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Implantable microfluidic device for the formation of three-dimensional vasculature by human endothelial progenitor cells

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Abstract

Vasculogenesis is an important morphogenetic event for vascular tissue engineering and ischemic disease treatment. Stem and progenitor cells can contribute to vasculogenesis via endothelial differentiation and direct participation in blood vessel formation. In this study, we developed an implantable microfluidic device to facilitate formation of three-dimensional (3D) vascular structures by human endothelial progenitor cells (hEPCs). The microfluidic device was made of biodegradable poly(lactic-co-glycolic acid) (PLGA) using a microchannel patterned silicon wafer made by soft lithography. A collagen type I (Col I) hydrogel containing hEPCs filled the microfluidic channels to reconstitute a 3D microenvironment for facilitating vascular structure formation by hEPCs. The device seeded with hEPCs was implanted into the subcutaneous space of athymic mice and retrieved one and four weeks after implantation. Histology and immunohistochemistry revealed that hEPCs formed a 3D capillary network expressing endothelial cell-specific proteins in the channel of the PLGA microfluidic device. This result indicates that a 3D microscale extracellular matrix reconstituted in the microchannel can promote the endothelial differentiation of hEPCs and in turn hEPC-mediated vasculogenesis. The PLGA microfluidic device reported herein may be useful as an implantable tissue-engineering scaffold for vascularized tissue reconstruction and therapeutic angiogenesis.

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Refrerences

  1. Asahara, T., T. Murohara, A. Sullivan, M. Silver, R. van der Zee, T. Li, B. Witzenbichler, G. Schatteman, and J. M. Isner (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Sci. 275: 964–967.

    Article  CAS  Google Scholar 

  2. Urbich, C. and S. Dimmeler (2004) Endothelial progenitor cells characterization and role in vascular biology. Circ. Res. 95: 343–353.

    Article  CAS  Google Scholar 

  3. Kamihata, H., H. Matsubara, T. Nishiue, S. Fujiyama, Y. Tsutsumi, R. Ozono, H. Masaki, Y. Mori, O. Iba, and E. Tateishi (2001) Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 104: 1046–1052.

    Article  CAS  Google Scholar 

  4. Kawamoto, A., T. Tkebuchava, J. Yamaguchi, H. Nishimura, Y. S. Yoon, C. Milliken, S. Uchida, O. Masuo, H. Iwaguro, H. Ma, A. Hanley, M. Silver, M. Kearney, D. W. Losordo, J. M. Isner, and T. Asahara (2003) Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation 107: 461–468.

    Article  Google Scholar 

  5. Yang, C., Z. H. Zhang, Z. J. Li, R. C. Yang, G. Q. Qian, and Z. C. Han (2004) Enhancement of neovascularization with cord blood CD133+ cell-derived endothelial progenitor cell transplantation. Thromb. Haemost. 91: 1202–1212.

    CAS  Google Scholar 

  6. Cho, S. W., I. K. Kim, S. H. Bhang, B. Joung, Y. J. Kim, K. J. Yoo, Y. S. Yang, C. Y. Choi, and B. S. Kim (2007) Combined therapy with human cord blood cell transplantation and basic fibroblast growth factor delivery for treatment of myocardial infarction. Eur. J. Heart Fail. 9: 974–985.

    Article  CAS  Google Scholar 

  7. Iskander, A. R., A. Knight, Z. G. Zhang, J. R. Ewing, A. Shankar, N. R. Varma, H. Bagher-Ebadian, M. M. Ali, A. S. Arbab, and B. Janic (2013) Intravenous administration of human umbilical cord blood-derived AC133+ endothelial progenitor cells in rat stroke model reduces infarct volume: Magnetic resonance imaging and histological findings. Stem Cells Transl. Med. 2: 703–714.

    Article  CAS  Google Scholar 

  8. Ryu, J. H., I. K. Kim, S. W. Cho, M. C. Cho, K. K. Hwang, H. Piao, S. Piao, S. H. Lim, Y. S. Hong, C. Y. Choi, K. J. Yoo, and B. S. Kim (2005) Implantation of bone marrow mononuclear cells using injectable fibrin matrix enhances neovascularization in infarcted myocardium. Biomat. 26: 319–326.

    Article  CAS  Google Scholar 

  9. Tateishi-Yuyama, E., H. Matsubara, T. Murohara, U. Ikeda, S. Shintani, H. Masaki, K. Amano, Y. Kishimoto, K. Yoshimoto, H. Akashi, K. Shimada, T. Iwasaka, and T. Imaizumi (2002) Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: A pilot study and a randomised controlled trial. Lancet 360: 427–435.

