BLOOD VESSEL REGENERATION - 3D Bioprinting and Nanotechnology in Tissue Engineering and Regenerative Medicine - page 147

(PDGF), transforming growth factor- b (TGF b ), and endothelial nitric oxide synthase (eNOS), can be
manipulated. These proteins and cytokines can be utilized to help with the endothelialization process
as well as maintain the implant integrity after implantation.
7.1.2 IMPORTANT PROTEINS FOR VASCULATURE
Platelet-derived growth factor is known to play a role in the regulation of cell growth and prolifera-
tion. Specifically, PDGF is important for angiogenesis and has been the focus of many tissue engi-
neering applications that wish to make use of existing vasculature to invade into a tissue-engineered
implant. PDGF can act as a chemoattractant for fibroblasts and influence the division of vascular
smooth muscle cells.
TGF b is involved in the production of ECM by modulating the production of elastin ( Sales
et al., 2006 ). Elastin itself has two main functions in the ECM. First, it is critical for the elastic proper-
ties of the blood vessel ( Kozel et al., 2011 ). The development of tissue-engineered materials or implants
that mimic the elastic properties is very difficult, but is absolutely necessary to prevent complications,
such as neointimal hyperplasia, which is generally caused by an elastic mismatch between the native
tissue and the implanted vascular graft ( Creager et al., 2012 ). The second function that elastin performs
is the sequestration and activation of secreted growth factors ( Creager et al., 2012 ). Therefore, the
presence of elastin at varying concentrations natively controls the activity of the proteins present in
the ECM and modulates their release.
Endothelial nitric oxide synthase (eNOS) is critical for the functioning of an intact endothelial
layer in blood vessels. It is involved in the generation of nitric oxide (NO) by endothelial cells, which
is important in the regulation of vascular resistance. NO produced by endothelial cells can cause the
relaxation of the smooth muscle cells surrounding the vasculature thereby resulting in vasodilatation.
However, if the endothelium is disrupted or damaged, the expression of eNOS is altered and vasocon-
striction can occur due to the decreased levels of NO. Additionally, the expression of eNOS can affect
vessel permeability through the levels of NO produced ( Dauphinee and Karsan, 2010 ).
Although there are many proteins and cytokines known to influence angiogenesis and vasculogen-
esis, the deposition of these proteins alone cannot guide the invasion of vasculature or generate new
vasculature. However, these proteins and others can be used in conjunction with materials and scaf-
folds designed for vascular regeneration. Traditionally, techniques such as electrospinning, molding,
and vapor deposition have been used to create the materials that these growth factors and signaling
molecules will be attached to for vascular applications ( Roy, 2010 ). There has, however, been a push
in the past several years to have more control over the surface topologies, the spatial organization of
these surface features and modifications, as well as the direct seeding of cells on the vascular implant.
As such, the goal of many tissue engineers is to develop a vascular implant that has tightly controlled
features and mechanical properties while at the same time has very heterogeneous properties to mimic
the native vasculature.
7.1.3 APPLICATION TO VASCULAR IMPLANTS
To accomplish this goal, many researchers have been investigating the application of additive manufac-
turing to create replacement vasculature. In the circulatory system there are many different components
that could be either replaced or mimicked using 3D printing. The three main classifications that we will
discuss here are: the arteries, which provide flow to the tissue; veins, which provide a return flow from