Nanotechnology and Cardiovascular Tissue Engineering - Stem-Cell Nanoengineering - page 272

integrity of the forming tissue and supporting an in vivo like mechanotransduction between
cells and their environment [20].
Hydrogels and porous polymers have been used successfully as scaffolds for many cardiac
tissue-engineering applications due to their mechanical and cell-viability properties.
Hydrophilic hydrogel environments are advantageous for maintaining cardiac-cell viability
and achieving even cell distributions in engineered cardiac tissues [21, 22]. Zimmerman et al.
(2002) have established a simple and effective system for mechanical conditioning of cardio-
myocytes encapsulated in ring-shaped hydrogels made of a mixture of collagen and Matrigel.
The study has shown considerable functional improvements in cardiomyocyte morphology
and mitochondrial density, leading to a more mature cardiac muscle structure [23]. Cardiac
cells can also be seeded on porous polymer support structures or scaffolds for added
mechanical strength, both with and without hydrogels for improved cell retention. Other
types of scaffolds used for heart tissue engineering are fibrous scaffolds and microsphere-
based scaffolds. These will be discussed in the subsequent sections.
Vascular Tissue Engineering
Coronary vasculogenesis is closely coordinated and is known to precede cardiac myogenesis
during mammalian development. In native cardiac tissue, capillaries are spaced at an average
distances of about 20 μm such that each myofiber is located between two capillaries [24]. The
need to supply sufficient oxygen and nutrients to engineered tissues has aggravated various
strategies to promote blood vessel formation, including: (i) cell tri-culture; (ii) use of growth
factors and peptides; and (iii) engineering of novel proangiogenic scaffolds. In cell tri-culture
model, pretreatment with cardiac fibroblasts has been proved to be effective in improving
survival of subsequently seeded cardiomyocytes and the functional properties of the
engineered heart tissue [25]. Initiation of prevascular networks by sandwiching endothelial
cells (ECs) between cardiac cell sheets has also been achieved. These vascular structures are
connected to the host vessels and enable improved sheet vascularization upon implantation
in an in vivo myocardial infarction model [26]. Another approach includes incorporation of
angiogenic growth factors, such as vascular endothelial growth factor (VEGF), into bioma-
terials for tissue engineering. Current delivery strategies include soluble factors, microparti-
cles, as well as physical and covalent immobilization. Release of multiple growth factors
from microparticles is required to achieve stable vasculature and homing of intravenously
administered progenitors [27, 28]. Small peptides and molecules such as thymosin β4 or
ascorbic acid can also be utilized to enhance angiogenesis [29, 30]. A comprehensive
understanding of vasculogenic factors and subsets of progenitor cells may help coordinate
cardiac myogenesis and vasculogenesis in an engineered heart patch.
Nanotechnology and Cardiovascular Tissue Engineering
Exhilarating advances in tissue engineering and regenerative medicine allow us to envision
in vitro creation or in vivo regeneration of cardiovascular tissues. Such accomplishments
have the potential to revolutionize medicine and greatly improve our standard of life.
However, enthusiasm has been hampered in recent years because of low success rates and
abnormal reactions at the implant-host interface, including cell proliferation, fibrosis,
calcification, degeneration, and apoptosis as compared to the highly desired healing and
remodeling. Animal and clinical studies have highlighted chronic inflammation and lack of
functional integration of the transplanted implant with the host structures as the main