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Cardiovascular Tissue Engineering Research Support at the
National Heart, Lung, and Blood Institute
Martha S. Lundberg
Abstract: Tissue engineering aims at building 3-dimensional living substitutes that are equal to or better than the
damaged tissue to be replaced. The development of such a tissue replacement requires a multidisciplinary approach
and careful attention to the optimal cell source, the interactions of growth factors and extracellular milieu, and
the scaffolding design. This article is a review of the tissue engineering programs of the National Heart, Lung, and
Blood Institute, which support research efforts to translate novel approaches for the treatment of cardiovascular
disease. Recent progress is discussed, which highlights some major questions relevant to cardiovascular tissue
engineering. The National Heart, Lung, and Blood Institute has a strong interest in tissue engineering and will
continue to foster the practical, clinical, and commercial development of research discoveries in this emerging
field. (Circ Res. 2013;112:1097-1103.)
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Key Words: biomaterials
■
cardiovascular
■
regenerative medicine
O
ver the last 40 years, death rates from cardiovascular
diseases (CVD) have declined significantly because of
advances in medical treatment options and improved healthcare. Americans are living longer, healthier lives with CVD
but along with this reality comes additional consequences.
For example, the total economic cost of CVD in the United
States rose to ≈$298 billion in 20081,2; CVD is becoming a
chronic and expensive ailment, which is compounded by an
aging population. Our ability to achieve alternative and more
cost-effective therapies is an urgent need, especially for the
treatment of atherosclerosis, peripheral arterial disease, and
congestive heart failure. Recently, improved understanding of
cells, tissue properties, and specialized biomaterials has enabled teams of scientists and engineers to create tissue substitutes destined for heart valve repair, reduction of scarring after
myocardial infarction, blood vessel replacement, and correction of pediatric heart malformations. Development of novel
tissue engineering strategies for heart failure and vascular disease is a research priority for the National Heart, Lung, and
Blood Institute ([NHLBI], http://www.nhlbi.nih.gov/about/
strategicplan/documents/StrategicPlan_Plain.pdf).
The Multi-Agency for Tissue Engineering Science
(MATES) Interagency Working Group defines tissue
engineering and science as the use of physical, chemical,
biological, and engineering processes to control and direct
the aggregate behavior of cells (http://www.tissueengineering.
gov/advancing_tissue_science_&_engineering.pdf). At the
■
stem cells
■
tissue engineering
core of tissue engineering is the construction of 3-dimensional
(3D) tissues using biomaterials. These materials provide
overall mechanical support and cell-instructive cues to guide
cell growth and tissue construct stability. Tissue engineering,
often used synonymously with regenerative medicine,
endeavors to combine the use of cells, engineering, and
biomaterials to empower the body’s own repair mechanisms
to heal damaged tissues or organs.
Since Weinberg and Bell3 first described the idea of growing a living blood vessel in 1986, the field of tissue engineering has grown tremendously. For example, healthcare is
already being changed by tissue engineering approaches; a
search on tissue engineering in ClinicalTrials.gov brings up
almost 50 trials, primarily in the eye, bone, cartilage, and
dental fields (http://clinicaltrials.gov/). Clinical studies are
also beginning to emerge in the cardiovascular, liver, kidney,
and endocrine areas.
At the National Institutes of Health, a survey of NHLBIspecific projects in tissue engineering was conducted using the
electronic research administration system. Overall, this survey
showed that NHLBI supports >200 projects in tissue engineering and regenerative medicine, which represents ≈$96.9 million in funding for fiscal year 2012. The NHLBI portfolio is
spread over a number of mechanisms, including Small Business
Innovation Research (R42, R44) but >50% fall in the R01 category. There is a sizeable training component in the F, K, and T
mechanisms. Comparable data can also be obtained using the
Original received November 28, 2012; revision received February 4, 2013; accepted March 6, 2013. In February 2013, the average time from submission
to first decision for all original research papers submitted to Circulation Research was 11.98 days.
The views expressed herein are those of the author and do not reflect those of the NHLBI, NIH, HHS or Federal Government.
From the Division of Cardiovascular Sciences (DCVS), National Heart, Lung and Blood Institute (NHLBI), Bethesda, MD.