    Article  Google Scholar 

  10. Numaguchi, Y., T. Sone, K. Okumura, M. Ishii, Y. Morita, R. Kubota, K. Yokouchi, H. Imai, M. Harada, H. Osanai, T. Kondo, and T. Murohara (2006) The impact of the capability of circulating progenitor cell to differentiate on myocardial salvage in patients with primary acute myocardial infarction. Circulation 114: 114–119.

    Article  Google Scholar 

  11. Yoo, K. J., H. O. Kim, Y. L. Kwak, S. M. Kang, Y. S. Jang, S. H. Lim, K. C. Hwang, S. W. Cho, Y. S. Yang, R. K. Li, and B. S. Kim (2008) Autologous bone marrow cell transplantation combined with off-pump coronary artery bypass grafting in patients with ischemic cardiomyopathy. Can. J. Surg. 51: 269–275.

    Google Scholar 

  12. Erbs, S., A. Linke, V. Adams, K. Lenk, H. Thiele, K. W. Diederich, F. Emmrich, R. Kluge, K. Kendziorra, O. Sabri, G. Schuler, and R. Hambrecht (2005) Transplantation of blood-derived progenitor cells after recanalization of chronic coronary artery occlusion: First randomized and placebo-controlled study. Circ. Res. 97: 756–762.

    Article  CAS  Google Scholar 

  13. Zisch, A. H. (2004) Tissue engineering of angiogenesis with autologous endothelial progenitor cells. Curr. Opin. Biotechnol. 15: 424–429.

    Article  CAS  Google Scholar 

  14. Cho, S. W., S. H. Lim, I. K. Kim, Y. S. Hong, S. S. Kim, K. J. Yoo, H. Y. Park, Y. Jang, B. C. Chang, C. Y. Choi, K. C. Hwang, and B. S. Kim (2005) Small-diameter blood vessels engineered with bone marrow-derived cells. Ann. Surg. 241: 506–515.

    Article  Google Scholar 

  15. Kaushal, S. G., E. Amiel, K. J. Guleserian, O. M. Shapira, T. Perry, F. W. Sutherland, E. Rabkin, A. M. Moran, F. J. Schoen, A. Atala, S. Soker, J. Bischoff, and J. E. Mayer Jr. (2001) Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo. Nat. Med. 7: 1035–1040.

    Article  CAS  Google Scholar 

  16. Liu, Y. S., H. Teoh, M. S. Chong, C. H. Yeow, R. D. Kamm, M. Choolani, and J. K. Chan (2013) Contrasting effects of vasculogenic induction upon biaxial bioreactor stimulation of mesenchymal stem cells and endothelial progenitor cells cocultures in three-dimensional scaffolds under in vitro and in vivo paradigms for vascularized bone tissue engineering. Tissue Eng. Part A 19: 893–904.

    Article  CAS  Google Scholar 

  17. He, X., R. Dziak, X. Yuan, K. Mao, R. Genco, M. Swihart, D. Sarkar, C. Li, C. Wang, L. Lu, S. Andreadis, and S. Yang (2013) BMP2 genetically engineered MSCs and EPCs promote vascularized bone regeneration in rat critical-sized calvarial bone defects. PLoS One 8: e60473.

    Article  Google Scholar 

  18. Baker, B., M. B. Trappmann, S. C. Stapleton, E. Toro, and C. S. Chen (2013) Microfluidics embedded within extracellular matrix to define vascular architectures and pattern diffusive gradients. Lab Chip 13: 3246–3252.

    Article  CAS  Google Scholar 

  19. Nguyen, D. H., S. C. Stapleton, M. T. Yang, S. S. Cha, C. K. Choi, P. A. Galie, and C. S. Chen (2013) Biomimetic model to reconstitute angiogenic sprouting morphogenesis in vitro. Proc. Natl. Acad. Sci. U.S.A 110: 6712–6717.

    Article  CAS  Google Scholar 

  20. Shin, Y., J. S. Jeon, S. Han, G. S. Jung, S. Shin, S. H. Lee, R. Sudo, R. D. Kamm, and S. Chung (2011) In vitro 3D collective sprouting angiogenesis under orchestrated ANG-1 and VEGF gradients. Lab Chip 11: 2175–2181.

    Article  CAS  Google Scholar 

  21. Zheng, Y., J. Chen, M. Craven, N. W. Choi, S. Totorica, A. Diaz-Santana, P. Kermani, B. Hempstead, C. Fischbach-Teschl, J. A. Lopez, and A. D. Stroock (2012) In vitro microvessels for the study of angiogenesis and thrombosis. Proc. Natl. Acad. Sci. U.S.A. 109: 9342–9347.

    Article  CAS  Google Scholar 

  22. Kim, S., H. Lee, M. Chung, and N. L. Jeon (2013) Engineering of functional, perfusable 3D microvascular networks on a chip. Lab Chip 13: 1489–1500.

