© 2012 Expert Reviews Ltd
Cardiovascular disease remains the leading
cause of death in the USA, resulting in nearly
US$300 billion in healthcare costs annually .
The irreversible organ damage from the disease
creates an urgent need for novel methods of repair
for the heart. Treatments for cardiac disease
include approaches ranging from medications
to surgical interventions. Most surgical options
involve circumventing the damaged tissues, as
in bypass grafts, or replacing them, as in heart
transplants. However, sources for human donor
tissues are in chronic shortage. Creating alterna-
tive therapies would significantly expand patient
care options. Efficient means for repairing, recon-
structing or regenerating damaged tissues would
greatly diminish the need for scarce donor organs.
Biomaterials have shown increasing potential as a
tool for such procedures. This article reviews the
different types of biomaterials used in cardiovas-
cular therapies and the cardiac conditions these
materials are designed to treat. Novel cardiovas-
cular treatments involving engineered tissue and
composite materials are also discussed.
A biomaterial is broadly defined as a material
that interacts with biological systems for medical
purposes. Biomaterials fall into two main cat-
egories: synthetic and natural (Figure 1). Synthetic
materials include the classically defined materi-
als of metals, polymers and ceramics. Natural
biomaterials are derived from native tissues from
autogenic (same individual), allogenic (same-
species donor) or xenogenic (animal) sources.
Nonhuman tissues are harvested from animal
sources such as cows or pigs. In medical applica-
tions, preference in the choice of biomaterial has
traditionally been for inert materials, in order to
minimize reaction with the biological tissues it
is in contact with. Examples are titanium metal
implants used in hip replacements that do not
react chemically with the local area, or biologi-
cally inert gold dental fillings. However, newer
research has revealed many advantages of inter-
active biomaterials for expanding treatments to
include drug delivery for therapeutics or stem cell
transplants for tissue repair and regeneration.
The term ‘biocompatibility’ is somewhat
ambiguous, as the field continues to redefine
the nomenclature based on the latest research
findings. Biocompatibility generally refers
to a biomaterial with properties favorable for
implantation while eliciting minimal adverse
reactions. Whether the need is for cardiovascular
reconstruction purposes or tissue replacement,
a biomaterial for implantation must have
Mai T Lam1 and
Joseph C Wu*2,3
1Department of Surgery, Division of
Plastic and Reconstructive Surgery,
Hagey Pediatric Regenerative Research
Laboratory, Stanford University School
of Medicine, CA, USA
2Department of Medicine, Division of
Cardiology, Stanford University School
of Medicine, Stanford, CA 94305, USA
3Department of Radiology, Stanford
University School of Medicine,
Stanford, CA 94305, USA
*Author for correspondence:
Tel.: +1 650 723 6145
Fax: +1 650 723 8392
Cardiovascular disease physically damages the heart, resulting in loss of cardiac function.
Medications can help alleviate symptoms, but it is more beneficial to treat the root cause by
repairing injured tissues, which gives patients better outcomes. Besides heart transplants, cardiac
surgeons use a variety of methods for repairing different areas of the heart such as the ventricular
septal wall and valves. A multitude of biomaterials are used in the repair and replacement of
impaired heart tissues. These biomaterials fall into two main categories: synthetic and natural.
Synthetic materials used in cardiovascular applications include polymers and metals. Natural
materials are derived from biological sources such as human donor or harvested animal tissues.
A new class of composite materials has emerged to take advantage of the benefits of the
strengths and minimize the weaknesses of both synthetic and natural materials. This article
reviews the current and prospective applications of biomaterials in cardiovascular therapies.
Biomaterial applications in
cardiovascular tissue repair
Expert Rev. Cardiovasc. Ther. 10(8), 1039–1049 (2012)
Keywords: biomaterials • cardiac repair • decellularized tissues • extracellular matrix • metals • polymers
• regeneration • stem cells • tissue reconstruction
THeMed ArTICLe y Cell and gene therapies
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Expert Rev. Cardiovasc. Ther. 10(8), (2012)
durability, strength and flexibility to withstand approximately
2 billion cardiac cycles expected to occur in an average lifetime.
