Publicação
Tissue engineered in vitro models on a chip for cancer research
| Resumo: | By 2030, the global burden is expected to grow to 21.7 million new cancer cases and 13 million cancer deaths simply due to the growth and aging of the population. Among all types of cancer, colorectal cancer is a major cause of morbidity and mortality worldwide, and accounts for over 9 % of all cancer incidence. It is the third most common cancer worldwide and affects men and women equally. In order to win the battle against cancer, further advances are in great need to unveil identification of cancer-causing agents in in vitro and in vivo animal models, as well as for the development of personalized therapies, drug screening, and to provide insightful knowledge on the mechanisms of tumor growth and metastasis. Microfluidic devices, together with tissue engineering strategies and nanotechnology have emerged as a powerful platform to tackle the previously mentioned hurdles. These themes are the focus of Section 1, in Chapters I, II and III. In this thesis we focus on the application of CMCht/PAMAM dendrimer nanoparticles.as the synthesis, uptake efficiency/internalization and cytotoxic effect of fluorescent-labeled CMCht/PAMAM dendrimer nanoparticles was investigated using different cancer cell lines in both traditional culture flasks and under physiological flow inside a microfluidic platform (Chapter V). Other than nanoparticles, the use of different biomaterials to modulate 3D microenvironment of tumors is of the utmost importance. Therefore, the use of HRP-crosslinked SF hydrogels with spatial tunable properties was proposed in a colorectal cancer extravasation 3D model on a commercial chip Vena4™ (Chapter VI). To increase the complexity of the cancer models, a microfluidic chip was designed and fabricated for the incorporation of tumor and vascular parts, allowing for gradients of gemcitabine released from CMCht/PAMAM nanoparticles to be tested (Chapter VII). Chemical modification in the CMCht/PAMAM dendrimer nanoparticles in order to target colorectal cancer was also achieved in Chapter VIII. In Chapter IX, a new proof of concept consisting of a microfluidic silk platform, flexible and implantable, was developed in house. The results and platforms developed in this thesis are discussed in Chapter X and represent a strong advance in the field of lab-on-chip research and will be a useful tool for drug discovery and study of migration/metastasis phenomena, allowing for a versatile choice of tissues, biomaterials and biological assays. |
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| Autores principais: | Carvalho, Mariana Rodrigues de |
| Assunto: | Biomaterials Cancer models Colorectal cancer Microfluidics Nanoparticles Biomateriais Cancro colorrectal Microfluídica Modelos de cancro Nanopartículas |
| Ano: | 2019 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | By 2030, the global burden is expected to grow to 21.7 million new cancer cases and 13 million cancer deaths simply due to the growth and aging of the population. Among all types of cancer, colorectal cancer is a major cause of morbidity and mortality worldwide, and accounts for over 9 % of all cancer incidence. It is the third most common cancer worldwide and affects men and women equally. In order to win the battle against cancer, further advances are in great need to unveil identification of cancer-causing agents in in vitro and in vivo animal models, as well as for the development of personalized therapies, drug screening, and to provide insightful knowledge on the mechanisms of tumor growth and metastasis. Microfluidic devices, together with tissue engineering strategies and nanotechnology have emerged as a powerful platform to tackle the previously mentioned hurdles. These themes are the focus of Section 1, in Chapters I, II and III. In this thesis we focus on the application of CMCht/PAMAM dendrimer nanoparticles.as the synthesis, uptake efficiency/internalization and cytotoxic effect of fluorescent-labeled CMCht/PAMAM dendrimer nanoparticles was investigated using different cancer cell lines in both traditional culture flasks and under physiological flow inside a microfluidic platform (Chapter V). Other than nanoparticles, the use of different biomaterials to modulate 3D microenvironment of tumors is of the utmost importance. Therefore, the use of HRP-crosslinked SF hydrogels with spatial tunable properties was proposed in a colorectal cancer extravasation 3D model on a commercial chip Vena4™ (Chapter VI). To increase the complexity of the cancer models, a microfluidic chip was designed and fabricated for the incorporation of tumor and vascular parts, allowing for gradients of gemcitabine released from CMCht/PAMAM nanoparticles to be tested (Chapter VII). Chemical modification in the CMCht/PAMAM dendrimer nanoparticles in order to target colorectal cancer was also achieved in Chapter VIII. In Chapter IX, a new proof of concept consisting of a microfluidic silk platform, flexible and implantable, was developed in house. The results and platforms developed in this thesis are discussed in Chapter X and represent a strong advance in the field of lab-on-chip research and will be a useful tool for drug discovery and study of migration/metastasis phenomena, allowing for a versatile choice of tissues, biomaterials and biological assays. |
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