implanted cells, loss of intracellular communication between CMs and ECM, acute
inflammation and injury caused by injection procedure and blockage of the
microcirculatory network by the injected cells. Some studies even reported negative
effect of cardiomyoplasty, resulting in arrhythmias due to inappropriate electrical
integration. Thus, in vitro developed cardiac tissue constructs, seeded with stem
cells or their progenitors, were explored as alternative options. Since then, the field
of CTE exponential advanced with advancements in the design and development of
ECM-mimicking scaffolds, efficient perfusion bioreactors and, newer sources of
stem cells, and advanced analytical techniques. This book chapter summarises
various approaches for CTE and the role of natural biomaterials in fabricating the
scaffolds for seeding of stem cells.
18.2 Approaches for CTE Using Natural Biomaterials,
Cell-Sheet and Decellularized Tissues
In ‘classical’ CTE, cardiac tissue construct is created by seeding desired cells into
biomaterial-derived scaffolds. The scaffolds are initially fabricated, without cells,
using natural or synthetic or hybrid biomaterials and, the cells are then seeded into
the scaffold. The scaffolds are expected to allow neovascularisation, neuronal
innervations and electromechanical cell coupling with host myocardium following
their transplantation into the host. In order to achieve these characteristics, several
modifications such as incorporation of growth factors and pro-angiogenic factors,
co-culturing of CMs with other cell types etc. are often required to further improve
the survival of the tissue construct (Fig. 18.1). The scaffolds are traditionally fabricated using natural biomaterials such as alginate, chitosan, collagen, fibrin, gelatin,
and glycosaminoglycan, fibronectin, laminin, nephronectin. Many natural polymers
have low elastic modulus and poor electrical conductivity required for the CTE and
necessitates doping with synthetic biomaterials or nanomaterials such as carbon
nanofibers to develop a conductive scaffold (Martins et al. 2014). Natural biomaterials such as gelatine, collagen, fibronectin, laminin, stromal-derived factor-1,
nephronectin, and bioactive glass etc. are also used to bio-functionalize the synthetic
biomaterials-derived scaffolds to enhance cell adhesion, cell-to-cell communication
and cellular interaction with scaffold (Oliver et al. 2019; Yang et al. 2018).
In a newer development, engineered heart tissue (EHT) were created by seeding
CMs into collagen I and Matrigel™ (an extracellular matrix compound derived
from Engelbreth-Holm-Swarm mouse sarcoma) matrix followed by mechanical
stretching into circular form (Yildirim et al. 2007). Guo et al. generated embryonic
stem cell (ESC)-derived myocardium in mouse wherein CMs were seeded into
circular moulds with collagen I and Matrigel™ to produce EHT, which were
subsequently subjected to unidirectional cyclic stretch at 10% strain and 2 Hz (Guo
et al. 2006). Transplantation of the EHT improved ventricular function in MI model
but formed transmural thrombus in a heterotropic heart transplant model
(Zimmermann et al. 2006).
18 Cardiac Tissue Engineering: A Role for Natural Biomaterials
619
inflammation and injury caused by injection procedure and blockage of the
microcirculatory network by the injected cells. Some studies even reported negative
effect of cardiomyoplasty, resulting in arrhythmias due to inappropriate electrical
integration. Thus, in vitro developed cardiac tissue constructs, seeded with stem
cells or their progenitors, were explored as alternative options. Since then, the field
of CTE exponential advanced with advancements in the design and development of
ECM-mimicking scaffolds, efficient perfusion bioreactors and, newer sources of
stem cells, and advanced analytical techniques. This book chapter summarises
various approaches for CTE and the role of natural biomaterials in fabricating the
scaffolds for seeding of stem cells.
18.2 Approaches for CTE Using Natural Biomaterials,
Cell-Sheet and Decellularized Tissues
In ‘classical’ CTE, cardiac tissue construct is created by seeding desired cells into
biomaterial-derived scaffolds. The scaffolds are initially fabricated, without cells,
using natural or synthetic or hybrid biomaterials and, the cells are then seeded into
the scaffold. The scaffolds are expected to allow neovascularisation, neuronal
innervations and electromechanical cell coupling with host myocardium following
their transplantation into the host. In order to achieve these characteristics, several
modifications such as incorporation of growth factors and pro-angiogenic factors,
co-culturing of CMs with other cell types etc. are often required to further improve
the survival of the tissue construct (Fig. 18.1). The scaffolds are traditionally fabricated using natural biomaterials such as alginate, chitosan, collagen, fibrin, gelatin,
and glycosaminoglycan, fibronectin, laminin, nephronectin. Many natural polymers
have low elastic modulus and poor electrical conductivity required for the CTE and
necessitates doping with synthetic biomaterials or nanomaterials such as carbon
nanofibers to develop a conductive scaffold (Martins et al. 2014). Natural biomaterials such as gelatine, collagen, fibronectin, laminin, stromal-derived factor-1,
nephronectin, and bioactive glass etc. are also used to bio-functionalize the synthetic
biomaterials-derived scaffolds to enhance cell adhesion, cell-to-cell communication
and cellular interaction with scaffold (Oliver et al. 2019; Yang et al. 2018).
In a newer development, engineered heart tissue (EHT) were created by seeding
CMs into collagen I and Matrigel™ (an extracellular matrix compound derived
from Engelbreth-Holm-Swarm mouse sarcoma) matrix followed by mechanical
stretching into circular form (Yildirim et al. 2007). Guo et al. generated embryonic
stem cell (ESC)-derived myocardium in mouse wherein CMs were seeded into
circular moulds with collagen I and Matrigel™ to produce EHT, which were
subsequently subjected to unidirectional cyclic stretch at 10% strain and 2 Hz (Guo
et al. 2006). Transplantation of the EHT improved ventricular function in MI model
but formed transmural thrombus in a heterotropic heart transplant model
(Zimmermann et al. 2006).
18 Cardiac Tissue Engineering: A Role for Natural Biomaterials
619