Microvascular Tissue Engineering-A Review

Abstract

Tissue engineering and regenerative medicine have come a long way in recent decades, but the lack of functioning vasculature is still a major obstacle preventing the development of thicker, physiologically relevant tissue constructs. A large part of this obstacle lies in the development of the vessels on a microscale-the microvasculature-that are crucial for oxygen and nutrient delivery. In this review, we present the state of the art in the field of microvascular tissue engineering and demonstrate the challenges for future research in various sections of the field. Finally, we illustrate the potential strategies for addressing some of those challenges.

Keywords: biomaterials; coculture; gradients; microvascularization; regenerative medicine; tissue engineering; vascularization.

Figure 1

A schematic showing crucial functions of the microvasculature (created with BioRender.com; accessed on 6 April 2021).

Figure 2

Cross sections of arteriole and capillary. On the left side of the image is the cross section of the arteriole showing four main layers: EC layer, basal lamina, smooth muscle cell layer, and connective tissue layer. The right side of the image shows the cross section of the capillary, which clearly lacks the smooth muscle cell and connective tissue layers compared to the arteriole (created with BioRender.com; accessed on 6 April 2021).

Figure 3

A histological image of different vessel types’ cross sections. The image shows the difference between different vessel walls—single layer wall of the capillary with only endothelial cells and occasional pericytes (not seen in this image), and multiple layer walls of arterioles and venules, which have many layers of muscle cells lining the endothelium [58]. For better visualization, the typical vessel diameters are as follows: arterioles (smallest, precapillary arteries), <100 μm; capillaries, 5–40 μm; venules (smallest, postcapillary veins), 10–200 μm [59]. Reprinted (adapted) from Creative Commons Attribution License CC BY-SA 4.0.

Figure 4

When there is insufficient oxygen supply to the cells (hypoxia), the cells begin to release growth factors that form gradients within the tissue that initiates new vessel sprouting. Reprinted and adapted with permission from Briquez, P.S. et al (2016) [76]. Copyright (2016) Springer Nature.

Figure 5

A visual overview of the gradient parameters for further research (created with BioRender.com; accessed on 20 May 2021).

Figure 6

Gradient-like distribution of VEGF-loaded strands (red) within the scaffold: (A) side view of the scaffold showing different densities of VEGF-loaded strands in each layer; (B) top view of the same scaffold. Reprinted with permission from Bittner, S.M. et al. (2018) [21]. Copyright (2018) Elsevier.

Figure 7

A visual comparison of bottom-up and top-down approaches in tissue engineering. In the bottom-up approach, ECs are seeded onto the microporous scaffold and the microvascular network is generated through vasculogenesis (including tubulogenesis) and angiogenesis. In the top-down approach, on the other hand, the scaffold with a specific network geometry is created using microfabricating techniques, with the aim of skipping the process of tubulogenesis [3] (created with BioRender.com; accessed on 6 April 2021).

Figure 8

A schematic showing two main mechanisms of vascularization: (A) vasculogenesis, a process of spontaneous blood vessel formation from EPCs, and (B) angiogenesis, the formation of new blood vessels from preexisting ones through vascular sprouting. Reprinted with permission from Cleaver, O. et al. (1999) [102]. Copyright (1999) Elsevier.

Figure 9

General overview of common approaches to additive manufacturing of scaffolds for tissue engineering: (A) inkjet-based bioprinting, (B) extrusion-based bioprinting, (C) laser-induced forward transfer, and (D) Stereolithography bioprinting [108,110]. Reprinted (adapted) from Creative Commons Attribution License CC BY 4.0.

Figure 10

Mathematically generated capillary networks with different geometries [120]. Reprinted (adapted) from Creative Commons Attribution License CC BY 4.0.

Figure 11

Visualization of the 3D microvasculature of the rat spinal cord by synchrotron radiation microcomputed tomography (SRµCT): (A) shows the transverse view and (B) shows the top view of the angioarchitecture [153]. Reprinted (adapted) from Creative Commons Attribution License CC BY 3.0.

Figure 12

A schematic showing the current state of the art in the field (left column) and the associated challenges for future research (right column); (created with BioRender.com; accessed on 20 May 2021).