Equally important are the materials’ biologic properties, the most
desirable of which being anti-thrombogenicity, noncalcification,
hemostasis, nonimmunogenicity and endothelialization
Synthetic biomaterials used in cardiovascular applications primar-
ily encompass polymers, metals or a combination of both (Figure 2).
Ceramics are used to a much lesser extent in cardiac-related treat-
ments. The main benefits of synthetic materials are their strength
and durability, although their biocompatibility issues can create
complications. Toxicity is of utmost concern with synthetic mate-
rials, especially in the case of biodegradable materials, which can
release potentially harmful byproducts of degradation into the body.
Chemically inert materials have served as a practical foundation for
implantable substances, allowing for stand-alone use or drug deliv-
ery through coatings. The most commonly used synthetic materials
for cardiac-related applications are described in this article and are
summarized in Table 1.
The use of expanded polytetrafluoroethylene (ePTFE) in cardio-
vascular applications has become routine owing to this material’s
performance and ease of use. Commercially, this material is better
known as Gore-tex®, and is manufactured by Gore Medical into
cardiovascular products for general cardiac reconstruction, vascular
grafts and pediatric shunts . ePTFE is composed of a fluorocar-
bon polymer, formed into sheets by extrusion. A three-layer polymer
is created, with a middle microporous, elastic layer surrounded by
two layers of polymer fibrils . The resultant structure provides
for a high strength-to-weight ratio and resistance to dilatation. The
chemical composition promotes low thrombogenicity, lower rates of
restenosis and hemostasis, less calcification and biochemically inert
properties [3–6]. In addition, ePTFE has been shown to have high
resistance to allergic reaction and inflammation . These material
properties have made ePTFE an excellent option for creating shunts
[8–10], reconstruction  and valve repair , and have even been
used for covering implantable devices to minimize inflammation .
However, since ePTFE is a synthetic material, it can elicit a negative
immune response and thrombosis.
Polyethylene terephthalate (PET), or Dacron®, is a thermoplastic
polymer manufactured by Maquet Cardiovascular, with a chemical
inertness contributing to its biocompatibility. This material can be
manufactured in many forms, but is typically used in cardiovascular
purposes as vascular grafts in the woven or knitted configuration.
Woven PET has smaller pores compared with the knitted form,
which therefore reduces blood leakage. In cardiovascular applica-
tions, PET is used for constructing vascular grafts. PET grafts are
available with a protein coating, usually collagen or albumin, in order
to reduce blood loss and to act as an antibiotic to prevent graft infec-
tion . The surfaces of PET grafts are often crimped to stimulate
tissue incorporation. Advantageously, PET grafts have been found
to promote endothelialization by recruiting endothelial cells to the
graft’s luminal surface, with no calcification or tissue overgrowth.
Collagen and glycosaminoglycan deposits have also been found in
implanted grafts, and circumferential mechanical properties show
little degradation over time . Similar to ePTFE, PET also has the
disadvantage of being a synthetic material and can cause a foreign
body reaction with increased chance of thrombus formation.
Prelining PET vascular grafts with endothelial cells has been
explored as a means for improving patency rates. In animals, this
approach has resulted in improved graft performance ; however,
Figure 1. Overview of biomaterials currently used in cardiovascular applications.
Lam & Wu
human clinical trials showed low patency
rates compared with autologous grafts .
Currently, PET grafts are used more often
than ePTFE ones, although new evidence
shows that ePTFE offers some advan-
tages such as lower thrombogenicity .
Application of either biomaterial is depend-
ent on the para meters required for the spe-
cific cardiovascular tissue to be repaired or
Polyurethanes (PUs) belong to a class of
compounds called reaction polymers, and
are formed by the reaction of an isocyanate
group with a hydroxyl group to form a
foam. Alternatively, PU can be manufac-
tured into a harder thermoplastic form used
in medical applications. Thermoplastic PU
has high shear strength, elasticity and trans-
parency. The microbial resistance is ideal
for preventing infection, and the material’s
pliability contributes to improved handling
characteristics. The probability for throm-
bosis of PU is similar to other materials
such as PTFE . This material was used
frequently in the past in valve replacements
, until metal and bioprosthetic replace-
ment valves emerged. Currently, PU is
mostly used in cardiac pacing leads as an
insulator . Although PU is durable, it
lacks flexibility. To solve this problem, pac-
ing leads are manufactured with the option
of a PU–silicone copolymer to take advantage of silicone’s flexibil-
ity . Pacing leads coated with silicone alone are also available
in the market. Silicone-coated leads have been shown to maintain
electrical properties important to pacing better than PU-insulated
leads . Each material (PU or silicone) has its own advantages,
and leads insulated in either material or a copolymer of both are
selected based on the specific requirements of the patient.
