Spheroids as vascularization units: From angiogenesis research to tissue engineering applications.

Multi-cellular spheroids mimic the complex three-dimensional environment of natural tissues. Accordingly, they are also used as vascularization units in angiogenesis research and regenerative medicine. Spheroid sprouting assays are versatile in vitro models for the analysis of molecular and cellular determinants of blood vessel development, including different endothelial cell phenotypes, pro- and anti-angiogenic factors as well as cell-matrix and cell-cell interactions. In tissue engineering, spheroids serve in vivo as paracrine stimulators of angiogenesis and building blocks for the generation of prevascularized microtissues and branched vascular trees in macrotissues. Rapid progress in the automatized high-throughput production of spheroids currently provides the conditions for a widespread use of these applications in future drug discovery and bioengineering of functional organ substitutes.