TABLE 2.

Lung cancer research utilizing Lung-on-a-chip models.

Construction materials	Cell types	Features	Mechanism	Drug testing	References
ECM-coated membrane	Human adenocarcinoma cells, H1975	Monitored the growth and invasion of the orthotopic lung cancer	The changes in signaling through EGFR- and MET protein kinase may cause resistance to therapy	Rociletinib	Hassell et al. (2017)
		Analysis the effects of mechanical breathing on cancer behaviors
		Analysis EGHR-TKI therapeutic responses to physical modulation
PLGA electrospinning nanofiber membrane	Human NSCLS cell A549, HFL1, HUVECs	Co-culture of A549 cells and HFL1 cells in a microchip	IGF-1 secreted by HFL1 cells could maintain the tumor cells by activating the PI3K/Akt signal pathway, resulting in decreased sensitivity of the tumor cells to drugs	Gefitinib	Yang et al. (2018)
		Prepared four kinds of PLGA nanofiber membranes
		Evaluation of EGFR-targeted anti-tumor drug
PLGA and PDMS membrane	Adenocarcinoma cell lines NCI-H460, Large cell carcinoma NCI-H1650	A novel poly PLGA nanofiber/PDMS microporous composite membrane	The mechanism of the resistance of NCI-H460 cells to gefitinib under normoxic and hypoxic conditions	Gefitinib	Li et al. (2020)
		EGFR-Targeted drug evaluation under normoxia and hypoxia conditions
ECM membrane	Human NSCLS cell A549, HUVECs	Delivered miR-497-loaded exosomes to co-cultured A549 cells with HUVECs in a microfluidic 3D lung cancer model	MiRNA-497 can suppress the tumor growth and the expression of their associated genes, like YAP1, HDGF, CCNE1, and VEGF-A, and decrease the VEGF-A-mediated angiogenic sprouting	MiRNA-497	Jeong et al. (2020)
		Investigated the anti-tumor and anti-angiogenic effects of miRNAs on NSCLCs
Hydrogel	Human NSCLS cell A549 and hAM-MSCs	Developed A549 and hAM-MSCs cells spheroid in a compartmentalized microfluidic device	Reduced the viability and the proliferative capacity of cancer by expressing cell proliferation marker Ki-67	A novel tryptophan-rich peptide P1, ACP	Dhiman et al. (2020)
		Tested cytotoxic effects of ACP on tumor spheroids
PDMS polydimethylsiloxane membrane	PC9-Br cell line	Established a model of lung cancer brain metastasis based on a newly microfluidic multi-organ chip	GSH metabolism and the overexpression of various GSH metabolism-related enzymes (GPX4, RRM2, GCLC, GPX1, GSTM4, GSTM1). ALDH1A1, ALDH3A1 upregulated in BM	Cisplatin	Xu et al. (2020)
	HBE hPMEC	Revealed the protein expression profile of PC9-Br to drug resistance		Carboplatin
	HFL1	Compared the different protein expression profile of PC9-Br with parental PC9		Pemetrexed
	THP-1			Gefitinib
				AZD3759
PDMS	A549 cell	Established an organ-level lung cancer and liver linkage model	HIF-1α pathway elevates EMT transcription factors (Snail 1 and Snail 2)	HIF-1α inhibitors (tirapazamine, SYP-5, and IDF-11774)	Zheng et al. (2021)
GelMA	HIF-1 cell line	Explored the gene expression of cancer related markers under the normoxic and hypoxic conditions
PMMA
PDMS	A-549 cell	A novel microfluidic chip with a dynamic environment and strategically placed U-shaped wells	—	Paclitaxel	Sankar et al. (2021)
		Combinatory drug treatment in dynamic and static culture		Vinorelbine
				Etoposide
PC membrane	NCI-H1650	Developed a microporous membrane lung chip based on 3D printing manufacturing technology	—	Gefitinib	Tan et al. (2022)
	Primary human lung cancer cells	Tested the effects of different EGFR-targeted drugs on NCI-H650 cells and primary lung cancer cells in 2D well plates and 3D lung chips		Afatinib
	HUVECs			Osimertinib

ECM-coated membrane, porous extracellular matrix-coated membrane; PLGA, poly lactic-co-glycolic acid; PDMS, nanofiber/polydimethylsiloxane; HBE, human bronchial epithelial cells; HFL1, human lung fibroblasts; THP-1, human mononuclear cells; hPMEC, human pulmonary microvascular endothelial cells; ACP, anticancer peptide; hAM-MSCs, human amniotic membrane mesenchymal stem cells; BM, brain metastases; GelMA, gelatin methacryloyl; PMMA, poly methyl methacrylate; PC, polycarbonate.