On the research side, PU is being investigated as a substrate in
cardiac stem cell therapy, with in vitro studies being carried out
on the influence of patterned PU substrates on stem-cell-derived
cardiomyocyte phenotype [22,23]. One disadvantage to PU cardio-
vascular implants is the material’s tendency to oxidize and degrade
in vivo, creating problems after implantation. Modifications to
the material have been effective, as it has been shown that chemi-
cally coating the surface with an antioxidant aids in reducing
Chemically nonreactive metals have been used for many medical
purposes for several decades because of their strength and
biocompatibility. Commonly used biocompatible metals include
titanium, stainless steel, gold and silver. In the cardiovascular
arena, metals are used in stents for opening the lumen of obstructed
vessels. Titanium and stainless steel have been classically used
in stent design, with newer stents utilizing cobalt–chromium
or platinum–chromium alloys for their greater strength [25,26].
Nitinol stents made from a nickel and titanium alloy dominated
the market in the past because of their shape memory properties,
but nickel allergies have since eliminated their use . Metals
are also extensively used in the replacement of heart valves.
Mechanical replacement heart valves are constructed from metals
such as stainless steel or titanium . Mechanical valves can last
the lifetime of a patient, although anticoagulant medications are
required for the remainder of their lives because of the higher
chance for blood clot formation . Patients who cannot take
anticoagulants must choose other valve options, such as natural
tissue valves discussed in more detail below.
Whereas synthetic materials have performed better in repair
and replacement of damaged cardiovascular tissues, they pale
in comparison with the functional capabilities of natural tissues.
Each of the tissues in the body is uniquely optimized to its specific
organ system, and offers an innate biocompatibility. Autologous
Figure 2. Examples of various biomaterials used in cardiovascular products.
Uses for synthetic biomaterials composed of polymers include (A) expanded
polytetrafluoroethylene, or Gore-tex®, for pericardial repair; (B) polyethylene
terephthalate, or Dacron®, for vascular grafts and (C) polyurethane in leads. Synthetic
biomaterials of metals are used in (D) heart valves and (E) coronary stents. Natural
biomaterials used for cardiovascular repair include (F) small intestine submucosa
extracellular matrix, (G) bovine pericardium and (H) human pulmonary heart valves.
(A) courtesy of W.L. Gore & Associates, Inc.; (B) courtesy of MAQUET Cardiovascular
LLC; (C) & (E) courtesy of Medtronic, Inc.; (D) courtesy of St Jude Medical, Inc.;
(F) courtesy of the authors (material from CorMatrix Cardiovascular, Inc.);
and (H) courtesy of CryoLife, Inc.
Biomaterial applications in cardiovascular tissue repair & regeneration
Expert Rev. Cardiovasc. Ther. 10(8), (2012)
tissue, or tissue harvested from and used for the same patient,
is the current gold standard for its superior functionality and
nonimmunogenicity. Supply of tissues needed and health status
of the patient are major hindrances to obtain autologous tissue.
The next best choice is allogenic tissues or donor tissues from
organisms of the same species; in humans, these tissues are called
homografts. Unfortunately, human donor tissues needed for
treating cardiovascular disease are in very limited supply, and
heart transplant lists remain long. Xenogenic tissues from animals
have helped to fill this need, particularly with tissue repairs or
valve replacements .
Immune response is of particular concern with allogenic and
xenogenic tissues. With allogenic human donor tissues, immuno-
suppressive drugs must be taken by the patient, and even then
Table 1. Applications of biomaterial products in treatment of cardiovascular conditions.
