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Review Article

Engineered Microvessels for the Study of Human Disease

[+] Author and Article Information
Samuel G. Rayner

Department of Pulmonary and
Critical Care Medicine,
University of Washington School of Medicine,
Campus Box 356522,
Seattle, WA 98195
e-mail: srayner@uw.edu

Ying Zheng

Department of Bioengineering,
University of Washington,
3720 15th Avenue NE,
Seattle, WA 98105;
Center for Cardiovascular Biology,
Institute for Stem Cell and
Regenerative Medicine,
University of Washington,
Seattle, WA 98109
e-mail: yingzy@uw.edu

Manuscript received May 25, 2016; final manuscript received August 3, 2016; published online October 21, 2016. Assoc. Editor: Jessica E. Wagenseil.

J Biomech Eng 138(11), 110801 (Oct 21, 2016) (11 pages) Paper No: BIO-16-1222; doi: 10.1115/1.4034428 History: Received May 25, 2016; Revised August 03, 2016

The microvasculature is an extensive, heterogeneous, and complex system that plays a critical role in human physiology and disease. It nourishes almost all living human cells and maintains a local microenvironment that is vital for tissue and organ function. Operating under a state of continuous flow, with an intricate architecture despite its small caliber, and subject to a multitude of biophysical and biochemical stimuli, the microvasculature can be a complex subject to study in the laboratory setting. Engineered microvessels provide an ideal platform that recapitulates essential elements of in vivo physiology and allows study of the microvasculature in a precise and reproducible way. Here, we review relevant structural and functional vascular biology, discuss different methods to engineer microvessels, and explore the applications of this exciting tool for the study of human disease.

