Microfluidic Platform For Biomimetic Construction Of Brain Tumor Microenvironment And Applications

Brain tumor microenvironment refers to the summation of internal and external microenvironment of tumor cells,and is closely related with the occurrence,proliferation and metastasis of tumor.Traditional models are difficult to reflect the complex structure and functional characteristics of the brain microenvironment in vivo.In this thesis,we take the micro fluidics as the key technology to simulate the brain tumor microenvironment regulated by multicellular and multicomponent complex factors,study the effects and mechanisms on tumor invasion and metastasis of a variety of biochemical and biophysical factors,providing a new way for the research of brain tumors.The detailed work in this thesis includes:1.We developed a series of functional microfluidic devices,and established tumor microvascular,tumor invasion,and brain metastasis microenviromnent.We carried out the methodology research for biomimetic vascular and three-dimensional dynamic blood-brain barrier model in vitro,laying the foundation for the follow-up application of tumor cell extravasation and brain metastasis2.We studied the rolling and adhesion phenomena on inflammatory endothelium of lung tumor cells under fluidic shear stress condition.Both the biochemical and mechanical factors were investigated the influences on the tumor extravasation.We verified the regulatory mechanism of Rho/ROCK signaling pathway in lung cancer extravasation,providing a new method for the study of circulating tumor cells in brain metastasis.3.We investigated the effects of hypoxia on the movement of glioma cells,finding out that the hypoxia microenvironment could promotes the invasion and EMT of glioma cells in three-dimensional matrix,and up-regulates the expression of HIF-,EMT-,and angiogenesis-associated genes in glioma cells.These findings indicated that hypoxia could promote the invasion of glioma cells through HIF signaling pathway,providing promising platform for the research for brain tumors.4.We proposed a novel dynamic physiological relevant three-dimensional blood-brain barrier microfluidic system,including complex cell compositon,three-dimensional matrix and mechanical factors.Furthermore,we studied the dynamic process of brain tumor and brain metastasis,and examined the ability of a varity of clinical antitumor drugs trans-across the blood-brain barrier,providing a new method for biomimetic of brain tumor microenvironment and evaluation of antitumor drugs,and also providing a new approach for exploring the pathogenesis of brain tumors...