## 5 Application as a Disease Model for Vascularized Lower Respiratory-Physiology-On-A-Chip  
### Cancer  
Although many researchers are attempting to overcome cancer, it remains the second leading cause of death in the world, it is difficult to study because of its heterogeneity. In addition, the complex microenvironments surrounding cancers are important, but are not considered in many cancer studies. One of the most important factors for reproducing the cancer microenvironment in vitro is the presence or absence of vasculatures around the cancer. Interactions between cancer and vasculatures affect \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Coating Material** & **Cell Population** & **Features** & **Ref.** \\ \hline Collagen I & Primary human small airway epithelial cells and primary & Microfluidic & [33] \\ Deeellularized & & human lung microvascular endothelial cells & [75] \\ extracellular matrix & Human dermal microvascular endothelial cells and primary & & [75] \\ bioink derived from & human tracheal epithelial cells and lung fibroblasts & & [75] \\ porcine tracheal mucosa & & human alveolar epithelial type II cell line A549 and the & & \\ Matrigel & & EA.hy926 hybrid human cell line & & [74] \\ \hline \hline \end{tabular}
\end{table} 
Table 4: Vascularized airway-on-a-chip. Figure 2: Vascularized airway-on-a-chips. Diagram of the timeline process for 3D bioprinting cell pattering of the cell-layer barrier. Reproduced with permission from [74]. Copyright © 2015 Springer Nature. the expression of target proteins, drug delivery, and clinical responses. In addition, vasculatures are known to play an important role in cancer metastasis. As the importance of vascularized 3D cancer models increases, co-culture studies of cancer cells or cancer spheroids and vascular cells in transwell or 3D scaffold environments have been conducted in order to study the interactions of vasculatures and cancer within the chip; numerous researcher have focused on the characteristics of cancer in the presence of vasculature. In particular, the lung actively facilitates gas exchange between the alveoli and surrounding capillaries, and the ability to simulate peripheral vasculatures is becoming increasingly important for modeling the lung cancer microenvironment. [PERSON] et al. [76] analyzed apoptosis through caspase-3 when non-small lung cancer cells (PC9) co-cultured with vascular endothelial cells (HMVEC) were exposed to four anticancer agents in a 3D microfluidic cell array (3D \(\upmu\)FCA) (Figure 3a). Their results demonstrate the potential for high-throughput drug screening using vascularized microfluidic lung cancer models. Dynamic caspase-3 activity in PC9 cells showed that cancer cells have different drug reactivity in different culture platforms, including static 2D or 3D culture, static 3D co-culture, and structured 3D co-culture with vasculatures in 3D \(\upmu\)FCA. This study shows the importance of a lung cancer model that can simulate vascularization, blood flow, and the air-liquid interface. In order to overcome cancer, not only are drug reactivity studies important, but also research on cancer metastasis mechanisms is critical. Therefore, the development of a vascularized cancer metastasis model is essential. Recently, in order to reproduce the complex interactions of lung and distant organs, [PERSON] et al. [77] designed a micro-engineered multi-organ microfluidic chip (Figure 3b). The device consists of one upstream chamber that mimics the lung and three downstream chambers for the brain, bone, and liver. The invasiveness of lung cancer cells was analyzed using RANKL for bone-specific metastasis, CXCR4 for brain-specific metastasis, and liver cell damage was evaluated by  
Figure 3: Vascularized cancer chip models. (**a**) Four anticancer agents were treated with non-small lung cancer cells (PC9) co-cultured with vascular endothelial cells (HMVEC) in a 3D microfluidic cell array (3D \(\upmu\)FCA).