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

Creative Commons Attribution 4.0 International 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.

Available for download on Tuesday, February 11, 2025

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Biochemistry Commons

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