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References

Zheng, Y. , Chen, J. , and López, J. A. , 2014, “ Microvascular Platforms for the Study of Platelet-Vessel Wall Interactions,” Thromb. Res., 133(4), pp. 525–531. [CrossRef] [PubMed]
Hasan, A. , Paul, A. , Vrana, N. E. , Zhao, X. , Memic, A. , Hwang, Y.-S. , Dokmeci, M. R. , and Khademhosseini, A. , 2014, “ Microfluidic Techniques for Development of 3D Vascularized Tissue,” Biomaterials, 35(26), pp. 7308–7325. [CrossRef] [PubMed]
Bae, H. , Puranik, A. S. , Gauvin, R. , Edalat, F. , Carrillo-Conde, B. , Peppas, N. A. , and Khademhosseini, A. , 2012, “ Building Vascular Networks,” Sci. Transl. Med., 4(160), p. 160ps23. [CrossRef] [PubMed]
Laschke, M. W. , and Menger, M. D. , 2015, “ Prevascularization in Tissue Engineering: Current Concepts and Future Directions,” Biotechnol. Adv., 34(2), pp. 112–121. [CrossRef] [PubMed]
Ross, M. H. , and Pawlina, W. , 2006, Histology: A Text and Atlas: With Correlated Cell and Molecular Biology, Lippincott Wiliams & Wilkins, Baltimore, MD.
Feihl, F. , Liaudet, L. , Waeber, B. , and Levy, B. I. , 2006, “ Hypertension: A Disease of the Microcirculation?,” Hypertension, 48(6), pp. 1012–1017. [CrossRef] [PubMed]
Gökçinar-Yagci, B. , Uçkan-Çetinkaya, D. , and Çelebi-Saltik, B. , 2015, “ Pericytes: Properties, Functions and Applications in Tissue Engineering,” Stem Cell Rev., 11(4), pp. 549–559. [CrossRef] [PubMed]
Van Dijk, C. G. M. , Nieuweboer, F. E. , Pei, J. Y. , Xu, Y. J. , Burgisser, P. , Van Mulligen, E. , El Azzouzi, H. , Duncker, D. J. , Verhaar, M. C. , and Cheng, C. , 2015, “ The Complex Mural Cell: Pericyte Function in Health and Disease,” Int. J. Cardiol., 190(1), pp. 75–89. [CrossRef] [PubMed]
Pries, A. , and Kuebler, W. , 2006, “ Normal Endothelium,” Handb. Exp. Pharmacol., 176(1), pp. 1–40.
Aird, W. C. , 2015, “ Endothelium and Haemostasis,” Hamostaseologie, 35(1), pp. 11–16. [CrossRef] [PubMed]
Weibel, E. R. , and Palade, G. E. , 1964, “ New Cytoplasmic Components in Arterial Endothelia,” J. Cell Biol., 23(1), pp. 101–112. [CrossRef] [PubMed]
Hack, C. E. , and Zeerleder, S. , 2001, “ The Endothelium in Sepsis: Source of and a Target for Inflammation,” Crit. Care Med., 29(7 Suppl.), pp. S21–S27. [CrossRef] [PubMed]
Flammer, A. J. , Anderson, T. , Celermajer, D. S. , Creager, M. A. , Deanfield, J. , Ganz, P. , Hamburg, N. M. , Lüscher, T. F. , Shechter, M. , Taddei, S. , Vita, J. A. , and Lerman, A. , 2012, “ The Assessment of Endothelial Function: From Research Into Clinical Practice,” Circulation, 126(6), pp. 753–767. [CrossRef] [PubMed]
Gutterman, D. D. , Chabowski, D. S. , Kadlec, A. O. , Durand, M. J. , Freed, J. K. , Ait-Aissa, K. , and Beyer, A. M. , 2016, “ The Human Microcirculation,” Circ. Res., 118(1), pp. 157–172. [CrossRef] [PubMed]
Levy, B. I. , Ambrosio, G. , Pries, A. R. , and Struijker-Boudier, H. A. , 2001, “ Microcirculation in Hypertension: A New Target for Treatment?,” Circulation, 104(6), pp. 735–740. [CrossRef] [PubMed]
Archer, S. L. , Weir, E. K. , and Wilkins, M. R. , 2010, “ Basic Science of Pulmonary Arterial Hypertension for Clinicians: New Concepts and Experimental Therapies,” Circulation, 121(18), pp. 2045–2066. [CrossRef] [PubMed]
Budhiraja, R. , Tuder, R. M. , and Hassoun, P. M. , 2004, “ Endothelial Dysfunction in Pulmonary Hypertension,” Circulation, 109(2), pp. 159–165. [CrossRef] [PubMed]
Gross, P. L. , and Aird, W. C. , 2000, “ The Endothelium and Thrombosis,” Semin. Thromb. Hemostasis, 26(5), pp. 463–478. [CrossRef]
López, J. A. , and Zheng, Y. , 2013, “ Synthetic Microvessels,” J. Thromb. Haemostasis, 11(Suppl. 1), pp. 67–74. [CrossRef]
Schouten, M. , Wiersinga, W. J. , Levi, M. , and van der Poll, T. , 2008, “ Inflammation, Endothelium, and Coagulation in Sepsis,” J. Leukocyte Biol., 83(3), pp. 536–545. [CrossRef]
Mehta, D. , Ravindran, K. , and Kuebler, W. M. , 2014, “ Novel Regulators of Endothelial Barrier Function,” Am. J. Physiol.: Lung Cell. Mol. Physiol., 307(12), pp. L924–935. [CrossRef] [PubMed]
Kerbel, R. S. , 2008, “ Tumor Angiogenesis,” N. Engl. J. Med., 358(19), pp. 2039–2049. [CrossRef] [PubMed]