Correspondence to Martha S. Lundberg, PhD, DCVS, NHLBI, Rockledge II, Rm 8210, 6701 Rockledge Dr, Bethesda, MD 20892. E-mail lundberm@
nhlbi.nih.gov
© 2013 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.112.300638
1097
1098 Circulation Research April 12, 2013
Nonstandard Abbreviations and Acronyms
CVD
ECM
hESCs
MATES
NHLBI
3D
cardiovascular disease
extracellular matrix
human embryonic stem cells
Multi-Agency for Tissue Engineering Science
National Heart, Lung, and Blood Institute
3-dimensional
public domain National Institutes of Health Research Portfolio
Reporting Tools system (http://www.projectreporter.nih.gov/
reporter.cfm). The purpose of this article is to describe NHLBI–
supported cardiovascular tissue engineering research programs,
discuss recent advances made possible by federal-wide collaboration through the MATES interagency working group (http://
www.tissueengineering.gov/), and summarize some of the major questions that may impact the future directions of this field.
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Innovative Technologies for Engineering Small
Blood Vessels
Demand for alternative vascular conduits has been driven by
the poor clinical efficacy of existing synthetic grafts for small
diameter artery applications in patients who lack adequate
saphenous veins. To address this demand, NHLBI released a
targeted initiative, Innovative Technologies for Engineering
Small Blood Vessels. Four R01 grants were funded for a total of
$13.7 million for 5 years in 2006 (http://grants.nih.gov/grants/
guide/rfa-files/rfa-hl-05-013.html). The major objective of this
program was to apply a broad range of multidisciplinary approaches to conduct research, and to design, fabricate, and engineer small (<5.0 mm) blood vessel substitutes with improved
biocompatibility and durability. The anticipated outcome was
to create an environment for establishing optimal conditions
(eg, cell types, protocols, animal models, and assessment tools)
for vessel replacement therapy in humans. Investigators who
were funded under this program have accomplished significant
preclinical proof of principle studies in animals, and these novel technologies are being further explored for translation into
human use by industry. As of October 2012, this program has
stimulated the tissue engineering area by producing 72 publications in peer-reviewed journals, which have been cited >860
times by others (excluding review articles).
Enabling Technologies for Tissue Engineering and
Regenerative Medicine
One ultimate application of tissue engineering is to develop
strategies for in vivo regeneration to permanently restore function to compromised tissues in humans but a more near-term
application is to develop in vitro disease models for drug testing. However, a critical roadblock is the difficulty in unifying
a broad array of disciplines and applying focused tools from
developmental and cell biologists, geneticists, clinicians, engineers, materials scientists, and mathematicians to better understand tissue formation. In particular, there is a critical need
for multidisciplinary teams to work together to identify the
mechanisms of cellular behavior that affect tissue dynamics.
In collaboration with the MATES working group, NHLBI
cosponsored another program, Enabling Technologies for
Tissue Engineering and Regenerative Medicine, and solicited
for grant applications (http://grants.nih.gov/grants/guide/pafiles/par-06-504.html) in an effort to cross-fertilize the field
with other scientific disciplines. In 2007, funding support for
7 R01 multidisciplinary research projects began, and our commitment totals $14.1 million. Active support continues through
2014. The overall outcome for this transagency effort was to
promote collaborative development of new technologies, tools,
methods, and devices that enable the engineering of functional
tissues. As of October 2012, the NHLBI-funded investigators
supported by this program have published ≈122 articles since
2007 on their findings, often in high-impact journals.
New Strategies for Growing 3D Tissues
Although the long-term goal of tissue engineering is to enhance
in vivo regeneration, a short-term opportunity is to improve our
understanding of how cells respond structurally to the features
of their environment, and to develop accurate approaches that
may guide the creation of 3D engineered cellular aggregates.
Consistent with this short-term goal, the NHLBI initiated a
new program in 2011 entitled, New Strategies for Growing
3D Tissues (http://grants.nih.gov/grants/guide/rfa-files/RFAHL-11–025.html, and http://grants.nih.gov/grants/guide/rfafiles/RFA-HL-11–026.html). The anticipated outcome for this
program is to demonstrate reproducible recapitulation in the
laboratory for events, such as differentiation, proliferation,
migration, and maturation. This program is jointly funded
with the National Institute of Arthritis and Musculoskeletal
and Skin Diseases, and the National Institute of Biomedical
Imaging and Bioengineering. Total support for 12 projects
shared between the 3 institutes is $18.4 million. Of the 12
projects funded, key multidisciplinary research questions
being addressed include how cells form a 3D structural
response to the dynamic elements of humanized heart (7),
lung (3), blood (1), and musculo-skeletal (1) biomatrices, as
well as the design of bioreactors that will sustain the growth,
development, and vascularization of functional human tissues.
