Review

Current Developments and Future Prospects for Heart Valve

Replacement Therapy
Asmeret G. Kidane,1 Gaetano Burriesci,2 Patricia Cornejo,1,3 Audrey Dooley,4 Sandip Sarkar,1,3
Philipp Bonhoeffer,5 Mohan Edirisinghe,2 Alexander M. Seifalian1,3
1
Biomaterial and Tissue Engineering Centre (BTEC), Academic Division of Surgery & Interventional Sciences,
University College London, London, United Kingdom

2
Department of Mechanical Engineering, University College London, London, United Kingdom
3
Cardiovascular Haemodynamic Center, University College London, London, United Kingdom
4
Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom
5
Cardiothoracic Unit, Institute of Child Health and Great Ormond Street Hospital for Children, London, United Kingdom

Received 30 April 2007; revised 28 March 2008; accepted 9 April 2008

Published online 9 July 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.b.31151

Abstract: Valve replacement is the most common surgical treatment in patients with
advanced valvular heart disease. Mechanical and bio-prostheses have been the traditional
heart valve replacements in these patients. However, currently the heart valves for
replacement therapy are imperfect and subject patients to one or more ongoing risks,
including thrombosis, limited durability, and need for re-operations due to the lack of growth
in pediatric populations. Furthermore, they require an open heart surgery, which is risky for
elderly and young children who are too weak or ill to undergo major surgery. This article
reviews the current state of the art of heart valve replacements in light of their potential
clinical applications. In recent years polymeric materials have been widely studied as potential
prosthetic heart valve material being designed to overcome the clinical problems associated
with both mechanical and bio-prosthetic valves. The review also addresses the advances in
polymer materials, tissue engineering approaches, and the development of percutaneous valve
replacement technology and discusses the future prospects in these fields. ' 2008 Wiley
Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 88B: 290–303, 2009

Keywords: heart valve replacement; polymers; tissue engineering; percutaneous heart valves

INTRODUCTION resulting in regurgitation of blood, which can lead to heart

Heart valve replacements are, at present, one of the most
widely used prosthetic devices. Recent statistics show that
in 2006 there were around 98,000 valve replacements in
the USA and 195,300 outside the USA.1 The most common
valve operation is aortic valve replacement for aortic steno-
sis or aortic insufficiency. The aortic valve regulates the
blood supply to all of the major vessels of the body. In aor-
tic stenosis, the aortic valve tightens or narrows, preventing
blood from easily flowing through. With aortic insuffi-
ciency, the aortic valve no longer adequately retains blood,
allowing leakage through the valve back into the heart
Correspondence to: A. M. Seifalian (e-mail: a.seifalian@ucl.ac.uk)
Contract grant sponsor: Engineering and Physical Sciences Research Council;
Contract grant number: EPSRC EP/D061555; Contract grant sponsor: British Heart
Foundation.
' 2008 Wiley Periodicals, Inc.
failure. The desirable prosthetic heart valve is considered
to function in the same manner as the native organ, and to
have a long-term durability together with high reliability,
safety, and biocompatibility.
There are two types of prosthetic heart valve, mechani-
cal valves, which are made entirely of synthetic materials,
such as plastics and metal and bio-prosthesis valves, which
are taken from animal or human sources. Mechanical pros-
thetic valves are divided into two kinds based on their flow
patterns, those with lateral flow, such as the ball in cage
valves and those with more central flow, such as the tilting
disc and bileaflet valves.
One of the major drawbacks, however, of currently
available prosthetic heart valves is that mechanical heart
valves require daily anticoagulant treatment because of an
increased risk of thrombosis and thromboembolism. More-

