Mimicking Embedded Vasculature Structure for 3D Cancer on a Chip Approaches through Micromilling

Abstract

The ability for cells to sense and respond to microenvironmental signals is influenced by their three dimensional (3D) surroundings, which includes the extracellular matrix (ECM). In the 3D environment, vascular structures supply cells with nutrients and oxygen thus affecting cell responses such as motility. Interpretation of cell motility studies though is often restricted by the applied approaches such as 2D conventional soft lithography methods that have rectangular channel cross-sectional morphology. To better simulate cell responses to vascular supply in 3D, we developed a cell on a chip system with microfluidic channels with curved cross-sections embedded within a 3D collagen matrix that emulates anatomical vasculature more closely than inorganic polymers, thus to mimic a more physiologically relevant 3D cellular environment. To accomplish this, we constructed perfusable microfluidic channels by embedding sacrificial circular gelatin vascular templates in collagen, which were removed through temperature control. Motile breast cancer cells were pre-seeded into the collagen matrix and when presented with a controlled chemical stimulation from the artificial vasculature, they migrated towards the vasculature structure. We believe this innovative vascular 3D ECM system can be used to provide novel insights into cellular dynamics during multidirectional chemokineses and chemotaxis that exist in cancer and other diseases.

Biophysics of Tumor Microenvironment and Cancer Metastasis - A Mini Review

“…Endothelial cells (ECs) are important in cancer progression, however, the influence of tumor stiffness on the endothelium is largely unknown. With newly developing device systems, we are learning more about how endothelial cells create a vascular network within tumor stroma and facilitate nutrients and oxygen supplies to the hypoxic core where solid stress as well as interstitial fluid pressure is high [ [120] , [121] , [122] ]. In addition, ECs secrete a number of “angiocrine factors” such as ANGPT2, FGF, IGF, IL, CSF, SDF1 etc.…”

Deconstructing Immune Microenvironments of Lymphoid Tissues for Reverse Engineering

“…Then, complete transendothelial migration assessment was made possible through the use of Transwells with LECs attached to the bottom of the membrane instead, as transmigration is in the direction of the basal side to the apical end. Vascular research has also led to the development of various types of microfluidic biomimetic models that can be used to study the circulatory system …”

“…Especially as the viability of cells in biomimetic devices can be prolonged, there is a need for continuous replenishment of medium and cell feeding . It is generally not only the availability of a chemical factor that is essential to control cell function, but also the presence of chemical factors as gradients that promotes specific cellular behaviors, cell phenotype or cell migration, such as in angiogenesis, and the vasculature helps create gradients of biomolecules such as proteins and oxygen …”

“…Key to this movement and function of the immune cells are the ECs lining these vasculature systems, including the BECs, LECs, and HEVs described earlier. Through the optimization of the biomaterial‐to‐EC interface, vascular research has led to the development of various types of microfluidic biomimetic models that can be used to study the blood vascular system, furthering our understanding of physiological and pathological conditions . Such setups have been used to study the blood vasculature in isolation, but as organ‐on‐chip and body‐on‐chip research expands, such microfluidic vasculature could be incorporated as the inflow and outflow of a single organ, or used to interlink interconnected organs on chips .…”

The Fabrication and Application Mechanism of Microfluidic Systems for High Throughput Biomedical Screening: A Review

“…Microfluidic chips are extensively applied in in-vitro biomedical models because of their flexibility, such as having control over fluid and gas flow, and a chip architecture able to replace the classical 2D and 3D cell cultures [1]. Many organ models were established in recent years, based on the microfluidic platform, such as brain-on-a-chip, liver-on-a-chip, lung-on-a-chip, and breast-on-a-chip [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Body-on-a-chip is designed to include more than one organ on one chip [20].…”