Cardiovascular Regenerative Medicine: Tissue Engineering and Clinical Applications

242 Pages·2019·7.582 MB·English

by  Vahid Serpooshan, Sean M. Wu

Cardiovascular
Regenerative
Medicine
Tissue Engineering and Clinical
Applications
Vahid Serpooshan
Sean M. Wu
Editors
123
Cardiovascular Regenerative Medicine
Vahid Serpooshan • Sean M. Wu
Editors
Cardiovascular
Regenerative Medicine
Tissue Engineering and Clinical
Applications
Editors
Vahid Serpooshan Sean M. Wu
Department of Biomedical Engineering Cardiovascular Institute and
Emory University School of Medicine Department of Medicine,
and Georgia Institute of Technology Division of Cardiovascular Medicine,
Atlanta, GA Stanford University
USA Stanford, CA
USA
Department of Pediatrics
Emory University School of Medicine
Atlanta, GA
USA
Children’s Healthcare of Atlanta
Atlanta, GA
USA
ISBN 978-3-030-20046-6 ISBN 978-3-030-20047-3 (eBook)
https://doi.org/10.1007/978-3-030-20047-3
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Cardiovascular Regenerative Medicine:
An Introduction
In the past decades, the progress made in cardiovascular regenerative medicine has
been nothing but spectacular. From an improved understanding of how the heart
develops in the earliest stages of fetal development to barriers that prevents an adult
cardiomyocytes to undergo cell division, we have come a long way to identify
potential therapeutic strategies that can mediate the repair and regeneration of the
mammalian heart. While much scientific progress has been celebrated and show-
cased at research conferences and in published studies, the stark reality remains that
cardiovascular disease is the number one cause of death in the Western world with
rapidly rising incidence in developing countries such as China and India. Given this,
the interest in developing new therapies for treating, if not curing, damaged hearts
remains strong.
Therapeutic approaches to treat cardiovascular diseases span a broad spectrum
from small molecules/drugs (least invasive) to heart transplant (most invasive).
Unfortunately, while drugs have helped improve the quality-of-life of patients with
heart failure, they have not significantly alter the overall course of disease. On the
other hand, heart transplant is life saving and provides a durable solution to heart
failure, the number of hearts available for transplant is limited to roughly 2200 per
year in the U.S. and this number has not changed significantly in the past three–four
decades. Given that there are in excess of 100,000 patients waiting and dying while
on the heart transplant waitlist, there is a great need to find innovative solutions to
stem the rising tide of mortality due to heart failure. Hence, cardiovascular investi-
gators have actively sought new therapeutic strategies that fills this large void
between these two therapeutic extremes.
With the discovery of stem cells from tissue/resident sources, early human
embryos, and more recently induced from somatic cells by the over-expression of
key pluripotent transcription factors, many investigators have turned to using stem
cell-derived cardiac cells as the therapeutic agent to help repair and regenerate lost
heart tissue. The remarkable potential for stem cells to differentiate into cardiac
cells has naturally led to the interest in applying these different types of stem cells
in clinical studies. The transplantation of autologous adult derived stem cells to treat
heart disease has received significant attention in the past 15 years and is a topic that
will be addressed in Chap. 9. In parallel, the rapidly expanding field of bioengineer-
ing has taken notice of the possibility of creating new cardiac tissues or even
replacement organs using stem cell-derived cardiac cells. The convergence of stem
v
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cell biology and bioengineering may represent one of the greatest synergy for gen-
erating new therapy for cardiovascular diseases and improving the care of heart
disease patients. Given the numerous advances that have been made in this area, we
have chosen to devote a number of Chaps. 3, 4, 5, and 6 to this topic.