290
 HEART VALVE REPLACEMENT THERAPY
over, several companies have developed different designs
of mechanical heart valves in an attempt to improve the
structural components of the flow orifice, thereby allowing
blood flow through a relatively unobstructed opening.2–5
Indeed the use of bio-prosthetic heart valves, although they
are more hemodynamic and hemocompatible than mechani-
cal heart valves with improved central blood flow, never-
theless have (i) limited durability due to leaflet calcification
(particularly in the young patients) and tearing, (ii)
mechanically induced fatigue damage and pannus over-
growth, and (iii) tissue failure.6–9 Several research groups
have been involved in developing effective anti-calcifica-
tion pretreatment methods to reduce the rate of calcifica-
tion.10–13 Pretreatment agents, such as aluminum chloride-
based and ethanol-based (BiLinX treatment), alpha oleic
acid (AOA treatment) have been shown to improve calcifi-
cation of bio-prosthetic heart valves in animal models and
clinical studies.11,14 Furthermore, both mechanical and bio-
prosthetic heart valve replacement requires open heart sur-
gery with increased risk for elderly and young children,
who are too weak or ill to undergo major surgery.
In recent years polymeric materials have been widely
studied as potential prosthetic heart valve material being
designed to overcome the clinical problems associated with
both mechanical and bio-prosthetic valves. Polymeric heart
valves can be molded into a complete trileaflet heart valve
without the need for suturing leaflets. The geometric simi-
larity of the polymeric trileaflet heart valve to the natural
valve provides a central, less disturbed, blood flow. Poly-
meric materials have also shown great potential in over-
coming problems of material fatigue and maintain
functional characteristics. Polymers such as polyurethanes
(PU) possess high tensile strength, excellent resistance to
cyclic fatigue, desirable hemodynamic characteristics, and
good biocompatibility.15 Current research data shows that
the disadvantage of polymeric heart valves is their suscepti-
bility to biodegradation and mineralization. This has some-
what limited the use of PU for prosthetic heart valves.
Nonetheless, great advances have been made by modifying
these polymers to improve the material degradation and
making these polymeric materials last longer in vivo.
The multi-disciplinary development field of tissue engi-
neering potentially offers an attractive pathway to over-
come the limitations of current heart valve replacements,
such as lack of growth, repair, and remodeling capacities,
which would benefit the significant portion of the patient
population, who are children with congenital defects. The
basic concept of tissue engineering is to engineer a new
‘‘tissue’’ from individual cellular components in vitro using
a scaffold to provide an architecture upon, which the cells
can organize and develop into the desired ‘‘tissue’’ prior to
implantation. The heart valve scaffold used for tissue engi-
neering may be based on either biological (such as donor
human heart valves and decellularized animal derived
valves) or synthetic materials [such as polyglycolic acid
(PGA), and polylactic acid (PLA)]. These scaffolds provide
Journal of Biomedical Materials Research Part B: Applied Biomaterials
291
the biomechanical profile for the replacement tissue until
the cells produce their own extracellular matrix (ECM).
The newly generated matrix would then ultimately provide
the structural integrity for the recently developed tissue
structure. At present, one of the main restraints of tissue
engineering heart valves has been finding a suitable cellular
source as cells harvested from the patients themselves may
be inappropriate for transplantation, due to the diseased or
elderly state of patients.16 Nevertheless, recent advances in
stem cell research have had a significant impact on the pro-
gress of tissue engineering and provided a new era in the
development of tissue engineered heart valves for future
generations.17
The development also of percutaneous heart valve
replacement technology has brought new hope for a number
of patients who currently cannot be treated with traditional
surgical techniques, such as open heart surgery. Percutaneous
valve implantation is the development of a foldable heart
valve stent that can be mounted on an expandable stent and
delivered percutaneously. It has been estimated that one-third
to two-third of patients do not receive surgery either due to
excessive risk factors of open heart surgery and patient re-
fusal, or due to fear of lifestyle changes following major sur-
gery in elderly patients.17,18 However, without replacing, the
mortality rate is 50–60%. Since the first human implant of a
percutaneous valve replacement was reported by Bonhoeffer
and colleagues in the year 2000,19 the concept of transcathe-
ter valve insertion has been proved to be technically feasible
and an exciting prospect in this field. This review focuses
upon the ways in which polymeric, tissue engineered, and
percutaneous heart valves are currently being developed in
the field of interventional cardiology.
POLYMERIC HEART VALVES
The use of plastics in heart valves dates back to the 1950s,
however, the available polymers of the time did not pro-
vide the necessary durability to become a serious alterna-
tive material in heart valve replacement technology.
Nonetheless, polymeric heart valves have started to draw
more attention in recent years because of their synthetically
enhanced mechanical properties. Several synthetic poly-
mers, such as silicone, polyolefin, polytetrafluoroethylene
(PTFE), and PU have been tested as leaflet materials. How-
ever, silicone and polyolefin rubbers had inadequate dura-
bility20,21 while in vivo, PTFE valves suffered from cusp
stiffening and calcification.22 PU have been a popular
choice of material, given their relatively good tensile
strength and biocompatibility. There have been problems,
however, associated with long-term implants, and with ma-
terial degradation causing premature failure of devices.
Thus, the development of heart valves using PU has been
slower than anticipated. During the past 20 years, the re-
markable progress in polymer synthesis has resulted in a
number of bio-stable PU.
292 KIDANE ET AL.
PU contains the urethane ( NH(CO)O ) group formed
from the reaction of isocyanates with an alcohol group.
The segmented nature of these materials is believed to per-
mit alteration of the polymer chemistry to achieve both
flexibility and increased mechanical strength. Depending on
the composition of its hard and soft segments, tensile
strength ranges between 20 and 90 MPa with a tensile
modulus of 5–1150 MPa. Researchers are also continuing
to explore alternative methods of improving the biostability
of PU while maintaining the excellent mechanical and bio-
compatibility properties. One area of research has focused
on chemically modifying or replacing the susceptible poly-
ether soft segment with poly(carbonate urethane) (Table I).
Poly(carbonate urethane)s have a more oxidatively stable
soft segment and are more stable than polyether ure-
thanes.28 In vitro and in vivo studies have demonstrated
that PU with polycarbonate soft segment are more stable
than polyether urethanes with similar hard segment content.
However, in vivo degradation showed that polycarbonate
urethanes suffer similar oxidation to polyether urethanes
although to a lesser extent.29,30 Another approach research-
ers have tried to improve in the biostability of the soft seg-
ment in polyether urethanes is to replace some or all of the
polyether with the more oxidation resistant polysiloxane.
Incorporation of poly(dimethylsiloxane) (PDMS) together
with the compatibilizing polyether, poly(hexamethylene
oxide) (PHMO), into the polymer backbone was also
achieved with polycarbonate urethane. These incorporations
resulted in substantial improvement in the long term bio-
compatibility with diverse physical and mechanical proper-
ties (Table I). To produce excellent biostability and good
mechanical properties, PDMS and PHMO are incorporated
in varying amounts into polyether urethanes and polycar-
bonate urethanes. Our department has developed a nano-
composite PU with a polycarbonate soft segment and
polyhedral oligomeric silsesquioxanes (POSS) covalently
bonded as a pendant cage to the hard segment.38 POSS has
characteristics which improve both strength and elasticity
profiles. The bonds between the alternating silicone and ox-
ygen atoms are both strong and highly flexible, which pro-
vides the polymer with its strength and elasticity at high
levels of stress. In an in vitro study, we demonstrated that
the POSS group protected the soft segment of the PU re-
sponsible for its flexibilty and elasticity from oxidative and
hydrolytic degradation.36 Hence, this polymer with its
excellent mechanical properties may have the potential to
be developed for heart valve fabrication and confirmed the
ability of PU to be chemically engineered to a specific pur-
pose (Table I).
Several groups have designed and developed PU based
polymeric heart valves and have reported preliminary key
findings in vitro. PU valves were observed to have an
excellent resistance to cycle fatigue being capable of
achieving more than 800 million cycles in laboratory fa-
tigue testing ([20 years of ‘‘normal’’ function) in long-
term in vitro durability.39,40 It has also been shown by
in vitro fatigue testing that leaflet thickness of 50 lm
lasted less than 100 million cycles, while 150–200 lm
thickness lasted 800 million cycles.39,41 More recent in
vivo fatigue testing found that the durability of PU valves
with leaflet thickness varying between 100 and 300 lm
was between 600 million cycles and 1 billion cycles (15.8–
26 years).42
Previous studies have also indicated that the flow char-
acteristics of polymeric heart valves are comparable to
those of bio-prostheses resulting in good hemodynamic
properties.43 Indeed, the geometric similarity of the poly-
meric tri-leaflet heart valve to the natural heart valve pro-
vides a large orifice in the ejection phase and helps keep
the aortic blood flow less disturbed. The flow distal of tri-
leaflet polymeric heart valves was shown to have a rela-
tively flat centralized profile with re-circulation flow in the
sinus cavity. A maximum Reynold shear stress of 1447
dynes/cm2 was recorded in one of the PU valves.43 When
the performance of ATS bi-leaflet mechanical heart valves,
Carpentier-Edwards porcine bio-prosthetic valves, and PU
heart valves were compared in sheep models, it was found
that PU heart valves had better hemodynamic properties
compared with those that were bio-prosthetic.44
Moreover, several polymeric heart valves have been
investigated and compared with the mechanical and bio-
prosthetic heart valves in regard to their thrombogenic
effect and biocompatibility. When polymeric heart valves
such as PU heart valves were compared with the ATS bi-
leaflet mechanical heart valve in sheep models, they
showed a lower thrombogenicity rate.44 It has also been
demonstrated that the poly(carbonate)urethane heart valves
can achieve thrombosis rates comparable to bio-prosthetic
heart valves in animal studies.42,45 However, the major
impediment to the success of these polymeric heart valves
is the material degradation.46 In a recent study a polymeric
heart valve (polystyrene–polyisobutylene–polystyrene),
which was oxidatively stable and showed no degradation in
a long term animal study, was compared for its thrombo-
genic potential to the mechanical (St. Jude Medical bi-leaf-
let) and bio-prosthetic heart valve (St. Jude tissue valve).
The result demonstrated no significant difference between
the polymeric valve and the tissue valve indicating that
they have comparable thrombogenic potential.47
TISSUE ENGINEERED HEART VALVES
Design of tissue engineered heart valves is challenged by
the complex and dynamic mechanical environment, in
which the engineered heart valve must perform.48 It must
open and close at a frequency of 1 Hz, resulting in con-
siderable bending stresses, and be exposed to high shear
stresses associated with blood flow. The basic protocol in
tissue engineering is that autologous cells, expanded and
isolated in the laboratory, are seeded onto appropriate scaf-
folds. In this case, cells from peripheral arteries, that is,
mixed vascular cell populations consisting of myofibro-
Journal of Biomedical Materials Research Part B: Applied Biomaterials
 TABLE I. Summary of Development of Polyurethane Polymers for Cardiovascular Devices

Date Trade-Name Material/Polymer Hard-Segment Soft-Segment Chain Extender Experimental Test Outcome
23–25
1967 Biomer, Polyether urethanes HMDI, MDI PTMEG BD, EDA & DAMCH Ovine Better hydrolytic
Elasthane stability but
suffered oxidative
degradation of the
soft segment and
environmental stress
cracking.
198026,27 Thoralon Silicone in backbone MDI PTMEG & PDMS EDA Rat Siloxane endgroups
of polyether provided certain
urethane as an end degree of protection
group to the polyether soft
segment, however,
provided low
strength.
199028–31 ChronoFlex, Polycarbonate HMDI, MDI PC or PHECD BD, EDA, EDA & In vitro and More stable than
Bionate urethane DAMCH in rabbit PEU, and crack
resistant but
susceptible to

Journal of Biomedical Materials Research Part B: Applied Biomaterials

hydrolysis.
199132,33 PurSil, Silicone end groups MDI PTMEG & PDMS, PC & BD, EDA, DMACH Rabbit Increased resistance to
Carbosil and midblocks with PDMS, PHECD & PDMS oxidation compared
polyether or to polyether
polycarbonate urethane and
urethane polycarbonate
urethane.
199631,33,34 ElastEon Silicone midblocks MDI PTMEG & PDMS, BD In vitro and in Good biostability and
and polyether PDMS & PHMO sheep model relatively low
HEART VALVE REPLACEMENT THERAPY

