Heart tissue possesses complex structural organization on multiple scales, from macro- to nano-, but nanoscale control of cardiac function has not been extensively analyzed. Inspired by ultrastructural analysis of the native tissue, we constructed a scalable, nanotopographically controlled model of myocardium mimicking the in vivo ventricular organization. Guided by nanoscale mechanical cues provided by the underlying hydrogel, the tissue constructs displayed anisotropic action potential propagation and contractility characteristic of the native tissue. Surprisingly, cell geometry, action potential conduction velocity, and the expression of a cell–cell coupling protein were exquisitely sensitive to differences in the substratum nanoscale features of the surrounding extracellular matrix. We propose that controlling cell–material interactions on the nanoscale can stipulate structure and function on the tissue level and yield novel insights into in vivo tissue physiology, while providing materials for tissue repair.

Assessment of anti-cancer drug efficacy in in vitro three-dimensional (3D) bioengineered cancer models provides important contextual and relevant information towards pre-clinical translation of potential drug candidates. However, currently established models fail to sufficiently recapitulate complex tumor heterogeneity. Here we present a chip-based tumor-mimetic platform incorporating a 3D in vitro breast cancer model with a tumor-mimetic microvascular network, replicating the pathophysiological architecture of native vascularized breast tumors. The microfluidic platform facilitated formation of mature, lumenized and flow-aligned endothelium under physiological flow recapitulating both high and low perfused tumor regions. Metastatic and non-metastatic breast cancer cells were maintained in long-term 3D co-culture with stromal fibroblasts in a poly(ethylene glycol)-fibrinogen hydrogel matrix within adjoining tissue chambers. The interstitial space between the chambers and endothelium contained pores to mimic the “leaky” vasculature found in vivo and facilitate cancer cell-endothelial cell communication. Microvascular pattern-dependent flow variations induced concentration gradients within the 3D tumor mass, leading to morphological tumor heterogeneity. Anti-cancer drugs displayed cell type- and flow pattern-dependent effects on cancer cell viability, viable tumor area and associated endothelial cytotoxicity. Overall, the developed microfluidic tumor-mimetic platform facilitates investigation of cancer-stromal-endothelial interactions and highlights the role of a fluidic, tumor-mimetic vascular network on anti-cancer drug delivery and efficacy for improved translation towards pre-clinical studies.