Premetastatic Niche Mimicking Bone‐On‐A‐Chip: A Microfluidic Platform to Study Bone Metastasis in Cancer Patients

Abstract

Primary cancer modulates the bone microenvironment to sow the seeds of dormancy and metastasis in tumor cells, leading to multiple organ metastasis and death. In this study, 3D printing and bone‐on‐a‐chip (BOC) are combined to develop a BOC platform that mimics the pre‐metastatic niches (PMNs) and facilitates elucidation of the interactions between bone‐resident cells and metastatic tumor cells under the influence of primary cancer. Photocrosslinkable gelatin methacrylate (GelMA) is used as a 3D culturing hydrogel to encapsulate cells, and circulate tumor culture medium (CM) adjacent to the hydrogel to verify the critical role of mesenchymal stem cells (MSCs) and osteoclasts (RAW264.7s). Three niches: the dormancy niche, the perivascular niche, and the “vicious cycle” niche, are devised to recapitulate bone metastasis in one chip with high cell viability and excellent nutrient exchange. With respect to tumor dormancy and reactivation, the invadopodia formation of A549 lung cancer cells in communication with MSCs and RAW264.7 via the cortactin pathway is researched. As a proof of concept, the functionality and practicality of the platform are demonstrated by analyzing the invadopodia formation and the influence of various cells, and the establishment of the dynamic niches paves the way to understanding PMN formation and related drug discovery.

Understanding organotropism in cancer metastasis using microphysiological systems

“…3C). 96–99 The cancer cells release enzymes that facilitate the breakdown of the ECM, enabling them to traverse the vessel wall. Microfluidic Once beyond the confines of the blood vessels, breast cancer cells and colorectal cancer cells encounter the bone matrix, a sophisticated network of proteins and minerals.…”

An Overview of Advancements and Technologies in Vascularization Strategies for Tumor‐On‐A‐Chip Models

“…Other lymphangiogenesis models use designs akin to vascular models employing micropost or straight channel devices with compartmentalized hydrogels and stromal cell scaffolds. [26,64,68,92,[103][104][105][106][107][108][109] Some variations include multiple lumens or vessel microchannels for co-cultures and stimulating factor sources. Lymphangiogenesis chips employ various endothelial cell sources, such as HMVECs and LECs, along with sprouting cells with growth factors (VEGF-A/C/D, S1P, PMA, bFGF, interleukin (IL-6)) using ECM biomaterials (collagen, GelMA, and fibrin,) according to the study-specific models.…”

“…[51,137] To better understand, Ji et al investigated biological stress, 3D printing, and a bone-on-a-chip (BOC) approach to create a platform mimicking PMNs. [106] This platform helps study interactions between bone-resident cells and metastatic tumor cells influenced by primary cancer. Using GelMA hydrogel, encapsulated cells were employed, and three niches were employed: dormancy, perivascular, and "vicious cycle."…”