urethanes hardness. Poor

tensile and flexural
moduli.
199735 ChronoFlex C Silicone midblocks MDI PC & PDMS BD In vitro High strength,
and polycarbonate hydrolytically and
urethanes proteolytically
stable.
200536,37 Seifalian Polyhedral oligomeric MDI PC EDA-POSS In vitro High strength with
silsesquioxane high elasticity at
integrated high levels of
poly(carbonate- stress. Improved
urea)urethane resistance to
degradation.
Abbreviations: PTMEG, polytetramethylene ether glycol; HMDI, hydrogenated methylene diisocyanate; MDI, methylene diisocyanate; PHECD, poly(1,6-hexyl 1,2-ethyl carbonate)diol; BD, 1,4-butanediol; EDA, ethylene diamine;
DAMCH, 1,3 diaminocyclohexane; PC, polycarbonate; POSS-PCU, polyhedral oligomeric silsesquioxane integrated poly(carbonate-urea)urethane.
293
294 KIDANE ET AL.
blasts and endothelial cells (EC), can be obtained. Pure via-
ble cell lines can then be easily isolated by cell sorters49
and the subsequent seeding onto the biodegradable scaffold
is undertaken in two steps. First, the myofibroblasts are
seeded and grown in vitro and second, the EC are seeded
on top of the generated neo-tissue leading to the formation
of a completely autologous valve.50
Scaffolds used for tissue engineered heart valves should
provide a suitable anatomical shape and are required to
possess both tensile and elastic properties. A number of
naturally occurring biodegradable polymers, such as small
intestinal submucosal, fibrin, and collagen have been inves-
tigated as potential scaffolds for tissue engineered heart
valves, as they offer a more native environment than syn-
thetic structures to the cells.51–53 However, their limited
availability, insufficient mechanical integrity for direct im-
plantation, and shrinkage of the fibrin or collagen gels
restrict their application for tissue engineering. Many
research groups have attempted to use native decellularized
heart valves matrix (donor heart valves or animal derived)
as scaffold for tissue engineered heart valves. The cellular
components of the heart valves are removed (decellular-
ized) resulting in a material composed of essentially ECM
proteins (allogeneic or xenogeneic) that can serve as a tem-
plate for cell attachment.54 These decellularized heart
valves have the advantage of being based in a correct anat-
omy. Currently, glutaraldehyde fixation is commonly used
for decellularization of heart valves, which reduces immu-
nogenicity by introducing cross-links between the matrix
and soluble proteins. However, the mechanical tissue prop-
erties deteriorate when cells are removed and the tertiary
structure of fibrous valve tissue constituents is altered dur-
ing the decellularization process.55 Moreover the decellula-
rization process leaves open collagen surfaces, which are
highly thrombogenic, causing platelet activation as well as
blood coagulation. It has been reported that the tissue
cross-links and the toxic effect of the residual glutaralde-
hyde in the tissue prevent cellular infiltration after implan-
tation. Another disadvantage of using animal derived heart
valves is the risk of infection transfer from animals to
human. When tissue engineered porcine heart valves were
implanted in vivo, a complete endothelialization of the
valve leaflets and infiltration by dense population of myofi-
broblasts was observed.56 However, an early failure of the
valve has been reported in human trials.57 Structural failure
or rapid degeneration associated with strong inflammatory
response occurred within a year. There was also evidence
of calcific deposition and no host cell re-population on the
valve matrix.57
Synthetic biodegradable materials have already been
broadly investigated for use as scaffolds in tissue engineer-
ing of aortic heart valve replacement (Table II). Initial
attempts to create single heart valve leaflets were based on
synthetic biodegradable polymers, such as polyglactin,
PGA, PLA, and a copolymer of PGA and PLA
(PLGA),65,66 which are members of the aliphatic polyester
family, which degrade by cleavage of the polymer chains
following hydrolysis of their ester bonds. The resultant
monomer is either secreted in the urine or enters the tricar-
boxylic acid cycle. The major limitations of aliphatic poly-
ester are its thickness and initial stiffness, which makes the
fabrication of a tri-leaflet heart valve difficult. To develop
complete tri-leaflet heart valve conduits, polyhydroxyalka-
noates (PHA) based materials were also used.67 However,
the general drawback is their slow degradation. Nonethe-
less, combination of aliphatic polyesters and PHA has
shown promising results. Hoerstrup and coworkers have
successfully engineered heart valves using a combined
polymer scaffold consisting of non-woven PGA and P4HB
scaffold63 in sheep. The heart valves were implanted in the
low pressure pulmonary artery of sheep and were func-
tional for up to 20 weeks. The valves showed the character-
istic three-layer structure of the native valve; however, they
were not mechanically strong enough to withstand the
high-pressure of the aorta.
Several studies have shown that the aortic valve leaflets
contain collagen fibers aligned primarily in a circumferen-
tial direction.68 This circumferential or nonlinear orienta-
tion results in material anisotropy behavior, which is
thought to give the normal native valve viscoelastic stress–
strain characteristics.69 The individual layers of valve leaf-
lets (the fibrosa, spongiosa, and ventricularis) show differ-
ent mechanical characteristics, due to their differences in
composition68 (Figure 1). The fibrosa, which comprises
mainly collagen fibers is considered to be the main load
bearing layer of the leaflet, and prevents excessive stretch-
ing. The leaflet shows an extremely low compressive mod-
ulus, which is most likely facilitated by the spongiosa.68
The overall mechanical response of the leaflet is a summa-
tion of the mechanics of the individual layers. The valvular
endothelium cells cover the surfaces of the leaflets and pro-
vide a protective, non-thrombogenic layer. The cells pres-
ent in the aortic valve leaflets between the endothelial
linings are referred to as valvular interstitial cells. Among
the valvular interstitial cells, three cellular phenotypes can
be identified as; smooth muscle cells, fibroblasts and myofi-
broblasts. The unique characteristics of the myofibroblasts,
expressing both skeletal and cardiac contractile proteins,
may play a major role to the lifelong durability of the
valve70 (Figure 1).
Source of Cells for Tissue Engineered Heart Valves
The cells instrumental in the success of any tissue engi-
neered heart valve are EC and ECM forming cells. A con-
fluent endothelial layer ensures a non-thrombogenic lining
to the valve structure whereas ECM imparts strength to the
valve structure, replacing the initial scaffold. These cells
need to be autologous to ensure immunological compatibil-
ity with the recipient’s tissues. In vivo models have
afforded investigators the chance to use glamorous yet
clinically impractical sources of cells; however, for human
Journal of Biomedical Materials Research Part B: Applied Biomaterials
 TABLE II. Summary of Tissue Engineered Heart Valves
Author/Year
58
Perry et al. (2003)
Dvorin et al. (2003)59
Hoerstrup et al. (2002)60
Rabkin et al. (2002)61
Journal of Biomedical Materials Research Part B: Applied Biomaterials
Taylor et al. (2002)70
Kim et al. (2001)62
Hoerstrup et al. (2000)63
Sodian et al. (2000)64
Shinoka et al. (1995)65
Abbreviations: ECs, endothelial cells; ECM, extracellular matrix; PGA, polyglycolic acid; P4HB, poly-4-hydroxybutyrate; TE, tissue engineering.
Material of Scaffold Source of Cell Design Test Outcome
PGA and P4HB composite Bone-marrow derived To develop TE trileaflet In vitro Tissue grew on and cells
scaffold mesenchymal stem cells heart valve expressed markers for
mesenchymal stem cell
and smooth muscle cell
lineage.
Non-woven PGA mesh Ovine aortic valve ECs and To investigate growth and In vitro Growth of ECs on PGA/
coated with 1% P4HB ovine circulating EC differentiation of cells on P4HB was observed.
progenitor the scaffold
Trileaflet heart valve made Human bone marrow To develop a TE heart valve In vitro Cells showed morphological
with PGA/P4HB stromal cells and mechanical
composite scaffold characteristics similar to
native heart valves.
Trileaflet heart valve made Ovine ECs and carotid To develop a TE heart valve Lamb ECM architecture of
with P4HB, coated PGA artery medial cells explanted TE heart valve
composite scaffold resembled that of native
valves.
3D scaffold made with Human heart valve 3D collagen sponge as In vitro Collagen sponge maintained
biodegradable Type I intersticial cells scaffold for TE the viability of intersticial
collagen sponge cells.
PGA and polylactic acid Myofibroblasts and ECs To compare cell seeded Ovine TE scaffold contained less
biodegradable scaffold as from ovine artery scaffold and acellular fibrin and protein
a pulmonary valve scaffold implanted in the compared with the
pulmonary valve leaflet in acellular scaffold, in short
the same animal term. But in longer term,
HEART VALVE REPLACEMENT THERAPY
new tissue was similar in
both cases.
Trileaflet heart valve Myofibroblasts and ECs To develop a TE trileaflet Lamb Fully functioning TE heart
made with PGA/P4HB from lamb carotid artery heart valve valve up to 5 months.
composite scaffold
Biodegradable trileaflet Vascular cells from ovine To assess a new TE heart Lamb New tissue was covering the
heart valve scaffold carotid arteries valve as pulmonary heart surface of the TE valve.
made from porous valve No thrombogenic episodes
polyhydroxyalkanoate were recorded.
Biodegradable scaffold made Fibroblasts and ECs from To develop a TE heart valve Lamb Development of ECM was
with PGA fibers ovine arteries using a cell seeded noticed in vivo.
scaffold
295
296 KIDANE ET AL.

Figure 1. Schematic diagram of the multilayered arrangement of heart valve leaflet. Naturally-occur-
ring cardiac valve leaflets have three internal layers-ventricularis, spongiosa, and fibrosa. Endothelial
cells are present in a single layer around the leaflet’s blood-contacting surface. Myofibroblasts are
found throughout the three layers, with the sparsest population in the fibrosa. Myofibroblasts are
aligned with the collagen fibrils in the matrix of the valve. [Color figure can be viewed in the online
issue, which is available at www.interscience.wiley.com.]

Figure 2. Diagram of heart valves developed by Edwards Lifescience: (a) compress and (b)
expanded; and (c) Advanced Bio Prosthetic Surfaces. [Color figure can be viewed in the online issue,
which is available at www.interscience.wiley.com.]