Van Hinsbergh, V. W. , 1997, “ Endothelial Permeability for Macromolecules. Mechanistic Aspects of Pathophysiological Modulation,” Arterioscler., Thromb., Vasc. Biol., 17(6), pp. 1018–1023. [CrossRef]
Vane, J. R. , Anggård, E. E. , and Botting, R. M. , 1990, “ Regulatory Functions of the Vascular Endothelium,” N. Engl. J. Med., 323(1), pp. 27–36. [CrossRef] [PubMed]
Wagner, D. D. , and Frenette, P. S. , 2008, “ The Vessel Wall and Its Interactions,” Blood, 111(11), pp. 5271–5281. [CrossRef] [PubMed]
Andreeva, E. R. , Pugach, I. M. , Gordon, D. , and Orekhov, A. N. , 1998, “ Continuous Subendothelial Network Formed by Pericyte-Like Cells in Human Vascular Bed,” Tissue Cell, 30(1), pp. 127–135. [CrossRef] [PubMed]
Bergers, G. , and Song, S. , 2005, “ The Role of Pericytes in Blood-Vessel Formation and Maintenance,” Neuro Oncol., 7(4), pp. 452–464. [CrossRef] [PubMed]
Crisan, M. , Corselli, M. , Chen, W. C. W. , and Péault, B. , 2012, “ Perivascular Cells for Regenerative Medicine,” J. Cell. Mol. Med., 16(12), pp. 2851–2860. [CrossRef] [PubMed]
Gerhardt, H. , and Betsholtz, C. , 2003, “ Endothelial-Pericyte Interactions in Angiogenesis,” Cell Tissue Res., 314(1), pp. 15–23. [CrossRef] [PubMed]
Sims, D. E. , 2000, “ Diversity Within Pericytes,” Clin. Exp. Pharmacol. Physiol., 27(10), pp. 842–846. [CrossRef] [PubMed]
Crisan, M. , Yap, S. , Casteilla, L. , Chen, C. W. , Corselli, M. , Park, T. S. , Andriolo, G. , Sun, B. , Zheng, B. , Zhang, L. , Norotte, C. , Teng, P. N. , Traas, J. , Schugar, R. , Deasy, B. M. , Badylak, S. , Buhring, H. J. , Giacobino, J. P. , Lazzari, L. , Huard, J. , and Péault, B. , 2008, “ A Perivascular Origin for Mesenchymal Stem Cells in Multiple Human Organs,” Cell Stem Cell, 3(3), pp. 301–313. [CrossRef] [PubMed]
Hung, C. , Linn, G. , Chow, Y. H. , Kobayashi, A. , Mittelsteadt, K. , Altemeier, W. A. , Gharib, S. A. , Schnapp, L. M. , and Duffield, J. S. , 2013, “ Role of Lung Pericytes and Resident Fibroblasts in the Pathogenesis of Pulmonary Fibrosis,” Am. J. Respir. Crit. Care Med., 188(7), pp. 820–830. [CrossRef] [PubMed]
Lin, S.-L. , Kisseleva, T. , Brenner, D. A. , and Duffield, J. S. , 2008, “ Pericytes and Perivascular Fibroblasts are the Primary Source of Collagen-Producing Cells in Obstructive Fibrosis of the Kidney,” Am. J. Pathol., 173(6), pp. 1617–1627. [CrossRef] [PubMed]
Majesky, M. W. , 2007, “ Developmental Basis of Vascular Smooth Muscle Diversity,” Arterioscler., Thromb., Vasc. Biol., 27(6), pp. 1248–1258. [CrossRef]
Rensen, S. S. M. , Doevendans, P. A. F. M. , and van Eys, G. J. J. M. , 2007, “ Regulation and Characteristics of Vascular Smooth Muscle Cell Phenotypic Diversity,” Neth. Heart J., 15(3), pp. 100–108. [CrossRef] [PubMed]
LeBleu, V. S. , Macdonald, B. , and Kalluri, R. , 2007, “ Structure and Function of Basement Membranes,” Exp. Biol. Med., 232(9), pp. 1121–1129. [CrossRef]
Carmeliet, P. , and Jain, R. K. , 2011, “ Molecular Mechanisms and Clinical Applications of Angiogenesis,” Nature, 473(7347), pp. 298–307. [CrossRef] [PubMed]
Frantz, C. , Stewart, K. M. , and Weaver, V. M. , 2010, “ The Extracellular Matrix at a Glance,” J. Cell Sci., 123(24), pp. 4195–4200. [CrossRef] [PubMed]
Davis, G. E. , and Senger, D. R. , 2005, “ Endothelial Extracellular Matrix: Biosynthesis, Remodeling, and Functions During Vascular Morphogenesis and Neovessel Stabilization,” Circ. Res., 97(11), pp. 1093–1107. [CrossRef] [PubMed]
Ribatti, D. , Vacca, A. , Nico, B. , Roncali, L. , and Dammacco, F. , 2001, “ Postnatal Vasculogenesis,” Mech. Dev., 100(2), pp. 157–163. [CrossRef] [PubMed]
McDonald, J. C. , and Whitesides, G. M. , 2002, “ Poly(Dimethylsiloxane) as a Material for Fabricating Microfluidic Devices,” Acc. Chem. Res., 35(7), pp. 491–499. [CrossRef] [PubMed]
Augst, A. D. , Kong, H. J. , and Mooney, D. J. , 2006, “ Alginate Hydrogels as Biomaterials,” Macromol. Biosci., 6(8), pp. 623–633. [CrossRef] [PubMed]
Ling, Y. , Rubin, J. , Deng, Y. , Huang, C. , Demirci, U. , Karp, J. M. , and Khademhosseini, A. , 2007, “ A Cell-Laden Microfluidic Hydrogel,” Lab Chip, 7(6), pp. 756–762. [CrossRef] [PubMed]
