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The Design of a Novel 3D Micropatterned Tumor Microenvironment Model to Study

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The Design of a Novel 3D Micropatterned Tumor Microenvironment Model to Study The design of a novel 3D micropatterned tumor microenvironment model to study the intercellular effects of fibroblasts and cancer cells A Thesis Submitted to the Faculty of Drexel University By Christine Maylin Ho in partial fulfillment of the requirements for the degree of Master of Science in Biomedical Engineering August 2013 © Copyright 2013 Christine M. Ho. All Rights Reserved. iii ACKNOWLEDGEMENTS I would like to thank the following people who were instrumental in the success of this thesis: Kenneth Barbee, Ph.D and Alisa Morss Clyne, Ph.D for serving on my thesis committee, Michael Yang, Ph.D and Anant Chopra, Ph.D, from the Tissue Microfabrication Laboratory of Christopher S. Chen, Ph.D, and Rebecca Urbano, Ph.D candidate, from the Vascular Kinetics Laboratory of Alisa Morss Clyne, Ph.D for assistance and instructions on specifics of my project, And I am especially grateful to Adrian Shieh, Ph.D for his guidance and teachings, and the rest of the Laboratory of Tumor Mechanobiology and Microenvironment for their constant support and encouragement. In particular, thank you Alima Tchafa, Ph.D candidate, and Arpit Shah, Ph.D candidate. iv TABLE OF CONTENTS ACKNOWLEDGEMENTS ......................................................................................... iii LIST OF FIGURES ..................................................................................................... vi ABSTRACT ............................................................................................................... viii CHAPTER 1: INTRODUCTION .................................................................................1 CHAPTER 2: BACKGROUND ....................................................................................3 2.1 Tumor microenvironment ......................................................................................3 2.2 Cancer associated fibroblasts (CAFs) .....................................................................4 2.3 Effects of soluble factors on the tumor environment ...............................................6 2.4 Mechanical effects on the tumor environment ........................................................7 2.5 Comparison of 2D and 3D cell culture ...................................................................8 2.6 In vitro microenvironments .................................................................................. 12 CHAPTER 3: OBJECTIVES AND DESIGN CRITERIA ........................................ 14 3.1 Research goals ..................................................................................................... 14 3.2 Problem identification .......................................................................................... 14 3.3 Technical design objectives and system design .................................................... 15 3.4 Design constraints ................................................................................................ 19 CHAPTER 4: METHODS .......................................................................................... 20 4.1 Initial design: cell-seeded collagen gels embedded in a collagen matrix ............... 20 4.2 Initial micropatterning experiments to determine substrate, incubation times, and seeding densities ........................................................................................................ 21 4.3 Micropatterned 3D system and a collagen gel overlay .......................................... 22 4.4.1 Formation of PDMS stamps .............................................................................. 22 4.4.2 Preparation of PDMS stamp and substrate for stamping with fibronectin ........... 23 4.4.3 Creation of the micropatterned substrate & cell seeding .................................... 24 4.5 Microscopy and data analysis ............................................................................... 25 4.6 Micropatterned 3D System with gasket ................................................................ 26 A PDMS gasket was fabricated to physically hold the collagen gel in place (Fig 8). .. 26 4.7 Fabrication of the gasket and treatment with poly-L-lysine................................... 26 4.8 Application of the gasket...................................................................................... 27 4.9 Myofibroblast differentiation ............................................................................... 27 CHAPTER 5: RESULTS ............................................................................................ 29 5.1 Observations of the CSCG system........................................................................ 