Tissue Engineering of the Microvasculature

Abstract

The ability of generate new microvessels in desired numbers and at desired locations has been a long-sought goal in vascular medicine, engineering, and biology. Historically, the need to revascularize ischemic tissues non-surgically (so-called therapeutic vascularization) served as the main driving force for the development of new methods of vascular growth. More recently, vascularization of engineered tissues and the generation of vascularized microphysiological systems have provided additional targets for these methods, and have required adaptation of therapeutic vascularization to biomaterial scaffolds and to microscale devices. Three complementary strategies have been investigated to engineer microvasculature: angiogenesis (the sprouting of existing vessels), vasculogenesis (the coalescence of adult or progenitor cells into vessels), and microfluidics (the vascularization of scaffolds that possess the open geometry of microvascular networks). Over the past several decades, vascularization techniques have grown tremendously in sophistication, from the crude implantation of arteries into myocardial tunnels by Vineberg in the 1940s, to the current use of micropatterning techniques to control the exact shape and placement of vessels within a scaffold. This review provides a broad historical view of methods to engineer the microvasculature, and offers a common framework for organizing and analyzing the numerous studies in this area of tissue engineering and regenerative medicine.

Microvascular Tissue Engineering—A Review

“…VEGF, the main endothelial growth factor, and other angiogenic growth factors, such as fibroblast growth factors (FGF, released by fibroblasts) and angiopoietin 1 (Ang-1, released by smooth muscle cells), are the major stimulating factors for the development of new blood vessels [ 3 , 77 , 78 ]. Different combinations of growth factors have been shown to influence tissue development by affecting the number of vascular branches, branch length, diameter, and vascularized area [ 55 ].…”

“…With this approach, vascular development can closely mimic in vivo conditions. However, the process cannot be (easily) controlled, and such 3D constructs are unlikely to be sufficiently perfused [ 3 , 100 ]. We discuss this approach in more detail in Section 3.1 .…”

“…The other, the “top-down” approach, involves seeding ECs into separately microfabricated scaffolds with specific geometries and dimensions [ 100 ]. The underlying motivation is to skip the process of tubulogenesis or lumen formation that is required in the vasculogenic and angiogenic approaches [ 3 ]. Furthermore, the advantage of this approach also lies in the possibility to precisely control the vessel diameter and tightness of EC junctions by applying different flow parameters (e.g., shear stress) [ 100 ].…”

“…Vascularization through a bottom-up approach is achieved by two different processes—vasculogenesis, which is the de novo assembly of endothelial progenitor cells that canalize into capillaries, and angiogenesis, the sprouting of new vessels from existing blood vessels. Since these processes are relatively slow, different growth factors are used to stimulate and accelerate vessel ingrowth [ 3 , 101 ]. Both processes are visually represented in Figure 8 below.…”

“…Blood vessels are often considered a uniform part of the circulatory system, maintaining a homeostatic environment in the tissues by supplying oxygen and nutrients and removing metabolic byproducts [ 1 , 2 ]. However, while the function of large vessels is conducting fluid through the body, microvasculature also enables the exchange of substances between the vascular lumen and the surrounding tissue [ 3 ]. Albeit there is no universal definition of microvasculature, it can best be described as a system of small diameter vessels (usually less than 100 µm) that exhibit a high surface-area-to-volume ratio and enable rapid exchange of fluid, solutes, and cells across the endothelial layer [ 3 ].…”