Heart Failure Reviews (2021) 26:1231–1248

https://doi.org/10.1007/s10741-020-09953-9

Extracellular matrix–based biomaterials for cardiac

regeneration and repair
Haotong Li 1 & Minghui Bao 2 & Yu Nie 1

Published online: 18 April 2020

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
The spectrum of ischemic heart diseases, encompassing acute myocardial infarction to heart failure, represents the leading cause
of death worldwide. Although extensive progress in cardiovascular diagnoses and therapy has been made, the prevalence of the
disease continues to increase. Cardiac regeneration has a promising perspective for the therapy of heart failure. Recently,
extracellular matrix (ECM) has been shown to play an important role in cardiac regeneration and repair after cardiac injury.
There is also evidence that the ECM could be directly used as a drug to promote cardiomyocyte proliferation and cardiac
regeneration. Increasing evidence supports that applying ECM biomaterials to maintain heart function recovery is an important
approach to apply the concept of cardiac regenerative medicine to clinical practice in the future. Here, we will introduce the
essential role of cardiac ECM in cardiac regeneration and summarize the approaches of delivering ECM biomaterials to promote
cardiac repair in this review.

Keywords Cardiac regeneration . Extracellular matrix . Cardiac injury . Myocardial infarction . Heart failure . Tissue engineering

Introduction
Ischemic heart disease is the leading cause of death and more
than 8.9 million individuals died of ischemic heart disease
globally in 2015 [1]. The rate of death of ischemic heart dis-
ease has steadily declined since 1960s due to great attention to
primary prevention and significant advances in medical, sur-
gical, and interventional therapies [2]. However, the heart
function of most cardiovascular disease patients is impaired
with cardiomyocyte loss and cardiac injury, which is the fun-
damental cause of heart failure [3]. There is no effective
* Yu Nie
nieyu@fuwaihospital.org
Haotong Li
lihaotongdoc@163.com
Minghui Bao
baominghui@mail.ccmu.edu.cn
1
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital,
National Center for Cardiovascular Disease, Chinese Academy of
Medical Sciences and Peking Union Medical College,
Beijing 100037, China
2
Department of Cardiology, Peking University First Hospital,
Beijing, China
treatment for heart failure besides left ventricular assist device
and heart transplantation. Promoting cardiomyocyte prolifer-
ation and heart regeneration will be a promising approach to
intervene heart failure and improve the prognosis of ischemic
heart disease in the future. Recently, with the role of extracel-
lular matrix (ECM)–oncogenic signalling emerging [4], the
clinical operating systems for heart regeneration and cardiac
repair begin to turn to the “Matrix Medicine” [5].
The ECM is essential for cells to connect and communicate
with each other. Previous studies have emphasized the func-
tional role of the ECM primarily in cell junction and tissue
structure organization; nevertheless, emerging studies have
revealed that the ECM can actively participate in intercellular
signalling [6, 7]. Tissue repair and regeneration after injury are
highly influenced by cytokines, proteases, and communica-
tion between different kinds of cells. The ECM contains many
signalling molecules that are essential for cell behaviors, in-
cluding growth, polarity, migration, differentiation, and pro-
liferation [4, 8]. Under physiological conditions, the ECM
components in mammals have been proven to be well con-
served while the proportion of each component changes with
development [9]. Once the tissue is injured, for example, myo-
cardial infarction (MI) or heart apical resection, the cardiac
ECM is likely to undergo temporal and spatial dynamic
changes, and as a result, substantial distinctions may occur
compared with an uninjured heart [10]. ECM can affect cell
1232
function; in turn, the phenotypic and functional changes of the
cell will enhance or attenuate the synthesis and secretion pro-
cedures of some ECM components and result in ECM remod-
elling. The bidirectional information flow between the ECM
and the cell within them indicates that the ECM can be
regarded as an information storage medium. Therefore, a
growing number of ECM reprogramming strategies have been
applied to tissue engineering and regenerative medicine which
could be used to treat multiple disorders, such as MI.
In this review, we introduce the composition of cardiac
ECM and focus on the topic of ECM in cardiac regeneration
and repair. We also summarize the delivery strategies of ECM-
based biomaterials for tissue engineering, which is essential
for the development of ECM-based biomaterials in the medi-
cine of heart regeneration and cardiac repair.
Cardiac ECM
Cardiac ECM in physiological conditions
The cardiac ECM is made up of proteins and polysaccharides
which can be further divided into three components: glyco-
proteins, proteoglycans, and glycosaminoglycans. The com-
ponents of these groups are all proteins decorated by glycosyl
groups. Glycoproteins include fiber proteins, fibronectin, lam-
inin, and prototypical matricellular proteins, such as periostin.
Different components play different roles in the cardiac ECM.
Two of the fiber proteins, collagen and elastin, are important
for the architectural structure of cardiac ECM [11]. Fibrillar
collagen accounts for the largest proportion of proteins in the
cardiac ECM. Cardiac collagens predominantly consist of
type I and type III collagens. Type I collagens are the major
structural component of the cardiac interstitium, accounting
for more than 80% of the collagenous matrix, while type III
collagens constitute less than 10%, and type VI collagens
comprise approximately 5% [12]. Compared with type I and
type III collagens, which are highly prevalent in the epimysi-
um and endomysium, respectively, type VI collagens and fi-
bronectin surround cells in the terminal aspects of the network
[12, 13]. Fibronectin can also support the ECM structure and
plays non-structural roles; for example, it is strongly associat-
ed with cell adhesion and migration, which are essential for
cell behaviors in embryogenesis and wound healing.
Knockout of the fibronectin (Fn1) gene resulted in early em-
bryonic lethality due to failure to form a heart tube [14].
Importantly, fibronectin can specifically bind to many cellular
or ECM molecules. This special function allows bidirectional
communication between cells and cardiac ECM. While the
role of matrix networks in maintaining ventricular morpholo-
gy, providing structural support, and facilitating force delivery
is intuitive, it can also transduce critical signals necessary for
cardiac cell function. Previous studies have shown that
Heart Fail Rev (2021) 26:1231–1248
periostin is required for maturation of the heart and stabiliza-
tion of the cardiac ECM. The majority of periostin knockout
mice survived well into adulthood whereas approximately
14% died before weaning due to cardiac architectural and
valvular anomalies [15].
Cardiac ECM in post-infarction conditions
ECM changes dynamically after MI which plays a critical role
in cardiac repair and regeneration [16–18]. Compared with
those in healthy heart tissue, many components of the cardiac
ECM of the infarction zone, particularly collagens, increase
with the progress of cardiac remodelling and lead to functional
adaptation [16]. The remodelling of the ECM is described
below in chronological order after MI.
Myocardial injury causes rapid activation of neutrophil and
macrophage infiltrate into the heart during the first days after
MI. Inflammatory mediators stimulate neutrophils and macro-
phages to produce and secrete matrix metalloproteinases
(MMPs), which subsequently play enzymatic roles in
degrading substrates [19]. For example, MMP9, the most
widely studied MMP, can proteolyze ECM components such
as collagen, fibronectin, osteopontin, tenascin C, and
thrombospondin 1 [19]. After MI, VEGF increases vascular
permeability and leads to extravasation of plasma fibrinogen
and fibronectin, forming a complex dynamic fibrin matrix
network [20]. In addition to its hemostatic role, the provisional
ECM may act as a scaffold for migrating inflammatory cells to
support the proliferation of endothelial and fibroblast cells
[10]. The provisional ECM may also serve as a reservoir for
cytokines and growth factors and play an important role in the
transition from the cardiac repair to the proliferative phase.
Then, plasma-derived ECM is phagocytosed by recruited
macrophages and replaced by fibronectin, hyaluronan, lami-
nin, and matricellular macromolecules secreted by fibroblasts
and macrophages that make up cell-derived ECM [20].
ECM remodelling is beneficial for structural repair, func-
tional adaptation, and preventing ventricular rupture.
However, excessive deposition of cell-derived ECM causes
impaired cardiac function [21]. Therefore, the balance be-
tween ECM degradation and deposition is critical for cardiac
repair. In the later phases of cardiac repair, many collagen
fibers are deposited in the infarcted area and scar maturation
occurs as a consequence of ECM cross-linking [22].
Additionally, some ECM components may not provide
structural support, but instead impact cellular phenotypes
and functions by regulating cytokines and growth factors
[23–25]. Osteopontin can prevent ventricular aneurysm and
ventricular dilatation by promoting ECM deposition [23].
SPARC has been shown to prevent heart rupture and heart
failure after infarction by activating growth factor signalling
to promote collagen maturation [24]. Selective endogenous
matricellular protein thrombospondin 1 (TSP-1) expression
Heart Fail Rev (2021) 26:1231–1248
in the border zone of the MI may act as a barrier to protect
non-infarcted myocardium from fibrotic remodelling by ac-
tivating anti-inflammatory signalling pathways [25]. After
various changes in ECM remodelling, upregulated collage-
nous proteins and matricellular proteins ultimately lead to
extensive myocardial fibrosis.
The relationship between ECM and cardiac
regeneration
Lower vertebrates such as salamander or zebrafish, upon in-
jury (amputation or apical resection), are able to achieve com-
plete regeneration, namely, the reconstruction of normal mor-
phological structure and function [26, 27]. However, mamma-
lian hearts cannot regenerate in adults but can regenerate
completely with cardiomyocyte proliferation in neonates after
cardiac injury [28]. It is generally accepted that the mamma-
lian heart regenerative capacity is gradually lost with postnatal
development. Therefore, in addition to learning from the re-
generation processes of lower vertebrates, the research strate-
gy in the field of heart regeneration is to uncover the differ-
ences between neonates and adults, and to analyze the contri-
bution of differentially expressed elements. One study com-
pared the composition and proportion of fetal, neonatal, and
adult rat cardiac ECM by using liquid chromatography–
tandem mass spectrometry. The results showed that collagen
I, collagen III, and laminin increased gradually, while fibro-
nectin and periostin decreased with development [29]. These
findings suggested that ECM components change during heart
development processes and may play essential roles in the
regulation of the regenerative capacity of cardiomyocytes
(Fig. 1). One notable question is whether ECM is the key for
cardiac regeneration.
Fibronectin, a core ECM component, is predominantly
synthesized and secreted by epicardial cells dynamically after
cardiac injury in zebrafish and plays an important role in car-
diac regeneration [30]. Although loss-of-function experiments
in zebrafish showed that fibronectin is necessary for cardiac
regeneration by mobilizing and integrating cardiomyocytes
Fig. 1 The role of the
extracellular matrix in heart
regeneration. The schematic
shows the significantly increased
or decreased extracellular matrix
components with the
development of mouse
1233
into the injured region, there is no evidence that fibronectin
could promote cardiomyocyte proliferation [30]. Co-culture
of mammalian embryonic cardiac fibroblasts and
cardiomyocytes can promote cardiomyocyte proliferation,
and fibronectin secreted by embryonic mouse cardiac fibro-
blasts plays a pro-proliferative role in this process [31]. In
contrast, knockdown of fibronectin expression in embryonic
cardiac fibroblasts impaired cardiomyocyte proliferation [31].
The mechanism of cardiomyocyte proliferation promoted by
fibronectin is still unclear but could be partially attributed to
the impacts of β1 integrin signalling and fibronectin signal-
ling on epicardial cell function [31].
To further determine whether ECM is the key for cardiac
regeneration, Chen et al. [17] used decellularized zebrafish
cardiac ECM to cure adult mice after MI by intramyocardial
injection. The results showed that zebrafish ECM could facil-
itate adult mammalian cardiomyocyte proliferation in ische-
mic myocardium and thus contribute to improved cardiac
function [17]. In addition to lower vertebrates, neonatal mam-
mals could be an important model to elucidate these process-
es. A recent study showed that the cell-free ECM derived from
postnatal day 1 (P1) mouse hearts could induce P1 and P7
cardiomyocyte proliferation in vitro [4]. By using liquid
chromatography-mass spectrometry, Bassat et al. [32] com-
pared the cardiac ECM fragments of P1 and P7 and identified
agrin, a large heparin sulfate proteoglycan, that was enriched
in neonatal but not in juvenile or adult hearts. Agrin promotes
cardiomyocyte proliferation and reduce infarct size after MI in
both juvenile and adult hearts by promoting disassembly of
the dystrophin-glycoprotein complex (DGC) through binding
to its receptor dystroglycan 1 (DAG1). This phenomenon
could subsequently result in myofiber disassembly which is
crucial for cardiomyocyte dedifferentiation. The regenerative
process from terminally differentiated cardiomyocytes to new
cardiomyocytes is achieved in a “dedifferentiation-prolifera-
tion-redifferentiation” manner.
Periostin, another important ECM component, is barely
detectable in the healthy adult heart but is highly expressed
in the neonatal heart [15]. Periostin can switch differentiated
1234
cardiomyocytes into the cell cycle and induce cardiac regen-
eration with improved myocardial function [33], although this
conclusion remains controversial in adult mice [34].
Furthermore, a recent study has shown that periostin can pro-
mote myocardial proliferation in neonatal mice by the
PI3K/GSK3b/cyclin D1 signalling pathway [35]. Overall,
these studies suggest that ECM components are essential for
cardiac regeneration and repair.
In addition to quantitative changes in ECM components,
mechanical properties influence cardiac regeneration and
function. Mechanotransduction can profoundly affect the
synthesis and secretion processes of various ECM molecules
through cell-matrix interactions [36]. The transmembrane
receptor integrins, as mechanotransducers for contracting
muscle cells, connect the ECM to the cytoskeleton and play
important roles in translating extracellular mechanical infor-
mation to intracellular biochemical information. With heart
postnatal development, the stiffness of the ECM in myocar-
dium increases progressively, which is correlated with car-
diomyocyte cell cycle arrest. Cell experiments showed that
reduced matrix rigidity promotes neonatal cardiomyocyte
dedifferentiation and proliferation [37]. In vitro, Akhyari
et al. found that cardiomyocyte proliferation could be en-
hanced by loading a 14-day treatment of 20% cyclic stretch
at 80 cycles/minute on human neonatal cardiomyocytes
[38]. However, 10% cyclic stretch at 60 cycles/minute for
1 day had no pro-proliferative effect on the neonatal
cardiomyocytes [39]. In vivo, unloading the human heart
after LVAD implantation increased cardiomyocyte prolifera-
tion, which was reflected by added phosphorylated histone
H3-positive, and Aurora B-positive cardiomyocytes [40].
The physical properties of the ECM can also influence the
efficiency of cardiac reprogramming, which is closely linked
to cardiac repair. The elasticities of the ECM differ from the
developing myocardium to pathologic myocardium and
have different effects on cardiac reprogramming. Kong
et al. [41] tested 0.2, 2, 20, and 200 kPa elasticities of
collagen I on polyacrylamide substrates and found that the
reprogramming efficiency peaked at 20 kPa and decreased
thereafter. According to a series of experiments, they created
a model to predict cardiac reprogramming outcomes on dif-
ferent biomaterials based on their mechanobiology. In the
field of heart regeneration, stem cell therapy is controversial
because of its lack of efficacy, reproducibility, and integra-
tion. Recently, an important study revealed that an acute
immune response that results in reduced ECM content of
the border zone and enhanced mechanical properties of the
injured area is the main mechanism of stem cell therapy for
ischemic heart disease [42]. The mechanical properties of
ECM are crucial for cardiac regeneration and repair, and
not only the biochemical but also the physical characteristics
of ECM components should be taken into consideration for
basic research and clinical application.
Heart Fail Rev (2021) 26:1231–1248
Sources of ECM-based biomaterials
As the ECM is specifically secreted by native cells of each
tissue [43], it is naturally a complex and bioactive scaffold,
whose structural and molecular components enable commu-
nication between native cells as well as the biological linkage
between native cells and the external environment and dictate
the fate of the cell, such as migration, differentiation, and
apoptosis [10]. Over the years, various attempts have been
made to recreate or simulate ECM by using either naturally
derived ECM components or synthetic polymers to facilitate
cardiac regeneration and repair [44–46]. The predominant
sources of ECM-based biomaterials are reviewed below
(Table 1).
Naturally derived ECM biomaterials
Purified ECM components
Cardiac regeneration and repair efforts mainly rely on the use
of naturally occurring polymers such as collagen, chitosan,
fibrin, gelatin, and alginate [81]. As naturally derived bioma-
terials, these materials exhibit biocompatible, non-immuno-
genic, and biodegradable characteristics and serve as natural
scaffolds for cellular attachment, proliferation, and differenti-
ation [10, 82]. Collagen, collagen-glycosaminoglycan, fibrin,
gelatin, and alginate have been extensively investigated for
myocardial tissue engineering [83, 84]. These ECM mole-
cules are isolated and purified from natural tissues and then
applied to impaired hearts as injectable hydrogels by
intramyocardial injection or intracoronary perfusion, or as col-
lagen patches directly attached to the surface of the infarcted
myocardium with or without co-delivery of cells and bioactive
molecules, either by a single component or mixtures of vari-
ous components [83, 85].
Decellularized ECM
Although purified ECM components are promising for clini-
cal introduction to ischemic heart disease, their applications
are sometimes compromised by the lack of structural integrity
and biological cues compared with those of native cardiac
ECM. Consequently, by removing cellular and nuclear sub-
stances from tissues and leaving the mixture of structural and
functional proteins, decellularized ECM has become a prefer-
able biomaterial for repairing cardiac tissue due to its ability to
provide 3D fibrous and porous topographies [86, 87], and
thus, recapitulate the complexity of matrix components of
natural ECM and provide biological cues for cardiac regener-
ation and repair after ischemic injury [88, 89].
Many approaches, such as physical and chemical as well as
enzymatic methods, have been used to remove cells from the
ECM [87, 90]. Decellularization strategies are required to
Heart Fail Rev (2021) 26:1231–1248 1235

