Using Microfluidics to Study Tumor Hypoxia Yunli E. Chu, Alan Soetikno, Sandra Lam, Steven C. George Department of Biomedical Engineering, Washington University in St. Louis INTRODUCTION MODELS AND RESULTS METHODS CONCLUSIONS ACKNOWLEDGEMENTS We have created a novel, physiologically-relevant microfluidic device capable of replicating the tumor microenvironment. By using an oxygen scavenger channel adjacent to the tumor chamber, we are able to precisely control the spatial and temporal distribution of oxygen surrounding the tumors. Therefore, we work to replicate tumor hypoxia, an important physiological event responsible for tumor metastasis. • The device consists of two tissue chambers, a tumor chamber and a vessel chamber, that are approximately 0.1 mm 3 in size and are connected by three 30 μm wide pores. • The vessel chamber was loaded with endothelial cells and fibroblasts on day 0, while the tumor chamber was loaded with MDA-MB-231 breast cancer cells on day 4. • Sodium sulfite was pumped through the adjacent scavenger channels to create an oxygen sink. COMSOL Model Figure 2. COMSOL model of oxygen tension. The computational model shows the creation of an oxygen gradient as indicated by the increasing oxygen tension as distance from the scavenger channels increases. PhLIM Figure 1. Schematic of the microfluidic device Tumor Response to Hypoxia • We are able to create a mature vascular network and culture MDA-MB-231 breast cancer cells in the device. • Our device provides fine control over oxygen tension in the tumor microenvironment. • Our device is capable of replicating key characteristics of tumor progression, making it a more physiologically-relevant model of cancer metastasis than traditional methods. Special thanks to Dr. George, Sandra Lam, and members of the George Lab. This research was supported by the NIH UH2-TR000481 (SCG). Figure 3. Angiogenesis and tumor cell migration. A) The low oxygen environment in the tumor chamber induced the sprouting of vessels from the vessel chamber, indicated by the arrow. B) Low oxygen tension also induced the migration of MDA-MB- 231 cancer cells toward the vessel network, a key sign of tumor progression Figure 4. Oxygen gradient. Phosphorescence lifetime microscopy confirmed the existence of an oxygen gradient in the device. Vessel Chamber Tumor Chamber Scavenger Channels Tumor Media Line Vessel Media Line 0 500 1000 1500 2000 2500 0 1 2 3 4 5 6 7 Oxygen Measurements No Cells No Scavenger Scavenger Position from Scavenger Channel (μm) Oxygen Concentration (%) Scavenger added A) B)

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Using Microfluidics to Study Tumor HypoxiaYunli E. Chu, Alan Soetikno, Sandra Lam, Steven C. George

Department of Biomedical Engineering, Washington University in St. Louis

INTRODUCTION MODELS AND RESULTS

METHODS

CONCLUSIONS

ACKNOWLEDGEMENTS

We have created a novel, physiologically-relevant microfluidic device capable of replicating the tumor microenvironment. By using an oxygen scavenger channel adjacent to the tumor chamber, we are able to precisely control the spatial and temporal distribution of oxygen surrounding the tumors. Therefore, we work to replicate tumor hypoxia, an important physiological event responsible for tumor metastasis.

• The device consists of two tissue chambers, a tumor chamber and a vessel chamber, that are approximately 0.1 mm3

in size and are connected by three 30 μm wide pores.

• The vessel chamber was loaded with endothelial cells and fibroblasts on day 0, while the tumor chamber was loaded with MDA-MB-231 breast cancer cells on day 4.

• Sodium sulfite was pumped through the adjacent scavenger channels to create an oxygen sink.

COMSOL ModelFigure 2. COMSOL model of oxygen tension. The computational model shows the creation of an oxygen gradient as indicated by the increasing oxygen tension as distance from the scavenger channels increases.

PhLIM

Figure 1. Schematic of the microfluidic device

Tumor Response to Hypoxia

• We are able to create a mature vascular network and culture MDA-MB-231 breast cancer cells in the device.

• Our device provides fine control over oxygen tension in the tumor microenvironment.

• Our device is capable of replicating key characteristics of tumor progression, making it a more physiologically-relevant model of cancer metastasis than traditional methods.

Special thanks to Dr. George, Sandra Lam, and members of the George Lab. This research was supported by the NIH UH2-TR000481 (SCG).

Figure 3. Angiogenesis and tumor cell migration. A) The low oxygen environment in the tumor chamber induced the sprouting of vessels from the vessel chamber, indicated by the arrow.B) Low oxygen tension also induced the migration of MDA-MB-231 cancer cells toward the vessel network, a key sign of tumor progression

Figure 4. Oxygen gradient. Phosphorescence lifetime microscopy confirmed the existence of an oxygen gradient in the device.

Vessel ChamberTumor ChamberScavenger ChannelsTumor Media LineVessel Media Line

0 500 1000 1500 2000 25000

7 Oxygen Measurements

No Cells No Scavenger

Scavenger

Position from Scavenger Channel (μm)

Oxy

gen

Conc

entr

ation