BiomaterialMaterial composition SourceApplicationsBenefits Ref.
vascular graft, atrial
septal defects, valve
good patency, avoidance of
excessive shunt flow, kink
resistance, improved handling,
better tissue approximation for
use in neonates, palliate or
correct interrupted aortic arch
Vascular graftTissue ingrowth, high patency,
St Jude Medical,
Pacing leads and
transparency, resists infection
and improved handling
Titanium, stainless steel,
valve and stents
Strength, durability, low
thrombogenicity and excellent
SISECM (collagen, elastin,
factors and others)
cardiac tissue repair,
(off-label use: valve
tissue remodeling, scaffold for
native cells to migrate and
integrate into, and hemostatic
Donor pericardial sheets Human (CryoLife)Reconstruction,
repair and aortic root
fixed) and pliable
Crosslinked collagen patch Bovine, porcine,
equine (St Jude
Atrial and ventricular
septal defect repair,
Good host tissue response,
reduced adhesion formation,
intraoperative suture line
bleeding, good tensile
strength, resists infection and
Self, donor valve Human (CryoLife) Ross procedure and
Low immune response,
biocompatibility and superior
Xenogenic valvesAnimal valve Bovine, porcine (St.
Jude Medical, Sorin
ECM: Extracellular matrix; ePTFE: Expanded polytetrafluoroethylene; NA: Not applicable; PET: Polyethylene terephthalate; SIS: Small intestine submucosa.
Lam & Wu
the tissue or organ may still be rejected . To eliminate immune
rejection with xenogenic tissues, they are decellularized before use
in patients . Mostly, extracellular matrix (ECM) materials such
as collagens and proteins remain after decellularization, leaving a
scaffold for damaged tissue to repair in and around the area. In
cardiovascular applications, bovine (cow), porcine (pig) and equine
(horse) tissue sources have become quite popular for their compat-
ibility to human-sized organs. In this article, common examples of
natural materials that are most often used in cardiovascular treat-
ments are described and are summarized in Table 1.
Small intestine submucosa
A material gaining recent popularity in cardiovascular applica-
tions is derived from the submucosa of the small intestine. This
material is retrieved from porcine sources. Though the small intes-
tine submucosa (SIS) can be processed in many ways, it is gener-
ally prepared by first opening the harvested small intestine lon-
gitudinally and then mechanically removing the submucosa layer
while keeping the basement membrane intact. Cells are removed
with an acid, and the resultant ECM sheets are sterilized for
patient use . The SIS-ECM is comprised of collagens I, III, IV,
V and VII, fibronectin, elastin, glycosaminoglycans, glyco proteins
and growth factors such as VEGF, FGF-2 and TGF-β .
Used successfully for decades as a wound dressing, other clinical
applications have been explored for SIS. In cardiac treatments, so
far SIS has been used for pericardial reconstruction and carotid
repair [35,36]. Advantages to this material include its biodegrada-
bility, hemostatic capability, nonencapsulation and noncalcifica-
tion . Disadvantages include a relative shortage in supply and
potential immunogenicity issues from the decellularized xeno-
genic tissue. Interestingly, in an orthopedic application, SIS was
shown to promote cell migration into itself once implanted and
to encourage subsequent local tissue remodeling and regeneration
. These results are promising for regenerating cardiac tissue.
Several animal studies have been conducted to investigate other
possible cardiac-related applications of SIS. An emulsion form of
SIS has been tested for effectiveness in treating myocardial infarc-
tion (MI). Infarcted animal hearts were injected with the SIS
emulsion. Angiogenesis was significantly increased compared with
control infarcted hearts injected with saline. Echocardiography
showed improved fractional shortening, ejection fraction and
stroke volume . The potential of SIS to serve as a scaffold for
cardiac tissue engineering has also been examined. In one study,
neonatal rat cardiac cells were mixed with a gel form of SIS and
deposited onto polymer substrates. The resulting tissue constructs
showed significantly higher contraction rates and greater tro-
ponin T expression compared with Matrigel™ (BD Biosciences)
controls . A combined SIS and stem cell therapy for treating
chronic MI was also investigated. Bone marrow mesenchymal
stem cells (MSCs) were seeded onto patches of SIS and grafts were
implanted onto the epicardial surface of infarcted myocardium in
rabbits. Patches of SIS alone were also implanted for comparison.
Left ventricular contractile function and dimension, capillary den-
sity of the infarcted area and myocardial pathological changes were
significantly improved in both SIS groups with and without cells.