Funding support for the R01 projects continues through 2015
and is expected to make significant advancements in this area.
NHLBI Support for Federal-wide Efforts in Tissue
Engineering Research
Parallel to efforts at the NHLBI, a federal-wide strategic plan
was developed by the MATES Interagency Working Group regarding tissue science and engineering. Since the term tissue
engineering was initially defined in 1988,4 several fundamental questions about how cells work within engineered matrices
still remain unsolved. The MATES plan laid out the priorities
and implementation steps for Federal Government agencies to
focus their activities to have the greatest impact in advancing
tissue science and engineering. New innovations that address
understanding the cellular response, formulating biomaterial
scaffolds and the tissue matrix environment, and developing
enabling tools are recognized needs to launch tissue engineering applications into an increasingly sophisticated medical
marketplace.
An explosion of interest and research in tissue engineering has occurred during the last 10 years, and the NHLBI has
Lundberg Cardiovascular Tissue Engineering Support at NHLBI 1099
played a critical role in accelerating our understanding of the
field. First generation tissue-engineered products have been
designed as simplified model systems to answer fundamental
cell biology and engineering questions needed for moving to
the next level of functional organ complexity. Additionally,
stem cell research has contributed much toward the scientific
underpinnings of cell biology and engineering, as well as providing reliable, robust sources of characterized cells. Many
near-term challenges and opportunities for integrating current
knowledge and best practices are now being sought, so that
gap areas can be rapidly identified and addressed. Recent examples of where the NHLBI has funded the growth of federal-wide strategic research areas, as described in the MATES
plan, are provided in 3 broadly defined categories below.
Understanding the Cellular Response
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An important challenge for the field of tissue engineering and
science is to model the normal process by which cells self-assemble into tissues and then organs; in general, the cell is considered the central functional unit within a given organ system.
Cells receive messages from physical, chemical, and electric
sources, each of which begins a cascade of internal cellular
events that ultimately determines phenotypic change. Cells also
share information by releasing molecular signals that regulate
their own behavior and that of nearby or even distant cells.
In the cardiac regeneration field, the biological complexity
of the tissue has driven researchers to focus efforts toward that
of in vivo repair as opposed to replacement. Animal studies are
in progress to understand the ability of human embryonic stem
cells (hESCs)–derived cardiomyocytes to repair injured hearts.
Shiba et al5 used a guinea-pig model to show that transplanted
heart cells, grown from human stem cells and delivered with a
prosurvival cocktail of Matrigel, insulin-like growth factor-1,
and multiple cell death pathway inhibitors, electrically couple
and beat in sync with the own muscle of the heart. More surprising is that with transplantation of the cells, the overall incidence of arrhythmia was lower, an effect that may be clinically
useful if shown successful in larger animals (Figure 1).
Furthermore, matrices that promote differentiation and
proliferation of stem cells for use in tissue engineering are of
great interest. For example, hESCs have been used to promote
neovascularization and myogenesis in the areas damaged by
a heart attack; however, because of minimal cell-based retention, more suitable biomatrices are needed to improve survival
and integration of cells transplanted into the host tissue. Duan
et al6, funded under PAR-06-504, aim to further our understanding of hESCs in a 3D environment to determine whether
native cardiac extracellular matrix (ECM) hydrogels can drive
differentiation of hESCs into cardiac lineages, and whether
the use of cardiac ECM hydrogels can alleviate the need for
supplemental growth factors. The authors show that hydrogel
with a high ECM content (75% EM, 25% collagen) increased
the fraction of hESCs expressing cardiac marker troponin T,
improved mature striation patterns, and improved overall contractile function. These results serve as the basis for future
studies of the mechanisms by which the native ECM hydrogel
regulates cardiomyocyte phenotype and the use of the native
ECM hydrogel as a cell delivery vehicle for heart repair.