Table 1 ECM-based biomaterials for cardiac regeneration and repair

Advantages Disadvantages Functional roles References

Naturally derived ECM biomaterials

Purified ECM components Biocompatible; biodegradable;
non-immunogenic
Decellularized ECM Biocompatible; biodegradable;
non-immunogenic; retained 3D
fibrous and porous topogra-
phies as well as macrostructures
such
as the vasculature
Cell culture–derived bio- Natural ECM with bioactivity,
materials biocompatibility and
biodegradability
Biohybrid ECM-based biomaterials
Biohybrid ECM-based Desirable mechanical properties; Foreign body reactions;
biomaterials able to mimic the biological
functions of native ECM, while
maintaining good control over
multiple physical properties
ECM-based biomimetic materials
ECM-based biomimetic Preferable physical and
materials mechanical properties;
can be precisely characterized
and fabricated with good
control over physical and
chemical properties
Poor mechanical
properties; uncontrolled
degradation process
Lack of standardized
decellularization process;
decellularization processes may
potentially damage
ultrastructure of ECM;
inflammatory responses due to
incomplete decellularization,
endotoxin residues, as well as
detergent residues
Limited thickness; poor
mechanical properties
compromised degradability
Lack of comprehensive
understanding of natural ECM;
foreign body reactions
Can be applied as injectable [45,
hydrogels or as collagen 47–57]
patches with or without
co-delivery of cells and bioac-
tive molecules
Provide 3D structure to [58–64]
recapitulate the matrix
components of natural ECM
and provide biological cues for
cardiac regeneration after
ischemic injury
Can be adhered to the heart surface [65–69]
spontaneously without sutures
during epicardial implantation
to promote cardiac regeneration
Can be applied as injectable [52,
hydrogels or as patches with or 70–74]
without co-delivery of cells and
bioactive molecules
Can be applied as scaffold [75–80]
materials or constructs to
deliver cells or drugs

ECM extracellular matrix

efficiently remove cells with minimal adverse effects on the
components, biological activity, and mechanical integrity of
the remaining ECM. Several factors may affect the composi-
tion and ultrastructure of decellularized ECM and further in-
fluence the host response to the implants as well as the func-
tional performances of the implants. Inflammatory responses
may occur due to altered ECM ultrastructure, incomplete
decellularization, endotoxin residues, and detergent residues
[87]. In recent years, decellularized ECM-based biomaterials
have been used in clinical management of cardiovascular dis-
eases limited to heart valve disease and congenital heart dis-
ease, whereas only two main decellularized ECM products
(VentriGel and CorMatrix) are being evaluated in clinical test-
ing for ischemic heart disease [91].
isopropylacrylamide, and secrete their own ECM [92]. The
dishes were hydrophobic and cell adhesive at 37 °C. When
the cells are confluent on dishes, the culture temperature is
decreased to 32 °C, which could lead to the detachment of
the monolayer cultured cells along with the ECM and attach-
ment proteins as intact, free-floating 2D cell sheets. Once the
2D cell layers are piled, they can quickly attach and form cell-
to-cell connections [93, 94]. Further, multiple cell sheets can
be stacked into a thicker 3D tissue that can survive for longer
time either in culture or in living heart tissues [95–97] and can
spontaneously adhere to the heart surface without sutures dur-
ing epicardial implantation. Furthermore, cell sheets exhibit
low immunogenicity after transplantation due to their non-
scaffold nature [98].