Results with cells were slightly better . These animal studies
show that SIS has potential to be used for treating MI and also for
cell delivery with the purpose of regenerating the damaged areas
of the heart. Finally, in a clinical study on patients undergoing
primary isolated coronary artery bypass grafting, a statistically sig-
nificant decrease in the rate of postoperative atrial fibrillation was
seen in patients who also underwent pericardial reconstruction
using SIS compared with those without any reconstruction .
The pericardium is a fibroserous sac surrounding the mammalian
heart. It has long been used in cardiac repair for reconstruction,
valve repair and pericardial closure [41,42]. Xenogenic pericardium
is commonly derived from bovine, porcine and, less frequently,
equine sources. Tissues from these sources are available in large
patches, allowing custom configuration to a variety of cardio-
vascular applications. It is largely comprised of collagen fibers and
has elastic properties allowing conformity to complex anatomy.
Pericardial tissue has exceptional handling characteristics and
uniform suture retention. In addition, it is nonthrombogenic and
naturally resists infection .
To reduce the probability of an adverse immune response, the
pericardium is decellularized using one of many possible process-
ing procedures, resulting in predominantly ECM components.
Tissue morphology and collagen structures are dependent on the
decellularization process chosen . Following removal of cellular
content, the tissue is typically crosslinked using glutaraldehyde for
preservation and to increase strength of the biomaterial. However,
calcification of pericardial grafts postimplantation is attributed
to glutaraldehyde processing [45,46]. Hence, several studies have
investigated new methods for processing the pericardium to main-
tain ECM content and structure, and to strengthen the biologi-
cal tissue without causing calcification in vivo. Approaches have
included treating the glutaraldehyde-processed pericardium with
glutamic acid , modifying the decellularization procedure
, and nanocoating pericardial grafts with titanium to prevent
immune reactions and thus calcification . Some anticalcifica-
tion technologies are being used in commercially available peri-
cardial grafts , although most techniques still require more
testing in order to become routine practices.
There are slight differences between pericardium from the dif-
ferent sources. Pericardium from bovine sources has higher col-
lagen content than that derived from porcine origins [48,49]. Valves
fabricated from bovine pericardium have shown less obstruction
than valves made from porcine pericardial tissue, although both
valves show similar hemodynamic results . Bovine and porcine
tissues did not exhibit a significant difference in the degree of
calcification under varying glutaraldehyde treatments .
Severely damaged heart valves require replacement. Generally,
metal mechanical valves or bioprosthetic (i.e., biological) valves
obtained from human donor or animal sources are used. Blood
has a tendency to adhere to the metal in mechanical valves, result-
ing in blood clots. Therefore, patients with mechanical valves
Biomaterial applications in cardiovascular tissue repair & regeneration
Expert Rev. Cardiovasc. Ther. 10(8), (2012)
must take anticoagulant medications for the rest of their lives
. Natural tissue valves do not require the use of anticoagulants,
which is an advantage over mechanical valves. The most common
animal sources for biological valves are bovine or porcine tissues
. On average, bovine valves typically last 15–20 years whereas
porcine valves last 8–15 years . Differences between com-
mercial valves are mostly due to the variation in manufacturers’
specifications, including variable parameters such as hemodynam-
ics, implantation method, suturability and valve dimensions .
When bioprosthetic valves fail, it is usually due to calcification
and tearing .
Although mechanical valves made of titanium or carbon are
stronger and last longer than biological valves (typically up to
25 years), patients implanted with mechanical valves must contin-
ually take an anticoagulant medication (e.g., Coumadin®; Bristol-
Myers Squibb). Age is a major factor in longevity of a replacement
valve. Children and younger patients use up replacement valves
faster than older patients because of activity and metabolism
. Patients younger than 65–70 years of age typically receive
mechanical valves, while patients older than that receive biopros-
thetic valves. Middle-aged patients may select either type of valve,
although there is evidence that bioprosthetic valves are a better
choice for this age group because these valves are likely to last the
remainder of the patients’ lives without the use of anticoagulant
In recent years, injectable biomaterials have seen significant increase
in application towards treating MI [56–58]. Injectable materials
mostly encompass: hydrogels composed of alginate, fibrin, chi-
tosan, collagen or matrigel; and self-assembling peptides generally
in the form of nanofibers. Injectables originally generated interest
owing to their biocompatibility, ability to provide beneficial chemi-
cal environments and, above all, for their potential to be delivered
noninvasively. Efficacy of these materials has been explored exten-
sively in animal infarct models and has shown success in improving
cardiac function, reducing infarct size, increasing wall thickness
in the infarcted area and increasing neovascularization. Alginate
hydrogel is a polysaccharide derived from seaweed. It is used as
a temporary ECM substitute and has affinity-binding moieties,
enabling binding of proteins and their controlled release for drug
delivery and transfer of growth factors . Alginate gel has been
shown to reverse left ventricular remodeling following MI .
