163
6.6.4 Electrical and Mechanical Stimulation
Electrical and mechanical stimulation applied in culture can have a significant
impact on the maturation of CMs and the development of vasculature in tissue-engineered constructs. In the development of engineered cardiac tissues that recapitulate
the behavior of native myocardium, the ability to control the cellular environment
and apply external stimuli is very important. Therefore, significant investment has
been made in developing devices capable of reliably applying electrical and mechanical stimulation to these tissues and investigating optimal stimulation for cardiac
development and angiogenesis.
6.6.5 Electrical Stimulation
Electrical forces play a key role in cardiac development, as spontaneous electrical
activity begins in what will become the sinoatrial node as early as 20 days after
fertilization [44]. Electrical stimulation has proven a useful tool in cardiac tissue
engineering. Radisic and colleagues showed that applying electrical pulses at 1 Hz
to cardiomyocyte-laden hydrogels resulted in improved CM alignment, a 50%
increase in maximum capture rate, a threefold increase in gap junctions, and a
fourfold increase in the fractional change in the surface area of the construct
induced by each beat, suggesting increases in electrical coupling, electromechanical coupling, and force of contraction [93]. It has since been demonstrated that a
±2.5 V biphasic pulse, applied at 1 Hz, can drive progenitor cells toward cardiomyocyte lineages. This is evidenced by increases in cell length and alignment,
along with increased expression of GATA-4, Cx43, and troponin T apparent after
only 1 day of stimulation [89]. It has also been suggested that “electrical conditioning” can help establish automaticity in CMs, since the cultures electrically paced
for 7 days displayed autonomous beating at the stimulated rate, even after the stimulus has been removed [27].
Electrical activity certainly has some effect on vasculature, as sympathetic nervous signaling is an important regulator of vascular tone. Sub-millisecond, 250 V
electrical pulses applied at 10 Hz have been shown to cause vascular contraction in
less than 10 s and reduces blood loss in models of acute traumatic injury [75].
However, the effects of electrical stimulation on endothelial cells and angiogenesis
are more poorly understood. Various kinds of electrical stimulation have been shown
to increase angiogenesis in a wide array of settings, including diabetic ischemia and
neural progenitor cell treatment for ischemic stroke [5, 36]. These effects are
believed to be primarily mediated by upregulation of VEGF in other cell types, as
opposed to acting directly on endothelial cells [40], though there is some evidence
that direct current electrical stimulation can upregulate VEGF receptors on endothelial cells, essentially priming them for biochemical stimulation [4, 141].
6 Strategies for Tissue Engineering Vascularized Cardiac Patches to Treat Myocardial…
6.6.4 Electrical and Mechanical Stimulation
Electrical and mechanical stimulation applied in culture can have a significant
impact on the maturation of CMs and the development of vasculature in tissue-engineered constructs. In the development of engineered cardiac tissues that recapitulate
the behavior of native myocardium, the ability to control the cellular environment
and apply external stimuli is very important. Therefore, significant investment has
been made in developing devices capable of reliably applying electrical and mechanical stimulation to these tissues and investigating optimal stimulation for cardiac
development and angiogenesis.
6.6.5 Electrical Stimulation
Electrical forces play a key role in cardiac development, as spontaneous electrical
activity begins in what will become the sinoatrial node as early as 20 days after
fertilization [44]. Electrical stimulation has proven a useful tool in cardiac tissue
engineering. Radisic and colleagues showed that applying electrical pulses at 1 Hz
to cardiomyocyte-laden hydrogels resulted in improved CM alignment, a 50%
increase in maximum capture rate, a threefold increase in gap junctions, and a
fourfold increase in the fractional change in the surface area of the construct
induced by each beat, suggesting increases in electrical coupling, electromechanical coupling, and force of contraction [93]. It has since been demonstrated that a
±2.5 V biphasic pulse, applied at 1 Hz, can drive progenitor cells toward cardiomyocyte lineages. This is evidenced by increases in cell length and alignment,
along with increased expression of GATA-4, Cx43, and troponin T apparent after
only 1 day of stimulation [89]. It has also been suggested that “electrical conditioning” can help establish automaticity in CMs, since the cultures electrically paced
for 7 days displayed autonomous beating at the stimulated rate, even after the stimulus has been removed [27].
Electrical activity certainly has some effect on vasculature, as sympathetic nervous signaling is an important regulator of vascular tone. Sub-millisecond, 250 V
electrical pulses applied at 10 Hz have been shown to cause vascular contraction in
less than 10 s and reduces blood loss in models of acute traumatic injury [75].
However, the effects of electrical stimulation on endothelial cells and angiogenesis
are more poorly understood. Various kinds of electrical stimulation have been shown
to increase angiogenesis in a wide array of settings, including diabetic ischemia and
neural progenitor cell treatment for ischemic stroke [5, 36]. These effects are
believed to be primarily mediated by upregulation of VEGF in other cell types, as
opposed to acting directly on endothelial cells [40], though there is some evidence
that direct current electrical stimulation can upregulate VEGF receptors on endothelial cells, essentially priming them for biochemical stimulation [4, 141].
6 Strategies for Tissue Engineering Vascularized Cardiac Patches to Treat Myocardial…