29 5.2 Verification of homogeneous and repeatable micropatterns .................................. 29 5.3 Determining optimal seeding density, seeding ratio, and seeding time .................. 30 5.3 Micropatterning, collagen overlay, and live cell microscopy results ..................... 32 5.4 Myofibroblast differentiation ............................................................................... 40 CHAPTER 6: DISCUSSION ...................................................................................... 42 6.1 Cell seeded collagen gels within a collagen matrix ............................................... 42 6.2 Micropattern cell seeding optimization ................................................................. 42 6.4 Myofibroblast differentiation ............................................................................... 48 6.5 Design constraints ................................................................................................ 50 v CHAPTER 7: SIGNIFICANCE & FUTURE DIRECTIONS ................................... 52 LIST OF REFERENCES ............................................................................................ 55 APPENDIX A .............................................................................................................. 60 MATLAB code to find the distances between tumor and cancer cells and plot the results as a histogram ................................................................................................. 60 MATLAB code to find the percentage of cells expressing α-SMA ............................. 61 MATLAB code to calculate distances between patterns ............................................. 62 vi LIST OF FIGURES 1. The components of the tumor microenvironment……..……..……..……… 4 2. Soluble factors secreted by fibroblasts that aid in tumor progression……... 5 3. Differences between 2D and 3D cell culture……..……..……..……..……. 9 4. Current 3D models……..……..……..……..……..……..……..…………... 13 5. 40 µm diameter fibronectin circle stamps……..……..……..……..………. 16 6. Cell seeded gels in a collagen matrix……..……..……..……..……..……... 20 7. Micropatterned system with collagen overlay……..……..……..…………. 22 8. Micropatterned gasket system……..……..……..……..……..……..……... 26 9. The edge of a cell seeded collagen gel showing MDA-MB-231 migration.. 29 10. Circle patterns……..……..……..……..……..…………………………….. 30 11. Patterned fibroblasts and tumor cells co-cultured……..……..……..……… 31 12. Comparison of cell attachment on plastic and PDMS……..……..……….. 32 13. Patterned fibroblasts (red) with tumor cells and only tumor cells………… 32 14. Fibroblasts and cancer cell interaction within collagen gel……..………… 33 15. Live cell microscopy of migrating cell……..……..……..……..…………. 34 16. Cell spread on patterns over time……..……..……..……..……..………… 35 17. Example MATLAB distance quantification……..……..……..……..…….. 36 18. MATLAB distance histogram comparing total number of fibroblasts to cancer cells……..……..……..……..……..……..……..……..……………. 37 19. Histogram from a central pattern to every other pattern……..……..……… 37 20. Histogram of only cancer cell distances over time……..……..…………… 38 21. Histogram comparing individual fibroblasts to cancer cells……..………… 39 22. Myofibroblasts stained for α-SMA……..……..……..……..……..……….. 40 23. Steps to quantify percentage of fibroblasts expressing α-SMA……..……... 41 24. Bar graph showing percentage of α-SMA expressing cells………………... 41 vii viii ABSTRACT The design of a novel 3D micropatterned tumor microenvironment model to study the intercellular effects of fibroblasts and cancer cells Christine M. Ho Adrian C. Shieh, Ph.D. The tumor microenvironment contains a multitude of biomolecules, stromal cells such as fibroblasts, endothelial cells, inflammatory cells, and signaling molecules that support the tumor’s growth and progression. Particularly around the site of tumors, fibroblasts are “primed” to adopt a myofibroblastic phenotype, and are known as cancer associated fibroblasts (CAFs) that promote tumor growth and progression instead of aiding the body. Much interest has been taken in the individual cellular interactions between tumor cells and the surrounding cancer-associated fibroblasts. Systems are constantly being designed to better emulate the complex internal environment around the tumor in order to understand how the tumor stroma communicates and affects the tumor growth. In this thesis, a 3D microenvironment model was developed that simulates the native extracellular matrix and allows for the study of individual cellular interactions between cancer cells and fibroblasts, particularly those involving transmission of cell- generated contractile forces. The final system design in brief involves spatially constraining MDA-MB-231 human breast adenocarcinoma cells and human dermal fibroblasts on fibronectin micropatterns on a polydimethylsiloxane (PDMS) substrate. A poly-L-lysine/glutaraldehyde
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