Fibrin is formed from the interaction of the blood proteins fibrino-
gen and thrombin during the process of clotting in a wound fol-
lowing injury. Fibrin glue is used surgically as a sealant, to control
bleeding, speed wound healing, to fill holes after surgery, and in
drug and cell delivery [61,62]. Chitosan is a polysaccharide extracted
from the exoskeleton of crustaceans and is primarily used to pro-
mote rapid blood clotting. In addition, chitosan hydrogel has been
used as a delivery vehicle for proteins [63,64] and cells, which in the
latter case resulted in enhanced stem cell engraftment, survival and
homing in an ischemic heart . As a major ECM component,
collagen plays an important role in the remodeling process that
occurs in infarcted tissue. Collagen gel has been a popular material
to test for its ability to repair infarcted heart wall because its ECM
origins have potential to recruit endogenous cells for regeneration.
For this reason, collagen gel was one of the first materials to be
used for cell encapsulation and delivery into the heart [56,65]. Many
studies have used collagen gels to deliver MSCs to infarcted regions
and have shown improvement in cardiac function by increased
vascular density . Matrigel is a protein mixture derived from
mouse sarcoma cells, and contains many important ECM proteins
such as laminin and collagen, and growth factors that promote
proliferation and differentiation [56,67]. Matrigel is widely used as
an attachment substrate for embryonic and induced pluripotent
stem cells in culture, with logical follow-up application to support
stem cell survival in in vivo animal studies. Matrigel is able to retain
stem cells after injection into infarcted tissue and subsequently
improve cardiac function. However, as this gel is derived from
mouse tumors, it is not applicable to human use. Self-assembling
peptides are nanostructures formed from spontaneous aggrega-
tion of peptides, usually into nanofibers. These peptide chains are
able to provide 3D microenvironments capable of recruiting cells,
promoting vascularization and delivering growth factors. When
injected into an infarcted heart, infarct size was reduced, vascular
density was increased and cardiac function was recovered . Self-
assembling peptides have also been coinjected with MSCs, resulting
in sustained growth, survival and differentiation of the stem cells,
and reduced infarct size and significant improvement in cardiac
functional measures (e.g., systolic function indices, left ventricle
ejection fraction and left ventricle fractional shortening) .
Many attempts have been made to engineer various cardiac tis-
sues, particularly of the heart valve. Although mechanical and
bioprosthetic valves have been valuable for restoring heart func-
tion and quality of life for patients, each valve has its drawbacks,
mostly owing to dependency on anticoagulants and limited dura-
bility due to tissue deterioration. More importantly, neither valve
type is able to grow and expand with the patient as they grow
older. For these reasons, tissue-engineered heart valves have been
explored extensively. Desirable parameters for tissue-engineered
valves include nonthrombogenicity, biocompatibility, capability
for growth and remodeling, easily implantable, hemodynami-
cally compatible and life-long durability . Tissue-engineered
valves would be particularly applicable to pediatric cases. The
current challenge is to produce a tissue-engineered valve with the
mechanical strength to withstand the blood pressure and contrac-
tility forces of the heart that is capable of seamlessly integrating
with the native cells and tissues . The classic approach for
engineering valves is to use decellularized allo- or xeno-grafts
on which different types of cells are seeded. Some examples of
various combinations are homografts seeded with cardiac-derived
mesenchymal stromal cells , porcine valve and pericardium
seeded with bovine fibroblasts  and a fibrin gel combined with
human dermal fibroblasts .
