Tissue Engineering: Focus on the Cardiovascular System - Biomaterials Science: An Integrated Clinical and Engineering Approach - page 179

hESC-CMs, endothelial cells, and embryonic fibroblasts results in increased
graft vascularization (Figure 8.2c, d) and in anastomosis of the pre-existing
human vessels with host rat vascular networks.
In-vivo Prevascularization Protocols
In-vivo prevascularization protocols recruit the body as a bioreactor for
induction of construct vascularization in vivo. Constructs are implanted into
environments rich in vascular supply (intra-abdominal, subcutaneous, or
intramuscular regions), where they can be invaded with newly formed vas-
cular networks. Within a few days of implantation, host-derived blood vessels
penetrate the graft, forming a stable and functional vascular network within
the construct. Subsequently, the vascularized constructs are transferred into
infarcted hearts to determine functionality. In a recent work pioneered by
Dvir et al. [132], a cardiac patch was first engineered in vitro and then vascu-
larized upon implantation onto the omentum, a blood vessel-enriched region.
After graft vascularization and subsequent implantation into infracted hearts,
the cardiac patches underwent structural and electrical coupling with the host
myocardium, leading to beneficial effects on both systolic and diastolic left
ventricular function. The arteriovenous loop (AV loop), another attractive
in-vivo configuration model, has been employed to prevascularize cardiac
patches as well. In this model, intrinsic vascularization is induced in an iso-
lated and protected space, created by a polycarbonate chamber in which a
macrovascular arteriovenous shunt loop (AVL) is enclosed [133], and has been
successfully applied toward production of contractile 3D cardiac tissue [134].
For this purpose, neonatal cardiac myocytes embedded within fibrin gel were
cultured in vivo in silicone chambers in proximity to the femoral artery and
vein of adult rats. At 3 weeks post-transplantation, cardiac cells were found
to be organized, vascularized, and functional within the chambers. In a sub-
sequent publication, Morritt et al. successfully designed thick, vascularized
cardiac tissue constructs (maximum thickness of ~2 mm) by placing an AV
loop inside a semi-sealed polycarbonate chamber later implanted into the
groin of a rat [135]. The chamber was seeded with cardiomyocytes in matrigel
and contained differentiated, spontaneously contracting cardiomyocytes and
abundant vascularization within a few weeks of implantation.
GF-Induced Vascularization
Scaffolds designed to release one or a combination of angiogenic GFs have
proven an exciting strategy for vascularization induction both in vitro and
in vivo. GFs, such as VEGF, PDGF, angiopoietin, and FGF, all critical to
angiogenesis [136], all present a unique platform for accelerating vascular-
ization. GFs can be incorporated into scaffolds by their simple addition to
scaffold polymer solutions, or can be encapsulated in microspheres to enable
sustained and controlled release. Administration of multiple GFs has been