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Transport-mediated angiogenesis in 3D epithelial coculture

Ryo Sudo^*, Seok Chung^*,1, Ioannis K. Zervantonakis, Vernella Vickerman, Yasuko Toshimitsu^*, Linda G. Griffith^*, and Roger D. Kamm^*,,2

^* Department of Biological Engineering,

Department of Mechanical Engineering, and

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

² Correspondence: Departments of Biological Engineering and Mechanical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave., NE47-321, Cambridge MA 02139, USA. E-mail: rdkamm{at}mit.edu

Increasing interest has focused on capturing the complexity of tissues and organs in vitro as models of human pathophysiological processes. In particular, a need exists for a model that can investigate the interactions in three dimensions (3D) between epithelial tissues and a microvascular network since vascularization is vital for reconstructing functional tissues in vitro. Here, we implement a microfluidic platform to analyze angiogenesis in 3D cultures of rat primary hepatocytes and rat/human microvascular endothelial cells (rMVECs/hMVECs). Liver and vascular cells were cultured on each sidewall of a collagen gel scaffold between two microfluidic channels under static or flow conditions. Morphogenesis of 3D hepatocyte cultures was found to depend on diffusion and convection across the nascent tissue. Furthermore, rMVECs formed 3D capillary-like structures that extended across an intervening gel to the hepatocyte tissues in hepatocyte-rMVEC coculture while they formed 2D sheet-like structures in rMVEC monoculture. In addition, diffusion of fluorescent dextran across the gel scaffold was analyzed, demonstrating that secreted proteins from the hepatocytes and MVECs can be exchanged across the gel scaffold by diffusional transport. The experimental approach described here is useful more generally for investigating microvascular networks within 3D engineered tissues with multiple cell types in vitro.—Sudo, R., Chung, S., Zervantonakis, I. K., Vickerman, V., Toshimitsu, Y., Griffith, L. G., Kamm, R. D. Transport-mediated angiogenesis in 3D epithelial coculture.

Key Words: microfluidics • vascularization • tissue engineering