159
[96, 116, 128]. Recently, fibrin was electrospun into microfibers. Electrospun
microfibers offer the added advantage of tunable mechanical properties and alignment cues, which is critical for myocardial tissue [140]. Other groups initiated a
bilayer scaffold approach, which includes culturing cardiomyocyte gels and vascular gels both independently and in combination for therapy [101].
Decellularized matrices are also attractive for the development of tissues because
they utilize nature’s platform. Most recently, the Gaudette group developed vascularized cardiac tissue on a decellularized spinach leaf. The spinach leaf was specifically used because it possesses an intrinsic network that could be used for the
development of dense vessel networks alongside contractile cardiomyocytes [37].
Other groups have decellularized rat, porcine, and human myocardium and reseeded
them with cardiomyocytes and endothelial cells [86]. Currently, the drawbacks to
decellularized matrix are the reseeding efficiency and that the detergents used to
decellularize can alter the stiffness of the matrix.
6.6 Biophysical Cues
Cellular behavior is strongly influenced by the properties of the cells’ microenvironment. Hence, tissue engineering strategies aim to tightly regulate the biochemical,
mechanical, and electrical cues experienced by cells, to influence cell- and tissuelevel behaviors. However, the ideal microenvironment for cardiac development is
not necessarily conducive to angiogenesis and vice versa. This discord presents a
challenge in the engineering of tissues with both mature cardiac function and functional vasculature and necessitates a firm understanding of how environmental
factors contribute to each process.
6.6.1 Biochemical Cues
Embryological studies have proven that cardiac development relies heavily on the
biochemical makeup of its surroundings, as small variations in localization, timing,
or concentration of certain signaling molecules can result in hugely consequential
cardiac defects. The earliest stage of cardiogenesis, the formation of cardiac progenitor cells, relies on nodal, a cytokine in the TGF-β family [11]. Wnt/β-catenin
and bone morphogenic protein (BMP) signaling also play critical roles in early differentiation by facilitating the proliferation of cardiac progenitors, although evidence suggests that both factors can exert an inhibitory effect on terminal cardiac
differentiation [60, 61, 83, 137]. These embryological revelations have yielded a
variety of approaches to promote myocardial differentiation in pluripotent cells, the
most efficient of which rely on modulating Wnt, BMP, and fibroblast growth factor
(FGF) signaling, with small molecule regimens [68]. In a widely cited report,
6 Strategies for Tissue Engineering Vascularized Cardiac Patches to Treat Myocardial…
[96, 116, 128]. Recently, fibrin was electrospun into microfibers. Electrospun
microfibers offer the added advantage of tunable mechanical properties and alignment cues, which is critical for myocardial tissue [140]. Other groups initiated a
bilayer scaffold approach, which includes culturing cardiomyocyte gels and vascular gels both independently and in combination for therapy [101].
Decellularized matrices are also attractive for the development of tissues because
they utilize nature’s platform. Most recently, the Gaudette group developed vascularized cardiac tissue on a decellularized spinach leaf. The spinach leaf was specifically used because it possesses an intrinsic network that could be used for the
development of dense vessel networks alongside contractile cardiomyocytes [37].
Other groups have decellularized rat, porcine, and human myocardium and reseeded
them with cardiomyocytes and endothelial cells [86]. Currently, the drawbacks to
decellularized matrix are the reseeding efficiency and that the detergents used to
decellularize can alter the stiffness of the matrix.
6.6 Biophysical Cues
Cellular behavior is strongly influenced by the properties of the cells’ microenvironment. Hence, tissue engineering strategies aim to tightly regulate the biochemical,
mechanical, and electrical cues experienced by cells, to influence cell- and tissuelevel behaviors. However, the ideal microenvironment for cardiac development is
not necessarily conducive to angiogenesis and vice versa. This discord presents a
challenge in the engineering of tissues with both mature cardiac function and functional vasculature and necessitates a firm understanding of how environmental
factors contribute to each process.
6.6.1 Biochemical Cues
Embryological studies have proven that cardiac development relies heavily on the
biochemical makeup of its surroundings, as small variations in localization, timing,
or concentration of certain signaling molecules can result in hugely consequential
cardiac defects. The earliest stage of cardiogenesis, the formation of cardiac progenitor cells, relies on nodal, a cytokine in the TGF-β family [11]. Wnt/β-catenin
and bone morphogenic protein (BMP) signaling also play critical roles in early differentiation by facilitating the proliferation of cardiac progenitors, although evidence suggests that both factors can exert an inhibitory effect on terminal cardiac
differentiation [60, 61, 83, 137]. These embryological revelations have yielded a
variety of approaches to promote myocardial differentiation in pluripotent cells, the
most efficient of which rely on modulating Wnt, BMP, and fibroblast growth factor
(FGF) signaling, with small molecule regimens [68]. In a widely cited report,
6 Strategies for Tissue Engineering Vascularized Cardiac Patches to Treat Myocardial…