Vascularized microfluidic platforms to mimic the tumor microenvironment

Abstract

Microfluidic technology has led to the development of advanced in vitro tumor platforms that overcome the challenges of in vivo animal and in vitro two dimensional models. This paper presents platform designs and methods used to develop complex vascularized in vitro models to mimic the tumor microenvironment. Features of these platforms include a continuous, aligned endothelium that allows for cell-cell interactions between vasculature and tumor cells. A novel platform for fabrication of a single endothelialized microchannel encased within a collagen platform hosting breast cancer cells was developed and utilized to study the influence of cellular interaction on transport phenomenon through vasculature in a hyperpermeable tumor microenvironment. This platform relies on subtractive tissue engineering fabrication techniques. Through confocal imaging we have demonstrated that the platform produces enhanced vessel leakiness recapitulating physiological features of the tumor microenvironment. The influence of tumor endothelial interactions on transport of particles was also demonstrated. Additionally, we designed two more complex and intricate endothelialized microfluidic networks by combining lithographic techniques with additive tissue engineering methods. We created a network platform consisting of interconnected microchannels to model a highly vascularized system and successfully perfused the system with fluorescent particles. Finally, we developed a physiologically representative in vitro microfluidic platform with vasculature patterned from in vivo data showing the versatility of these systems to replicate the complex geometries of tumor microvasculature and dynamically measured particle transport. Overall, we have shown the ability to develop functional microfluidic vascular tumor platforms of varying complexities and demonstrated their utility for studying spatial particle transport within these systems.

In vitro vascularized liver and tumor tissue microenvironments on a chip for dynamic determination of nanoparticle transport and toxicity

“…The collagen‐based vascularized breast cancer platform developed by Zervantonakis et al () determined the fold change between Control− (Tumorigenic) and Control+ as 1.79 ± 0.27, which is in a good agreement with the quantified value of 1.59 ± 0.13 in this study. Moreover, a permeability coefficient of 70 kDa dextran particles was reported as 2.58 × 10 −6 ± 0.19 × 10 −6 cm/s in vascularized collagen‐based tumor microenvironments under the same shear stress (Buchanan et al, ; Michna et al, ), which compares well with our permeability results (2.68 × 10 −6 ± 0.29 × 10 −6 cm/s).…”

“…Scale bar is 500 µm. TIME: Moreover, a permeability coefficient of 70 kDa dextran particles was reported as 2.58 × 10 −6 ± 0.19 × 10 −6 cm/s in vascularized collagenbased tumor microenvironments under the same shear stress (Buchanan et al, 2014;Michna et al, 2018), which compares well with our permeability results (2.68 × 10 −6 ± 0.29 × 10 −6 cm/s).…”

“…Although these studies reported permeability coefficients of the tumor tissue and vessel in response to different treatments, vessels were not fully surrounded by extracellular matrix (ECM), which limited physiological response and estimation of transport spatially. To address these concerns with the clinical relevance of existing 3D models, we have created microfluidic breast tumor microenvironments in which tumor cells are cultured in collagen surrounding an endothelialized vessel in which physiological flow can be introduced (Buchanan et al, ; Buchanan, Verbridge, Vlachos, & Rylander, ; Michna, Gadde, Ozkan, DeWitt, & Rylander, ). These platforms have been utilized to determine the influence of flow and tumor‐endothelial cross‐talk on vessel permeability and angiogenesis but they have not yet been applied to critical questions of a chemotherapy drug and nanoparticle transport.…”

Engineering of Hydrogel Materials with Perfusable Microchannels for Building Vascularized Tissues

“…Vascularized tumor tissues were developed for the investigation of these processes. Michna et al utilized a collagen scaffold with perfusable channel to model the vascularized tumor and demonstrated that the existence of tumor cells within the scaffold would lead to a leakier vascular barrier . Gorlman et al modeled the tumor microenvironment by coculturing human breast adenocarcinoma cells and mouse macrophage cells in extruded hollow microfibers in different patterned geometries.…”

Design and Fabrication of Three-Dimensional Printed Scaffolds for Cancer Precision Medicine

“…Vascularization is an important factor in tumor growth and metastasis; hence, vascularization prevention has been widely studied as a unique antitumor therapy. 56,68 Recently, tissue-engineered tumor models explored the contribution of vascular tissue on tumor cell biology by the development of coculture systems and the utilization of microfluidic techniques for the development of 3D vascularized tissues. 68,69 The microvascular endothelial cells have been cocultured with tumor cells to explore the interactions between these cells and eventually develop new therapeutics.…”