Among the different stem cells types that are being explored, induced pluripotent
stem cells (iPSCs) has received significant attention due to the lesser concerns ethi-
cally compare with human embryonic stem cells (ESCs) and greater differentiation
potential into various cardiac cell types compare with autologous stem cells from
the blood, bone marrow, or adipose tissues. Indeed, these iPSC cells derived from
human carrying specific genetic mutation has been actively explored by cardiovas-
cular investigators in a strategy akin to “disease-in-a-dish”. In Chaps. 1 and 2, the
use of iPSC to model arrhythmia, sarcomeric gene mutation with contractile defect,
and metabolic syndrome will be discussed. The use of patient/disease-specific iPSC
has raised the exciting prospect for being able to deliver personalized treatment in a
way that meets the intent of precision medicine. Indeed, numerous studies have now
shown the faithful recapitulation of cardiac disease phenotype in the in vitro dif-
ferentiated iPSC-derived cardiomyocytes and endothelial cells. Furthermore, the
use of these disease models for high throughput drug discovery will be highlighted
in Chap. 2, since there is no longer a limitation on the number of cardiac cells avail-
able for screening hundreds of thousands of compounds at a time.
While iPSC-derived cardiac cells show significant promise as a drug discovery
and disease modeling platform, they represent another source of stem cells that may
be used for autologous cell-based therapy. Thus far, very few clinical studies have
utilized human iPSC as the cell source due to concerns for teratoma formation, low
rate of cell engraftment, and toxicity from potentially lethal arrhythmia. Fortunately,
there has been no reported incidence of teratoma formation when human ESC/
iPSC-derived cardiac cells were injected into hearts of large animal models.
However, the size of the transplanted cell graft is generally small and declines in
size over time. Notably, there was an extremely high incidence of ventricular tachy-
cardia in non-human primates that receiving iPSC-CM injection. To overcome this
challenge, cardiovascular investigator have turn to creating engineered tissue that
can be perfused and integrated to connect with the host. The hope is that these engi-
neered tissues will be better aligned and organized so that their arrhythmogenic
potential will be reduced as well. This strategy will be explored in Chaps. 8 and 9
on engineering of cardiac patch for regenerative medicine.
Aside from the goal of remuscularization of the damaged heart, it has been
shown that some improvement in cardiac function may be achieved when the
adverse remodeling of the heart can be prevented after myocardial infarction. This
was originally shown in an unique surgical procedure where the latissimus dorsi
muscle of the patient is resected and used as a flap to wrap around the epicardial
surface of the infarcted region of the heart. This was intended to prevent the aneu-
rysmal ballooning of that region of the heart and promote normal pump function of
the left ventricle. Subsequent studies have found that much if not all of the benefit
from this invasive surgical procedure can be recapitulated by injection of biomateri-
als into the infarcted regions. A number of biomaterials such as fibrin, alginate, and
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decellularized cardiac matrix have been studied in recent year. These studies will be
discussed in Chap. 10 on injectable hydrogel biomaterial for treatment of myocar-
dial infarction.
Beyond the treatment of adult cardiac diseases, a special consideration needs to
be given to the treatment of pediatric patients with congenital heart diseases. As
detailed in Chap. 11, the treatment of children with congenital heart diseases has
been particularly challenging due to the severity of their disease, the need for con-
tinued growth during childhood, and the complexity of their cardiac anatomy.
Furthermore, the number of patients available for clinical study is generally small
so conclusions are harder to reach when the error bars for studies are large.
Nevertheless, significant advances have been made in generating engineered heart
valves and vascular grafts for surgical and percutaneous repair of children with
heart disease. These advances will be covered in Chap. 11 on regenerative medicine
for the treatment of congenita heart diseases.
In summary, we hope this book will illustrate both the challenges and excitement
of regenerative medicine and tissue engineering for cardiovascular applications. By
incorporating advances in stem cell biology, biomaterials, and high through put
drug screen, we hope that new therapies for children and adults with heart disease
will be available in the near future.