Journal of Biomedical Materials Research Part B: Applied Biomaterials

 HEART VALVE REPLACEMENT THERAPY
purposes, cell availability is of paramount concern, to
ensure marketability and applicability of the tissue-engi-
neered product. Mechanical conditioning at the time of
seeding is important to maximize the adherence of cells, in
the same way that pulsatile pre-conditioning increases seed-
ing rates in tissue engineered vascular bypass grafts. Indeed
there is evidence to suggest that EC seeding of valve leaf-
lets may be more successful than that for bypass conduits,
due to the leaflet position impinging in the blood flow
channel directly, and so reducing the shearing effects expe-
rienced by ECs lining bypass grafts. Endothelialization of
PTFE sheets is readily observed in sheep models if the
sheet is positioned to oppose blood flow,71 whereas the
same has never been achieved for PTFE bypass conduits in
an ovine model. Mechanical conditioning also stimulates
the laying down of collagen from fibroblasts both physio-
logically, and in the case of seeded cells.72
Human EC have been extracted and successfully seeded
to scaffolds from arteries, veins, and adipose tissue. In
addition, umbilical cord blood as well as fetal chorionic
villi73 have a high proportion of endothelial progenitor
cells, which can be multiplied in vitro as a ready source
of EC for valve leaflet seeding. Adipose tissue has been
used to extract stromal progenitor cells, which are multi-
potent, with the ability to differentiate into EC amongst
others.74 Stem cells are similarly available directly from
the bone marrow.75 These also have the advantage of dif-
ferentiating into a range of cells depending on local signals
and environment,76 and so are a source of ECM-secreting
cells too.75
Mesenchymal cells (fibroblasts/myofibroblasts) have
greater matrix producing ability if sourced from veins
rather than arteries.77 In addition, vein is a far more acces-
sible living autologous source; principally the saphenous
vein, which can be examined, harvested, and cells extracted
at the time of operation. The field of pediatric vascular
surgery would benefit hugely from advances in tissue-
engineered prostheses, due to the possibility of implants
growing with the child. In these cases, harvesting of vessels
is undesirable and could be avoided by the use of fibro-
blasts obtained from the wall of the umbilical cord.78 As
with EC, stem cell technology is being investigated widely
with distinct advantages emerging from the use of mesen-
chymal stem cells. As well as being a proliferative source
of fibroblasts, they can afford anti-inflammatory proper-
ties75 in the developing valve.
PERCUTANEOUS HEART VALVES
The catheter-based valve devices (first suggested by Davies
in 1965), simulated a unicuspid aortic valve and consisted
of a distally oriented cone mounted on a catheter.79 How-
ever, it was only after the extensive advances in the field
of interventional cardiology and the development of endo-
vascular stent technologies that percutaneous valve replace-
Journal of Biomedical Materials Research Part B: Applied Biomaterials
297
ment became practically feasible. In 2000, Philipp
Bonhoeffer reported the first successful percutaneous
human valve replacement (PVR) formed from jugular bo-
vine vein sutured into platinum stent in the pulmonic posi-
tion.19 This successful experience demonstrated that the
approach is feasible and opened a new perspective on the
percutaneous heart valve in the aortic position. In 2002,
Alain Cribier and colleagues reported the first successful
human implant of a percutaneous aortic valve. The valve
was developed by Edwards Lifescience PVT (Irvine, CA)
and consisted of a tricuspid valve made of bovine pericar-
dium, sutured on a 23-mm balloon-expandable stainless
steel stent, crimped into a 24-French sheath.80 At present
the development of a technique for PVR in the aortic posi-
tion is a bigger challenge because of the higher hemody-
namic stresses and the proximity of both the mitral valve
and coronary artery orifices.81 The access of the aortic
valve for PVR can be antegrade or retrograde. Antegrade
starts from the femoral vein, and reaches the aortic valve
after puncturing of the inter-atrial septum, and crossing the
mitral valve and the cordae tendinee, with the risk of dam-
aging these structures.82,83 The retrograde approach offers a
direct access to the aortic valve from the femoral artery,
which resulted in the technique being much safer for the
clinical trials. However, this implantation requires smaller
collapsed valves, the ability to pass through the stiff and
tortuous aortic vessels, and to cross the small gaps between
the leaflets of calcific aortic valves.82
There are many limitations related to device technology,
valve durability and stability, and anatomical obstacles
(including the severity of disease in patient). Currently,
biomedical companies, such as Edwards Lifescience, Sor-
inGroup, and CoreValve, are engaged in the development
of different designs of percutaneous aortic valves formed
from equine pericardial, porcine pericardial, and bovine
pericardial tissue valves, respectively.84–86 Edwards Life-
science have used stainless steel and balloon expandable
stent technology whereas CoreValve and SorinGroup used
super-elastic alloy and self-expanding stents. A common
problem to all percutaneous biological valves is the fra-
gility of the biological tissue, which should advisedly be
kept in its crimped configuration for a relatively brief pe-
riod, to avoid damage and dehydration. This implies the
need of preparation prior to implantation, with the rela-
tive logistical concerns. Recently, Advanced Bio Pros-
thetic Surfaces patented a metal micro-porous eNitinol
aortic percutaneous valve with self-expanding super-elas-
tic alloy stent (Figure 2).87 Both the Edwards Lifescience
and the CoreValve have been limited to elderly patients
with calcific aortic stenosis and co-morbidities for whom
surgical intervention is considered to high risk. The pre-
liminary experience however, has shown the feasibility
and effectiveness of the technique. Percutaneous valve
implantation has been limited to elderly patients who
have been considered as high risk for surgical valve
replacement.88
298 KIDANE ET AL.

TABLE III. Summary of the Advantages and Challenges of Heart Valve Replacement Prostheses

Heart Valve Replacement

Prosthesis Advantages Challenges
Polymeric Wide range of polymer properties. Long term bio-stability.
Ease of fabrication. Long term biocompatibility.
Excellent physical properties of polyurethane. Mechanical performance.
Similar flow dynamics to those of human heart
valves.
Tissue Engineered Improve biocompatibility. Lack of optimal scaffold material.
Increase life expectancy of heart valve. Cell source for clinical use.
Repair, remodelling and growth capacity. Obtaining the number and type of cells.
Less risk of calcification.
Less risk of infection.
Percutaneous Less invasive therapy. Selecting an appropriate patient population for
development of the device.
The potential for re-replacement. Device durability.
Potential for children and elderly patients to ill Interruption of coronary blood flow in patients
to have open heart surgery. during implantation.
Shorter recovery time. Operators skills.
Used as a bridge treatment before surgery. Size/dimension of PHV- too big to be delivered
through retrograde.
Cost of therapy. Facility of replacement.
Availability in extreme conditions- in non- Removal of the actual/native valve.
sterile conditions.

FUTURE PROSPECTIVE OF HEART VALVE
REPLACEMENT
Polymeric Heart Valve
According to the recent advancement of medical technol-
ogy, polymer materials are becoming desirable for develop-
ment of heart valves, due to their wide variety of functions.
Long-term material degradation and biocompatibility have
been the major factors, which limited the success of poly-
meric heart valves (Table III). To overcome these draw-
backs, several attempts have been made to modify PU
materials by incorporating soft segments, such as polycar-
bonate and polysiloxane into the backbone. These modifica-
tions resulted in substantial improvement in the long term
biocompatibility and bio-stability. Currently, several groups
have been involved in designing and developing PU based
polymeric heart valves and has reported preliminary key
findings in vitro.
Our group here in UCL have developed and patented a
nanocomposite based polymer, POSS-PCU [POSS-poly(car-
bonate–urea)urethane] with a polycarbonate soft segment
and covalently bonded POSS as a pendant cage to the hard
segment.38 The polymer demonstrated good surface proper-
ties and excellent mechanical strength in both in vitro and
in vivo study,36,89 which would provide the potential for
development and fabrication of polymeric heart valves. It
has also been widely demonstrated that improving valve
design to reduce the stresses in the leaflets is considered to
improve performance and durability in long term applica-
tions. Hence several groups including ours have been work-
ing on heart valve design, which can reproduce the
behavior of native valves, combining the advantage of both
mechanical and bio-prosthetic valves to offer an optimum
alternative to current prostheses.
Tissue Engineered Heart Valves
The first successful tissue engineered heart valve using a
synthetic biodegradable scaffold implanted in sheep has
demonstrated the general feasibility of current tissue engi-
neering concepts to replace heart valves in pulmonary
valve position.63 Decellularized xenogenic bovine pericar-
dial and porcine valves treated with glutaraldehyde have
been widely used as natural scaffolds due to the advantage
of adequate anatomic structure and unlimited availability.
Several researchers have attempted to engineer aortic and
pulmonary valve using these decellularized animal derived
scaffold, including donor valves (allograft) for tissue engi-
neered heart valve. However, a clinical study on the im-
plantation of FDA-approved engineered heart valves, based
on decellularized porcine valves has failed leading to the
death of three out of four pediatric patients57 and the sub-
sequent early termination of the study. The cause of these
failures had been described as rejection or inflammation,
degeneration, and graft rupture. Thus, the commonly used
animal model has failed to predict the failures in humans.
This suggests that appropriate test models need to be devel-
oped to be able to further develop valves in the future. It
has also been described that the commonly used glutaralde-
hyde treatment inhibits scaffold recellularization by autolo-
gous cells90 and causes valve weakening.57 Subsequently,
decellularization through a non-enzymatic process, has
demonstrated improved mechanical properties.91 This has