Formulating Biomaterial Scaffolds and the Tissue
Matrix Environment
Because of advancements in materials science, there are a
wide variety of synthetic and natural polymers that may be
used for tissue scaffolds. Increasingly, materials are being
selected based on the properties for a particular application.
Scaffold porosity and matrix stiffness are both important considerations for structural integrity, cellular infiltration, and final maturation of the construct. Following up on studies that
demonstrated the clinical feasibility of engineered vascular
grafts in humans, Hibino et al7 developed a tissue-engineered
vascular graft composed of a biodegradable, polyglycolic acid
scaffold with autologous bonemarrow–derived mononuclear
cells. The authors demonstrated in mice that bone marrow is
not a significant source of endothelial or smooth muscle cells
in the formation of neovessels, and further, that the adjacent
vessel wall is the principal source of cells, making up 93%
of the proximal neotissue. The authors conclude that in this
setting, the tissue-engineered construct functions by mobilizing the innate healing capabilities of the body to regenerate
neotissue from preexisting committed tissue cells. This technology is currently in clinical trial to evaluate the safety and
growth potential in children undergoing surgery for congenital
heart disease.
A major limitation for use of tissue-engineered vascular
grafts is that it often requires months-long processing to culture
a functional and mechanically robust arterial prosthesis that
are suitable for repair. Recently although, Quint et al8 funded
under RFA-HL-05-013 showed that 1 mm decellularized
human tissue–engineered vessels can be used as a biological
graft that resists both clotting and intimal hyperplasia. Their
results demonstrated that engineered vessels can be grown
from banked cells, rendered acellular, and then be used for
tissue regeneration in vivo. Even more remarkable was that the
decellularized human tissue–engineered vessels were found
to have recruited endogenous cells that included a confluent
endothelium and coaxial subendothelial smooth muscle cells
(Figure 2). Their results offer an inventive solution to the
widespread scarcity of vessels available for revascularization
procedures. Moreover, they show that engineered vessels
can feasibly be produced offline, not requiring cells from the
actual recipient, and thereby reducing the waiting time for the
production of the vascular substitute.
There are ≈80 000 heart valve replacements or repairs
performed in the United States each year, however, mechanical
or bioprosthetic devices for heart valve disease are associated
with significant drawbacks, such as the fact that they cannot
grow, remodel, or repair in vivo. The field of tissue engineering
has emerged as an exciting alternative in the search for
improved heart valve replacement structures, especially for
those individuals who cannot receive conventional therapy. For
example, studies by Tseng et al9 are exploring the fabrication
of trilayer hydrogel quasilaminates. This novel approach looks
at the challenge of layer-specific valve mechanical properties
for the purpose of tailoring matrix-specific formulas for cell
encapsulation. In another study, Tedder et al10 describe the
development of 2 novel types of acellular collagen scaffolds,
one scaffold was designed to mimic natural valve fibrous layers,
and the other scaffold was developed to mimic the delicate and
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Figure 1. Transplanted human embryonic stem cells–cardiomyocyte (hESC–CMs) partially remuscularize injured guinea-pig
hearts, preserve mechanical function, and reduce arrhythmia susceptibility. To determine the arrhythmic potential of hESC–CM
transplantation in an infarct model, guinea pigs were implanted with a telemetric ECG transmitter and subjected to cardiac cryoinjury.
