Date of Award

1-10-2024

Publication Type

Thesis

Degree Name

M.Sc.

Department

Chemistry and Biochemistry

Keywords

3D-Bioprinting;Alveolus;Fibrosis;Inhalation toxicity;Lung;Microphysiological System

Supervisor

Charu Chandrasekera

Supervisor

Drew Marquardt

Rights

info:eu-repo/semantics/embargoedAccess

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Abstract

Inhalation toxicity testing assesses chemical hazards and risks linked to respiratory tract exposure with the potential to induce interstitial lung diseases such as idiopathic pulmonary fibrosis. With 350,000 registered chemicals and mixtures with limited toxicity data, current gold-standard animal methods are costly, time-consuming, and lack adequate human relevance—underscoring the need for human biology-based new approach methods (NAMs) to capture complex, organ-level adverse outcomes more predictive of human respiratory biology. The overarching objective was to develop and validate a novel human microphysiological system (MPS), Alveoli-in-a-Dish, to emulate human inhalation toxicity in vitro. Our first-of-kind, vascularized, 3D-bioprinted, multicellular human alveolar MPS has the cytoarchitectural integrity (distinct epithelial and endothelial layers comprising Type I and II alveolar epithelial cells, endothelial cells, and fibroblasts, with an added immune component) and the functional sophistication necessary to capture complex physiologic endpoints of alveolar injury (fibrosis and phospholipidosis). Guided by the mechanistic framework, fibrosis adverse outcome pathway (AOP-173), our Alveoli-in-a-Dish showcases remarkable reproducibility, specificity, and sensitivity to robust drug and chemical-induced fibrosis (extracellular matrix collagen deposition) and phospholipidosis (intracellular phospholipid accumulation) over biologically relevant doses (human plasma Cmax) within experimentally feasible time parameters (2-5 days). With the ability to engineer cytoarchitectural versatility to reproducibly capture intricate biological endpoints for acute and repeated-dose inhalation toxicity, the ultimate goal of this project is to standardize this novel MPS for integrated approaches for 21st century regulatory toxicology and pulmonary disease modelling—to replace reliance on animal testing.

Available for download on Tuesday, February 11, 2025

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