Stanford, CA, USA Sean M. Wu
Atlanta, GA, USA Vahid Serpooshan
Contents
1 Tissue-Engineered Stem Cell Models of Cardiovascular Diseases . . . . 1
Christopher W. Anderson, Jiesi Luo, Lorenzo R. Sewanan,
Mehmet H. Kural, Muhammad Riaz, Jinkyu Park, Yan Huang,
Laura E. Niklason, Stuart G. Campbell, and Yibing Qyang
2 Phenotypic Screening of iPSC-Derived Cardiomyocytes for
Cardiotoxicity Testing and Therapeutic Target Discovery . . . . . . . . . . 19
Arne A. N. Bruyneel, Tyler Muser, Vaidya Parthasarathy,
Dries Feyen, and Mark Mercola
3 Decellularized Extracellular Matrix- Based Cardiovascular
Tissue Engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Kristin M. French and Michael E. Davis
4 3D Bioprinting of Cardiovascular Tissue Constructs:
Cardiac Bioinks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Martin L. Tomov, Andrea Theus, Rithvik Sarasani, Huyun Chen,
and Vahid Serpooshan
5 Nanobiomaterial Advances in Cardiovascular Tissue Engineering . . . 79
Michael J. Hill, Morteza Mahmoudi, and Parisa P. S. S. Abadi
6 Bioengineering 3D Cardiac Microtissues Using Bioassembly. . . . . . . . 107
Longjun Gu, Jinghan Feng, Donghui Zhang, and Pu Chen
7 From Bench to Clinic: Translation of Cardiovascular
Tissue Engineering Products to Clinical Applications . . . . . . . . . . . . . . 125
Amanda N. Steele and Y. Joseph Woo
8 Cardiac Patch-Based Therapies of Ischemic Heart Injuries . . . . . . . . 141
Wuqiang Zhu, Danielle Pretorius, and Jianyi Zhang
9 Cell-Based Cardiovascular Regenerative Therapies . . . . . . . . . . . . . . . 173
Ray P. Prajnamitra, Yuan-Yuan Cheng, Li-Lun Chen,
and Patrick C. H. Hsieh
10 Injectable Hydrogels to Treat Myocardial Infarction . . . . . . . . . . . . . . 185
Miranda D. Diaz and Karen L. Christman
ix
x
11 Regenerative Medicine for the Treatment of Congenital
Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Elda Dzilic, Stefanie Doppler, Rüdiger Lange, and Markus Krane
12 Cardiovascular Regenerative Medicine: Challenges,
Perspectives, and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
Sean M. Wu and Vahid Serpooshan
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Contributors
Parisa P. S. S. Abadi, Ph.D. Department of Mechanical Engineering-Engineering
Mechanics, Michigan Technological University, Houghton, MI, USA
Department of Biomedical Engineering, Department of Materials Science and
Engineering, Michigan Technological University, Houghton, MI, USA
Christopher W. Anderson, Ph.D. Vascular Biology and Therapeutics Program,
Yale University, New Haven, CT, USA
Department of Pathology, Yale University, New Haven, CT, USA
Arne A. N. Bruyneel, Ph.D. Cardiovascular Institute and the Department of
Medicine, Stanford University, Stanford, CA, USA
Stuart G. Campbell, Ph.D. Department of Biomedical Engineering, Yale
University, New Haven, CT, USA
Yale Stem Cell Center, New Haven, CT, USA
Huyun Chen Wallace H. Coulter Department of Biomedical Engineering, Emory
University School of Medicine and Georgia Institute of Technology, Atlanta, GA,
USA
Li-Lun Chen, Ph.D. Institute of Biomedical Sciences, Academia Sinica, Taipei,
Taiwan
Pu Chen, Ph.D. Department of Biomedical Engineering, School of Basic Medical
Sciences, Wuhan University, Wuhan, China
Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of
Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation,
Wuhan, China
Yuan-Yuan Cheng, Ph.D. Institute of Biomedical Sciences, Academia Sinica,
Taipei, Taiwan
Karen  L.  Christman, Ph.D. Department of Bioengineering, University of
California, San Diego, La Jolla, CA, USA
Sanford Consortium for Regenerative Medicine, San Diego, La Jolla, CA, USA
xi