Ten days after cryoinjury, animals underwent a repeat thoracotomy and intracardiac injection of either hESC–CMs in pro-survival
cocktail (PSC), non-CMs in PSC, or PSC vehicle only. End points included echocardiography, telemetric monitoring of spontaneous
arrhythmias, and induced arrhythmias by programmed electric stimulation (PES) (performed on day +28 post-transplantation). A,
Twenty-eight-day-old hESC–CM grafts in a cryoinjured heart stained with picrosirius red, and anti–β-myosin heavy chain (βMHC, red,
higher magnification shown) plus human-specific in situ probe (HumCent, brown). Second row, confocal image of host–graft contact,
dual-labeled for HumCent (white) and βMHC (red). Third row, destained and then immunostained for βMHC (red) and either connexin
43 (C×43) or cadherin (green). Fourth row, C×43 and cadherin shared between graft and host myocytes. B, Fractional shortening (FS)
by echocardiography in uninjured and injured animals receiving hESC–CMs in PSC, non-CMs in PSC, or PSC vehicle only at 2 days
before and 28 days after transplantation. C, Representative telemetric ECG traces showing episodes of spontaneous nonsustained and
sustained ventricular tachycardia (VT). D, Percentage of animals by group that showed spontaneous VT during monitoring from days 3
to 28 after transplantation. E, Frequency of spontaneous VT by group. F, Representative ECG (red) and stimulation (blue) traces from a
cryoinjured non-CM recipient induced to sustained VT by PES. G, Percentage of animals by group that showed induced VT by PES. All
data are presented as mean±SEM; n≥13 per group. *P<0.05; **P<0.01. †P<0.05 vs day −2. Reprinted from Shiba et al5 with permission
from Macmillan Publishers, Ltd.
highly hydrated spongiosa layer. Human bone marrow stem
cells were seeded onto both scaffolds. Trilayered constructs
were created using a cell-seeded spongiosa scaffold sandwiched
between 2 fibrous scaffolds using a protein-based glue and then
placed into anatomically analogous 3D heart valve shapes.
The valves were conditioned in bioreactors to induce cellular
differentiation, and cell viability was assessed after 8 days.
To evaluate biocompatibility, the structures were implanted
subdermally in juvenile rats and showed good integration
after 5 weeks.10 These examples are foundational toward
the development of new approaches to reduce the burdens
associated with conventional, mechanical, and bioprosthetic
(animal or human) heart valve replacement therapies.
Developing Enabling Tools
Tissue development is the result of molecular and supramolecular interactions, and great progress has been made toward
that understanding; yet additional research is needed to improve our appreciation between living and nonliving components of engineered tissues. Reliable protocols and tests, as
well as improved real-time imaging, are required for collecting data that are comparable, and to inform predictive models
for assessing the state of engineered tissues.
Currently, studies of engineered tissues often are conducted
by implantation of the construct into an animal; however,
this approach can be inefficient because of inadequate
vascularization. Vascularization is a limiting factor because of
Lundberg Cardiovascular Tissue Engineering Support at NHLBI 1101
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Figure 2. Explant immunohistochemistry of decellularized human tissue–engineered vessel at 6 weeks. Stained with (A)
hematoxylin and eosin stain (H&E; red and blue), (B) smooth muscle α-actin (brown), (C) von Willebrand Factor (brown), and (D) elastin
Van Gieson (black stain near lumen). By H&E (A), explanted grafts were negative for evidence of graft dilation, with relatively uniform graft
wall architecture. Although there was no significant dilation within each segment of the explanted vessels, only one time point at 6 weeks
was obtained for histology. The decellularized human tissue–engineered graft exhibited host cell infiltration on the luminal and abluminal
side of the matrix. Host cells did not completely infiltrate through the entire wall of the graft by 6 weeks, and there was a remaining
acellular matrix. The neotissue investing and adjacent to the grafts was characterized by immunohistochemistry for smooth muscle and
endothelial cell markers. The cells on the outer side of the engineered vessels were predominately positive for smooth muscle α-actin
(B), indicating a smooth muscle or myofibroblast phenotype. The neointima also had a thin layer of smooth muscle cells. The luminal
surface displayed a confluent lining of endothelial cells on all samples, which were positive for von Willebrand factor (C). Because the
decellularized graft was acellular at the time of implantation, the endothelial cells were host derived. The endothelialized neointima likely
aided in preventing graft thrombosis and was thin and did not cause narrowing of the lumen. The decellularized human tissue–engineered
vessels provided a matrix that supported the host cellular infiltration and stimulated a functional neointima. Elastin formation within the
neointima was shown on elastic van Gieson staining (D). Scale bar, 100 µm. Reproduced from Quint et al8 with permission of MOSBY, Inc
and Elsevier.
the role of oxygen and nutrient diffusion limitations within
bulk engineered tissues, which underlies the importance of
preformed vasculature. In engineered tissues with preformed
vascular networks, this is attributable to the inability of
preassembled vascular networks to connect with the host’s
microcirculation. To overcome this limitation, Kang et al11
has developed a technology for generating vascularized
tissue–engineered constructs. In this study, the authors
designed a transplantation model in immunodeficient mice,
which consisted of human endothelial colony forming cells
and mesenchymal progenitor cells in Matrigel. The cellcontaining Matrigel implants were harvested for microvessel
density analysis or transplanted into secondary mice at day
7. In vivo labeling of human-specific cells with fluorescently
conjugated lectins allowed for the visualization of functional
connections between bioengineered and host vessels.