Cell culture–derived biomaterials Biohybrid ECM-based biomaterials

Cell culture–derived biomaterials are another type of ECM- Although naturally derived ECM-based biomaterials have
based biomaterial. The cells are initially cultured on dishes been widely applied to the fields of cardiac regeneration and
coated with a temperature-sensitive polymer, poly-N- repair and are considered the biomaterials that best resemble
1236
the biocompatibility, biodegradability, and bioactivity of na-
tive cardiac tissue, some ever-present limitations such as un-
desirable mechanical strength may hinder their clinical trans-
lation. Given the requirement for optimizing multiple proper-
ties of ECM-based biomaterials, biohybrid materials are de-
veloped to address these challenges. By cross-linking natural-
ly derived ECM-based biomaterials with natural [99] or syn-
thetic polymers [100], hybrid ECM-based biomaterials allow
increased control of their components and physical features,
such as stiffness, contractibility, conductivity, and porosity
[101]. More importantly, they exhibit considerable potential
to mimic the native ECM in biological functions, while main-
tain a variety of physical properties at the same time [102,
103]. Therefore, biohybrid ECM-based biomaterials have
been introduced to the clinical applications of ischemic heart
diseases [85, 104].
ECM-based biomimetic materials
The natural ECM is considered as a natural scaffold that
provides essential biological cues and mechanical sup-
ports for native cells [105]. As the ultimate aim of car-
diac regeneration and repair is to repair injured myocar-
dium by using biomaterials and further promote endoge-
nous regeneration with cardiomyocyte proliferation, an
emerging strategy is to fabricate biomaterials that mimic
the biological and mechanical characteristics of the na-
tive cardiac ECM. Over the past few decades, extensive
research has illustrated the structural and functional roles
of natural ECM. Simulating the natural ECM to optimize
the biological and mechanical performances of biomate-
rials is a promising approach to achieve cardiac regener-
ation and repair.
Fig. 2 Functionalized ECM-
based biomaterials and delivery
approaches. ECM extracellular
matrix
Heart Fail Rev (2021) 26:1231–1248
Functionalized ECM-based biomaterials
and delivery systems
With the rapid development of tissue engineering, various
types of functionalized ECM-based biomaterials have been
devised for repair of injured myocardium either to serve as
structural supports or constructs that efficiently deliver cells
and/or bioactive molecules to injured myocardial tissue [106,
107]. Multiple biomaterials have been used for co-delivery of
cell sources to promote cell retention and improve the thera-
peutic outcomes of cell therapy [44, 108]. Primary types of
functionalized ECM-based biomaterials are reviewed in both
cell-loaded and cell-free manners (Fig. 2).
Acellular patches
Cell-free ECM-based biomaterials have long been a hot re-
search area for their simplicity. Acellular patches, as well as
decellularized injectable hydrogels, are among the most in-
vestigated strategies in cardiac regeneration medicine.
Engineered cell-free ECM biomaterials are produced to offer
mechanical support and deliver cells, drugs, or other bioac-
tive factors to the injured myocardium, promoting the regen-
eration of cardiomyocytes and the formation of vasculature
[46]. Naturally derived ECM components (such as collagen,
fibrin, and chitosan), natural polymers (such as alginate), and
synthetic polymers (such as polycaprolactone [PCL] and
polyglycerol sebacate [PGS]) are applied to fabricate acellu-
lar ECM-based biomaterials in either a solo or combined
manner [109, 110].
Acellular cardiac patches are designed predominantly to
provide mechanical support for impaired cardiac tissues and
offer microenvironments for native cell integration and
Heart Fail Rev (2021) 26:1231–1248
vascularization post-MI with limited immune reaction and
relatively low cost. As collagens account for a large propor-
tion of the cardiac ECM contents, extensive research has been
conducted to develop collagen patches and explore their ap-
plications in MI models. After grafting 3D collagen I patches
onto the injured myocardium of rats with MI, researchers ob-
served new vessel formation and reduced ventricular remod-
elling after implantation [111]. Some physical processing ap-
proaches have also been adopted to optimize the mechanical
properties of collagen patches and result in preferable cell
integration, vessel formation, and cardiac function with
inhibited ventricular dilation [112]. Moreover, some hybrid
collagen-based patches made by incorporating collagens with
other natural or synthetic polymers have been produced to
modify their mechanical characteristics to provide improved
structural supports [113]. However, other ECM components
and polymers are commonly used to fabricate injectable ma-
terials in gel formats based on their biological, physical, and
chemical properties.
Decellularized injectable hydrogels
Hydrogels are one of the most promising biomaterials be-
cause of their high water content, biocompatibility, and easy
tunability for mimicking the properties of the ECM [114]. To
date, various types of ECM-based hydrogels with optimized
biological properties have been devised for cardiac regenera-
tion and repair [115]. Injectable hydrogels for cardiac engi-
neering can be fabricated from natural materials, synthetic
materials, or a hybrid of the two [116]. The most commonly
used natural hydrogels include collagen, hyaluronic acid, gel-
atin, chitosan, alginate, and chondroitin sulfate [117], while
synthetic polymers include poly(ethylene glycol) (PEG),
poly(N-isopropylacrylamide) (PNIPAm), poly(glycolic acid)
(PGA), and poly(lactic-co-glycolic) acid (PLGA) [118, 119].
To improve the biological and physical properties of inject-
able hydrogels, researchers have developed synthetic
hydrogels such as chitosan-PEG, collagen-PNIPAm, and chi-
tosan-poly(vinyl alcohol) (PVA) [120, 121]. In recent years,
hydrogels derived from decellularized materials have drawn
much attention due to their ability to recapitulate the physical
and biological characteristics of native ECM and minimize
the immunogenic response [122]. For ischemic heart dis-
eases, hydrogels can serve as constructs for cells [123, 124],
drugs, and other bioactive molecules [125, 126] by directly
injected into the injured myocardium or delivered through
catheter-based systems.
To evaluate the use of an injectable hydrogel derived from
cardiac ECM for treating MI, Singelyn et al. developed a
myocardial-specific decellularized ventricular ECM hydrogel
and injected the hydrogel 2 weeks post-MI. The researchers
found that injection of the material in the rat MI model in-
creased endogenous cardiomyocytes in the infarct area and
1237
maintained cardiac function without inducing arrhythmias.
The researchers also tested the ability of this hydrogel to be
delivered percutaneously by catheter in large animal model. In
a porcine model, the hydrogel was delivered using the
NOGA-guided MyoStar catheter and the material retention
was assessed using a histological strategy. The results demon-
strated the feasibility of transendocardial catheter injection in a
large animal model, suggesting that it is a promising novel
therapy for treating MI [127].
Cell sheets with ECM-based biomaterials
Another approach to generate ECM-based biomaterials is cell
sheets. Cells are instructed to produce their own ECM under
defined in vitro culture conditions to form a scaffold-free
ECM-based biomaterial. In recent years, cell sheets have been
successfully applied to clinical settings of regenerative medi-
cine for the heart [128], cornea [129], cartilage [130], and
esophagus [131]. In cardiac regeneration, human iPSC–
derived cardiomyocytes were also cultivated as cell sheets
and implanted into MI pig models. The cell sheets could con-
duct action potentials [132] and beat spontaneously [133].
When the cell sheets were piled in layers, they became elec-
tronically coupled [134, 135] and were associated with im-
proved cardiac function, vascularity, and fibrosis after trans-
plantation [136].
Attempts to transplant these materials into patients with
cardiovascular diseases have been made and have shown pos-
itive effects. In 2012, a cell sheet–based cardiac patch was
reported to be used in a 56-year-old male who suffered from
dilated cardiomyopathy. Skeletal muscle pieces were excised
from this patient and the autologous myoblasts derived from
this muscle were cultured and grown on temperature-
responsive culture dishes. After 48 h, they formed cell sheets
with diameters of approximately 4 cm. Researchers implanted
4-layered myoblast sheets on one site and a total of 20 myo-
blast sheets on five sites to the anterior to the lateral surface of
the dilated heart through a left lateral thoracotomy, observed
markedly improved left ventricular ejection fraction without
arrhythmia, and could remove the left ventricular assist system
[128]. Generally, the findings above may indicate that the cell
sheet strategy may be an effective alternative to heart trans-
plantation in the near future.
Delivery approaches
The administration of biomaterials is an important clinical
procedure. Various routes can be used to deliver biomaterials
to the heart. These approaches include catheter-based mini-
mally invasive delivery approaches, including intracoronary
perfusion, endocardial delivery, transvenous delivery, and
open-chest surgery–based invasive delivery approaches (Fig.
1238
2). The choice of ideal delivery approaches predominantly
depends on the characteristics of biomaterials, the specific
type of heart disease, the disease intervention approach, and
the availability of multiple delivery systems.
Catheter-based minimally invasive delivery
approaches
The development of injectable hydrogels based on stimuli-
sensitive systems enables the application of catheter technol-
ogy. Such hydrogels are administered in a liquid state and
become a gel only when they have reached the myocardium,
without blocking catheters and vessels [137].
With catheter-based approaches, intracoronary injection
can be accessed with a catheter via a percutaneous translumi-
nal coronary angioplasty (PTCA) balloon. After injection, the
leaky vasculature allows the transported materials to enter the
infarcted zone, and therefore increases the number of cells
delivered to the injured area. Endocardial injection obtains
access to the myocardium from the interior of the ventricle.
After puncture of the radial artery or femoral artery, catheters
are introduced to the arterial system and penetrate through the
aortic valve. Combined with imaging technology, endocardial
delivery could achieve targeted injection towards ischemic
sites. The transvenous delivery system approaches the myo-
cardium via the epicardial route. Catheters are placed through
the femoral veins and then pass through one of the coronary
veins. Under the assistance of intravascular ultrasound
(IVUS), the coronary vein is punctured and the catheter passes
through the puncture site to the epicardial wall.
Open-chest surgery–based invasive delivery
approaches
Direct injection of injectable biomaterials
A direct injection strategy is extensively applied in small an-
imal models (such as rats, mouse, and rabbits) in which inject-
able hydrogels are assessed. The hydrogel is injected directly
into the desired location. This method has the most location
control for delivery but requires invasive surgery [138]. The
advantage of intramyocardial injection is its ability to achieve
precise administration of the biomaterials to the target region
under direct visualization.
Implantation of non-injectable biomaterials
For prefabricated patches and cell sheets, there is no available
catheter-based approach that can be used either experimental-
ly or clinically. To date, cardiac patches and cell sheets have
been delivered to the epicardium via open-chest surgery.
However, this invasive delivery approach could utilize
transapical delivery approaches by undertaking a mini-
Heart Fail Rev (2021) 26:1231–1248
thoracotomy and a pericardial incision to access the epicardi-
um [139]. Future development of minimally invasive or even
non-invasive delivery approaches for non-injectable biomate-
rials may significantly facilitate the clinical translation of such
cardiac repair strategies.
ECM-based biomaterial requirements
for tissue engineering and cardiac
regeneration
Biomaterials, either used to retain ventricular geometry, or
used as scaffolds to generate tissue patches, should be func-
tionalized materials that meet several basic requirements, in-
cluding biocompatibility, non-allergenicity, non-toxicity, bio-
degradability, adequate mechanical strength, conductivity, and
injectability. Some pathological conditions, typically heart
failure and arrhythmia, may occur if biological substitutes
for lost or failing tissues do not possess identical or approxi-
mate biochemical and biomechanical characteristics as the
native cardiac tissue.
Since one of the essential roles of biomaterials is serving as
a suitable environment or construct for transplanted or native
cells, tissue engineering strategies can be adopted to repair
injured myocardium by carrying signalling molecules to stim-
ulate endogenous cell adhesion processes [47, 140]. The
ECM-based biomaterials should exhibit biocompatible prop-
erties with native myocardial tissue and remain bioactive after
implantation, consequently leading to improved functional
outcomes of impaired myocardium [49]. Biocompatible
ECM-based materials are required to maintain an appropriate
host response instead of stimulating severe immune responses
[141]. However, some beneficial inflammatory and immune
responses could be retained due to their tissue reparative na-
ture [142]. Biocompatibility also lies in resistance to
thrombogenesis as well as bacterial colonization, which could
guarantee the functioning and survival of biomaterials both
in vivo and in vitro. Over the past decades, ECM-based natu-
rally occurring polymers such as collagen, chitosan, fibrin,
gelatin, and alginate have been extensively investigated in
myocardial tissue engineering [45, 47, 48, 143]. As natural
biomaterials, they can provide a natural substrate for cell ad-
hesion, proliferation, and differentiation in a relatively native
state without causing immune reactions [49, 144]. Various
forms of ECM-derived biomaterials have been commercially
used as scaffolds across many clinical settings for their
bioinductive properties [49].
Biodegradability indicates the ability of an implanted ma-
terial to break down through various mechanisms, such as
hydrolytic mechanisms (bioerosion), cellular activity mecha-
nisms (bioresorption), and enzymatic mechanisms (biodegra-
dation). Equally important is that the degradation products
should also meet the requirements of both biocompatibility
Heart Fail Rev (2021) 26:1231–1248
and biodegradability because incompletely degradable mate-
rial or toxic degraded products cannot be used for clinical
application [145]. ECM-based biomaterials, such as collagen
and fibrin, can perfectly meet the requirements above because
they possess the natural molecular components required for
cell attachment and survival and are able to degrade into bio-
compatible and nontoxic products through the enzymatic ef-
fect of cells [146]. Benefitting from these merits, several
ECM-based biomaterials have been commercialized and ap-
plied to clinical use [147]. However, as biomaterials degrade,
the degradation rate and survival time of ECM-based bioma-
terials have emerged as other issues of concern. By enzymatic
digestion, ECM-derived materials degrade considerably post-
implantation. Therefore, controlling the degradation rate of
biomaterials to match the specific rate requirements of new
tissue formation and ensuring the biomaterials exert the de-
sired function remains a priority in biomaterial design [148].
Some chemical groups, such as glutaraldehyde and ethyl
carbodiimide, have been used to form cross-links with
ECM-based materials to obtain a controlled degradation rate
[149]. Additionally, photolabile chemical strategies have also
been used to form these cross-links [150].
The mechanical properties of ECM-based materials are an-
other important concern of tissue engineering and cardiac re-
generation. The mechanical requirements for ECM-based bio-
materials differed based on the specific types of tissue engi-
neering usage. The engineered tissue, especially patch-like
materials, should harbor the proper mechanical properties to
withstand the consistent contraction and dilation of the heart
[44]. Generally, a healthy adult heart contracts approximately
100,000 times a day and 3 × 109 times in a lifetime. The cyclic
hemodynamic changes in the circulatory system require heart
tissue to have enormous strength, flexibility, and durability.
When in vivo tissue engineering is used, the biomaterial has
to function as an alternative to injured tissue. Their mechanical
properties need to be precisely tuned to ensure that they can
withstand the mechanical demands that will be placed upon
them immediately after application. Additionally, the im-
planted material should not hinder the surrounding tissues to
exert their normal mechanical functions. In a cardiac contrac-
tion cycle, the pressure load of the left ventricle ranges from
1.3 to 16 kPa, while the myofiber stress along the myofiber
axis ranges from 5 to 50 kPa [151].
If the ECM-based biomaterial is intended to be used to
strengthen the ventricle wall or to maintain ventricular integ-
rity, the mechanical property of the implanted material should
achieve the upper limit of the mechanical range of the native
ventricle. However, if the biomaterial is designed to be used as
an injectable hydrogel or a temporary scaffold to deliver cells
or initiate adhesion processes of endogenous cells, a stiffness
reaching the low-end of the mechanical range of native tissue
might be enough, since the seeded cells are able to remodel the
ECM-derived scaffold and form a mechanically similar tissue
1239
as natural cardiac tissue. Given that natural ECM-based ma-
terials are likely to have weak mechanical properties and are
prone to degradation, functional chemical groups have been
added to them to obtain mechanically controllable materials
that are more suitable for clinical application [152]. As the
heart is a constantly contracting organ driven by spontaneous
electrical activities, the electrophysiological and conductive
performances of the biomaterials should match the physical
needs of the beating heart in addition to barely withstanding
the biomechanical forces of the cardiac contractile cycle
[145]. Given that bioengineered ECM-based materials offer-
ing a three-dimensional (3D) combination of cell sources, tis-
sue growth factors, and scaffolds could result in improved
tissue reconstruction [153, 154], attempts have been made
by implanting cardiomyocytes, cardiac progenitors, skeletal
muscle cells, and mesenchymal stem cells (MSCs) together
and cultured as a sheet format on bioscaffolds and these pro-
cesses ultimately resulted in promoted cell connections, func-
tional integration, and synchronic contraction [155].
Limitations of the ECM-based biomaterials
and challenges of the delivery approaches
Limitations of the ECM-based biomaterials
In the past few decades, studies involving the development
of biomaterials for tissue engineering and cardiac regenera-
tion have significantly progressed by continuously improv-
ing material properties to mimic native cardiac tissue.
Currently, researchers can recapitulate the structural, molec-
ular, and mechanical properties of the native cardiac ECM to
mimic the native cellular environment to a large extent
[156]. However, some problems involving ECM-based de-
livery need to be addressed.
Although natural tissue–derived biomaterials are ideal can-
didates for cardiac repair because they offer suitable substrates
for cellular attachment, proliferation, and differentiation in the
native state [157], the poor mechanical properties and ease of
degradation of these materials remain a major obstacle for
clinical application. Some efforts have been made to modulate
these mechanical properties. Through generation of compos-
ites of two or more types of natural biomaterials, the mechan-
ical strength and elasticity can be improved without
compromising the compatibility [158]. Glycosaminoglycans
(GAGs) can also be used to cross-link with collagen fibers to
enhance the mechanical properties of collagen gels [159].
Therefore, the development of hybrid biomaterials containing
natural ECM with biodegradable synthetic materials may offer
practical solutions for the applications of biomaterials in car-
diac repair from bench to bedside.
The electrical integration of these materials to develop con-
ductive and contractile cardiac constructs is another important
1240
concern. The contractile activity of cardiomyocyte sheets is
expected to contribute directly to myocardial performance.
However, the transplanted sheet may remain electronically
isolated from the native myocardium. Although cell sheets
have been applied to cardiac regeneration engineering and
displayed beneficial effects on cardiac function after trans-
plantation into the infarcted myocardium in animal models
[130], the implanted cells cannot electro-physiologically cou-
ple to the native cardiomyocytes, which may lead to an in-
creased risk for ventricular arrhythmia after transplantation.
However, this limitation may hamper the clinical application
of cell sheets. Evidence has shown that electrical stimulation
could induce synchronous contractions of cultured cardiac
constructs and significant ultrastructural organization charac-
terized by an increased density of intercalated discs, gap junc-
tions, and t-tubules [160]. Additionally, physiological load
and electrical stimulation have been adopted in the construc-
tion of 3D myocardial tissue in vitro and result in the genera-
tion of pump function [161], which provides a possibility for
the regeneration of the whole functional heart [45].
To mimic the natural ECM of tissues under physiological
conditions, constructs are required to maintain structural in-
tegrity and support cell adhesion and tissue growth without
activating foreign bodies or harmful immune responses [162,
163]. Therefore, using natural ECM components or cell-free
ECM scaffolds may be optimal choices for tissue engineering.
Ideally, the decellularized ECM is predominantly composed
of collagen and elastin [164]. Since cellular antigens are elim-
inated, the decellularization process could theoretically result
in a non-immunogenic acellular scaffold with a native intact
structure for new tissue regeneration. However, harmful im-
mune responses can also be observed after implantation for
cellular components that have not been completely eliminated.
Thus, to minimize the immune response, novel strategies need
to be developed and adopted to achieve efficient and complete
decellularization. Considering the layered and hierarchical
structure of myocardium tissue, it is important for ECM-
based materials to offer exact spatiotemporal delivery of mo-
lecular and biophysical cues to facilitate the processes of cell
adhesion, differentiation, migration, new ECM synthesis, and
remodelling [165]. Therefore, optimizing the timing and ad-
ministration procedures of biomaterial delivery remains a
daunting task for cardiac engineering.
Challenges of the delivery approaches
Although catheter-based delivery approaches have been ex-
tensively used in humans to deliver cell sources without con-
structs derived from natural or synthetic biomaterials, existing
“on the shelf” catheters are not suitable to deliver injectable
biomaterials because of some hurdles such as rapid gelation
kinetics and high viscosity. Therefore, various studies have
Heart Fail Rev (2021) 26:1231–1248
been carried out to explore the feasibility and optimize ap-
proaches to catheter-based biomaterial delivery.
To investigate whether biomaterials can be delivered effec-
tively into the infarcted myocardium by intracoronary injec-
tion, Leor et al. [166] prepared a calcium cross-linked alginate
solution that undergoes liquid to gel phase transition after
deposition in the infarcted myocardium. In a porcine model,
the alginate solution was injected 4 days after MI. The results
showed that intracoronary injection of alginate reversed left
ventricular enlargement at 60 days. This attempt demonstrated
the feasibility and effectiveness of delivering injectable
hydrogels using a catheter system for the first time. Singelyn
et al. [127] evaluated the use of an in situ gelling injectable
hydrogel derived from ventricular ECM for treating MI and its
ability to be delivered by catheter system in a porcine model.
The hydrogel self-assembles could lead to increased endoge-
nous cardiomyocytes in the infarct area and maintain cardiac
function without inducing arrhythmias, which demonstrated
that the in situ gelling decellularized ECM hydrogel was com-
patible with catheter delivery.
Moreover, to adapt the hydrogels to be delivered by a range
of commercially available catheters, Martens et al. investigat-
ed the polymerization kinetics of fibrin hydrogels and identi-
fied the ranges of concentrations compatible with catheter
delivery in a nude rat model of MI [167]. To achieve a soft
hydrogel with stiffening to enhance the therapeutic efficacy of
preventing left ventricular remodelling, Rodell et al. devel-
oped a catheter-deliverable hyaluronic acid hydrogel by using
a tandem cross-linking approach where the first cross-linking
(guest-host) enabled injection and localized retention of a soft
hydrogel and a second cross-linking reaction (dual-cross-
linking) stiffened the hydrogel after injection. In an ovine
MI model, hydrogels with increased stiffness were found to
be most effective at ameliorating left ventricular remodelling
and preserving function [168].
The intramyocardial injection approach requires open-
chest surgery, and this invasive approach may limit its appli-
cation. Moreover, solutions other than saline are needed to
prevent hydrogels from leaking into the ventricle under con-
stant contraction and dilation in cardiac cycles [169, 170].
Clinical trials and perspectives
Clinical trials for ECM-based biomaterials in cardiac
repair
Although various biomaterials have been shown to be appli-
cable matrices for cardiac regeneration, only a few of these
biomaterials would be assessed in clinical settings. To date,
several clinical trials have been carried out to test the effec-
tiveness and safety of some ECM-based biomaterials
(Table 2).
Table 2 Clinical trials for ECM-based biomaterials in cardiac repair