Journal of Biomedical Materials Research Part B: Applied Biomaterials

 HEART VALVE REPLACEMENT THERAPY
been demonstrated in a recent publication of mid-term
clinical follow-up (5-years) of 22 patients, mean age of
44 years, implanted with tissue engineered pulmonary allo-
graft and xenograft seeded with vascular EC. The valve
showed excellent hemodynamic performance and no failure
due to degeneration.92
Additionally, scaffold recellularization by autologous
cells in a bioreactor before implantation has been described
as an appropriate strategy to obtain a fully recolonized liv-
ing autologous valve. Several groups have demonstrated
that in vitro seeding of cells on artificial or on natural mat-
rices scaffolds in a biomimetic environment succeeded in
the generation of functional tissue engineered heart
valves.93 However, this in vitro culture step is delicate,
requires time, sophisticated devices and methods. Hence, a
procedure which avoids this in vitro step and allows direct
injection of autologous cells into a decellularized xenogenic
scaffold, immediately before surgical implantation and
additionally induces in vivo recolonization would be ideal
and simplify clinical applications.94 The best cell source
for such strategies is not known yet, however, recently
stem cells or progenitor cells, such as bone marrow cells,
have been demonstrated to contain endothelial progenitors
and mesenchymal lineage cells, which can promote tissue
regeneration95,96 when injected into cardiovascular struc-
tures97 and improve healing after myocardial infraction and
limb ischemia.98 Taken together these findings indicate that
the prospect of tissue engineered heart valves may progress
faster in the coming few years. Using allogenic cell sources
(such as progenitor and stem cells), proper test models and
appropriate selection of patients for clinical trials would
also offer enormous potential development for future tissue
engineered heart valves. Additionally, solving problems
relating to tissue engineering of valves on the left side of
heart (aortic and mitral) has been a challenge because of
high pressure of the aortic flow condition. At present, the
biomaterial scaffold used in tissue engineering valves lack
the mechanical strength needed to withstand the high pres-
sure on the left-hand side of the heart. In particular, for
aortic heart valves the leaflets have to carry substantial he-
modynamic load both during systolic and diastolic phase.
Furthermore, the use of synthetic biomaterials scaffold
introduces more challenges, due to the lack of source of
signaling and cell attachment molecules, which promote
and direct cell proliferation, differentiation and three-
dimensional tissue re-organization.99 Although, in vitro me-
chanical stimulation through the use of bioreactors during
tissue development has been widely employed in tissue en-
gineering for improving tissue formation, organization, and
function, designing a bioreactor for three-dimensional struc-
ture, which provides well controlled environmental condi-
tions has been a major challenge.48,100
Percutaneous Heart Valve
Percutaneous heart valve replacement therapy is still in the
early stages of development. Among the several potential
Journal of Biomedical Materials Research Part B: Applied Biomaterials
299
uses of the percutaneous heart valve replacement therapy,
the main advantage for patients is the less invasive proce-
dure, which has attracted many researchers and clinicians
(Table III). The first human successful percutaneous valve
replacement was performed by Bonhoeffer (2000) on pul-
monary position and by Cribier et al. (2002) on the aortic
position. Since then, numerous advances have been
achieved on percutaneous replacement, and several clinical
studies have been carried out.101–104 Valve design, valve
delivery system and patient type have been described as
major limiting factors for the progress of percutaneous
valve replacement therapy. Bonhoeffer et al. reported that
significant limitations of the technique was the size of the
sheath (outer diameter 21 French), which had limited its
application to patients older than 5 years of age and heavier
than 20 kg weight. Furthermore, the application of this
approach is presently restricted to certain right ventricular
outflow tract morphologies because the device needs to be
anchored safely to prevent device dislodgment and right
ventricular outflow tract dimensions greater than 22 mm,
which are currently not suitable for percutaneous approach.
Currently, available percutaneous heart valves are tissue
derived prostheses, which have been used in experimental
and clinical trials. For example, bovine jugular-vein valve
fitted in a platinum stent was initially used by Bonhoeffer
group for percutaneous pulmonary valve replacement. In a
recent clinical trial the group further went on to implant
the bovine jugular vein valve in the pulmonic position of
59 patients,102 although there was no mortality during the
10 months follow-up period. However, significant proce-
dural and device complications were reported, including
dislodging of the stent, stenosis, and fracture. Major limita-
tions of the technique are described as the size of the
sheath, which limits its application to patients because of
the mismatch between the size of the femoral vessels of
small children and the application devices. This study sug-
gests that device design, particularly size, is a problem that
will need to be resolved in the future. Moreover, the use of
the device developed by the Bonhoeffer group requires a
cautious selection of the patients’ population. In fact, the
valve is implanted in young subjects with pulmonary artery
prosthetic conduits, whose geometry does not follow the
natural growth of the root, and that are destined to re-oper-
ations. The development of novel valve designs, ensuring
functional operative conditions at different expansion con-
figurations, together with the use of smart stent materials,
such as self-expanding memory shape alloys, that can be
designed to administrate a progressive radial force over an
expanding root, may open new prospective to this clinical
approach.
The percutaneous approach for the treatment of valve
disease in the aortic position is more challenging than the
pulmonary position. Difficulties of vascular access due to
complex anatomy, the size of delivery system, and prob-
lems in secure positioning of the valve in aortic annulus
are the main challenges in percutaneous aortic valve
300 KIDANE ET AL.
replacement. In a recent study Cribier et al., reported the
result of mid-term follow-up of high risk elderly patients
who received an equine pericardium valve in a balloon-
expandable, stainless-steel stent on aortic position.104
Among 33 patients, the aortic valve was implanted success-
fully in 27 of the patients. The implanted valve function
remained unchanged during follow-up, and no device-
related deaths were reported. However, the valve delivery
technique via retrograde approach and valve size were
described to contribute to the early complications. Although
the retrograde approach offers an easier and direct access
to the aortic valve from the femoral artery, the implantation
procedure requires smaller collapsed valves, able to pass
through the stiff and complex aortic vessels, and to cross
the leaflets of calcified aortic valve. A major problem expe-
rienced in this device is the risk of migration, being the
anchoring of the valve mainly due to the presence of calcium
and fibrotic lesion.80 This makes the device suitable for the
treatment of calcific stenosis, now the most common form of
valve disease in western world, but it limits the applications
to other valve diseases. However, valve migration has not
been reported to be a major issue in the experiences with
superelastic self-expanding stents that may represent a valid
alternative for the less common pathologies.
Furthermore, there is currently no developed percutane-
ous procedure for the removal of the initially diseased or
calcified heart valve, which needs replacement. This leads
to problems for the newly implanted percutaneous heart
valve, due to limitations in the valve size, which will need
to be addressed.
Thus, it seems that the way forward for the percutaneous
heart valve replacement technique lies in the continued