Importantly, their results show that prebuilt perfused human
vessels are transplantable from one in vivo site to another
(Figure 3).11 Kang’s work extends the range of applications
of cell-based technology for transplantable tissue–engineered
constructs. NHLBI looks forward to the expansion of this field
using new approaches for scaffold design.
One advantage of studying cell behavior at the microscale
level is to identify mechanisms of in vivo multicellular migration.12,13 Hydrogels represent a mostly biocompatible class
of materials that are capable of mimicking the basic, 3D
properties of native tissues. Their properties can be tailored
to enable precise control of surface features to study cell behavior mechanisms in vitro. For example, Du et al14 developed
a clever method using hydrophilic microgels (20% [wt/wt]
poly(ethylene glycol)-diacrylate) mixed with a photo-initiator
and applied to a glass slide as a way to study cells discretely.
Specifically, a drop of photocrosslinkable polyethylene glycol
diacrylate prepolymer was pipetted onto a glass slide. A cover glass slide was applied on top of the solution drop, which
formed an evenly distributed film of prepolymer solution. A
photomask was put on top of the cover slide, and microgels
were formed by exposing the prepolymer solution to ultraviolet
Table. Some Major Questions in Cardiovascular Tissue
Engineering
Domain
Question
Soft tissues
What is the best way to establish a blood supply to a tissueengineered construct, such as a cardiac patch?
Cells
How do very few hESC–CMs surviving in the heart affect
ventricular arrhythmia?
Are patient-specific (autologous) approaches best, or can we
address issues with allogenic donors?
Imaging
What approaches and methods are best to assess viability and
function of an engineered tissue in vivo?
hESC–CM indicates human embryonic stem cells–cardiomyocytes.
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Figure 3. Microvessel density analysis before and after transplantation of Matrigel implants containing 2×106 cells at a ratio of
2 endothelial colony forming cells: 3 mesenchymal progenitor cells. Matrigel implants were harvested at multiple time points before
and after transplantation. A, Diagram of transplantation model. B–E, Perfused human and murine vessels were identified by tail-vein
injection of a mixture of rhodamine (red)–conjugated ulex europaeus agglutinin-I and fluorescein isothiocyanate (FITC; green)–conjugated
GS-IB4. B, Representative confocal images of 3 distinct patterns of lectin-labeled vessels in the implants at pretransplantation day 7.
White arrowheads indicate human, murine, and chimeric vessels. C, Representative confocal images of lectin-labeled vessels in the
implants at multiple time points. White dotted line in the day 3 panel of pretransplantation indicates the border of implant. D, Graph of
microvessel density before and after transplantation (n=3–8; mean±SEM). *Significant difference (P≤0.05) between groups for total MVD.
†Significant difference (P≤0.05) between groups for human MVD. E, Representative confocal images of green fluorescent protein (GFP)/
UEA-I (rhodamine)–positive vessels in the implants at day 7 after transplantation into GFP-transgenic mice. White dotted line indicates the
border of implant. Scale bars represent 100 μm. Reproduced from Kang et al11 with permission of the American Society of Hematology.
light through the photomask. The glass slide of prefabricated
array of microgels was immersed in mineral oil, and the microgels were assembled into tubular structures by swiping a needle
underneath them. The assembly was subsequently stabilized by
a secondary crosslinking step. By varying the internal designs
of each individual microgel, the sequential assembly allowed
for the creation of vascular-like microchannels with a circular
lumen and was interconnected in a network to model the bifurcating structure of native vasculature. This simple yet elegant
design may be used as a powerful research tool for building
biomimetic tissue models, such as for studying cardiac progenitor cells differentiated to mimic native muscle fibers.