Trial name Trial identifier Substrate Administration strategy Sample size Cardiac injury Study phase Recruitment states and References
Heart Fail Rev (2021) 26:1231–1248

outcomes

PRESERVATION-1 NCT01226563 Sodium alginate Intracoronary 303 Recent STEMI NA Recruitment completed; no [171, 172]
calcium gluconate functional improvement;
no safety concerns
AUGMENT-HF NCT01311791 Calcium alginate Intramyocardial 58 Congestive heart failure; Phase 2, Recruitment completed; [173]
EF < 35% phase 3 mildly improved peak
VO2; mildly improved
6-min walk test
AUGMENT-HF II NCT03082508 Calcium alginate Intramyocardial > 200 planned Congestive heart failure; NA Not yet recruiting NA
EF < 35%
VentriGel NCT02305602 Porcine ECM Transendocardial 15 Remote STEMI Phase 1 Recruitment completed; no NA
results published
EIR NCT02887768 CorMatrix-extracellular Surgically applied 8 STEMI within 6 weeks Early phase 1 Recruitment completed; no [174, 175]
matrix to the epicardial surface and underwent CABG human results published
ESCORT NCT02057900 Human ESC–derived Surgically applied 10 Congestive heart failure; Phase 1 Recruitment completed; [176]
progenitors embed- to the epicardial surface EF < 35% short-term and
ded into a fibrin patch medium-term safety;
symptomatically im-
proved with increased
systolic motion of the
cell-treated segments
CARDIOMESH NCT03746938 Adipose-derived stem Surgically applied 10 Ischemic heart disease Phase 1 Recruiting NA
cells seeded into a to the epicardial surface and left ventricular
collagen membrane dysfunction, EF < 35%