Bayless, K. J. , and Davis, G. E. , 2003, “ Sphingosine-1-Phosphate Markedly Induces Matrix Metalloproteinase and Integrin-Dependent Human Endothelial Cell Invasion and Lumen Formation in Three-Dimensional Collagen and Fibrin Matrices,” Biochem. Biophys. Res. Commun., 312(4), pp. 903–913. [CrossRef] [PubMed]
Hutson, C. B. , Nichol, J. W. , Aubin, H. , Bae, H. , Yamanlar, S. , Al-Haque, S. , Koshy, S. T. , and Khademhosseini, A. , 2011, “ Synthesis and Characterization of Tunable Poly(Ethylene Glycol): Gelatin Methacrylate Composite Hydrogels,” Tissue Eng., Part A, 17(13–14), pp. 1713–1723. [CrossRef]
Nichol, J. W. , Koshy, S. T. , Bae, H. , Hwang, C. M. , Yamanlar, S. , and Khademhosseini, A. , 2010, “ Cell-Laden Microengineered Gelatin Methacrylate Hydrogels,” Biomaterials, 31(21), pp. 5536–5544. [CrossRef] [PubMed]
Lee, H. , Chung, M. , and Jeon, N. L. , 2014, “ Microvasculature: An Essential Component for Organ-on-Chip Systems,” MRS Bull., 39(01), pp. 51–59. [CrossRef]
Chrobak, K. M. , Potter, D. R. , and Tien, J. , 2006, “ Formation of Perfused, Functional Microvascular Tubes In Vitro,” Microvasc. Res., 71(3), pp. 185–196. [CrossRef] [PubMed]
Golden, A. P. , and Tien, J. , 2007, “ Fabrication of Microfluidic Hydrogels Using Molded Gelatin as a Sacrificial Element,” Lab Chip, 7(6), pp. 720–725. [CrossRef] [PubMed]
Zheng, Y. , Chen, J. , Craven, M. , Choi, N. W. , Totorica, S. , Diaz-Santana, A. , Kermani, P. , Hempstead, B. , Fischbach-Teschl, C. , López, J. A. , and Stroock, A. D. , 2012, “ In Vitro Microvessels for the Study of Angiogenesis and Thrombosis,” Proc. Natl. Acad. Sci. U.S.A., 109(24), pp. 9342–9347. [CrossRef] [PubMed]
Yeon, J. H. , Ryu, H. R. , Chung, M. , Hu, Q. P. , and Jeon, N. L. , 2012, “ In Vitro Formation and Characterization of a Perfusable Three-Dimensional Tubular Capillary Network in Microfluidic Devices,” Lab Chip, 12(16), pp. 2815–2822. [CrossRef] [PubMed]
Price, G. M. , Wong, K. H. K. , Truslow, J. G. , Leung, A. D. , Acharya, C. , and Tien, J. , 2010, “ Effect of Mechanical Factors on the Function of Engineered Human Blood Microvessels in Microfluidic Collagen Gels,” Biomaterials, 31(24), pp. 6182–6189. [CrossRef] [PubMed]
Yoshida, H. , Matsusaki, M. , and Akashi, M. , 2013, “ Multilayered Blood Capillary Analogs in Biodegradable Hydrogels for In Vitro Drug Permeability Assays,” Adv. Funct. Mater., 23(14), pp. 1736–1742. [CrossRef]
Bischel, L. L. , Young, E. W. K. , Mader, B. R. , and Beebe, D. J. , 2013, “ Tubeless Microfluidic Angiogenesis Assay With Three-Dimensional Endothelial-Lined Microvessels,” Biomaterials, 34(5), pp. 1471–1477. [CrossRef] [PubMed]
Miller, J. S. , Stevens, K. R. , Yang, M. T. , Baker, B. M. , Nguyen, D.-H. T. , Cohen, D. M. , Toro, E. , Chen, A. A. , Galie, P. A. , Yu, X. , Chaturvedi, R. , Bhatia, S. N. , and Chen, C. S. , 2012, “ Rapid Casting of Patterned Vascular Networks for Perfusable Engineered Three-Dimensional Tissues,” Nat. Mater., 11(7), pp. 768–774. [CrossRef] [PubMed]
Bogorad, M. I. , DeStefano, J. , Karlsson, J. , Wong, A. D. , Gerecht, S. , and Searson, P. C. , 2015, “ Review: In Vitro Microvessel Models,” Lab Chip, 15(22), pp. 4242–4255. [CrossRef] [PubMed]
Nikkhah, M. , Edalat, F. , Manoucheri, S. , and Khademhosseini, A. , 2012, “ Engineering Microscale Topographies to Control the Cell-Substrate Interface,” Biomaterials, 33(21), pp. 5230–5246. [CrossRef] [PubMed]
Raghavan, S. , Nelson, C. M. , Baranski, J. D. , Lim, E. , and Chen, C. S. , 2010, “ Geometrically Controlled Endothelial Tubulogenesis in Micropatterned Gels,” Tissue Eng., Part A, 16(7), pp. 2255–2263. [CrossRef]
Nikkhah, M. , Eshak, N. , Zorlutuna, P. , Annabi, N. , Castello, M. , Kim, K. , Dolatshahi-Pirouz, A. , Edalat, F. , Bae, H. , Yang, Y. , and Khademhosseini, A. , 2012, “ Directed Endothelial Cell Morphogenesis in Micropatterned Gelatin Methacrylate Hydrogels,” Biomaterials, 33(35), pp. 9009–9018. [CrossRef] [PubMed]
