Date of Award
1-10-2024
Publication Type
Thesis
Degree Name
M.Sc.
Department
Chemistry and Biochemistry
Keywords
3D-Bioprinting;Fibrosis;Hepatotoxicity;Liver;Microphysiological System;Toxicology
Supervisor
Charu Chandrasekera
Supervisor
Sirinart Ananvoranich
Rights
info:eu-repo/semantics/embargoedAccess
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Abstract
The liver plays a pivotal role in drug metabolism and toxicity, with drug-induced liver injury (DILI) and chemical-induced liver injury (CILI) representing adverse reactions to pharmaceuticals or chemicals. DILI is the main reason for drug attrition and post-market withdrawal and CILI poses a global concern given 350,000 chemicals and mixtures with limited toxicology data. The legacy gold-standard animal-based methods lack species relevance, and are expensive, time-consuming, and ethically questionable—underscoring the necessity for predictive new approach methods (NAMs). The overarching objective was to develop and validate a novel human liver microphysiological system (MPS) to recapitulate HepatoToxicity-in-a-Dish. To our knowledge, this is the first human liver MPS of-its-kind—a vascularized, 3D-bioprinted liver tissue with 7 cell-types, including an immune component, at physiologic densities (hepatocytes, stellates, cholangiocytes, endothelial cells, lymphocytes, macrophages, and fibroblasts)—with the cytoarchitectural sophistication and functional integrity to capture hallmark endpoints of acute (48 hrs) and repeated-dose (5-10 days) hepatotoxicity at human-relevant concentrations (human plasma Cmax). Guided by the adverse outcome pathway for liver fibrosis (AOP-38), our MPS reproducibly captured DILI/CILI with the requisite specificity and sensitivity for a panel of benchmark drugs & chemicals: fibrosis (extracellular matrix collagen deposition), steatosis (triglyceride accumulation), cholestasis (impairment of trabeculae-like structures), phospholipidosis (intracellular phospholipid accumulation), and impaired albumin production. With engineerable versatility, our MPS exhibits promising capacity to emulate human liver injury in vitro to bridge the animal-to-human translational gap in DILI & CILI—to replace animals in hepatotoxicity testing and liver disease modelling.
Recommended Citation
Vajko Siddall, Lucas Joseph Aaron Marie, "HepatoToxicity-in-a-Dish: Human Microphysiological System for Liver Injury" (2024). Electronic Theses and Dissertations. 9197.
https://scholar.uwindsor.ca/etd/9197