PRESERVATION-1 IK-5001 for the prevention of remodelling of the ventricle and congestive heart failure after acute myocardial infarction, AUGMENT-HF a randomized, controlled study to evaluate
Algisyl-LVR™ as a method of left ventricular augmentation for heart failure, AUGMENT-HF II a pivotal trial to establish the efficacy and safety of Algisyl in patients with moderate to severe heart failure,
VentriGel a study of ventrigel in post-mi patients, EIR epicardial infarct repair using CorMatrix®-ECM: Clinical Feasibility Study, ESCORT transplantation of human embryonic stem cell-derived
progenitors in severe heart failure, CARDIOMESH first in humans to evaluate collagen patches with stem cells in patients with ischemic left ventricular dysfunction, NA not applicable
1241
1242
Two types of alginate-based injectable hydrogels have been
developed and assessed in two clinical trials (PRESERVATION-
I trial: NCT01226563 [171, 172]; AUGMENT-HF trial:
NCT01311791 [173]). The hydrogel used in PRESERVATION-
I is an injectable bioabsorbable cardiac matrix, composed of an
aqueous mixture of 1% sodium alginate and 0.3% calcium glu-
conate (IK-5001). When exposed to excess ionized calcium
present in infarcted myocardium, it assembles to form a flexible
gel, structurally resembling ECM, which provides a temporary
bioabsorbable cardiac scaffold. IK-5001 was delivered by a
catheter to the infarct-related coronary artery within 7 days
post-MI. The effectiveness and safety endpoints were evaluated
after a 6-month follow-up. However, intracoronary deployment
of IK-5001 failed to reduce adverse left ventricular remodelling
or cardiac clinical events at 6 months, although no device-related
adverse events, serious arrhythmias, blood abnormalities, or
death were noted.
The AUGMENT-HF trial is aimed at assessing the effect of
biomaterials and superior to standard medical therapy (SMT)
for improving the functional capacity and clinical outcomes of
patients with advanced heart failure. The injectable hydrogel
(Algisyl) consists of sodium alginate solution in 4.6% manni-
tol and calcium alginate particles suspended in 4.6% mannitol.
Algisyl was injected into the myocardium under direct visu-
alization during the surgical procedure. After a 1-year follow-
up, Algisyl in addition to SMT was more effective than SMT
alone for improving exercise capacity, symptoms, and clinical
status for patients, which supports larger clinical evaluations
of this novel therapy. Given the promising results identified by
AUGMENT-HF (NCT03082508), AUGMENT-HF II was es-
timated to start in August 2017 and enroll 240 participants
with dilated cardiomyopathy. Algisyl will be injected into
the myocardium under direct visualization during the surgical
procedure. The purpose of this study is to investigate Algisyl
employed as a method of left ventricular augmentation and
restoration in patients with dilated cardiomyopathy. However,
the current stage of AUGMENT-HF II is “not yet recruiting.”
Apart from alginate-based injectable hydrogels, porcine-
derived materials have also been applied and assessed in a
clinical setting. By trans-endocardially delivering VentriGel
(a porcine-derived acellular hydrogel), the VentriGel trial
(NCT02305602) aimed to investigate the effectiveness, safety,
and feasibility of VentriGel in patients who have experienced
ST-elevation MI (STEMI) treated by PCI within the past
3 years and have evidence of left ventricular remodelling.
This trial is estimated to be completed by December 2018;
however, no results have been released thus far.
Perspectives
In recent years, the importance of ECM in restoring tissue
organization and functionality to the heart after myocardial
injury has been well established. Although some of the
Heart Fail Rev (2021) 26:1231–1248
ongoing trials involving the clinical application of ECM-
based biomaterials have not been completed with sufficient
promising results, there is still much hope in the field of
cardiac tissue engineering aiming to improve regenerative
therapies for ischemic heart disease and heart failure.
Through optimization of the mechanical, degradation,
and bioactivity properties, biomaterials may exert prefera-
ble functions in providing mechanical support for injured
myocardium after MI. Moreover, precisely modifying the
immune and regenerative signalling characteristics, realiz-
ing spatiotemporally controlled delivery of biomaterials,
and rationally designing electrically conductive scaffolds
could also largely benefit the development of functional
engineered cardiac tissue and enhance the progress of car-
diac regenerative medicine.
Due to the increasing demand for clinical translation, the
development of injectable biomaterials has entered a new
generation and some novel strategies have been included
to improve the bioactivity of biomaterials. Increasing evi-
dence has shown that actively secreted membrane vesicles,
especially exosomes, may serve as new candidates with im-
portant roles in the repair mechanisms after MI [177]. A
recent study has shown that hydrogel patches slowly releas-
ing extracellular vesicles secreted from cardiomyocytes de-
rived from induced pluripotent stem (iPS) cells could reduce
arrhythmic burden, promote ejection fraction, decrease car-
diomyocyte apoptosis 24 h after infarction, and reduce in-
farct size and cell hypertrophy 4 weeks post-infarction when
implanted onto infarcted rat hearts [178]. Other attempts
have also been established by adding cell-sourced products
to injectable hydrogels to improve the bioactivity of bioma-
terials. Some secreted ECM modulatory proteins [179],
cardiac-specific miRNAs [180], and PLGA-based micropar-
ticles containing oxygen-releasing moieties [181] or mixed
with stem cell membrane fragments [182] have been fused
with injectable biomaterials and were demonstrated to im-
prove the functional outcomes of MI animal models.
Although these novel biomaterial and cell therapy strate-
gies employed for constructing and delivering engineered car-
diac tissues will likely play key roles in improving the func-
tional integration of engrafted materials, the reproducibility
and long-term viability of these strategies remain unknown.
Therefore, further investigation is needed to verify the efficacy
and safety of these emerging strategies in either animal models
or clinical settings. Moreover, the reproducibility of the pro-
duction process and the stability of the products are also some
of the factors that should be standardized to achieve valid
comparisons among all research outcomes in the field and
facilitate collaboration between groups and future develop-
ments of cardiac repair.
Author contributions Conceptualization: Y.N.; Writing: H.L., M.B., and
Y.N.; Editing: H.L. and Y.N.
Heart Fail Rev (2021) 26:1231–1248
Funding information This research was funded by Innovation Fund for
Medical Sciences (CIFMS, 2016-I2M-1-015); National Natural Science
Foundation of China (NSFC, 81770308, 81500239); the National Key
Research and Development Project of China (2019YFA0801500); and
CAMS Beijing Natural Science Foundation (7172183).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflicts of
interest.
References
1. Joseph P, Leong D, McKee M, Anand SS, Schwalm JD, Teo K
et al (2017) Reducing the global burden of cardiovascular disease,
part 1: the epidemiology and risk factors. Circ Res 121(6):677–
694. https://doi.org/10.1161/circresaha.117.308903
2. Nabel EG, Braunwald E (2012) A tale of coronary artery disease
and myocardial infarction. N Engl J Med 366(1):54–63. https://
doi.org/10.1056/NEJMra1112570
3. Xin M, Olson EN, Bassel-Duby R (2013) Mending broken hearts:
cardiac development as a basis for adult heart regeneration and
repair. Nat Rev Mol Cell Biol 14(8):529–541. https://doi.org/10.
1038/nrm3619
4. Bassat E, Mutlak YE, Genzelinakh A, Shadrin IY, Baruch
Umansky K, Yifa O et al (2017) The extracellular matrix protein
agrin promotes heart regeneration in mice. Nature 547(7662):
179–184. https://doi.org/10.1038/nature22978
5. Eroglu E, Chien KR (2017) Heart regeneration 4.0: Matrix
Medicine. Dev Cell 42(1):7–8. https://doi.org/10.1016/j.devcel.
2017.06.017
6. Shiro Yui LA, Maimets M, Pedersen MT, Fordham RP, Hansen
SL, Larsen HL, Guiu J, Alves MRP, Rundsten CF, Johansen JV, Li
Y, Madsen CD, Nakamura T, Watanabe M, Nielsen OH,
Schweiger PJ, Piccolo S, Jensen KB (2018) YAP/TAZ-
dependent reprogramming of colonic epithelium links ECM re-
modeling to tissue regeneration. Cell Stem Cell 22(1):35–49 e7
7. Fry CS, Kirby TJ, Kosmac K, McCarthy JJ, Peterson CA (2017)
Myogenic progenitor cells control extracellular matrix production
by fibroblasts during skeletal muscle hypertrophy. Cell Stem Cell
20(1):56–59. https://doi.org/10.1016/j.stem.2016.09.010
8. Kutys ML, Yamada KM (2014) An extracellular-matrix-specific
GEF-GAP interaction regulates Rho GTPase crosstalk for 3D col-
lagen migration. Nat Cell Biol 16(9):909–917. https://doi.org/10.
1038/ncb3026
9. Rozario T, DeSimone DW (2010) The extracellular matrix in de-
velopment and morphogenesis: a dynamic view. Dev Biol 341(1):
126–140. https://doi.org/10.1016/j.ydbio.2009.10.026
10. Frangogiannis NG (2017) The extracellular matrix in myocardial
injury, repair, and remodeling. J Clin Invest 127(5):1600–1612.
https://doi.org/10.1172/jci87491
11. Karsdal MA, Nielsen SH, Leeming DJ, Langholm LL, Nielsen
MJ, Manon-Jensen T et al (2017) The good and the bad collagens
of fibrosis - their role in signaling and organ function. Adv Drug
Deliv Rev 121:43–56. https://doi.org/10.1016/j.addr.2017.07.014
12. Bashey RI, Martinez-Hernandez A, Jimenez SA (1992) Isolation,
characterization, and localization of cardiac collagen type VI.
Associations with other extracellular matrix components. Circ
Res 70(5):1006–1017
13. Jugdutt BI (2003) Ventricular remodeling after infarction and the
extracellular collagen matrix: when is enough enough?
Circulation. 108(11):1395–1403. https://doi.org/10.1161/01.cir.
0000085658.98621.49
1243
14. Astrof S, Kirby A, Lindblad-Toh K, Daly M, Hynes RO (2007)
Heart development in fibronectin-null mice is governed by a ge-
netic modifier on chromosome four. Mech Dev 124(7-8):551–
558. https://doi.org/10.1016/j.mod.2007.05.004
15. Snider P, Hinton RB, Moreno-Rodriguez RA, Wang J, Rogers R,
Lindsley A et al (2008) Periostin is required for maturation and
extracellular matrix stabilization of noncardiomyocyte lineages of
the heart. Circ Res 102(7):752–760. https://doi.org/10.1161/
circresaha.107.159517
16. Sullivan KE, Quinn KP, Tang KM, Georgakoudi I, Black LD 3rd.
(2014) Extracellular matrix remodeling following myocardial in-
farction influences the therapeutic potential of mesenchymal stem
cells. Stem Cell Res Ther 5(1):14. https://doi.org/10.1186/scrt403
17. Chen WC, Wang Z, Missinato MA, Park DW, Long DW, Liu HJ
et al (2016) Decellularized zebrafish cardiac extracellular matrix
induces mammalian heart regeneration. Sci Adv 2(11):e1600844.
https://doi.org/10.1126/sciadv.1600844
18. Mercer SE, Odelberg SJ, Simon HG (2013) A dynamic spatiotem-
poral extracellular matrix facilitates epicardial-mediated vertebrate
heart regeneration. Dev Biol 382(2):457–469. https://doi.org/10.
1016/j.ydbio.2013.08.002
19. Lindsey ML (2018) Assigning matrix metalloproteinase roles in
ischaemic cardiac remodelling. Nat Rev Cardiol 15(8):471–479.
https://doi.org/10.1038/s41569-018-0022-z
20. Dobaczewski M, Bujak M, Zymek P, Ren G, Entman ML,
Frangogiannis NG (2006) Extracellular matrix remodeling in ca-
nine and mouse myocardial infarcts. Cell Tissue Res 324(3):475–
488. https://doi.org/10.1007/s00441-005-0144-6
21. Li L, Zhao Q, Kong W (2018) Extracellular matrix remodeling
and cardiac fibrosis. Matrix Biol 68-69:490–506. https://doi.org/
10.1016/j.matbio.2018.01.013
22. Ren G, Michael LH, Entman ML, Frangogiannis NG (2002)
Morphological characteristics of the microvasculature in healing
myocardial infarcts. J Histochem Cytochem 50(1):71–79. https://
doi.org/10.1177/002215540205000108
23. Trueblood NA, Xie Z, Communal C, Sam F, Ngoy S, Liaw L et al
(2001) Exaggerated left ventricular dilation and reduced collagen
deposition after myocardial infarction in mice lacking osteopontin.
Circ Res 88(10):1080–1087. https://doi.org/10.1161/hh1001.
090842
24. Schellings MW, Vanhoutte D, Swinnen M, Cleutjens JP, Debets J,
van Leeuwen RE et al (2009) Absence of SPARC results in in-
creased cardiac rupture and dysfunction after acute myocardial
