Development of in vitro cardiovascular tissue models within capillary circuit microfluidic devices fabricated with 3D Stereolithography printing

Abstract

Abstract Human cardiovascular tissue and diseases are difficult to study for novel drug discovery and fundamental cellular/molecular processes due to limited availability of physiologically-relevant models in vitro.[1–3] Animal models may resemble human heart structure, however there are significant differences from human cardiovascular physiology including biochemical signaling, and gene expression.[4–6] In vitro microfluidic tissue models provide a less expensive, more controlled, and reproducible platform for better quantification of isolated cellular processes in response to biochemical or biophysical stimulus.[6–12] The capillary driven-flow microfluidic device in this study was manufactured with a 3D stereolithography (SLA) printed mold and is a closed circuit system operating on principles of capillary action allowing continuous fluid movement without external power supply. Human umbilical vein endothelial cells (HUVECs) and human cardiomyocytes (AC16) were encapsulated into a fibrin hydrogel to form vascular (VTM) and cardiac (CTM) tissue models respectively. To determine response to biophysical stimulus, the 3D cardiovascular tissue was directly loaded into the device tissue culture chambers that either had no microposts (DWoP) or microposts (DWPG) for 1, 3 and 5 days. The tissues were analyzed with fluorescent microscopy for morphological differences, average tube length, and cell orientation between tissues cultured in both conditions. In DWPG VTMs displayed capillary-like tube formation with visible cell alignment and orientation, while AC16s continued to elongate around microposts by day 5. VTM and CTM models in devices with posts (DWPG) displayed cell alignment and orientation after 5 days, indicated the microposts induced biophysical cues to guide cell structure and specific organization.