An in-vivo-mimicking 3D lung cancer-on-a-chip model to study the effect of external stimulus on the progress and inhibition of cancer metastasis

Metastatic lung cancer is one of the leading causes of high mortality worldwide. Here, an in-vivo mimicking 3D-lung- cancer-on-a-chip (IVM3DLCOC) model is introduced, developed, and fully characterized to represent lung pathogenesis in-vitro more precisely. In this model, the mechanical and biological features of the human lung are established in a co-culture of lung cancer cells (A549) with human lung fibroblasts inside 3D hydrogels. These structures have mechanical characteristics comparable to those of native lung extracellular matrix and offer the required biological cues for cell adhesion and proliferation. Physical cues are reproduced by structures at multiple levels (in the z-axis), including fluidic channels that are connected to air channels by a porous membrane on top of the lung epithelial cells, to provide an air-liquid interface that enables inhalation and exhalation cycles. Diffusion of media is also controlled via the physical barrier of stromal cells to reproduce the dynamic physiological microenvironment. Such an in-vivo mimicking model is ideal for accurate study of disease progression (i.e., lung cancer metastasis) and validation of drug efficacy. To demonstrate the utility of the system to model disease progression, the effect of cigarette smoke extract (CSE), was examined; the results showed preservation of metastatic characteristics (N-Cad, etc.) along with translational properties (IL-6 secretion). As the second model of study, dose-dependent drug efficacy testing was carried out by monitoring the model cells' response to anti-cancer therapeutic agents. It is also important that the entire lung-representative IVM3DLCOC model, including contacts with cell constructs along with the lung's representative air and fluid compartments, was developed as an all-inclusive unit, rapidly and efficiently prototyped using the 3D extrusion bioprinting approach. The IVM3DLCOC model presented here is envisioned to find application as a preclinical tool for precise study on the effect of potential chemotherapeutic drugs and effect of toxins on metastatic advancement of lung cancer cells in-vitro.