Despite the success in creating different types of tissue-
engineered heart valves, clinical use has yet to be achieved due
to lack of in vivo verification of feasibility. There have been a
Lam & Wu
few clinical studies with conflicting results. One study involved
93 patients undergoing right ventricular outflow tract reconstruc-
tion using the Matrix P/Matrix Plus® (AutoTissue GmbH) xeno-
genic decellularized tissue-engineered pulmonary valve conduit.
Conduit failure occurred in 33 patients (35.5%) and conduit
dysfunction occurred in 27 patients (29%). Reasons for failure
were conduit stenosis, pseudoaneurysm, conduit dilatation, ste-
nosis of distal anastomosis involving pulmonary bifurcation and
allograft dissection. Histological analysis showed inflammatory
cells and poor endogenous cell seeding in all explanted specimens
. Conversely, in another study of 11 patients undergoing right
ventricular outflow tract reconstruction, valves were replaced
with pulmonary allografts seeded with autologous endothelial
cells. At 10 years, multislice computed tomography showed no
evidence of calcification, and echocardiography showed a mean
pressure gradient of 5.4 ± 2.0 mmHg. Biopsies showed a conflu-
ent monolayer of endothelial cells covering the allograft’s inner
surface . In addition, another study involving the Matrix P
conduit showed mixed negative and positive results of valve fail-
ure and no calcification . These conflicting results demonstrate
the need for further testing.
Other myocardial tissues have been created in vitro, based on
the general approach of seeding cells onto a scaffolding material.
Commonly used cell types have been skeletal myoblasts, murine
neonatal cardiomyocytes, MSCs mainly from bone marrow or
adipose tissue, cardiac progenitor cells, cardiosphere-derived
stem cells, endothelial progenitor cells, embryonic stem cells
and induced pluripotent stem cells [78–80]. Scaffolding mate-
rial has included hydrogels, polymeric fibers (randomly con-
figured and aligned), decellularized ECM and peptides [80–83].
Monolayers of cells have also been stacked to form scaffold-free
tissues . These materials are favored for their chemical, struc-
tural, biocompatible, degradability and formable characteristics.
Engineered tissues transplanted into various animal models help
to restore or improve tissue function, and clinical trials have
shown some success [84–86]. However, as in the case of tissue-
engineered valves, engineered myocardium and vascular tissue
still need further developments to make them more relevant to
Composite & modified biomaterials
Both natural and synthetic biomaterials have their limitations
and can produce unwanted effects, such as limited durability
and a higher chance for thrombosis. Natural biomaterials are
superior in functionality and biocompatibility, but lack robust-
ness. Synthetic biomaterials have advantages of strength and
durability, but are deficient in functional capabilities. Combining
materials into composites has created better options that ben-
efit from the strengths of different materials and minimizes the
weaknesses. Composite materials are achieved through the meth-
ods of blending (physically combined without forming chemical
bonds), coating (by submersion or spraying), copolymerizing
(polymer structure modified to form multiple block monomers
then polymerized) and multilayering (sandwiching of materials
followed by mechanical fixation) [87,88]. Injectable hydrogels are
commonly combined with each other and other elements, and
have the benefit of tunable properties that can be controlled by
modifying crosslinking [89–91]. Bioprosthetic valves have been
reinforced with polymeric material to abate the natural tissue’s
innate lack of strength , providing an example of a composite
taking advantage of the assets of each biomaterial.
Biomaterials can be combined with cells to provide support
structure to enhance cellular growth and survival. Tissue regen-
eration using cellular material has been investigated as a healing
mechanism for damaged and diseased heart tissue. Their pro-
liferative capability and potential to differentiate into cardio-
vascular lineages make stem cells an ideal option . Many dif-
ferent adult stem cells have been investigated in preclinical and
clinical studies [56–64]. The major issue delaying stem cell ther-
apy from widespread use is the fact that once injected in vivo,
engraftment is low due to cell migration out of the wound
site, and/or the cells simply die . Delivering stem cells with
biomaterials has become an increasingly popular method, and
has developed into a field of its own. Numerous studies are test-
ing biomaterials such as injectable hydrogels or patch material
from natural and synthetic sources, or growth factors as solu-
tions for maintaining stem cells to the wound site to improve
engraftment and to aid in their survival and proliferation post-
transplantation [40,56,93–95]. Most of these studies are at the
preclinical stage. In one study, human MSCs incorporated into
a collagen patch-assisted engraftment decreased left ventricle
systolic interior diameter, increased anterior wall thickness and
increased fractional shortening by 30% . In another study,
human bone marrow CD133+-derived cells transplanted on
a collagen patch onto an injured heart resulted in formation
of new microvessels, thought to be induced by the patch .