Hsu, Y.-H. , Moya, M. L. , Hughes, C. C. W. , George, S. C. , and Lee, A. P. , 2013, “ A Microfluidic Platform for Generating Large-Scale Nearly Identical Human Microphysiological Vascularized Tissue Arrays,” Lab Chip, 13(15), pp. 2990–2998. [CrossRef] [PubMed]
Kusuma, S. , Shen, Y.-I. , Hanjaya-Putra, D. , Mali, P. , Cheng, L. , and Gerecht, S. , 2013, “ Self-Organized Vascular Networks From Human Pluripotent Stem Cells in a Synthetic Matrix,” Proc. Natl. Acad. Sci. U.S.A., 110(31), pp. 12601–12606. [CrossRef] [PubMed]
Kim, S. , Lee, H. , Chung, M. , and Jeon, N. L. , 2013, “ Engineering of Functional, Perfusable 3D Microvascular Networks on a Chip,” Lab Chip, 13(8), pp. 1489–1500. [CrossRef] [PubMed]
Nillesen, S. T. M. , Geutjes, P. J. , Wismans, R. , Schalkwijk, J. , Daamen, W. F. , and van Kuppevelt, T. H. , 2007, “ Increased Angiogenesis and Blood Vessel Maturation in Acellular Collagen-Heparin Scaffolds Containing Both FGF2 and VEGF,” Biomaterials, 28(6), pp. 1123–1131. [CrossRef] [PubMed]
Barkefors, I. , Le Jan, S. , Jakobsson, L. , Hejll, E. , Carlson, G. , Johansson, H. , Jarvius, J. , Jeong, W. P. , Noo, L. J. , and Kreuger, J. , 2008, “ Endothelial Cell Migration in Stable Gradients of Vascular Endothelial Growth Factor A and Fibroblast Growth Factor 2: Effects on Chemotaxis and Chemokinesis,” J. Biol. Chem., 283(20), pp. 13905–13912. [CrossRef] [PubMed]
Nguyen, D.-H. T. , Stapleton, S. C. , Yang, M. T. , Cha, S. S. , Choi, C. K. , Galie, P. A. , and Chen, C. S. , 2013, “ Biomimetic Model to Reconstitute Angiogenic Sprouting Morphogenesis In Vitro,” Proc. Natl. Acad. Sci. U.S.A., 110(17), pp. 6712–6717. [CrossRef] [PubMed]
Wong, K. H. K. , Chan, J. M. , Kamm, R. D. , and Tien, J. , 2012, “ Microfluidic Models of Vascular Functions,” Annu. Rev. Biomed. Eng., 14(1), pp. 205–230. [CrossRef] [PubMed]
Estrada, R. , Giridharan, G. A. , Nguyen, M. D. , Prabhu, S. D. , and Sethu, P. , 2011, “ Microfluidic Endothelial Cell Culture Model to Replicate Disturbed Flow Conditions Seen in Atherosclerosis Susceptible Regions,” Biomicrofluidics, 5(3), pp. 1–11. [CrossRef]
Westein, E. , van der Meer, A. D. , Kuijpers, M. J. E. , Frimat, J.-P. , van den Berg, A. , and Heemskerk, J. W. M. , 2013, “ Atherosclerotic Geometries Exacerbate Pathological Thrombus Formation Poststenosis in a Von Willebrand Factor-Dependent Manner,” Proc. Natl. Acad. Sci. U.S.A., 110(4), pp. 1357–1362. [CrossRef] [PubMed]
Zheng, Y. , Chen, J. , and López, J. A. , 2015, “ Flow-Driven Assembly of VWF Fibres and Webs in In Vitro Microvessels,” Nat. Commun., 6(7858), p. 7858. [CrossRef] [PubMed]
Dimasi, A. , Rasponi, M. , Sheriff, J. , Chiu, W. C. , Bluestein, D. , Tran, P. L. , Slepian, M. J. , and Redaelli, A. , 2015, “ Microfluidic Emulation of Mechanical Circulatory Support Device Shear-Mediated Platelet Activation,” Biomed. Microdevices, 17(6), pp. 1–11. [CrossRef] [PubMed]
Young, E. W. K. , Watson, M. W. L. , Srigunapalan, S. , Wheeler, A. R. , and Simmons, C. A. , 2010, “ Technique for Real-Time Measurements of Endothelial Permeability in a Microfluidic Membrane Chip Using Laser-Induced Fluorescence Detection,” Anal. Chem., 82(3), pp. 808–816. [CrossRef] [PubMed]
Zervantonakis, I. K. , Hughes-Alford, S. K. , Charest, J. L. , Condeelis, J. S. , Gertler, F. B. , and Kamm, R. D. , 2012, “ Three-Dimensional Microfluidic Model for Tumor Cell Intravasation and Endothelial Barrier Function,” Proc. Natl. Acad. Sci. U.S.A., 109(34), pp. 13515–13520. [CrossRef] [PubMed]
Booth, R. , and Kim, H. , 2012, “ Characterization of a Microfluidic In Vitro Model of the Blood–Brain Barrier (μBBB),” Lab Chip, 12(10), pp. 1784–1792. [CrossRef] [PubMed]
Rusanov, A. L. , Luzgina, N. G. , Barreto, G. E. , and Aliev, G. , 2016, “ Role of Microfluidics in Blood–Brain Barrier Permeability Cell Culture Modeling: Relevance to CNS Disorders,” CNS Neurol. Disord.: Drug Targets, 15(3), pp. 301–309. [CrossRef] [PubMed]
Butcher, E. C. , 1991, “ Leukocyte-Endothelial Cell Recognition: Three (or More) Steps to Specificity and Diversity,” Cell, 67(6), pp. 1033–1036. [CrossRef] [PubMed]
Kim, E. , Schueller, O. , and Sweetnam, P. M. , 2012, “ Targeting the Leukocyte Activation Cascade: Getting to the Site of Inflammation Using Microfabricated Assays,” Lab Chip, 12(12), pp. 2255–2264. [CrossRef] [PubMed]
