Three-Dimensional Tissue-Engineered Cancer Models for Tumorigenic Studies and Drug-Testing Applications
Type of DegreePhD Dissertation
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Cancer is one of the most prevalent diseases, affecting millions of people throughout the world in various forms. Significant multidisciplinary efforts are being conducted to improve detection, diagnosis and treatment of the disease. One important research focus is to identify key disease mechanisms which can be exploited for the development of efficient drugs, thereby reducing cancer recurrence, improving patient mortality and ensuring progression-free survival. The emerging field of cancer tissue engineering aims to provide platforms whereby cancer tissue can be closely reproduced and simulated in a three-dimensional (3D) in vitro setup, facilitating the study of the disease outside the body and testing efficacy of different drugs prior to translation in clinical trials. This research focuses on the development of 3D in vitro models of breast cancer, amongst other cancer types, which closely mimic the microenvironmental conditions of native cancer tissue, and ultimately facilitate the investigation of specific tumorigenic mechanisms and testing anti-cancer drug efficacy. This work highlights the use of biomimetic PEG-based hydrogels for the encapsulation and long-term 3D culture of various cancer cell types and subsequent investigation of cancer cell behavior and disease progression within 3D hydrogel scaffolds and subsequent testing of anti cancer drug efficacy. Chapter 1 introduces the current state of cancer tissue engineering, the use of various biomimetic materials for mimicking the native tumor microenvironment and different biofabrication techniques employed for the development of tissue-engineered cancer models and drug-testing. In Chapter 2, generation of a millimeter-scale breast cancer model via a novel dual-phase, surface tension-based fabrication method for generation of poly(ethylene glycol diacrylate) (PEGDA) hydrogel millibeads and tumor millibeads encapsulating breast cancer cells is presented. Chapter 3 provides background on the use of fibrinogen coupled with PEGDA (PEG-fibrinogen, PF), and its use in creating the tumor microsphere model for encapsulation of breast cancer cells and investigation of subsequent tumorigenic characteristics with relation to spontaneously aggregated tumor spheroids formed via the hanging droplet method. In Chapter 4, the effect of matrix stiffness and physical properties of PF-based hydrogels on the 3D growth and behavior of three breast cancer cell types is investigated. In Chapter 5, a study establishing a microfluidic oncomimetic model for co-culture of vascularized endothelium, breast cancer cells and fibroblasts and subsequent drug-testing is reported.