This 5-year proposal will develop methods to synthesize functional microvascular networks in vitro. Central to this work are: 1) the use of lithography to generate three-dimensional (3D) constructs that have open internal topologies in the shape of human microvascular beds, and 2) maturation of as-synthesized structures by sequential optimization of culture conditions (shear stress, lumenal pressure, oxidative stress, and matrix proteolytic activity). Conditions tailored for maturation of cylindrical microvessels, in which the flow profile is easily determined, will serve as a starting point for maturation of microfabricated channels and networks that have non-circular cross-sections. This work will provide culture conditions that enhance the development of 2 characteristic microvascular functions (barrier function and reactivity to cytokines) and will determine to what extent these functions may co-exist in vitro. Temporal correlation between the emergence of these behaviors and changes in histology will suggest strategies to further enhance maturation. This work will also determine how microvascular networks remodel (i.e., how their cross-sectional shapes and network topologies change over time), and will suggest design principles for 3D networks that preserve their initial topologies in the presence of continuous perfusion. More generally, this work will illustrate the unique capabilities of a lithographic approach to tissue engineering. In the short-term, these networks will serve as surrogate human vascular tissues for high-throughput screening of drugs that may perturb or enhance microvascular function. In the long-term, engineered networks may enhance the perfusion of artificial tissues in vitro, and thereby overcome 1 of the primary obstacles in tissue engineering. ? ?
| Linville, Raleigh M; Boland, Nelson F; Covarrubias, Gil et al. (2016) Physical and Chemical Signals That Promote Vascularization of Capillary-Scale Channels. Cell Mol Bioeng 9:73-84 |
| Wong, Keith H K; Truslow, James G; Khankhel, Aimal H et al. (2013) Artificial lymphatic drainage systems for vascularized microfluidic scaffolds. J Biomed Mater Res A 101:2181-90 |
| Wong, Keith H K; Chan, Juliana M; Kamm, Roger D et al. (2012) Microfluidic models of vascular functions. Annu Rev Biomed Eng 14:205-30 |
| Leung, Alexander D; Wong, Keith H K; Tien, Joe (2012) Plasma expanders stabilize human microvessels in microfluidic scaffolds. J Biomed Mater Res A 100:1815-22 |
| Price, Gavrielle M; Tien, Joe (2011) Methods for forming human microvascular tubes in vitro and measuring their macromolecular permeability. Methods Mol Biol 671:281-93 |
| Wong, Keith H K; Truslow, James G; Tien, Joe (2010) The role of cyclic AMP in normalizing the function of engineered human blood microvessels in microfluidic collagen gels. Biomaterials 31:4706-14 |
| Price, Gavrielle M; Wong, Keith H K; Truslow, James G et al. (2010) Effect of mechanical factors on the function of engineered human blood microvessels in microfluidic collagen gels. Biomaterials 31:6182-9 |
| Truslow, James G; Price, Gavrielle M; Tien, Joe (2009) Computational design of drainage systems for vascularized scaffolds. Biomaterials 30:4435-43 |
| Price, Gavrielle M; Chrobak, Kenneth M; Tien, Joe (2008) Effect of cyclic AMP on barrier function of human lymphatic microvascular tubes. Microvasc Res 76:46-51 |
| Price, Gavrielle M; Chu, Kengyeh K; Truslow, James G et al. (2008) Bonding of macromolecular hydrogels using perturbants. J Am Chem Soc 130:6664-5 |
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