Molteni, R. , Bianchi, E. , Patete, P. , Fabbri, M. , Baroni, G. , Dubini, G. , and Pardi, R. , 2014, “ A Novel Device to Concurrently Assess Leukocyte Extravasation and Interstitial Migration Within a Defined 3D Environment,” Lab Chip, 15(1), pp. 195–207. [CrossRef]
Han, S. , Yan, J.-J. , Shin, Y. , Jeon, J. J. , Won, J. , Jeong, H. E. , Kamm, R. D. , Kim, Y.-J. , and Chung, S. , 2012, “ A Versatile Assay for Monitoring In Vivo-Like Transendothelial Migration of Neutrophils,” Lab Chip, 12(20), pp. 3861–3865. [CrossRef] [PubMed]
Hamza, B. , and Irimia, D. , 2015, “ Whole Blood Human Neutrophil Trafficking in a Microfluidic Model of Infection and Inflammation,” Lab Chip, 15(12), pp. 2625–2633. [CrossRef] [PubMed]
Jain, N. G. , Wong, E. A. , Aranyosi, A. J. , Boneschansker, L. , Markmann, J. F. , Briscoe, D. M. , and Irimia, D. , 2015, “ Microfluidic Mazes to Characterize T-Cell Exploration Patterns Following Activation In Vitro,” Integr. Biol., 7(11), pp. 1423–1431. [CrossRef]
Preira, P. , Forel, J.-M. , Robert, P. , Nègre, P. , Biarnes-Pelicot, M. , Xeridat, F. , Bongrand, P. , Papazian, L. , Theodoly, O. , Negre, P. , Biarnes-Pelicot, M. , Xeridat, F. , Bongrand, P. , Papazian, L. , and Theodoly, O. , 2016, “ The Leukocyte-Stiffening Property of Plasma in Early Acute Respiratory Distress Syndrome (ARDS) Revealed by a Microfluidic Single-Cell Study: The Role of Cytokines and Protection With Antibodies,” Crit. Care, 20(1), p. 8. [CrossRef] [PubMed]
Kotz, K. T. , Xiao, W. , Miller-Graziano, C. , Qian, W. , Russom, A. , Warner, E. A. , Moldawer, L. L. , De, A. , Bankey, P. E. , Petritis, B. O. , Camp, D. G. , Rosenbach, A. E. , Goverman, J. , Fagan, S. P. , Brownstein, B. H. , Irimia, D. , Xu, W. , Wilhelmy, J. , Mindrinos, M. N. , Smith, R. D. , Davis, R. W. , Tompkins, R. G. , and Toner, M. , Inflammation and the Host Response to Injury Collaborative Research Program, 2010, “ Clinical Microfluidics for Neutrophil Genomics and Proteomics,” Nat. Med., 16(9), pp. 1042–1047. [CrossRef] [PubMed]
Rosenberg, R. D. , and Aird, W. C. , 1999, “ Vascular-Bed Specific Hemostasis and Hypercoagulable States,” N. Engl. J. Med., 340(20), pp. 1555–1564. [CrossRef] [PubMed]
Rumbaut, R. E. , Slaff, D. W. , and Burns, A. R. , 2005, “ Microvascular Thrombosis Models in Venules and Arterioles In Vivo,” Microcirculation, 12(3), pp. 259–274. [CrossRef] [PubMed]
Levi, M. , Keller, T. T. , van Gorp, E. , and ten Cate, H. , 2003, “ Infection and Inflammation and the Coagulation System,” Cardiovasc. Res., 60(1), pp. 26–39. [CrossRef] [PubMed]
Ruggeri, Z. M. , 2009, “ Platelet Adhesion Under Flow,” Microcirculation, 16(1), pp. 58–83. [CrossRef] [PubMed]
Higgins, J. M. , Eddington, D. T. , Bhatia, S. N. , and Mahadevan, L. , 2007, “ Sickle Cell Vasoocclusion and Rescue in a Microfluidic Device,” Proc. Natl. Acad. Sci. U.S.A., 104(51), pp. 20496–20500. [CrossRef] [PubMed]
Tsai, M. , Kita, A. , Leach, J. , Rounsevell, R. , Huang, J. N. , Moake, J. , Ware, R. E. , Fletcher, D. A. , and Lam, W. A. , 2012, “ In Vitro Modeling of the Microvascular Occlusion and Thrombosis That Occur in Hematologic Diseases Using Microfluidic Technology,” J. Clin. Invest., 122(1), pp. 408–418. [CrossRef] [PubMed]
Jeon, J. S. , Bersini, S. , Gilardi, M. , Dubini, G. , Charest, J. L. , Moretti, M. , and Kamm, R. D. , 2015, “ Human 3D Vascularized Organotypic Microfluidic Assays to Study Breast Cancer Cell Extravasation,” Proc. Natl. Acad. Sci. U.S.A., 112(1), pp. 214–219. [CrossRef] [PubMed]
Skommer, J. , and Wlodkowic, D. , 2015, “ Successes and Future Outlook for Microfluidics-Based Cardiovascular Drug Discovery,” Expert Opin. Drug Discovery, 10(3), pp. 231–244. [CrossRef]
Chang, W. G. , Andrejecsk, J. W. , Kluger, M. S. , Saltzman, W. M. , and Pober, J. S. , 2013, “ Pericytes Modulate Endothelial Sprouting,” Cardiovasc. Res., 100(3), pp. 492–500. [CrossRef] [PubMed]
Stratman, A. N. , Schwindt, A. E. , Malotte, K. M. , and Davis, G. E. , 2010, “ Endothelial-Derived PDGF-BB and HB-EGF Coordinately Regulate Pericyte Recruitment During Vasculogenic Tube Assembly and Stabilization,” Blood, 116(22), pp. 4720–4730. [CrossRef] [PubMed]