advances in device design, and developing increased expe-
rience in implantation technique to combat these limita-
tions. Percutaneous pulmonary and aortic valve
replacement should become a very realistic way of treating
a select population of patients in the near future.
CONCLUSIONS
Heart valve replacement with mechanical or bio-prosthetic
valves remains the most common treatment for advanced
heart valve disease. Despite the many limitations of the
currently available heart valve replacements, there has been
significant progress in the design and performance of both
mechanical and bio-prosthetic heart valves in the field of
interventional cardiology. It is believed that these heart
valve prostheses will still be widely used for the next dec-
ade. In adults, these prosthetic heart valves have been
largely efficacious, although they are associated with a
number of major complications, which limit their suc-
cess.105 Currently, 55% of implanted valves world wide are
mechanical heart valves, while the remaining 45% are bio-
prosthetic heart valves.106 One major area of concern is
their inability to grow and remodel with the surrounding
tissue limiting their use in infants and children. Tissue en-
gineering of heart valves offers a potential pathway to
overcome these limitations. However, all tissue engineered
heart valves constructed to date lack the mechanical
strength needed for the required functional performance.
The mechanical function of heart valves is determined by
the geometry and structural characteristics, by the mechani-
cal support environment, and by the momentum of the
valve leaflets and flow behavior. In this respect, significant
progress has been made in engineering materials such as
polymers, which have enabled the design of improved
valve prostheses.
Polymeric-based heart valve fabrication has started to
draw more attention in recent years due to their improved
durability and hemodynamic performance. In addition,
from the manufacturing stand point, there is the advantage
of creating an endless variety of sizes and designs. Never-
theless, the major drawback to the success of the polymeric
heart valves is the valve material degradation.46 In recent
years, researchers have shown particular interest in the PU-
based polymeric valves because of their stable degradation
property. It has been found that the PU valves also had bet-
ter hemodynamic properties compared with the bio-pros-
thetic valve and lower thrombogenicity rates compared
with the mechanical heart valves. Polymeric heart valves
may also be utilized for the emerging percutaneous valve
implantation procedure which, due to their flexibility,
would be easily compressed and expanded during valve
delivery. In the coming few years, polymeric heart valves
can be expected to be investigated more for clinical appli-
cations and new materials may be developed to solve their
degradation problems.
It is also expected that the use of percutaneous heart
valve replacements will increase dramatically as technology
develops to overcome the present limitations, and effective
and safe techniques are practiced. The advantage of using
less invasive therapeutic procedures for patients and
improving the durability and hemodynamic performance of
polymeric valves will considerably attract clinicians and
companies. At present, there are still several limitations
that exist for the use of polymeric, tissue engineered and
percutaneous heart valves to become a part of conventional
heart valve replacement therapy. There, however, remains
an exciting prospect ahead in the future development of
these new technologies.
REFERENCES
1. Friedewald VE, Bonow RO, Borer JS, Carabello BA, Kleine
PP, Akins CW, Roberts WC. The Editor’s Roundtable: Car-
diac valve surgery. Am J Cardiol 2007;99:1269–1278.
2. Gallegos RP, Rivard AL, Suwan PT, Black S, Bertog S,
Steinseifer U, Armien A, Lahti M, Bianco RW. In-vivo ex-
perience with the Triflo trileaflet mechanical heart valve.
J Heart Valve Dis 2006;15:791–799.
3. Wu Y, Gregorio R, Renzulli A, Onorati F, De Feo M, Grun-
kemeier G, Cotrufo M. Mechanical heart valves: Are two
leaflets better than one? J Thorac Cardiovasc Surg
2004;127:1171–1179.
Journal of Biomedical Materials Research Part B: Applied Biomaterials
 HEART VALVE REPLACEMENT THERAPY
4. Bryan AJ, Rogers CA, Bayliss K, Wild J, Angelini GD. Pro-
spective randomized comparison of CarboMedics and St.
Jude Medical bileaflet mechanical heart valve prostheses:
Ten-year follow-up. J Thorac Cardiovasc Surg 2007;133:
614–622.
5. Gregoric ID, Eya K, Tamez D, Cervera R, Byler D, Conger
J, Tuzun E, Chee HK, Clubb FJ, Kadipasaoglu K, Frazier
OH. Preclinical hemodynamic assessment of a new trileaflet
mechanical valve in the aortic position in a bovine model.
J Heart Valve Dis 2004;13:254–259.
6. Schoen FJ, Levy RJ. Founder’s Award, 25th Annual Meeting
of the Society for Biomaterials, perspectives. Providence, RI,
April 28–May 2, 1999. Tissue heart valves: Current chal-
lenges and future research perspectives. J Biomed Mater Res
1999;47:439–465.
7. Wells SM, Sellaro T, Sacks MS. Cyclic loading response of
bioprosthetic heart valves: Effects of fixation stress state on
the collagen fiber architecture. Biomaterials 2005;26:2611–
2619.
8. Sacks MS, Schoen FJ. Collagen fiber disruption occurs inde-
pendent of calcification in clinically explanted bioprosthetic
heart valves. J Biomed Mater Res 2002;62:359–371.
9. Schoen FJ, Levy RJ. Calcification of tissue heart valve sub-
stitutes: Progress toward understanding and prevention. Ann
Thorac Surg 2005;79:1072–1080.
10. Walther T, Falk V, Diegeler A, Rauch T, Weigl C, Gummert
J, Autschbach R, Mohr FW. Effectiveness of different anti-
calcification treatments for stentless aortic bioprostheses.
Thorac Cardiovasc Surg 1999;47:23–25.
11. Flameng W, Meuris B, Yperman J, De Visscher G, Herijgers
P, Verbeken E. Factors influencing calcification of cardiac
bioprostheses in adolescent sheep. J Thorac Cardiovasc Surg
2006;132:89–98.
12. Zilla P, Bezuidenhout D, Human P. Carbodiimide treatment
dramatically potentiates the anticalcific effect of a-amino
oleic acid on glutaraldehyde-fixed aortic wall tissue. Ann
Thorac Surg 2005;79:905–910.
13. Rapoport HS, Connolly JM, Fulmer J, Dai N, Murti BH,
Gorman RC, Gorman JH, Alferiev I, Levy RJ. Mechanisms
of the in vivo inhibition of calcification of bioprosthetic por-
cine aortic valve cusps and aortic wall with triglycidylamine/
mercapto bisphosphonate. Biomaterials 2007;28:690–699.
14. Gleason TG, David TE, Coselli JS, Hammon JW Jr, Bavaria
JE. St. Jude Medical Toronto biologic aortic root prosthesis:
Early FDA phase II IDE study results. Ann Thorac Surg
2004;78:786–793.
15. Hilbert SL, Ferrans VJ, Tomita Y, Eidbo EE, Jones M. Eval-
uation of explanted polyurethane trileaflet cardiac valve
prostheses. J Thorac Cardiovasc Surg 1987;94:419–429.
16. Heath CA. Cells for tissue engineering. Trends Biotechnol
2000;18:17–19.
17. Iung B, Baron G, Butchart EG, Delahaye F, Gohlke-Barwolf
C, Levang OW, Tornos P, Vanoverschelde JL, Vermeer F,
Boersma E, Ravaud P, Vahanian A. A prospective survey of
patients with valvular heart disease in Europe: The Euro
Heart Survey on Valvular Heart Disease. Eur Heart J
2003;24:1231–1243.
18. Kvidal P, Bergstrom R, Horte LG, Stahle E. Observed and
relative survival after aortic valve replacement. J Am Coll
Cardiol 2000;35:747–756.
19. Bonhoeffer P, Boudjemline Y, Saliba Z, Merckx J, Aggoun
Y, Bonnet D, Acar P, Le Bidois J, Sidi D, Kachaner J. Per-
cutaneous replacement of pulmonary valve in a right-ventri-
cle to pulmonary-artery prosthetic conduit with valve
dysfunction. Lancet 2000;356:1403–1405.
20. Kiraly R, Yozu R, Hillegass D, Harasaki H, Murabayashi S,
Snow J, Nose Y. Hexsyn trileaflet valve: application to tem-
porary blood pumps. Artif Organs 1982;6:190–197.
Journal of Biomedical Materials Research Part B: Applied Biomaterials
301
21. Chetta GE, Lloyd JR. The design, fabrication and evaluation
of a trileaflet prosthetic heart valve. J Biomech Eng 1980;
102:34–41.
22. Imamura E, Kaye MP. Function of expanded-polytetrafluoro-
ethylene laminated trileaflet valves in animals. Mayo Clin
Proc 1977;52:770–775.
23. Boretos JW, Pierce WS. Segmented polyurethane: A new
elastomer for biomedical applications. Science 1967;158:
1481–1482.
24. Stokes KB. Polyether polyurethanes: Biostable or not? J Bio-
mater Appl 1988;3:228–259.