A mixture of growth factors was able to prolong survival of
transplanted cardiomyocytes derived from human embryonic
stem cells, improving cell engraftment after infarct . In a
clinical trial, a collagen matrix seeded with bone marrow cells
was applied to the heart in patients with left ventricular pos-
tischemic myocardial scars. At 10 months after treatment, left
ventricular end-diastolic volume beneficially decreased and left
ventricular filling deceleration time significantly improved with
the collagen matrix. Scar area thickness was increased in the
matrix group through the addition of viable tissue. Ejection
fraction results were independent of treatment group, as left
ventricular ejection factor improved with or without the colla-
gen matrix . Overall, the research findings show that there is
much potential for stem cells to effectively treat cardiovascular
ailments, as long as methods for administering such treatments
are developed to optimize therapeutic outcomes. In the future,
successful application of stem cells will most probably involve
delivery with biomaterials.
Biomaterials can be modified to extend their usefulness for
drug delivery and gene therapy. Polymers are engrafted, and gels
easily mixed with growth factors, cytokines and pharmaceuti-
cals to allow drug-releasing systems capable of controlled release
[96,97]. Different drugs and growth factors can be delivered, such
as anticoagulants and peptides that promote endogenous cell
Biomaterial applications in cardiovascular tissue repair & regeneration
Expert Rev. Cardiovasc. Ther. 10(8), (2012)
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
Roger VL, Go AS, Lloyd-Jones DM et al.;
American Heart Association Statistics
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proliferation and angiogenesis [96,98]. Tissue-engineered grafts
have incorporated various drugs and growth factors into their
scaffolding structure to enhance differentiation of the cells
seeded onto it. Growth factors such as EGF, TGF, VEGF and
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Expert commentary & five-year view
Future efforts should focus on perfecting composite materials to
take full advantage of the optimal combination of both synthetic
and natural biomaterials to improve the overall performance of
implantable materials. This approach will exploit the combined
advantages of both material types. Composite biomaterials have
the potential to solve the current dilemma of having to choose
between either synthetics or natural tissues and foregoing the
benefits of one or the other material. Given the diversity of cardio-
vascular conditions and resulting variable treatments needed, the
wider use of composite biomaterials may the best approach for
improving disease management.
In addition, efforts for supporting stem cell retainment and
survival using biomaterials should become more aggressive.
There is much potential for translation of stem cell therapy
to be realized using this approach. This could lead to regular
application of tissue regeneration techniques, creating the ideal
solution for cardiovascular tissue repair.
As the field develops, stem cells will increasingly enter the arena
of cardiovascular therapy. Solutions to the challenges of stem
cell survivability and proliferation post-transplantation are under
intense exploration in the laboratory, and will probably involve
the use of biomaterials. With the countless efforts towards this
end, development on the material side will conceivably come to a
conclusion and produce a narrowed down list of efficacious mate-
rials coupled with the appropriate stem cell. While tissue repair
and replacement have been acceptable means of treatment, tissue
regeneration would be far more ideal for restoring full function of
the diseased heart, and is the next frontier to aim for.
Financial & competing interests disclosure
The authors would like to thank the NIH for providing funding
through grants T32 EB009035-02 to MT Lam and R33HL089027,
R01EB009689 and R01HL093172 to JC Wu, and to the Burroughs
Wellcome Foundation for providing support to JC Wu. The authors have no
other relevant affiliations or financial involvement with any organization
or entity with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
• Biomaterials used in cardiovascular therapies fall into two major categories: synthetic and natural materials.
• Synthetic materials used for cardiac repair mostly encompass polymeric materials, with a few applications of metals, and offer
advantages of strength and durability.
• Natural materials are derived from autologous, allogenic or xenogenic sources, and have superior functional properties but lack
• Stem cells have potential to develop into a viable cardiovascular therapy by facilitating tissue regeneration, although problems involving
cell survivability need to be overcome first and solutions thus far are heavily dependent on biomaterials.
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