Stratman, A. N. , Malotte, K. M. , Mahan, R. D. , Davis, M. J. , and Davis, G. E. , 2009, “ Pericyte Recruitment During Vasculogenic Tube Assembly Stimulates Endothelial Basement Membrane Matrix Formation,” Blood, 114(24), pp. 5091–5101. [CrossRef] [PubMed]
Waters, J. P. , Kluger, M. S. , Graham, M. , Chang, W. G. , Bradley, J. R. , and Pober, J. S. , 2013, “ In Vitro Self-Assembly of Human Pericyte-Supported Endothelial Microvessels in Three-Dimensional Coculture: A Simple Model for Interrogating Endothelial-Pericyte Interactions,” J. Vasc. Res., 50(4), pp. 324–331. [CrossRef] [PubMed]
Kim, J. , Chung, M. , Kim, S. , Jo, D. H. , Kim, J. H. , and Jeon, N. L. , 2015, “ Engineering of a Biomimetic Pericyte-Covered 3D Microvascular Network,” PLoS One, 10(7), pp. 1–15.
Van der Meer, A. D. , Orlova, V. V. , ten Dijke, P. , van den Berg, A. , and Mummery, C. L. , 2013, “ Three-Dimensional Co-Cultures of Human Endothelial Cells and Embryonic Stem Cell-Derived Pericytes Inside a Microfluidic Device,” Lab Chip, 13(18), pp. 3562–3568. [CrossRef] [PubMed]
Katt, M. E. , Placone, A. L. , Wong, A. D. , Xu, Z. S. , and Searson, P. C. , 2016, “ In Vitro Tumor Models: Advantages, Disadvantages, Variables, and Selecting the Right Platform,” Front. Bioeng. Biotechnol., 4(12), pp. 1–14. [CrossRef] [PubMed]
Carmeliet, P. , and Jain, R. K. , 2000, “ Angiogenesis in Cancer and Other Diseases,” Nature, 407(6801), pp. 249–257. [CrossRef] [PubMed]
Wirtz, D. , Konstantopoulos, K. , and Searson, P. C. , 2011, “ The Physics of Cancer: The Role of Physical Interactions and Mechanical Forces in Metastasis,” Nat. Rev. Cancer, 11(7), pp. 512–522. [CrossRef] [PubMed]
Wong, A. D. , and Searson, P. C. , 2014, “ Live-Cell Imaging of Invasion and Intravasation in an Artificial Microvessel Platform,” Cancer Res., 74(17), pp. 4937–4945. [CrossRef] [PubMed]
Buchanan, C. F. , Verbridge, S. S. , Vlachos, P. P. , and Rylander, M. N. , 2014, “ Flow Shear Stress Regulates Endothelial Barrier Function and Expression of Angiogenic Factors in a 3D Microfluidic Tumor Vascular Model,” Cell Adhes. Migr., 8(5), pp. 517–524. [CrossRef]
Chen, M. B. , Whisler, J. A. , Jeon, J. S. , and Kamm, R. D. , 2013, “ Mechanisms of Tumor Cell Extravasation in an In Vitro Microvascular Network Platform,” Integr. Biol. (Cambridge), 5(10), pp. 1262–1271. [CrossRef]
Zheng, F. , Fu, F. , Cheng, Y. , Wang, C. , Zhao, Y. , and Gu, Z. , 2016, “ Organ-on-a-Chip Systems: Microengineering to Biomimic Living Systems,” Small, 12(17), pp. 2253–2282. [CrossRef] [PubMed]
Huh, D. , Matthews, B. D. , Mammoto, A. , Montoya-Zavala, M. , Hsin, H. Y. , and Ingber, D. E. , 2010, “ Reconstituting Organ-Level Lung Functions on a Chip,” Science, 328(5986), pp. 1662–1668. [CrossRef] [PubMed]
Chiu, L. L. Y. , Montgomery, M. , Liang, Y. , Liu, H. , and Radisic, M. , 2012, “ Perfusable Branching Microvessel Bed for Vascularization of Engineered Tissues,” Proc. Natl. Acad. Sci. U.S.A., 109(50), pp. E3414–3423. [CrossRef] [PubMed]
Brown, J. A. , Pensabene, V. , Markov, D. A. , Allwardt, V. , Neely, M. D. , Shi, M. , Britt, C. M. , Hoilett, O. S. , Yang, Q. , Brewer, B. M. , Samson, P. C. , McCawley, L. J. , May, J. M. , Webb, D. J. , Li, D. , Bowman, A. B. , Reiserer, R. S. , and Wikswo, J. P. , 2015, “ Recreating Blood-Brain Barrier Physiology and Structure on Chip: A Novel Neurovascular Microfluidic Bioreactor,” Biomicrofluidics, 9(5), pp. 1–15. [CrossRef]
Ligresti, G. , Nagao, R. J. , Xue, J. , Choi, Y. J. , Xu, J. , Ren, S. , Aburatani, T. , Anderson, S. K. , MacDonald, J. W. , Bammler, T. K. , Schwartz, S. M. , Muczynski, K. A. , Duffield, J. S. , Himmelfarb, J. , and Zheng, Y. , 2015, “ A Novel Three-Dimensional Human Peritubular Microvascular System,” J. Am. Soc. Nephrol., 27(8), pp. 2370–2381. [CrossRef] [PubMed]
Williamson, A. , Singh, S. , Fernekorn, U. , and Schober, A. , 2013, “ The Future of the Patient-Specific Body-on-a-Chip,” Lab Chip, 13(18), pp. 3471–3480. [CrossRef] [PubMed]