25. McCarthy SJ, Meijs GF, Mitchell N, Gunatillake PA, Heath
G, Brandwood A, Schindhelm K. In-vivo degradation of pol-
yurethanes: transmission-FTIR microscopic characterization
of polyurethanes sectioned by cryomicrotomy. Biomaterials
1997;18:1387–1409.
26. Ward RS. Surface modification prior to surface formation:
Control of polymer surface properties via bulk composition.
Med Plastics Biomater 1995;2:34–41.
27. Mathur AB, Collier TO, Kao WJ, Wiggins M, Schubert MA,
Hiltner A, Anderson JM. In vivo biocompatibility and bio-
stability of modified polyurethanes. J Biomed Mater Res
1997;36:246–257.
28. Christenson EM, Dadsetan M, Wiggins M, Anderson JM,
Hiltner A. Poly(carbonate urethane) and poly(ether urethane)
biodegradation: In vivo studies. J Biomed Mater Res A
2004;69:407–416.
29. Christenson EM, Anderson JM, Hiltner A. Oxidative mecha-
nisms of poly(carbonate urethane) and poly(ether urethane)
biodegradation: In vivo and in vitro correlations. J Biomed
Mater Res A 2004;70:245–255.
30. Tang YW, Labow RS, Santerre JP. Enzyme-induced biodegra-
dation of polycarbonate-polyurethanes: Dependence on hard-
segment chemistry. J Biomed Mater Res 2001;57:597–611.
31. Martin DJ, Warren LA, Gunatillake PA, McCarthy SJ, Meijs
GF, Schindhelm K. Polydimethylsiloxane/polyether-mixed
macrodiol-based polyurethane elastomers: Biostability. Bio-
materials 2000;21:1021–1029.
32. Christenson EM, Dadsetan M, Hiltner A. Biostability and
macrophage-mediated foreign body reaction of silicone-
modified polyurethanes. J Biomed Mater Res A 2005;74:
141–155.
33. Ward B, Anderson J, Ebert M, McVenes R, Stokes K. In
vivo biostability of polysiloxane polyether polyurethanes:
Resistance to metal ion oxidation. J Biomed Mater Res A
2006;77:380–389.
34. Simmons A, Hyvarinen J, Odell RA, Martin DJ, Gunatillake
PA, Noble KR, Poole-Warren LA. Long-term in vivo bio-
stability of poly(dimethylsiloxane)/poly(hexamethylene oxide)
mixed macrodiol-based polyurethane elastomers. Biomaterials
2004;25:4887–4900.
35. Szycher M, Dempsey D, Edwards A. Hydrolytically and pro-
teolytically stable polycarbonate polyurethane silicone copo-
lymers. US Pat. No. 5,863,637;1999.
36. Kannan RY, Salacinski HJ, Odlyha M, Butler PE, Seifalian
AM. The degradative resistance of polyhedral oligomeric sil-
sesquioxane nanocore integrated polyurethanes: An in vitro
study. Biomaterials 2006;27:1971–1979.
37. Kannan RY, Sales KM, Salacinski HJ, Butler PE, Seifalian
AM. Cytotoxicity analysis of poly(carbonate–siloxane–urea)
urethane. Med J Malaysia 2004;59(Suppl. B):99–100.
38. Kannan RY, Salacinski HJ, Butler PE, Seifalian AM. Poly-
hedral oligomeric silsesquioxane nanocomposites: The next
generation material for biomedical applications. Acc Chem
Res 2005;38:879–884.
39. Bernacca GM, Mackay TG, Wheatley DJ. In vitro function
and durability of a polyurethane heart valve: Material con-
siderations. J Heart Valve Dis 1996;5:538–542.
302 KIDANE ET AL.
40. Jansen J, Reul H. A synthetic three-leaflet valve. J Med Eng
Technol 1992;16:27–33.
41. Bernacca GM, Mackay TG, Gulbransen MJ, Donn AW,
Wheatley DJ. Polyurethane heart valve durability: Effects of
leaflet thickness and material. Int J Artif Organs 1997;20:
327–331.
42. Daebritz SH, Fausten B, Hermanns B, Schroeder J, Groetz-
ner J, Autschbach R, Messmer BJ, Sachweh JS. Introduction
of a flexible polymeric heart valve prosthesis with special
design for aortic position. Eur J Cardiothorac Surg 2004;25:
946–952.
43. Chandran KB, Fatemi R, Schoephoerster R, Wurzel D, Han-
sen G, Pantalos G, Yu LS, Kolff WJ. In vitro comparison of
velocity profiles and turbulent shear distal to polyurethane
trileaflet and pericardial prosthetic valves. Artif Organs
1989;13:148–154.
44. Wheatley DJ, Raco L, Bernacca GM, Sim I, Belcher PR,
Boyd JS. Polyurethane: Material for the next generation of
heart valve prostheses? Eur J Cardiothorac Surg 2000;17:
440–448.
45. Sachweh JS, Daebritz SH. Novel ‘‘biomechanical’’ polymeric
valve prostheses with special design for aortic and mitral
position: A future option for pediatric patients? ASAIO J
2006;52:575–580.
46. Bernacca GM, Straub I, Wheatley DJ. Mechanical and mor-
phological study of biostable polyurethane heart valve leaf-
lets explanted from sheep. J Biomed Mater Res 2002;61:
138–145.
47. Yin W, Gallocher S, Pinchuk L, Schoephoerster RT, Jesty
J, Bluestein D. Flow-induced platelet activation in a St.
Jude mechanical heart valve, a trileaflet polymeric heart
valve, and a St. Jude tissue valve. Artif Organs 2005;29:
826–831.
48. Mendelson K, Schoen FJ. Heart valve tissue engineering:
Concepts, approaches, progress, and challenges. Ann Biomed
Eng 2006;34:1799–1819.
49. Hoerstrup SP, Zund G, Lachat M, Schoeberlein A, Uhlschmid
G, Vogt P, Turina M. Tissue engineering: A new approach in
cardiovascular surgery—Seeding of human fibroblasts on
resorbable mesh. Swiss Surg 1998;(Suppl. 2):23–25.
50. Zund G, Hoerstrup SP, Schoeberlein A, Lachat M, Uhlsch-
mid G, Vogt PR, Turina M. Tissue engineering: a new
approach in cardiovascular surgery: Seeding of human fibro-
blasts followed by human endothelial cells on resorbable
mesh. Eur J Cardiothorac Surg 1998;13:160–164.
51. Matheny RG, Hutchison ML, Dryden PE, Hiles MD, Shaar
CJ. Porcine small intestine submucosa as a pulmonary valve
leaflet substitute. J Heart Valve Dis 2000;9:769–774.
52. Ye Q, Zund G, Benedikt P, Jockenhoevel S, Hoerstrup SP,
Sakyama S, Hubbell JA, Turina M. Fibrin gel as a three
dimensional matrix in cardiovascular tissue engineering. Eur
J Cardiothorac Surg 2000;17:587–591.
53. Flanagan TC, Wilkins B, Black A, Jockenhoevel S, Smith
TJ, Pandit AS. A collagen-glycosaminoglycan co-culture
model for heart valve tissue engineering applications. Bio-
materials 2006;27:2233–2246.
54. Samouillan V, Dandurand-Lods J, Lamure A, Maurel E,
Lacabanne C, Gerosa G, Venturini A, Casarotto D, Gherar-
dini L, Spina M. Thermal analysis characterization of aortic
tissues for cardiac valve bioprostheses. J Biomed Mater Res
1999;46:531–538.
55. UK Department of Health. The United Kingdom Heart
Valve Registry. Department of Health, UK; 2005.
56. Steinhoff G, Stock U, Karim N, Mertsching H, Timke A,
Meliss RR, Pethig K, Haverich A, Bader A. Tissue engineer-
ing of pulmonary heart valves on allogenic acellular matrix
conduits: in vivo restoration of valve tissue. Circulation
2000;102:III50–III55.
57. Simon P, Kasimir MT, Seebacher G, Weigel G, Ullrich R,
Salzer-Muhar U, Rieder E, Wolner E. Early failure of the
tissue engineered porcine heart valve SYNERGRAFT in pe-
diatric patients. Eur J Cardiothorac Surg 2003;23:1002–
1006.
58. Perry TE, Kaushal S, Sutherland FW, Guleserian KJ, Bis-
choff J, Sacks M, Mayer JE. Thoracic Surgery Directors
Association Award. Bone marrow as a cell source for tissue
engineering heart valves. Ann Thorac Surg 2003;75:761–
767.
59. Dvorin EL, Wylie-Sears J, Kaushal S, Martin DP, Bischoff
J. Quantitative evaluation of endothelial progenitors and car-
diac valve endothelial cells: Proliferation and differentiation
on poly-glycolic acid/poly-4-hydroxybutyrate scaffold in
response to vascular endothelial growth factor and transform-
ing growth factor b1. Tissue Eng 2003;9:487–493.
60. Hoerstrup SP, Kadner A, Melnitchouk S, Trojan A, Eid K,
Tracy J, Sodian R, Visjager JF, Kolb SA, Grunenfelder J,
Zund G, Turina MI. Tissue engineering of functional trileaf-
let heart valves from human marrow stromal cells. Circula-
tion 2002;106:I143–I150.
61. Rabkin E, Hoerstrup SP, Aikawa M, Mayer JE Jr, Schoen
FJ. Evolution of cell phenotype and extracellular matrix
in tissue-engineered heart valves during in-vitro maturation
and in-vivo remodeling. J Heart Valve Dis 2002;11:308–
314.
62. Kim WG, Cho SK, Kang MC, Lee TY, Park JK. Tissue-
engineered heart valve leaflets: An animal study. Int J Artif
Organs 2001;24:642–648.
63. Hoerstrup SP, Sodian R, Daebritz S, Wang J, Bacha EA,
Martin DP, Moran AM, Guleserian KJ, Sperling JS, Kaushal
S, Vacanti JP, Schoen FJ, Mayer JE Jr. Functional living tri-
leaflet heart valves grown in vitro. Circulation 2000;102:
III44–III49.
64. Sodian R, Hoerstrup SP, Sperling JS, Daebritz S, Martin DP,
Moran AM, Kim BS, Schoen FJ, Vacanti JP, Mayer JE Jr.
Early in vivo experience with tissue-engineered trileaflet
heart valves. Circulation 2000;102:III22–III29.
65. Shinoka T, Breuer CK, Tanel RE, Zund G, Miura T, Ma