Future Directions
The use of tissue engineering approaches for the treatment of
CVD holds significant promise for new therapeutic approaches,
especially given the growth of nanoscale approaches for biomaterial design. Further exploration of stem cell technologies,
particularly the use of cells differentiated from hESCs and induced pluripotent stem cells, and the creation of a suitable microenvironment for long-term tissue formation are directions
likely to advance our understanding of how tissues repair and
regrow. These advancements should lead to improved options
for arterial revascularization, heart valve repair, arrhythmias,
and congenital malformations in pediatric populations.
Lundberg Cardiovascular Tissue Engineering Support at NHLBI 1103
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However, the practicality of implementing clinically­­viable
tissue–engineered constructs on a day-to-day level will require answers to some of the major questions and provocative issues facing this field (Table). Some of these concerns
are hampered by research gaps, which include: (1) validated
biomarkers to identify the intracellular machinery that guides
cells to become functional tissues; they are also required to
assess the immunologic requirements and fate of engineered
tissues over time; (2) quantitative biological assays to improve the assessment of tissue-engineered construct safety,
function, and stability that assist the development pathway
and regulatory acceptance of these products; and (3) computationally efficient methods and models, to link gene and protein dynamics to cellular phenotypic outcomes. Additional
constraints are universal standards and protocols for longterm storage of cells and tissue constructs, and standardized
clinical and preclinical approaches consistent with regulatory
requirements. Perhaps the greatest roadblock to therapeutic
application is how to combine the vast number of parameters
that influence 3D biological responses to produce the necessary outcome.
In terms of NHLBI support for tissue engineering research,
the RFA-HL-11–025, New Strategies for Growing 3D Tissues
program has 3 more years to run. It is hoped that this program,
together with other Agency efforts, will provide a robust scientific underpinning to aid tissue engineering approaches for
heart, lung, and blood diseases. Leveraging both nano- and
microsystem technologies will lead to innovations for the
treatment of disease in vivo and may serve as a conduit to
spur corporate growth activity in this area. For example, microsystems could be useful for the identification of regeneration-inducing ligand systems to treat chronic inflammation
and ischemia or potentially enable the monitoring of real-time
angiogenesis. Strategies that improve nondestructive assessment tools for regenerative medicine remain an important goal
(http://www.nist.gov/mml/bbd/biomaterials/functional_imaging_regenerative_medicine_workshop.cfm). It is anticipated
that these efforts will be highly interactive with discovery science and clinical research and thereby, provide design blueprints for realistic expectations and marketplace needs for
tissue-based tools and approaches.
Summary
Considerable progress has been made in the field of tissue
engineering, however the search for the best technologies to
create functional cardiovascular tissues are still being investigated. The targeted research programs of the NHLBI are
aimed toward improving the understanding of the physical,
electric, and chemical factors that affect 3D cellular structures
and transferring that knowledge into the testing and translation of novel CVD treatments. As a medical treatment concept, tissue engineering aims to control cell phenotype and direct tissue formation that is functionally equal to or better than
the tissue to be replaced. The development of such a tissue
replacement will require careful attention to the cell/growth
factor/matrix interactions, optimal cell sources, and the design
of biomimetic scaffolds. The NHLBI has a strong interest in
tissue engineering and will continue to foster the practical,
clinical, and commercial development of research discoveries
in this emerging field. Future steps will be taken to identify
opportunities for leveraging between the research priorities of
the NHLBI and other Federal initiatives.
Additional information regarding the research funded at the
NHLBI can be found at www.nhlbi.nih.gov and by using the
National Institutes of Health Research Portfolio Reporting Tools
available at: http://www.projectreporter.nih.gov/reporter.cfm.
Acknowledgments
We thank Michael Laflamme for contributing to Figure 1, Laura
Niklason for contributing to Figure 2, and Joyce Bischoff for contributing to Figure 3.
Sources of Funding
Dr Lundberg is a full-time employee in the Division of Cardiovascular
Sciences of the National Heart, Lung, and Blood Institute (NHLBI),
and Bioengineering Research Partnership Coordinator for the
NHLBI. The NHLBI provided partial monetary support for the figures reused in this publication.
Disclosures
None.
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Cardiovascular Tissue Engineering Research Support at the National Heart, Lung, and
Blood Institute
Martha S. Lundberg
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Circ Res. 2013;112:1097-1103
doi: 10.1161/CIRCRESAHA.112.300638
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