University of Twente Student Theses


Bioengineered 3D multicellular hepatic model to study the mechanobiological induction and progression of liver tussue fibrotic stages

Sacchi, Marta (2021) Bioengineered 3D multicellular hepatic model to study the mechanobiological induction and progression of liver tussue fibrotic stages.

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Abstract:Fibrosis, characterized by an aberrant accumulation of extracellular matrix (ECM) leading to scar tissue and impaired organ function, is a significant health condition impacting millions of people worldwide and accounting for about 45% of total deaths. The constant increase of metabolic disorders and chronic medical conditions (such as diabetes and obesity) in the world aging population will significantly impact on the incidence of fibrotic diseases and subsequently on the number of fibrosisrelated deaths. Fibrosis is a common outcome of many chronic diseases, involving different organs, including liver. Currently, there are no therapies available to reverse chronic fibrosis and organ transplantation is the only option available. However, this option is limited due to organ shortage and chronic rejection and it is only possible when diagnosed in a very early stage. The persistence of this unmet clinical need is due to the complexity of the disease process that involves numerous cell types and signaling pathways. Lack of reliable, reproducible, easy-to-handle quantitative in vitro models recapitulating the biological mechanisms underpinning tissue fibrosis pathophysiology, partially, hampered the testing and development of clinically relevant anti-fibrotic drugs. In this context, several combined 3D fibrotic liver tissue models have been developed by integrating physiological-relevant hepatic 3D co-culture models with microfluidic platforms. Surprisingly, the main focus of such models verted to the establishment of a relevant liver tissue models for the study of drug metabolism and for toxicity screening upon pro-fibrotic induction by soluble chemicals. Not much attention has been directed towards the development of complex bioengineered 3D liver models aimed at recapitulating the key mechanobiological aspects underlying tissue fibrosis development and functioning, by providing key in vivo ECM mechanical features and hepatic multicellular 3D culture models, independently on exogenous pro-fibrotic chemical factors induction. In such a context, in this project, we hypothesized that the resemble of key tissue mechanical properties (stiffness, interstitial flow, hydrostatic pressure) over typical pathophysiological ranges of value could promote cell differentiation into pro-fibrotic phenotype via the activation of latent profibrogenic growth factors generating a pro-fibrotic cascade of event, thus leading, and perpetuating a fibrotic microenvironment. In order to prove that, a physiological-relevant in vitro 3D model to study the effects of the mechanical properties of the matrix on liver tissue fibrosis development and functioning was developed, by i) establishing a liver microtissue model in form of a multicellular hepatic spheroid model; ii) providing it with a physio-pathological relevant tissue microenvironment mimicking key mechanical and biological feature.
Item Type:Essay (Master)
Faculty:ET: Engineering Technology
Subject:02 science and culture in general
Programme:Biomedical Engineering MSc (66226)
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