PX, Langer R, Vacanti JP, Mayer JE Jr. Tissue engineering
heart valves: valve leaflet replacement study in a lamb
model. Ann Thorac Surg 1995;60:S513–S516.
66. Shinoka T. Tissue engineered heart valves: autologous cell
seeding on biodegradable polymer scaffold. Artif Organs
2002;26:402–406.
67. Sodian R, Hoerstrup SP, Sperling JS, Martin DP, Daebritz S,
Mayer JE Jr, Vacanti JP. Evaluation of biodegradable, three-
dimensional matrices for tissue engineering of heart valves.
ASAIO J 2000;46:107–110.
68. Vesely I, Noseworthy R. Micromechanics of the fibrosa and
the ventricularis in aortic valve leaflets. J Biomech 1992;25:
101–113.
69. Christie GW, Barratt-Boyes BG. Mechanical properties of
porcine pulmonary valve leaflets: How do they differ from
aortic leaflets? Ann Thorac Surg 1995;60:S195–S199.
70. Taylor PM, Batten P, Brand NJ, Thomas PS, Yacoub MH.
The cardiac valve interstitial cell. Int J Biochem Cell Biol
2003;35:113–118.
71. Yavuz K, Geyik S, Pavcnik D, Uchida BT, Corless CL,
Hartley DE, Goktay A, Correa LO, Timmermans H, Hodde
JP, Kaufman JA, Keller FS, Rosch J. Comparison of the en-
dothelialization of small intestinal submucosa, dacron and
expanded polytetrafluoroethylene suspended in the thora-
coabdominal aorta of sheep. J Vasc Interv Radiol 2006;17:
873–882.
72. Ku CH, Johnson PH, Batten P, Sarathchandra P, Chambers
RC, Taylor PM, Yacoub MH, Chester AH. Collagen synthe-
sis by mesenchymal stem cells and aortic valve interstitial
Journal of Biomedical Materials Research Part B: Applied Biomaterials
 HEART VALVE REPLACEMENT THERAPY
cells in response to mechanical stretch. Cardiovascular
Research 2006;71:548–556.
73. Schmidt D, Mol A, Breymann C, Achermann J, Odermatt B,
Gossi M, Neuenschwander S, Pretre R, Genoni M, Zund G,
Hoerstrup SP. Living autologous heart valves engineered
from human prenatally harvested progenitors. Circulation
2006;114:I–125.
74. Nakagami H, Morishita R, Maeda K, Kikuchi Y, Ogihara T,
Kaneda Y. Adipose tissue-derived stromal cells as a novel
option for regenerative cell therapy. J Atheroscler Thromb
2006;13:77–81.
75. Kim SS, Lim SH, Hong YS, Cho SW, Ryu JH, Chang BC,
Choi CY, Kim BS. Tissue engineering of heart valves in
vivo using bone marrow-derived cells. Artificial Organs 2006;
30:554–557.
76. Shin’oka T, Matsumura G, Hibino N, Naito Y, Watanabe M,
Konuma T, Sakamoto T, Nagatsu M, Kurosawa H. Midterm
clinical result of tissue-engineered vascular autografts seeded
with autologous bone marrow cells. J Thorac Cardiovasc
Surg 2005;129:1330–1338.
77. Schnell AM, Hoerstrup SP, Zund G, Kolb S, Sodian R, Visj-
ager JF, Grunenfelder J, Suter A, Turina M. Optimal cell
source for cardiovascular tissue engineering: venous vs. aor-
tic human myofibroblasts. Thorac Cardiovasc Surg 2001;49:
221–225.
78. Kadner A, Hoerstrup SP, Tracy J, Breymann C, Maurus CF,
Melnitchouk S, Kadner G, Zund G, Turina M. Human um-
bilical cord cells: a new source for cardiovascular tissue en-
gineering. Ann Thorac Surg 2002;74:S1422–S1428.
79. Davies H. Catheter-mounted valve for temporary relief of
aortic insufficiency. Lancet 1965;1:250.
80. Cribier A, Eltchaninoff H, Bash A, Borenstein N, Tron C,
Bauer F, Derumeaux G, Anselme F, Laborde F, Leon MB.
Percutaneous transcatheter implantation of an aortic valve
prosthesis for calcific aortic stenosis: first human case
description. Circulation 2002;106:3006–3008.
81. Boudjemline Y, Bonhoeffer P. Percutaneous valve replace-
ment: A fad or an advance? Nat Clin Pract Cardiovasc Med
2004;1:62–63.
82. Sakata Y, Syed Z, Salinger MH, Feldman T. Percutaneous
balloon aortic valvuloplasty: Antegrade transseptal vs. con-
ventional retrograde transarterial approach. Catheter Cardio-
vasc Interv 2005;64:314–321.
83. Cribier A, Eltchaninoff H, Tron C, Bauer F, Gerber L. Percu-
taneous implantation of aortic valve prosthesis in patients with
calcific aortic stenosis: Technical advances, clinical results and
future strategies. J Interv Cardiol 2006;19:S87–S96.
84. Spenser B, Benichu N, Bash A, Zakai A. Implantable pros-
thetic valve. US Pat. No. 2005192665; 2005.
85. Seguin J, Bortlein G. Prosthetic valve for transluminal deliv-
ery. US Pat. No. 2004210304; 2004.
86. Stacchino C, Bergamasco G, Burriesci G. Minimally-inva-
sive cardiac-valve prosthesis. US Pat. No. 20050197695;
2005.
87. Boyle CT, Bailey SR. Endoluminal cardiac and venous valve
prostheses and methods of manufacture and delivery thereof.
US Pat. No. 2004106976; 2004.
88. Babaliaros V, Cribier A, Agatiello C. Surgery insight: Cur-
rent advances in percutaneous heart valve replacement and
repair. Nat Clin Pract Cardiovasc Med 2006;3:256–264.
89. Kannan RY, Salacinski HJ, Ghanavi JE, Narula A, Odlyha
M, Peirovi H, Butler PE, Seifalian AM. Silsesquioxane
nanocomposites as tissue implants. Plast Reconstr Surg
2007;119:1653–1662.
90. Gulbins H, Goldemund A, Anderson I, Haas U, Uhlig A,
Meiser B, Reichart B. Preseeding with autologous fibroblasts
Journal of Biomedical Materials Research Part B: Applied Biomaterials
303
improves endothelialization of glutaraldehyde-fixed porcine
aortic valves. J Thorac Cardiovasc Surg 2003;125:592–601.
91. Goubergrits L, Affeld K, Kertzscher U. Innovative develop-
ments of the heart valves designed for use in ventricular
assist devices. Expert Rev Med Devices 2005;2:61–71.
92. Dohmen PM, Lembcke A, Holinski S, Kivelitz D, Braun JP,
Pruss A, Konertz W. Mid-term clinical results using a tissue-
engineered pulmonary valve to reconstruct the right ventricu-
lar outflow tract during the Ross procedure. Ann Thorac
Surg 2007;84:729–736.
93. Breuer CK, Mettler BA, Anthony T, Sales VL, Schoen FJ,
Mayer JE. Application of tissue-engineering principles to-
ward the development of a semilunar heart valve substitute.
Tissue Eng 2004;10:1725–1736.
94. Vesely I. Heart valve tissue engineering. Circ Res 2005;
97:743–755.
95. Wu K, Liu YL, Cui B, Han Z. Application of stem cells for
cardiovascular grafts tissue engineering. Transpl Immunol
2006;16:1–7.
96. Wu KH, Liu YL, Zhou B, Han ZC. Cellular therapy and
myocardial tissue engineering: The role of adult stem and
progenitor cells. Eur J Cardiothorac Surg 2006;30:770–
781.
97. Vincentelli A, Wautot F, Juthier F, Fouquet O, Corseaux D,
Marechaux S, Le Tourneau T, Fabre O, Susen S, Van Belle
E, Mouquet F, Decoene C, Prat A, Jude B. In vivo autolo-
gous recellularization of a tissue-engineered heart valve: are
bone marrow mesenchymal stem cells the best candidates?
J Thorac Cardiovasc Surg 2007;134:424–432.
98. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM,
Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri
A, Anversa P. Bone marrow cells regenerate infarcted myo-
cardium. Nature 2001;410:701–705.
99. Taylor PM. Biological matrices and bionanotechnology.
Philos Trans R Soc Lond B Biol Sci 2007;362:1313–1320.
100. Barron V, Lyons E, Stenson-Cox C, McHugh PE, Pandit A.
Bioreactors for cardiovascular cell and tissue growth: A
review. Ann Biomed Eng 2003;31:1017–1030.
101. Hanzel GS, Harrity PJ, Schreiber TL, O’Neill WW. Retro-
grade percutaneous aortic valve implantation for critical
aortic stenosis. Catheter Cardiovasc Interv 2005;64:322–
326.
102. Khambadkone S, Coats L, Taylor A, Boudjemline Y, Der-
rick G, Tsang V, Cooper J, Muthurangu V, Hegde SR,
Razavi RS, Pellerin D, Deanfield J, Bonhoeffer P. Percutane-
ous pulmonary valve implantation in humans: results in 59
consecutive patients. Circulation 2005;112:1189–1197.
103. Grube E, Laborde JC, Gerckens U, Felderhoff T, Sauren B,
Buellesfeld L, Mueller R, Menichelli M, Schmidt T, Zick-
mann B, Iversen S, Stone GW. Percutaneous implantation of
the CoreValve self-expanding valve prosthesis in high-risk
patients with aortic valve disease: the Siegburg first-in-man
study. Circulation 2006;114:1616–1624.
104. Cribier A, Eltchaninoff H, Tron C, Bauer F, Agatiello C,
Nercolini D, Tapiero S, Litzler PY, Bessou JP, Babaliaros
V. Treatment of calcific aortic stenosis with the percutaneous
heart valve: mid-term follow-up from the initial feasibility
studies: the French experience. J Am Coll Cardiol 2006;47:
1214–1223.
105. Schoen FJ, Levy RJ. Pathology of substitute heart valves:
New concepts and developments. J Card Surg 1994;9:222–
227.
106. Butany J, Ahluwalia MS, Munroe C, Fayet C, Ahn C, Blit
P, Kepron C, Cusimano RJ, Leask RL. Mechanical heart
valve prostheses: identification and evaluation (erratum).
Cardiovasc Pathol 2003;12:322–344.