infarction. J Exp Med 206(1):113–123. https://doi.org/10.1084/
jem.20081244
25. Frangogiannis NG, Ren G, Dewald O, Zymek P, Haudek S,
Koerting A et al (2005) Critical role of endogenous
thrombospondin-1 in preventing expansion of healing myocardial
infarcts. Circulation. 111(22):2935–2942. https://doi.org/10.1161/
circulationaha.104.510354
26. Brockes JP (1997) Amphibian limb regeneration: rebuilding a
complex structure. Science (New York, NY) 276(5309):81–87
27. Poss KD, Wilson LG, Keating MT (2002) Heart regeneration in
zebrafish. Science (New York, NY) 298(5601):2188–2190.
https://doi.org/10.1126/science.1077857
28. Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA,
Olson EN et al (2011) Transient regenerative potential of the neo-
natal mouse heart. Science (New York, NY) 331(6020):1078–
1080. https://doi.org/10.1126/science.1200708
29. Williams C, Quinn KP, Georgakoudi I, Black LD 3rd. (2014)
Young developmental age cardiac extracellular matrix promotes
the expansion of neonatal cardiomyocytes in vitro. Acta Biomater
10(1):194–204. https://doi.org/10.1016/j.actbio.2013.08.037
30. Wang J, Karra R, Dickson AL, Poss KD (2013) Fibronectin is
deposited by injury-activated epicardial cells and is necessary for
1244
zebrafish heart regeneration. Dev Biol 382(2):427–435. https://
doi.org/10.1016/j.ydbio.2013.08.012
31. Ieda M, Tsuchihashi T, Ivey KN, Ross RS, Hong TT, Shaw RM
et al (2009) Cardiac fibroblasts regulate myocardial proliferation
through beta1 integrin signaling. Dev Cell 16(2):233–244. https://
doi.org/10.1016/j.devcel.2008.12.007
32. Wang WE, Li L, Xia X, Fu W, Liao Q, Lan C et al (2017)
Dedifferentiation, proliferation, and redifferentiation of adult
mammalian cardiomyocytes after ischemic injury. Circulation.
136(9):834–848. https://doi.org/10.1161/circulationaha.116.
024307
33. Kuhn B, del Monte F, Hajjar RJ, Chang YS, Lebeche D, Arab S
et al (2007) Periostin induces proliferation of differentiated
cardiomyocytes and promotes cardiac repair. Nat Med 13(8):
962–969. https://doi.org/10.1038/nm1619
34. Lorts A, Schwanekamp JA, Elrod JW, Sargent MA, Molkentin JD
(2009) Genetic manipulation of periostin expression in the heart
does not affect myocyte content, cell cycle activity, or cardiac
repair. Circ Res 104(1):e1–e7. https://doi.org/10.1161/circresaha.
108.188649
35. Chen Z, Xie J, Hao H, Lin H, Wang L, Zhang Y et al (2017)
Ablation of periostin inhibits post-infarction myocardial regener-
ation in neonatal mice mediated by the phosphatidylinositol 3
kinase/glycogen synthase kinase 3beta/cyclin D1 signalling path-
way. Cardiovasc Res 113(6):620–632. https://doi.org/10.1093/
cvr/cvx001
36. Gupta V, Grande-Allen KJ (2006) Effects of static and cyclic
loading in regulating extracellular matrix synthesis by cardiovas-
cular cells. Cardiovasc Res 72(3):375–383. https://doi.org/10.
1016/j.cardiores.2006.08.017
37. Yahalom-Ronen Y, Rajchman D, Sarig R, Geiger B, Tzahor E
(2015) Reduced matrix rigidity promotes neonatal cardiomyocyte
dedifferentiation, proliferation and clonal expansion. eLife. 4.
https://doi.org/10.7554/eLife.07455
38. Akhyari P, Fedak PW, Weisel RD, Lee TY, Verma S, Mickle DA
et al (2002) Mechanical stretch regimen enhances the formation of
bioengineered autologous cardiac muscle grafts. Circulation.
106(12 Suppl 1):I137–I142
39. Birla RK, Huang YC, Dennis RG (2007) Development of a novel
bioreactor for the mechanical loading of tissue-engineered heart
muscle. Tissue Eng 13(9):2239–2248. https://doi.org/10.1089/ten.
2006.0359
40. Canseco DC, Kimura W, Garg S, Mukherjee S, Bhattacharya S,
Abdisalaam S et al (2015) Human ventricular unloading induces
cardiomyocyte proliferation. J Am Coll Cardiol 65(9):892–900.
https://doi.org/10.1016/j.jacc.2014.12.027
41. Kong YP, Rioja AY, Xue X, Sun Y, Fu J, Putnam AJ (2018) A
systems mechanobiology model to predict cardiac reprogramming
outcomes on different biomaterials. Biomaterials. 181:280–292.
https://doi.org/10.1016/j.biomaterials.2018.07.036
42. Vagnozzi RJ, Maillet M, Sargent MA, Khalil H, Johansen AKZ,
Schwanekamp JA et al (2020) An acute immune response under-
lies the benefit of cardiac stem cell therapy. Nature. 577(7790):
405–409. https://doi.org/10.1038/s41586-019-1802-2
43. Bissell MJ, Aggeler J (1987) Dynamic reciprocity: how do extra-
cellular matrix and hormones direct gene expression? Prog Clin
Biol Res 249:251–262
44. Pomeroy JE, Helfer A, Bursac N (2019) Biomaterializing the
promise of cardiac tissue engineering. Biotechnol Adv. https://
doi.org/10.1016/j.biotechadv.2019.02.009
45. Wang F, Guan J (2010) Cellular cardiomyoplasty and cardiac tis-
sue engineering for myocardial therapy. Adv Drug Deliv Rev
62(7-8):784–797. https://doi.org/10.1016/j.addr.2010.03.001
46. Radisic M, Christman KL (2013) Materials science and tissue
engineering: repairing the heart. Mayo Clin Proc 88(8):884–898.
https://doi.org/10.1016/j.mayocp.2013.05.003
Heart Fail Rev (2021) 26:1231–1248
47. Christman KL, Lee RJ (2006) Biomaterials for the treatment of
myocardial infarction. J Am Coll Cardiol 48(5):907–913. https://
doi.org/10.1016/j.jacc.2006.06.005
48. Zimmermann WH, Melnychenko I, Eschenhagen T (2004)
Engineered heart tissue for regeneration of diseased hearts.
Biomaterials. 25(9):1639–1647
49. Reis LA, Chiu LL, Feric N, Fu L, Radisic M (2016) Biomaterials
in myocardial tissue engineering. J Tissue Eng Regen Med 10(1):
11–28. https://doi.org/10.1002/term.1944
50. Johnson TD, Braden RL, Christman KL (2014) Injectable ECM
scaffolds for cardiac repair. Methods Mol Biol (Clifton, NJ) 1181:
109–120. https://doi.org/10.1007/978-1-4939-1047-2_10
51. Duan Y, Liu Z, O'Neill J, Wan LQ, Freytes DO, Vunjak-
Novakovic G (2011) Hybrid gel composed of native heart matrix
and collagen induces cardiac differentiation of human embryonic
stem cells without supplemental growth factors. J Cardiovasc
Transl Res 4(5):605–615. https://doi.org/10.1007/s12265-011-
9304-0
52. Segers VF, Lee RT (2011) Biomaterials to enhance stem cell func-
tion in the heart. Circ Res 109(8):910–922. https://doi.org/10.
1161/circresaha.111.249052
53. Tiburcy M, Hudson JE, Balfanz P, Schlick S, Meyer T, Chang
Liao ML et al (2017) Defined engineered human myocardium
with advanced maturation for applications in heart failure model-
ing and repair. Circulation. 135(19):1832–1847. https://doi.org/
10.1161/circulationaha.116.024145
54. Hirt MN, Boeddinghaus J, Mitchell A, Schaaf S, Bornchen C,
Muller C et al (2014) Functional improvement and maturation of
rat and human engineered heart tissue by chronic electrical stim-
ulation. J Mol Cell Cardiol 74:151–161. https://doi.org/10.1016/j.
yjmcc.2014.05.009
55. Nawroth JC, Scudder LL, Halvorson RT, Tresback J, Ferrier JP,
Sheehy SP et al (2018) Automated fabrication of photopatterned
gelatin hydrogels for organ-on-chips applications. Biofabrication.
10(2):025004. https://doi.org/10.1088/1758-5090/aa96de
56. Shin SR, Jung SM, Zalabany M, Kim K, Zorlutuna P, Kim SB et al
(2013) Carbon-nanotube-embedded hydrogel sheets for engineer-
ing cardiac constructs and bioactuators. ACS Nano 7(3):2369–
2380. https://doi.org/10.1021/nn305559j
57. Gaetani R, Feyen DA, Verhage V, Slaats R, Messina E, Christman
KL et al (2015) Epicardial application of cardiac progenitor cells
in a 3D-printed gelatin/hyaluronic acid patch preserves cardiac
function after myocardial infarction. Biomaterials. 61:339–348.
https://doi.org/10.1016/j.biomaterials.2015.05.005
58. Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI
et al (2008) Perfusion-decellularized matrix: using nature’s plat-
form to engineer a bioartificial heart. Nat Med 14(2):213–221.
https://doi.org/10.1038/nm1684
59. Robertson MJ, Dries-Devlin JL, Kren SM, Burchfield JS, Taylor
DA (2014) Optimizing recellularization of whole decellularized
heart extracellular matrix. PLoS One 9(2):e90406. https://doi.
org/10.1371/journal.pone.0090406
60. Tondreau MY, Laterreur V, Gauvin R, Vallieres K, Bourget JM,
Lacroix D et al (2015) Mechanical properties of endothelialized
fibroblast-derived vascular scaffolds stimulated in a bioreactor.
Acta Biomater 18:176–185. https://doi.org/10.1016/j.actbio.
2015.02.026
61. Wang Z, Long DW, Huang Y, Chen WCW, Kim K, Wang Y
(2019) Decellularized neonatal cardiac extracellular matrix pre-
vents widespread ventricular remodeling in adult mammals after
myocardial infarction. Acta Biomater 87:140–151. https://doi.org/
10.1016/j.actbio.2019.01.062
62. Tang-Quan KR, Mehta NA, Sampaio LC, Taylor DA (2018)
Whole cardiac tissue bioscaffolds. Adv Exp Med Biol 1098:85–
114. https://doi.org/10.1007/978-3-319-97421-7_5
Heart Fail Rev (2021) 26:1231–1248
63. Daley MC, Fenn SL, Black LD 3rd. (2018) Applications of car-
diac extracellular matrix in tissue engineering and regenerative
medicine. Adv Exp Med Biol 1098:59–83. https://doi.org/10.
1007/978-3-319-97421-7_4
64. Seo Y, Jung Y, Kim SH (2018) Decellularized heart ECM hydro-
gel using supercritical carbon dioxide for improved angiogenesis.
Acta Biomater 67:270–281. https://doi.org/10.1016/j.actbio.2017.
11.046
65. Shudo Y, Cohen JE, MacArthur JW, Goldstone AB, Otsuru S,
Trubelja A et al (2015) A tissue-engineered chondrocyte cell sheet
induces extracellular matrix modification to enhance ventricular
biomechanics and attenuate myocardial stiffness in ischemic car-
diomyopathy. Tissue Eng A 21(19-20):2515–2525. https://doi.
org/10.1089/ten.TEA.2014.0155
66. Lee KM, Kim H, Nemeno JG, Yang W, Yoon J, Lee S et al (2015)
Natural cardiac extracellular matrix sheet as a biomaterial for car-
diomyocyte transplantation. Transplant Proc 47(3):751–756.
https://doi.org/10.1016/j.transproceed.2014.12.030
67. Ishii M, Shibata R, Shimizu Y, Yamamoto T, Kondo K, Inoue Y
et al (2014) Multilayered adipose-derived regenerative cell sheets
created by a novel magnetite tissue engineering method for myo-
cardial infarction. Int J Cardiol 175(3):545–553. https://doi.org/
10.1016/j.ijcard.2014.06.034
68. Yeh YC, Lee WY, Yu CL, Hwang SM, Chung MF, Hsu LW et al
(2010) Cardiac repair with injectable cell sheet fragments of hu-
man amniotic fluid stem cells in an immune-suppressed rat model.
Biomaterials. 31(25):6444–6453. https://doi.org/10.1016/j.
biomaterials.2010.04.069
69. Wang CC, Chen CH, Lin WW, Hwang SM, Hsieh PC, Lai PH et al
(2008) Direct intramyocardial injection of mesenchymal stem cell
sheet fragments improves cardiac functions after infarction.
Cardiovasc Res 77(3):515–524. https://doi.org/10.1093/cvr/
cvm046
70. Bracaglia LG, Winston S, Powell DA, Fisher JP (2019) Synthetic
polymer coatings diminish chronic inflammation risk in large
ECM-based materials. J Biomed Mater Res A 107(3):494–504.
https://doi.org/10.1002/jbm.a.36564
71. Guan J, Wang F, Li Z, Chen J, Guo X, Liao J et al (2011) The
stimulation of the cardiac differentiation of mesenchymal stem
cells in tissue constructs that mimic myocardium structure and
biomechanics. Biomaterials. 32(24):5568–5580. https://doi.org/
10.1016/j.biomaterials.2011.04.038
72. Loke WK, Khor E, Wee A, Teoh SH, Chian KS (1996) Hybrid
biomaterials based on the interaction of polyurethane oligomers
with porcine pericardium. Biomaterials. 17(22):2163–2172
73. Yang MC, Wang SS, Chou NK, Chi NH, Huang YY, Chang YL
et al (2009) The cardiomyogenic differentiation of rat mesenchy-
mal stem cells on silk fibroin-polysaccharide cardiac patches
in vitro. Biomaterials. 30(22):3757–3765. https://doi.org/10.
1016/j.biomaterials.2009.03.057
74. Zhang B, Xiao Y, Hsieh A, Thavandiran N, Radisic M (2011)
Micro- and nanotechnology in cardiovascular tissue engineering.
Nanotechnology. 22(49):494003. https://doi.org/10.1088/0957-
4484/22/49/494003
75. Kim TG, Shin H, Lim DW (2012) Biomimetic scaffolds for tissue
engineering. Adv Funct Mater 22(12):2446–2468. https://doi.org/
10.1002/adfm.201103083
76. Boffito M, Di Meglio F, Mozetic P, Giannitelli SM, Carmagnola I,
Castaldo C et al (2018) Surface functionalization of polyurethane
scaffolds mimicking the myocardial microenvironment to support
cardiac primitive cells. PLoS One 13(7):e0199896. https://doi.org/
10.1371/journal.pone.0199896
77. Kyburz KA, Anseth KS (2015) Synthetic mimics of the extracel-
lular matrix: how simple is complex enough? Ann Biomed Eng
43(3):489–500. https://doi.org/10.1007/s10439-015-1297-4
1245
78. Frydrych M, Roman S, MacNeil S, Chen B (2015) Biomimetic
poly(glycerol sebacate)/poly(l-lactic acid) blend scaffolds for adi-
pose tissue engineering. Acta Biomater 18:40–49. https://doi.org/
10.1016/j.actbio.2015.03.004
