Tumor-on-chip devices are becoming ideal platforms to recreate in vitro the particular physiological microenvironment of interest for onco-nanomedicine testing and development. This work presents a strategy to produce a round artificial microvessel on-a-chip device for the study of physiologically relevant nanomedicine transport dynamics. The microchannels have a diameter in the range of the tumor capillaries and a semicircular geometry. This geometry is obtained through an intermediate thermal nanoimprint step using a master mold with square-shaped channel structures produced by standard silicon micromachining or by stereolithography three-dimensional (3D) printing. The working microfluidic chip devices are made by casting polydimethylsiloxane on the imprinted intermediate mold. Artificial blood microvessels are created by seeding human endothelial cells into the round-shaped channels acting as the scaffold. The microchip is connected by 3D-printed reservoirs to a pressure controller, allowing for a fine fluidic control. Under physiological flow conditions, the dynamic interaction of nanoparticles (NPs) with the artificial endothelium was assessed by high-magnification fluorescence microscopy. Overtime, internalization of NPs and clustering was observed and the accumulation rate into the endothelial cells could be characterized in real time.

Nanotechnology has emerged as a promising tool for the early diagnosis and treatment of cancer. [1][2][3] During the past decades, several nanotechnology-based therapies have been approved for clinical use. [4] However, the success rate of nanomedicines entering clinical trials is extremely low. [5][6][7] There is also a great number of nanomedicines being developed that show high efficacy in studies in vitro, yet they fail at in vivo tests. [8,9] Thus, new more advanced preclinical models with improved predictive value are required to be able to advance the clinical translation of nanomedicines. In this regard, tumor-on-a-chip (ToC) microfluidic devices are new testing platforms with greater physiological relevance than the traditional 2D cell cultures. They are capable of recapitulating key physiological aspects of the tumor microenvironment, like perfused 3D cellular microenvironments, allowing for the dynamic tuning of the physicochemical parameters. [9][10][11][12][13] As such, these devices may provide more clinically relevant models to study the transport process of nanomedicines across the biological barriers for a better prediction of their in vivo performance. [14,15] During the recent years, several ToC devices have been developed as in vitro models to investigate different processes of the tumor biology. ToCs have been used to get a better understanding of cancer progression and metastasis, [16][17][18][19][20] as well as angiogenesis and blood vessel formation. [21][22][23][24] ToC devices have been also developed for the evaluation of new therapeutic approaches against cancer, including nanomedicines. [25][26][27][28] However, up-to-date, ToC devices have failed to model some of the main critical components involved in nanomedicine delivery to the tumor site. During the tumor delivery process, nanomedicines need to leave the bloodstream, penetrate into the interstitial tumor matrix and, ultimately, into the tumor cells. Here,