Figures

Grahic Jump Location
Fig. 1

(a) Schematic of the systemic circulation. An artery is shown dividing into smaller arteries, arterioles, and capillaries. These drain into postcapillary venules, which collect into veins. A capillary is shown in magnification, consisting of a single layer of endothelial cells supported by scattered pericytes. (b) Circulating blood, including red blood cells, platelets, and a neutrophil are shown within a blood vessel bounded by endothelial cells. Vessels are supported by ECM components within the interstitium. (c) Leukocyte recruitment in response to inflammation. Cytokines released in response to inflammatory stimuli, such as infection, injury, allergen, or tumor, prompt endothelial cells to express leukocyte adhesion molecules including P-selectin and E-selectin. Initial capture occurs when these molecules bind ligands on circulating leukocytes such as P-selectin glycoprotein ligand-1 (PSGL-1) or E-selectin ligand-1 (ESL1). Leukocytes “roll” on these receptors and slow, allowing time for additional ligands on leukocytes to firmly adhere to the endothelium via receptors such as intercellular adhesion molecule (ICAM) 1 and 2. Leukocytes then transmigrate through the endothelium and toward inflammatory stimuli (chemotaxis). (d) Endothelial interactions and primary hemostasis. Upon vessel injury the endothelium rapidly adopts a procoagulant profile, secreting endothelin (which promotes local vasoconstriction), and releasing VWF which binds circulating platelets via their GP1B receptors. VWF is also expressed on subendothelial collagen and is exposed by injury. Platelets “carpet” the endothelium and roll forward until they slow and firmly adhere to exposed collagen. Platelet activation then occurs, which leads platelets to change shape, degranulate, and aggregate, forming the platelet plug of primary hemostasis.

Grahic Jump Location
Fig. 2

Methods for formation of engineered microvessels. (a) Needle-removal technique. A needle is embedded in collagen gel and removed to form a channel. This is then seeded with endothelial cells and perfused, as shown. An endothelialized microvessel is shown under magnification on the right side of the figure (scale bar is 100 μm). (Reproduced with permission from Lee et al. [47]. Copyright 2014 by Materials Research Society, based on original figure found in Ref. [48].) (b) Dissolvable matrix technique. A gelatin mesh is formed on a PDMS stamp and then embedded within ECM materials (here, Matrigel). Heating leads to dissolution of the gelatin, leaving behind channels which can be seeded with endothelial cells as shown in the rightward portion of the figure. (Reprinted with permission from Golden and Tien [49]. Copyright 2007 by The Royal Society of Chemistry.) (c) Layering method. A collagen slab is formed on top of a patterned PDMS (i). A separate top collagen is similarly formed (ii). The two collagen slabs are joined, and channels within the collagen are seeded with endothelial cells (iii). The microvascular network is then cultured under flow conditions (iv). At the far right, a fluorescent micrograph shows cultured/stained endothelial cells within engineered microvessels (scale bar 100 μm). Adapted from Ref. [50]. (d) Angiogenesis/vasculogenesis-based technique. HUVECs were placed at either end of a PDMS construct, next to a fibrin-filled channel, and cocultured with fibroblast cells. Over time, perfusable capillaries formed via angiogenesis, spanning this fibrin channel. (Reprinted with permission from Yeon et al. [51]. Copyright 2012 by The Royal Society of Chemistry.)

Grahic Jump Location
Fig. 3

(a) Engineered microvessels for the study of thrombosis and microhemodynamics. Engineered microvessels were seeded with HUVEC cells and exposed to phorbol-12-myristate-13-acetate (PMA) to stimulate VWF secretion (left image). Platelet aggregation in these stimulated vessels was compared with control vessels which did not have PMA exposure. In the upper right image, VWF can be seen oriented along stimulated vessels in the direction of flow. VWF aggregates in narrow vessels with high shear stress, strong flow acceleration, or sharp turns, as demonstrated in the lower right image. Figure adapted from Refs. [50] and [69]. (b) Engineered microvessels for the modeling of human thrombotic disease. A branching microfluidic network was created using soft lithography, consisting of a gas channel network separated from a vascular network by a PDMS membrane. Perfusing the vascular network with blood from patients with sickle cell disease and varying the oxygen content of the gas channel network, the authors were able to provoke vascular occlusion events (detailed on the right side of the figure). (Reprinted with permission from Higgins et al. [87]. Copyright 2007 by The National Academy of Sciences of the U.S.A.) A similar construct was endothelialized in later work, for further examination of microangiopathic diseases (see Ref. [88]). (c) Engineered microvessels for the study of tumor metastasis. A microvessel model was created with microfluidic channels flanking either side of a larger chamber filled with fibrin gel matrix. A tricellular culture was created within the center chamber, with HUVECs, human bone human bone marrow-derived mesenchymal stem cells (MSCs), and bone marrow-derived mesenchymal stem cells with partial differentiation toward bone (OB). Growth factors were added and capillary formation occurred over 4 days, spanning the two center chamber and connecting the two flanking chambers. Breast cells were then introduced into these microvessels, and extravasation observed (middle image). The rate of extravasation in this “bone microenvironment” was compared with extravasation in a muscle environment (using myoblast cell line C2C12), or a control of acellular matrix material, and found to be highest in the bone microenvironment (see figure on the right). This is consistent with the clinical tendency of breast cancer to metastasize to bone tissue. (Reprinted with permission from Jeon et al. [89]. Copyright 2015 by The National Academy of Sciences of the U.S.A.)

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