79. Neal RA, McClugage SG, Link MC, Sefcik LS, Ogle RC,
Botchwey EA (2009) Laminin nanofiber meshes that mimic mor-
phological properties and bioactivity of basement membranes.
Tissue Eng C Methods 15(1):11–21. https://doi.org/10.1089/ten.
tec.2007.0366
80. Migliorini E, Thakar D, Sadir R, Pleiner T, Baleux F, Lortat-Jacob
H et al (2014) Well-defined biomimetic surfaces to characterize
glycosaminoglycan-mediated interactions on the molecular, su-
pramolecular and cellular levels. Biomaterials. 35(32):8903–
8915. https://doi.org/10.1016/j.biomaterials.2014.07.017
81. Hematti P (2018) Role of extracellular matrix in cardiac cellular
therapies. Adv Exp Med Biol 1098:173–188. https://doi.org/10.
1007/978-3-319-97421-7_9
82. Singelyn JM, DeQuach JA, Seif-Naraghi SB, Littlefield RB,
Schup-Magoffin PJ, Christman KL (2009) Naturally derived
myocardial matrix as an injectable scaffold for cardiac tissue en-
gineering. Biomaterials. 30(29):5409–5416. https://doi.org/10.
1016/j.biomaterials.2009.06.045
83. Wu WQ, Peng S, Song ZY, Lin S (2019) Collagen biomaterial for
the treatment of myocardial infarction: an update on cardiac tissue
engineering and myocardial regeneration. Drug Deliv Transl Res.
https://doi.org/10.1007/s13346-019-00627-0
84. Roura S, Galvez-Monton C, Bayes-Genis A (2017) Fibrin, the
preferred scaffold for cell transplantation after myocardial infarc-
tion? An old molecule with a new life. J Tissue Eng Regen Med
11(8):2304–2313. https://doi.org/10.1002/term.2129
85. Rufaihah AJ, Seliktar D (2016) Hydrogels for therapeutic cardio-
vascular angiogenesis. Adv Drug Deliv Rev 96:31–39. https://doi.
org/10.1016/j.addr.2015.07.003
86. Arenas-Herrera JE, Ko IK, Atala A, Yoo JJ (2013)
Decellularization for whole organ bioengineering. Biomed
Mater (Bristol, England) 8(1):014106. https://doi.org/10.1088/
1748-6041/8/1/014106
87. Keane TJ, Swinehart IT, Badylak SF (2015) Methods of tissue
decellularization used for preparation of biologic scaffolds and
in vivo relevance. Methods (San Diego, Calif) 84:25–34. https://
doi.org/10.1016/j.ymeth.2015.03.005
88. Taylor DA, Sampaio LC, Ferdous Z, Gobin AS, Taite LJ (2018)
Decellularized matrices in regenerative medicine. Acta Biomater
74:74–89. https://doi.org/10.1016/j.actbio.2018.04.044
89. Spang MT, Christman KL (2018) Extracellular matrix hydrogel
therapies: in vivo applications and development. Acta Biomater
68:1–14. https://doi.org/10.1016/j.actbio.2017.12.019
90. Badylak SF, Taylor D, Uygun K (2011) Whole-organ tissue engi-
neering: decellularization and recellularization of three-
dimensional matrix scaffolds. Annu Rev Biomed Eng 13:27–53.
https://doi.org/10.1146/annurev-bioeng-071910-124743
91. Bejleri D, Davis ME (2019) Decellularized extracellular matrix
materials for cardiac repair and regeneration. Adv Healthc Mater
8(5):e1801217. https://doi.org/10.1002/adhm.201801217
92. Schenke-Layland K, Rofail F, Heydarkhan S, Gluck JM, Ingle NP,
Angelis E et al (2009) The use of three-dimensional nanostruc-
tures to instruct cells to produce extracellular matrix for regenera-
tive medicine strategies. Biomaterials. 30(27):4665–4675. https://
doi.org/10.1016/j.biomaterials.2009.05.033
93. Alrefai MT, Murali D, Paul A, Ridwan KM, Connell JM, Shum-
Tim D (2015) Cardiac tissue engineering and regeneration using
cell-based therapy. Stem Cells Cloning 8:81–101. https://doi.org/
10.2147/sccaa.s54204
94. Sakaguchi K, Shimizu T, Okano T (2015) Construction of three-
dimensional vascularized cardiac tissue with cell sheet
1246
engineering. J Control Release 205:83–88. https://doi.org/10.
1016/j.jconrel.2014.12.016
95. Cyranoski D (2018) ‘Reprogrammed’ stem cells approved to
mend human hearts for the first time. Nature. 557(7707):619–
620. https://doi.org/10.1038/d41586-018-05278-8
96. Kawamura M, Miyagawa S, Fukushima S, Saito A, Miki K,
Funakoshi S et al (2017) Enhanced therapeutic effects of human
iPS cell derived-cardiomyocyte by combined cell-sheets with
omental flap technique in porcine ischemic cardiomyopathy mod-
el. Sci Rep 7(1):8824. https://doi.org/10.1038/s41598-017-08869-
z cardiac remodeling and ventricular function post myocardial in-
97. Shimizu T, Sekine H, Yamato M, Okano T (2009) Cell sheet-
based myocardial tissue engineering: new hope for damaged heart
rescue. Curr Pharm Des 15(24):2807–2814
98. Matsuura K, Utoh R, Nagase K, Okano T (2014) Cell sheet ap-
proach for tissue engineering and regenerative medicine. J Control
Release 190:228–239. https://doi.org/10.1016/j.jconrel.2014.05.
024
99. Efraim Y, Sarig H, Cohen Anavy N, Sarig U, de Berardinis E,
Chaw SY et al (2017) Biohybrid cardiac ECM-based hydrogels
improve long term cardiac function post myocardial infarction.
Acta Biomater 50:220–233. https://doi.org/10.1016/j.actbio.
2016.12.015
100. Klouda L (2015) Thermoresponsive hydrogels in biomedical ap-
plications: a seven-year update. Eur J Pharm Biopharm 97(Pt B):
338–349. https://doi.org/10.1016/j.ejpb.2015.05.017
101. Zhu J, Marchant RE (2011) Design properties of hydrogel tissue-
engineering scaffolds. Expert Rev Med Dev 8(5):607–626. https://
doi.org/10.1586/erd.11.27
102. Ravichandran R, Venugopal JR, Sundarrajan S, Mukherjee S,
Ramakrishna S (2012) Minimally invasive cell-seeded biomaterial
systems for injectable/epicardial implantation in ischemic heart
disease. Int J Nanomedicine 7:5969–5994. https://doi.org/10.
2147/ijn.s37575
103. Lau HK, Kiick KL (2015) Opportunities for multicomponent hy-
brid hydrogels in biomedical applications. Biomacromolecules.
16(1):28–42. https://doi.org/10.1021/bm501361c
104. Rufaihah AJ, Vaibavi SR, Plotkin M, Shen J, Nithya V, Wang J
et al (2013) Enhanced infarct stabilization and neovascularization
mediated by VEGF-loaded PEGylated fibrinogen hydrogel in a
rodent myocardial infarction model. Biomaterials. 34(33):8195–
8202. https://doi.org/10.1016/j.biomaterials.2013.07.031
105. Toba H, Lindsey ML (2019) Extracellular matrix roles in
cardiorenal fibrosis: potential therapeutic targets for CVD and
CKD in the elderly. Pharmacol Ther 193:99–120. https://doi.org/
10.1016/j.pharmthera.2018.08.014
106. Yanamandala M, Zhu W, Garry DJ, Kamp TJ, Hare JM, Jun HW
et al (2017) Overcoming the roadblocks to cardiac cell therapy
using tissue engineering. J Am Coll Cardiol 70(6):766–775.
https://doi.org/10.1016/j.jacc.2017.06.012
107. Zhu Y, Matsumura Y, Wagner WR (2017) Ventricular wall bioma-
terial injection therapy after myocardial infarction: advances in
material design, mechanistic insight and early clinical experiences.
Biomaterials. 129:37–53. https://doi.org/10.1016/j.biomaterials.
2017.02.032
108. Chien KR, Frisen J, Fritsche-Danielson R, Melton DA, Murry CE,
Weissman IL (2019) Regenerating the field of cardiovascular cell
therapy. Nat Biotechnol 37(3):232–237. https://doi.org/10.1038/
s41587-019-0042-1
109. Kai D, Wang QL, Wang HJ, Prabhakaran MP, Zhang Y, Tan YZ
et al (2014) Stem cell-loaded nanofibrous patch promotes the re-
generation of infarcted myocardium with functional improvement
in rat model. Acta Biomater 10(6):2727–2738. https://doi.org/10.
1016/j.actbio.2014.02.030
110. Wendel JS, Ye L, Zhang P, Tranquillo RT, Zhang JJ (2014)
Functional consequences of a tissue-engineered myocardial patch
Heart Fail Rev (2021) 26:1231–1248
for cardiac repair in a rat infarct model. Tissue Eng A 20(7-8):
1325–1335. https://doi.org/10.1089/ten.TEA.2013.0312
111. Gaballa MA, Sunkomat JN, Thai H, Morkin E, Ewy G, Goldman
S (2006) Grafting an acellular 3-dimensional collagen scaffold
onto a non-transmural infarcted myocardium induces neo-
angiogenesis and reduces cardiac remodeling. J Heart Lung
Transplant 25(8):946–954. https://doi.org/10.1016/j.healun.2006.
04.008
112. Serpooshan V, Zhao M, Metzler SA, Wei K, Shah PB, Wang A
et al (2013) The effect of bioengineered acellular collagen patch on
farction. Biomaterials. 34(36):9048–9055. https://doi.org/10.
1016/j.biomaterials.2013.08.017
113. Deng C, Zhang P, Vulesevic B, Kuraitis D, Li F, Yang AF et al
(2010) A collagen-chitosan hydrogel for endothelial differentia-
tion and angiogenesis. Tissue Eng A 16(10):3099–3109. https://
doi.org/10.1089/ten.tea.2009.0504
114. Slaughter BV, Khurshid SS, Fisher OZ, Khademhosseini A,
Peppas NA (2009) Hydrogels in regenerative medicine. Adv
Mater (Deerfield Beach, Fla) 21(32-33):3307–3329. https://doi.
org/10.1002/adma.200802106
115. Phelps EA, Enemchukwu NO, Fiore VF, Sy JC, Murthy N,
Sulchek TA et al (2012) Maleimide cross-linked bioactive PEG
hydrogel exhibits improved reaction kinetics and cross-linking for
cell encapsulation and in situ delivery. Adv Mater (Deerfield
Beach, Fla) 24(1):64–70, 2. https://doi.org/10.1002/adma.
201103574
116. Saludas L, Pascual-Gil S, Prosper F, Garbayo E, Blanco-Prieto M
(2017) Hydrogel based approaches for cardiac tissue engineering.
Int J Pharm 523(2):454–475. https://doi.org/10.1016/j.ijpharm.
2016.10.061
117. Annabi N, Tamayol A, Uquillas JA, Akbari M, Bertassoni LE,
Cha C et al (2014) 25th anniversary article: Rational design and
applications of hydrogels in regenerative medicine. Adv Mater
(Deerfield Beach, Fla) 26(1):85–123
118. Shi K, Wang YL, Qu Y, Liao JF, Chu BY, Zhang HP et al (2016)
Synthesis, characterization, and application of reversible PDLLA-
PEG-PDLLA copolymer thermogels in vitro and in vivo. Sci Rep
6:19077. https://doi.org/10.1038/srep19077
119. Vo TN, Ekenseair AK, Spicer PP, Watson BM, Tzouanas SN, Roh
TT et al (2015) In vitro and in vivo evaluation of self-
mineralization and biocompatibility of injectable, dual-gelling
hydrogels for bone tissue engineering. J Control Release 205:
25–34. https://doi.org/10.1016/j.jconrel.2014.11.028
120. Barnes AL, Genever PG, Rimmer S, Coles MC (2016) Collagen-
poly(N-isopropylacrylamide) hydrogels with tunable properties.
Biomacromolecules. 17(3):723–734. https://doi.org/10.1021/acs.
biomac.5b01251
121. Das D, Ghosh P, Ghosh A, Haldar C, Dhara S, Panda AB et al
(2015) Stimulus-responsive, biodegradable, biocompatible, cova-
lently cross-linked hydrogel based on dextrin and poly(N-
isopropylacrylamide) for in vitro/in vivo controlled drug release.
ACS Appl Mater Interfaces 7(26):14338–14351. https://doi.org/
10.1021/acsami.5b02975
122. Chen FM, Liu X (2016) Advancing biomaterials of human origin
for tissue engineering. Prog Polym Sci 53:86–168. https://doi.org/
10.1016/j.progpolymsci.2015.02.004
123. Hastings CL, Roche ET, Ruiz-Hernandez E, Schenke-Layland K,
Walsh CJ, Duffy GP (2015) Drug and cell delivery for cardiac
regeneration. Adv Drug Deliv Rev 84:85–106. https://doi.org/10.
1016/j.addr.2014.08.006
124. Wang H, Zhou J, Liu Z, Wang C (2010) Injectable cardiac tissue
engineering for the treatment of myocardial infarction. J Cell Mol
Med 14(5):1044–1055. https://doi.org/10.1111/j.1582-4934.2010.
01046.x
Heart Fail Rev (2021) 26:1231–1248
125. Ungerleider JL, Johnson TD, Rao N, Christman KL (2015)
Fabrication and characterization of injectable hydrogels derived
from decellularized skeletal and cardiac muscle. Methods (San
Diego, Calif) 84:53–59. https://doi.org/10.1016/j.ymeth.2015.03.
024
126. Shu Y, Hao T, Yao F, Qian Y, Wang Y, Yang B et al (2015) RoY
peptide-modified chitosan-based hydrogel to improve angiogene-
sis and cardiac repair under hypoxia. ACS Appl Mater Interfaces
7(12):6505–6517. https://doi.org/10.1021/acsami.5b01234
127. Singelyn JM, Sundaramurthy P, Johnson TD, Schup-Magoffin PJ,
Hu DP, Faulk DM et al (2012) Catheter-deliverable hydrogel de-
rived from decellularized ventricular extracellular matrix increases
endogenous cardiomyocytes and preserves cardiac function post-
myocardial infarction. J Am Coll Cardiol 59(8):751–763. https://
doi.org/10.1016/j.jacc.2011.10.888
128. Sawa Y, Miyagawa S, Sakaguchi T, Fujita T, Matsuyama A, Saito
A et al (2012) Tissue engineered myoblast sheets improved cardi-
ac function sufficiently to discontinue LVAS in a patient with
DCM: report of a case. Surg Today 42(2):181–184. https://doi.
org/10.1007/s00595-011-0106-4
129. Nishida K, Yamato M, Hayashida Y, Watanabe K, Yamamoto K,
Adachi E et al (2004) Corneal reconstruction with tissue-
engineered cell sheets composed of autologous oral mucosal epi-
thelium. N Engl J Med 351(12):1187–1196. https://doi.org/10.
1056/NEJMoa040455
130. Sato M, Yamato M, Hamahashi K, Okano T, Mochida J (2014)
Articular cartilage regeneration using cell sheet technology. Anat
Rec (Hoboken, NJ : 2007) 297(1):36–43. https://doi.org/10.1002/
ar.22829
131. Ohki T, Yamato M, Murakami D, Takagi R, Yang J, Namiki H et al
