Trends in Biotechnology
Volume 34, Issue 9, September 2016, Pages 733-745
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Review
Special Issue: Biofabrication
Vascularization and Angiogenesis in Tissue Engineering: Beyond Creating Static Networks

https://doi.org/10.1016/j.tibtech.2016.03.002Get rights and content

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Engineered tissues of a clinically relevant size need a vascular network to supply the cells with nutrients and oxygen. Including a vascular network before implantation can aid in this need, by connecting to the vasculature of the patient.

To supply all cells with sufficient nutrients, and to successfully connect to the patient vasculature, the engineered vascular network needs to be highly organized. Using microfabrication technology such as photo patterning and bioprinting, the initial organization of vascular networks can be designed and controlled.

The geometry of vascular networks can also be controlled by adapting local microenvironments. The patterning of mechanical signals, fluid flows, or the availability of growth factors leads to directed vascular organization.

Engineered tissues need a vascular network to supply cells with nutrients and oxygen after implantation. A network that can connect to the vasculature of the patient after implantation can be included during in vitro culture. For optimal integration, this network needs to be highly organized, including venules, capillaries, and arterioles, to supply all of the cells with sufficient nutrients. Owing to the importance of vascularization for the clinical applicability of tissue engineering, many approaches have been investigated to include an organized vascular network in tissue constructs. This review will give an overview of recent efforts, and will propose future perspectives to engineer the optimal, functional vascular network.

Section snippets

Importance of Vascularization in Tissue Engineering

One of the goals of tissue engineering is to generate tissues that can be used as alternatives for donor material to repair or replace damaged tissues or organs [1]. Tissues generated for this purpose will generally be of a size larger than the diffusional limit for nutrients and oxygen [2]. Therefore, a need for a system to distribute nutrients within the tissue is apparent. During culture in the lab this distribution can be facilitated by using, for instance, perfusion bioreactors, but after

Angiogenesis and Vascular Remodeling

To include an organized vascular network in an engineered tissue, it is important to understand the process of vascular formation and remodeling. A starting point for this process is to look at the formation of the vascular network during embryonic development and growth. Two processes can be distinguished during the formation of a natural vascular network: vasculogenesis and angiogenesis. Vasculogenesis is the process that takes place during early embryonic development where angioblasts (see

Natural Organization of Endothelial Cells in Engineered Tissues

Many research efforts in prevascularized tissue engineering have relied on the spontaneous organization of endothelial cells to form vascular networks on scaffolds 16, 17, 18, in extracellular matrix analogs 4, 19, or in cellular aggregates with other cells 20, 21. These studies show that endothelial cells are capable of forming vascular networks, often without the addition of specific cues or growth factors. First, the endothelial cells form a primitive network within a previously avascular

Patterning of Endothelial Cells in Engineered Tissues

Many studies have focused on the active patterning of vascular networks within engineered tissues to closer resemble the natural organization of a vascular tree. Using novel fabrication technologies, the initial organization of vascular cells can be designed and controlled. This approach offers the clear advantage that the resulting network can be designed such that all cells in the tissue are within 200 μm from a vessel, and provides clear locations for vascular anastomosis.

One strategy used to

Guiding Organization of Endothelial Cells in Engineered Tissues

An alternative approach to control the architecture of vascular structures in engineered tissues is to include local cues to guide vascular organization and remodeling. The adaptation of local microenvironments offers the possibility to engineer a complex, predictable vascular organization, starting from an initial random distribution of vascular cells. Even though this approach is less straightforward than the direct patterning of cells, guided morphogenesis may result in a better control of

Concluding Remarks and Future Perspectives

When regarding vascular networks for engineered tissues, it is important to realize that quality is more important than quantity. It is not about the number of vascular structures in a given volume of tissue but about the amount of blood that is perfused through the vascular network and the distribution of this blood over the tissue volume. Therefore, it is important that the vascular network is well organized and matured. In studies where angiogenesis is overstimulated resulting in excessive

Acknowledgments

J.R. was supported by the People Programme (Marie Curie Actions) under REA Grant Agreement no. 622294 (PreVascIn).

Glossary

Anastomosis
in the context of angiogenesis, the connection of two vascular structures.
Angioblast
a precursor of endothelial cells, originating from the mesenchyme.
Angiopoietins
a family of growth factors that mainly plays a role in vascular stabilization and destabilization. Generally, Angiopoietin 1 stabilizes vascular networks, while Angiopoietin 2 induces destabilization allowing for vascular remodeling.
Capillary bed
a finely distributed network of capillaries, which are the smallest of the

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