Tissue Engineering: Focus on the Cardiovascular System - Biomaterials Science: An Integrated Clinical and Engineering Approach - page 175

at body temperature, assume the infarcted zone geometry, and provide a
matrix for cell retention, migration, proliferation, and neovascularization
in vivo. The Leor and Cohen groups [105, 106] have been pioneers in the
use of injectable alginate hydrogels for repair of infarcted myocardium,
and have demonstrated improved rat cardiac function upon its delivery to
the heart [105]. More recently, these researchers reported reversed left ven-
tricular enlargement and increased scar thickness [106] upon intracoronary
injection of alginate biomaterial into the swine heart. Kofidis and colleagues
[107] successfully delivered mESCs by injectable matrigel to the infarcted
mouse heart and observed enhanced heart functioning when compared
with controls animals. In parallel, Lu et al. [108] considered an injectable,
temperature-sensitive chitosan hydrogel for delivery of mESCs to the
infarcted rat heart and reported effective cell transfer that correlated with
improved cardiac functioning.
Biomaterial-“Free” Tissue Engineering
Cell Aggregation
As biomaterials can introduce undesirable and/or toxic by-products, stim-
ulate unfavorable host responses, or interrupt critical cell-cell interactions,
biomaterial-free tissue engineering techniques, employing only cells and
their naturally secreted ECM for development of 3D tissues, have been
attracting much attention [109]. Murry et al . have practiced this method
in creating human cardiac patches of fully controllable sizes, formed by
forcing hES-CM cells to aggregate within a rotating shaker [109]. Cardiac
populations became increasingly enriched with mature CMs over time,
and the addition of endothelial and fibroblast cells led to enhanced in
vitro performance (higher force generation), and to improved rat heart
engraftment outcomes, as determined by graft sizes and viability after
transplantation [110].
Cell Sheets
The cell sheet biomaterial-free tissue engineering approach, first described
in 2002 by Shimizu et al. [111, 112], can be implemented toward preparation
of 3D cardiac tissue by harvesting confluent CM layers from culture dishes
and then laying them one over another to form 3D cardiac tissue. This pro-
cess utilizes temperature-sensitive cell culture dishes made of poly( N -iso-
propylacrylamide) (PIPAAm), which become hydrophilic and non-adhesive
at reduced temperatures. Alternatively, stimulation of protease activity can
induce detachment of whole cell layers. This approach to construct genera-
tion preserves critical cell-to-cell contacts, maintains expression of adhesion
proteins, and stimulates secretion of extracellular matrix components nat-
ural to the tissue, but lacks the mechanical stiffness required for mainte-
nance of physiological conditions. Cardiomyocyte sheets have been reported