    Article  CAS  Google Scholar 

  23. van der Meer, A. D., V. V. Orlova, P. ten Dijke, A. van den Berg, and C. L. Mummery (2013) Three-dimensional co-cultures of human endothelial cells and embryonic stem cell-derived pericytes inside a microfluidic device. Lab Chip 13: 3562–3568.

    Article  Google Scholar 

  24. Roeder, B. A., K. Kokini, J. E. Sturgis, J. P. Robinson, and S. L. Voytik-Harbin (2002) Tensile mechanical properties of threedimensional type I collagen extracellular matrices with varied microstructure. J. Biomech. Eng. 124: 214–222.

    Article  Google Scholar 

  25. Yang, K., S. Han, Y. Shin, E. Ko, J. Kim, K. I. Park, S. Chung, and S. W. Cho (2013) A microfluidic array for quantitative analysis of human neural stem cell self-renewal and differentiation in three-dimensional hypoxic microenvironment. Biomat. 34: 6607–6614.

    Article  CAS  Google Scholar 

  26. Moon, S. H., S. M. Kim, S. J. Park, H. Kim, D. Bae, Y. S. Choi, and H. M. Chung (2013) Development of a xeno-free autologous culture system for endothelial progenitor cells derived from human umbilical cord blood. PLoS One 8: e75224.

    Article  Google Scholar 

  27. Lee, C., J. Shin, J. S. Lee, E. Byun, J. H. Ryu, S. H. Um, D. I. Kim, H. Lee, and S. W. Cho (2013) Bioinspired, calcium-free alginate hydrogels with tunable physical and mechanical properties and improved biocompatibility. Biomacromol. 14: 2004–2013.

    Article  CAS  Google Scholar 

  28. Han, S., K. Yang, Y. Shin, J. S. Lee, R. D. Kamm, S. Chung, and S.-W. Cho (2012) Three-dimensional extracellular matrix-mediated neural stem cell differentiation in a microfluidic device. Lab Chip 12: 2305–2308.

    Article  CAS  Google Scholar 

  29. Kshitiz, J. P., P. Kim, W. Helen, A. J. Engler, A. Levchenko, and D. H. Kim (2012) Control of stem cell fate and function by engineering physical microenvironments. Integr. Biol. 4: 1008–1018.

    Article  CAS  Google Scholar 

  30. Yang, H. S., N. Ieronimakis, J. H. Tsui, H. N. Kim, K. Y. Suh, M. Reyes, and D. H. Kim(2014) Nanopatterned muscle cell patches for enhanced myogenesis and dystrophin expression in a mouse model of muscular dystrophy. Biomat. 35: 1478–1486.

    Article  CAS  Google Scholar 

  31. Zhao, Y., Z. Huang, M. Qi, P. Lazzarini, and T. Mazzone (2007) Immune regulation of T lymphocyte by a newly characterized human umbilical cord blood stem cell. Immunol. Lett. 108: 78–87.

    Article  CAS  Google Scholar 

  32. Zhao, Y., H. Wang, and T. Mazzone (2006) Identification of stem cells from human umbilical cord blood with embryonic and hematopoietic characteristics. Exp. Cell Res. 312: 2454–2464.

    Article  CAS  Google Scholar 

  33. Mayani, H. and P. M. Lansdorp (1994) Thy-1 expression is linked to functional properties of primitive hematopoietic progenitor cells from human umbilical cord blood. Blood 83: 2410–2417.

    CAS  Google Scholar 

  34. Lee, J. S. and S. W. Cho (2012) Liver tissue engineering: Recent advances in the development of a bio-artificial liver. Biotechnol. Bioproc. Eng. 17: 427–438.

    Article  CAS  Google Scholar 

  35. Zhao, Z. K., H. L. Yu, F. Xiao, S. W. Li, W. B. Liao, and K. L. Zhao (2012) Muscle-derived stem cells differentiate into functional smooth muscle cells for ureter tissue engineering: An experimental study. Biotechnol. Bioproc. Eng. 17: 456–464.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Biotechnology, Yonsei University, Seoul, 120-749, Korea

    Jin Kim, Kisuk Yang, Hyun-Ji Park & Seung-Woo Cho

  2. School of Mechanical Engineering, Korea University, Seoul, 136-713, Korea

    Sewoon Han, Yoojin Shin & Seok Chung

  3. Department of Chemical Engineering, Myongji University, Yongin, 449-728, Korea

    Jun Hyup Lee

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  1. Jin Kim
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Kim, J., Yang, K., Park, HJ. et al. Implantable microfluidic device for the formation of three-dimensional vasculature by human endothelial progenitor cells. Biotechnol Bioproc E 19, 379–385 (2014). https://doi.org/10.1007/s12257-014-0021-9

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  • DOI: https://doi.org/10.1007/s12257-014-0021-9

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