotic cytokine molecule, TGF-β1. Metastatic breast cancer conditioned media promoted HLF activation in these 3D gels and induced increased deposition of ECM protein, tenascin C (TNC) in immunocompromised mice. We designed another hydrogel where TNC mimetic peptides were incorporated to mimic the metastatic lung ECM. This metastatic lung hydrogel also promoted activation of encapsulated HLFs. Overall, this work describes a 3D synthetic lung ECM mimic as a bioengineered model to predict fibroblast phenotype in healthy and diseased lungs. This lung hydrogel system can be used as a new drug screening platform for several lung diseases including breast-to-lung metastasis and lung fibrosis.
Kundu, Aritra Nath, "Engineering Synthetic 3-Dimensional in vitro Lung ECM Mimic to Study Breast-to-Lung Metastasis" (2023). Doctoral Dissertations. 2827.
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