(2006) Treatment of oesophageal ulcerations using endoscopic
transplantation of tissue-engineered autologous oral mucosal epi-
thelial cell sheets in a canine model. Gut. 55(12):1704–1710.
https://doi.org/10.1136/gut.2005.088518
132. Itabashi Y, Miyoshi S, Yuasa S, Fujita J, Shimizu T, Okano T et al
(2005) Analysis of the electrophysiological properties and arrhyth-
mias in directly contacted skeletal and cardiac muscle cell sheets.
Cardiovasc Res 67(3):561–570. https://doi.org/10.1016/j.
cardiores.2005.03.014
133. Itabashi Y, Miyoshi S, Kawaguchi H, Yuasa S, Tanimoto K,
Furuta A et al (2005) A new method for manufacturing cardiac
cell sheets using fibrin-coated dishes and its electrophysiological
studies by optical mapping. Artif Organs 29(2):95–103. https://
doi.org/10.1111/j.1525-1594.2005.29020.x
134. Matsuura K, Wada M, Shimizu T, Haraguchi Y, Sato F, Sugiyama
K et al (2012) Creation of human cardiac cell sheets using plurip-
otent stem cells. Biochem Biophys Res Commun 425(2):321–
327. https://doi.org/10.1016/j.bbrc.2012.07.089
135. Lee P, Klos M, Bollensdorff C, Hou L, Ewart P, Kamp TJ et al
(2012) Simultaneous voltage and calcium mapping of genetically
purified human induced pluripotent stem cell-derived cardiac
myocyte monolayers. Circ Res 110(12):1556–1563. https://doi.
org/10.1161/circresaha.111.262535
136. Fujita J, Itabashi Y, Seki T, Tohyama S, Tamura Y, Sano M et al
(2012) Myocardial cell sheet therapy and cardiac function. Am J
Physiol Heart Circ Physiol 303(10):H1169–H1182. https://doi.
org/10.1152/ajpheart.00376.2012
137. Galaup A, Gomez E, Souktani R, Durand M, Cazes A, Monnot C
et al (2012) Protection against myocardial infarction and no-
reflow through preservation of vascular integrity by
angiopoietin-like 4. Circulation. 125(1):140–149. https://doi.org/
10.1161/circulationaha.111.049072
138. Kofidis T, de Bruin JL, Hoyt G, Lebl DR, Tanaka M, Yamane T
et al (2004) Injectable bioartificial myocardial tissue for large-
scale intramural cell transfer and functional recovery of injured
1247
heart muscle. J Thorac Cardiovasc Surg 128(4):571–578. https://
doi.org/10.1016/j.jtcvs.2004.05.021
139. Iyisoy A, Ozturk C, Celik T, Demirkol S, Cingoz F, Unlu M et al
(2015) Percutaneous transapical closure of cardiac apex with an
ADO-II device after successful transapical transcatheter prosthetic
mitral paravalvular leak closure. Int J Cardiol 189:289–292.
https://doi.org/10.1016/j.ijcard.2015.04.076
140. Wu KH, Liu YL, Zhou B, Han ZC (2006) Cellular therapy and
myocardial tissue engineering: the role of adult stem and progen-
itor cells. Eur J Cardiothorac Surg 30(5):770–781. https://doi.org/
10.1016/j.ejcts.2006.08.003
141. Aamodt JM, Grainger DW (2016) Extracellular matrix-based bio-
material scaffolds and the host response. Biomaterials. 86:68–82.
https://doi.org/10.1016/j.biomaterials.2016.02.003
142. Alvarez MM, Liu JC, Trujillo-de Santiago G, Cha BH,
Vishwakarma A, Ghaemmaghami AM et al (2016) Delivery strat-
egies to control inflammatory response: modulating M1-M2 po-
larization in tissue engineering applications. J Control Release
240:349–363. https://doi.org/10.1016/j.jconrel.2016.01.026
143. Du C, Cui FZ, Zhu XD, de Groot K (1999) Three-dimensional
nano-HAp/collagen matrix loading with osteogenic cells in organ
culture. J Biomed Mater Res 44(4):407–415
144. Badylak SF (2007) The extracellular matrix as a biologic scaffold
material. Biomaterials. 28(25):3587–3593. https://doi.org/10.
1016/j.biomaterials.2007.04.043
145. Bouten CV, Dankers PY, Driessen-Mol A, Pedron S, Brizard AM,
Baaijens FP (2011) Substrates for cardiovascular tissue engineer-
ing. Adv Drug Deliv Rev 63(4-5):221–241. https://doi.org/10.
1016/j.addr.2011.01.007
146. Bracaglia LG, Fisher JP (2015) Extracellular matrix-based
biohybrid materials for engineering compliant, matrix-dense tis-
sues. Adv Healthc Mater 4(16):2475–2487. https://doi.org/10.
1002/adhm.201500236
147. Mathur A, Ma Z, Loskill P, Jeeawoody S, Healy KE (2016)
In vitro cardiac tissue models: current status and future prospects.
Adv Drug Deliv Rev 96:203–213. https://doi.org/10.1016/j.addr.
2015.09.011
148. Leor J, Amsalem Y, Cohen S (2005) Cells, scaffolds, and mole-
cules for myocardial tissue engineering. Pharmacol Ther 105(2):
151–163. https://doi.org/10.1016/j.pharmthera.2004.10.003
149. Berglund JD, Galis ZS (2003) Designer blood vessels and thera-
peutic revascularization. Br J Pharmacol 140(4):627–636. https://
doi.org/10.1038/sj.bjp.0705457
150. Tedder ME, Liao J, Weed B, Stabler C, Zhang H, Simionescu A
et al (2009) Stabilized collagen scaffolds for heart valve tissue
engineering. Tissue Eng A 15(6):1257–1268. https://doi.org/10.
1089/ten.tea.2008.0263
151. Arts T, Bovendeerd PH, Prinzen FW, Reneman RS (1991)
Relation between left ventricular cavity pressure and volume
and systolic fiber stress and strain in the wall. Biophys J 59(1):
93–102. https://doi.org/10.1016/s0006-3495(91)82201-9
152. Mol A, van Lieshout MI, Dam-de Veen CG, Neuenschwander S,
Hoerstrup SP, Baaijens FP et al (2005) Fibrin as a cell carrier in
cardiovascular tissue engineering applications. Biomaterials.
26(16):3113–3121. https://doi.org/10.1016/j.biomaterials.2004.
08.007
153. Langer R, Vacanti JP (1993) Tissue engineering. Science.
260(5110):920–926
154. Fuchs JR, Nasseri BA, Vacanti JP (2001) Tissue engineering: a
21st century solution to surgical reconstruction. Ann Thorac Surg
72(2):577–591
155. Ishii O, Shin M, Sueda T, Vacanti JP (2005) In vitro tissue engi-
neering of a cardiac graft using a degradable scaffold with an
extracellular matrix-like topography. J Thorac Cardiovasc Surg
130(5):1358–1363. https://doi.org/10.1016/j.jtcvs.2005.05.048
1248
156. Freytes DO, Wan LQ, Vunjak-Novakovic G (2009) Geometry and
force control of cell function. J Cell Biochem 108(5):1047–1058.
https://doi.org/10.1002/jcb.22355
157. Adams JC, Watt FM (1993) Regulation of development and dif-
ferentiation by the extracellular matrix. Development (Cambridge,
England) 117(4):1183–1198
158. Brown RE, Butler JP, Rogers RA, Leith DE (1994) Mechanical
connections between elastin and collagen. Connect Tissue Res
30(4):295–308
159. Duffy GP, McFadden TM, Byrne EM, Gill SL, Farrell E, O'Brien
FJ (2011) Towards in vitro vascularisation of collagen-GAG scaf-
folds. Eur Cells Mater 21:15–30
160. Radisic M, Park H, Shing H, Consi T, Schoen FJ, Langer R et al
(2004) Functional assembly of engineered myocardium by elec-
trical stimulation of cardiac myocytes cultured on scaffolds. Proc
Natl Acad Sci U S A 101(52):18129–18134. https://doi.org/10.
1073/pnas.0407817101
161. Wei HJ, Chen CH, Lee WY, Chiu I, Hwang SM, Lin WW et al
(2008) Bioengineered cardiac patch constructed from multilayered
mesenchymal stem cells for myocardial repair. Biomaterials.
29(26):3547–3556. https://doi.org/10.1016/j.biomaterials.2008.
05.009
162. Huebsch N, Mooney DJ (2009) Inspiration and application in the
evolution of biomaterials. Nature. 462(7272):426–432. https://doi.
org/10.1038/nature08601
163. Williams DF (2009) On the nature of biomaterials. Biomaterials.
30(30):5897–5909. https://doi.org/10.1016/j.biomaterials.2009.
07.027
164. Wainwright JM, Czajka CA, Patel UB, Freytes DO, Tobita K,
Gilbert TW et al (2010) Preparation of cardiac extracellular matrix
from an intact porcine heart. Tissue Eng C Methods 16(3):525–
532. https://doi.org/10.1089/ten.TEC.2009.0392
165. Ismagilov RF, Maharbiz MM (2007) Can we build synthetic, mul-
ticellular systems by controlling developmental signaling in space
and time? Curr Opin Chem Biol 11(6):604–611. https://doi.org/
10.1016/j.cbpa.2007.10.003
166. Leor J, Tuvia S, Guetta V, Manczur F, Castel D, Willenz U et al
(2009) Intracoronary injection of in situ forming alginate hydrogel
reverses left ventricular remodeling after myocardial infarction in
Swine. J Am Coll Cardiol 54(11):1014–1023. https://doi.org/10.
1016/j.jacc.2009.06.010
167. Martens TP, Godier AF, Parks JJ, Wan LQ, Koeckert MS, Eng
GM et al (2009) Percutaneous cell delivery into the heart using
hydrogels polymerizing in situ. Cell Transplant 18(3):297–304.
https://doi.org/10.3727/096368909788534915
168. Rodell CB, Lee ME, Wang H, Takebayashi S, Takayama T,
Kawamura T et al (2016) Injectable shear-thinning hydrogels for
minimally invasive delivery to infarcted myocardium to limit left
ventricular remodeling. Circ Cardiovasc Interv 9(10). https://doi.
org/10.1161/circinterventions.116.004058
169. Johnson TD, Christman KL (2013) Injectable hydrogel therapies
and their delivery strategies for treating myocardial infarction.
Expert Opin Drug Deliv 10(1):59–72. https://doi.org/10.1517/
17425247.2013.739156
170. Dib N, Campbell A, Jacoby DB, Zawadzka A, Ratliff J,
Miedzybrocki BM et al (2006) Safety and feasibility of percuta-
neous autologous skeletal myoblast transplantation in the coil-
infarcted swine myocardium. J Pharmacol Toxicol Methods
54(1):71–77. https://doi.org/10.1016/j.vascn.2005.12.002
171. Rao SV, Zeymer U, Douglas PS, Al-Khalidi H, Liu J, Gibson CM
et al (2015) A randomized, double-blind, placebo-controlled trial
Heart Fail Rev (2021) 26:1231–1248
to evaluate the safety and effectiveness of intracoronary applica-
tion of a novel bioabsorbable cardiac matrix for the prevention of
ventricular remodeling after large ST-segment elevation myocar-
dial infarction: Rationale and design of the PRESERVATION I
trial. Am Heart J 170(5):929–937. https://doi.org/10.1016/j.ahj.
2015.08.017
172. Rao SV, Zeymer U, Douglas PS, Al-Khalidi H, White JA, Liu J
et al (2016) Bioabsorbable intracoronary matrix for prevention of
ventricular remodeling after myocardial infarction. J Am Coll
Cardiol 68(7):715–723. https://doi.org/10.1016/j.jacc.2016.05.
053
173. Mann DL, Lee RJ, Coats AJ, Neagoe G, Dragomir D, Pusineri E
et al (2016) One-year follow-up results from AUGMENT-HF: a
multicentre randomized controlled clinical trial of the efficacy of
left ventricular augmentation with Algisyl in the treatment of heart
failure. Eur J Heart Fail 18(3):314–325. https://doi.org/10.1002/
ejhf.449
174. Mewhort HE, Turnbull JD, Satriano A, Chow K, Flewitt JA,
Andrei AC et al (2016) Epicardial infarct repair with bioinductive
extracellular matrix promotes vasculogenesis and myocardial re-
covery. J Heart Lung Transplant 35(5):661–670. https://doi.org/
10.1016/j.healun.2016.01.012
175. Mewhort HE, Turnbull JD, Meijndert HC, Ngu JM, Fedak PW
(2014) Epicardial infarct repair with basic fibroblast growth factor-
enhanced CorMatrix-ECM biomaterial attenuates postischemic
cardiac remodeling. J Thorac Cardiovasc Surg 147(5):1650–
1659. https://doi.org/10.1016/j.jtcvs.2013.08.005
176. Menasche P, Vanneaux V, Hagege A, Bel A, Cholley B,
Parouchev A et al (2018) Transplantation of human embryonic
stem cell-derived cardiovascular progenitors for severe ischemic
left ventricular dysfunction. J Am Coll Cardiol 71(4):429–438.
https://doi.org/10.1016/j.jacc.2017.11.047
177. Sahoo S, Losordo DW (2014) Exosomes and cardiac repair after
myocardial infarction. Circ Res 114(2):333–344. https://doi.org/
10.1161/circresaha.114.300639
178. Liu B, Lee BW, Nakanishi K, Villasante A, Williamson R, Metz J
et al (2018) Cardiac recovery via extended cell-free delivery of
extracellular vesicles secreted by cardiomyocytes derived from
induced pluripotent stem cells. Nat Biomed Eng 2(5):293–303.
https://doi.org/10.1038/s41551-018-0229-7
179. Purcell BP, Lobb D, Charati MB, Dorsey SM, Wade RJ, Zellars
KN et al (2014) Injectable and bioresponsive hydrogels for on-
demand matrix metalloproteinase inhibition. Nat Mater 13(6):
653–661. https://doi.org/10.1038/nmat3922
180. Wang LL, Liu Y, Chung JJ, Wang T, Gaffey AC, Lu M et al (2017)
Local and sustained miRNA delivery from an injectable hydrogel
promotes cardiomyocyte proliferation and functional regeneration
after ischemic injury. Nat Biomed Eng 1:983–992. https://doi.org/
10.1038/s41551-017-0157-y
181. Fan Z, Xu Z, Niu H, Gao N, Guan Y, Li C et al (2018) An
injectable oxygen release system to augment cell survival and
promote cardiac repair following myocardial infarction. Sci Rep
8(1):1371. https://doi.org/10.1038/s41598-018-19906-w
182. Tang J, Shen D, Caranasos TG, Wang Z, Vandergriff AC, Allen
TA et al (2017) Therapeutic microparticles functionalized with
biomimetic cardiac stem cell membranes and secretome. Nat
Commun 8:13724. https://doi.org/10.1038/ncomms13724
Publisher’s note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.