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compatibility. Once a device shows signs of failure, the
patient requires a second open-heart surgery for replacement of the defective device. Reoperations are generally
risky and pose additional problems for children who naturally outgrow their implants.
Thus, the long-term goal of biomedical engineering is to
find better methods for treating valvular diseases and
thus impact lives of millions of patients worldwide. This
daunting effort brings together a multidisciplinary team of
specialists in medicine, biology, engineering, and mechanics. This chapter describes the structure, function, biology,
and pathology of heart valves; information on current replacement devices; and the necessary prerequisites for
constructing an ‘‘ideal’’ replacement valve. Ongoing research is aimed at improving existing devices by enhancing biocompatibility, as well as pioneering work on novel
tissue-engineering approaches, which would facilitate
complete regeneration of valve tissues.
ARTIFICIAL HEART VALVES
DAN T. SIMIONESCU
Clemson University
Clemson, South Carolina
1. INTRODUCTION
The cardiovascular system is a closed circulatory system
that ensures blood flow through the human body. Blood
circulates through two systems; the first is responsible for
pushing blood from the heart to the lungs to capture oxygen, and the second is responsible for distributing oxygenated blood to body organs. This system is composed of a
double pump with branched tubes that leads blood from
the heart to the organs (arteries) and returns it to the
heart (veins). The heart is essentially a muscular pump
with four rooms, two for receiving incoming blood (atria)
and two for pushing blood toward the organs (ventricles).
In order to maintain unidirectional flow of blood, 3-D
open-close ‘‘gateways’’ (valves) are optimally located between atria and ventricles, and between the ventricles and
the emerging arteries. The workload of heart valves is
nothing short of extraordinary. The valves open and close
once per second totaling more than 3 billion times in a
lifetime. These movements take place under constant
pressure and in flowing blood, a very viscous fluid rich
in minerals, proteins, lipids, and cells.
Valves may progressively become defective and critically influence the performance of the heart. These defects
are collectively named valve diseases. As the properties of
normal and diseased valves are not sufficiently understood, no drugs are available to treat and cure valve diseases. The only curative solution is to perform open-heart
surgery to replace diseased valves with artificially engineered devices. These valve substitutes are nonliving materials fashioned in the form of valves that reestablish
initial mechanical functions and restore the functionality
of the heart. However, these devices may eventually fail
because of imperfections in design, composition, or bio-
P
Ao
2. NATURAL HEART VALVES ARE SPECIALIZED
CARDIOVASCULAR TISSUES
The mechanical action of the human heart is similar to
that of the two-cylinder engine. Four natural heart valves
maintain the direction of blood flow within the circulatory
system (Fig. 1). The tricuspid and mitral valves (collectively called the atrioventricular valves) open to allow
blood to fill the ventricular cavities. These two ‘‘admission’’
(inflow) valves are connected to the subjacent heart muscle via fibrous extensions (chordae tendinae). When the
inflow valves are closed, blood is forced to flow through the
aortic and pulmonary valves (collectively called the semilunar valves). These two ‘‘ejection’’ (outflow) valves open
in response to blood flow and immediately close after ejection. Although not initially apparent, a structural and
functional correlation between the heart muscle and the
valves exists (Fig. 1). A 3-D network of extra cellular matrix (mainly collagen fibers), formally known as the ‘‘cardiac skeleton,’’ maintains the spatial structure and
function of the heart muscle. This cardiac skeleton includes large structures (macro-skeleton), such as the
Mi
Macroskeleton
Tri
Fibrous ring
Matrix
P
Ao
Tri
Mi
Tri
Tricuspid
P
Pulmonary
Ao
Aortic
Mi
Mitral
Figure 1. Functional anatomy of the heart
valves. Longitudinal section diagram depicting
venous blood (dark blue arrows) collecting in the
right ventricle via the tricuspid valve (Tri) and
sent through the pulmonary valve (P) to the
lungs. Oxygenated blood (red arrows) returns to
the left ventricle via the mitral valve (Mi) and is
directed to the organs via the aortic valve (Ao).
Insert at left shows a cross section through the
heart at the level of the four heart valves.
Microskeleton
1
Wiley Encyclopedia of Biomedical Engineering, Copyright & 2006 John Wiley & Sons, Inc.
2
ARTIFICIAL HEART VALVES
heart valves, the chordae tendinae, and the septum, and a
fibrous ‘‘micro-skeleton’’ of connective tissue, which comprises the entire collagenous network that encloses heart
muscle fibers. Besides providing structural support for the
cells, the cardiac skeleton allows a mechanical ‘‘coupling’’
function [i.e., the concomitant contraction of all muscle fibers during ventricular contraction (systole)] (1).
The heart valves are structurally composed of thin
sheets of tissue (cusps or leaflets), which represent anatomical extensions of the cardiac endocardium (Fig. 2).
These cusps are strengthened with a hydrophobic, collagenous, load-bearing tissue layer (fibrosa) that maintains continuity with the fibrous ring into which it is
inserted (2). Elastic fibers that provide resilience and recoil are predominantly present in the inflow layers of the
heart (e.g., the ventricularis of the semilunar valves) (3).
Between these two layers is a loose connective tissue comprised predominantly of hydrophilic, shock-absorbing
glycosaminoglycans (spongiosa) (4). This gel-like matrix
acts as a space-filler and a lubricant to permit continuous
bending, rearranging, straightening, and rotating of structural fibers with minimal friction (5).
In addition to these explicit biochemical and 3D constructs, specific cells exhibiting metabolic and contractile
Atrial
endocardium
Atrium
Auricularis
Spongiosa
Fibrosa
Ann
Fibr
Ventricularis
Ventricle
Chordae
Ventricular
endocardium
Aortic media
Aortic intima
Aorta
Arterialis
Fibrosa
Ann
Fibr
Ventricularis
Spongiosa
Ventricle
Ventricular
endocardium
Figure 2. General structure of the heart valves. Representative
schematic depicting a simplified cross section through an atrioventricular valve (top) and a semilunar valve (bottom); direction
of blood flow is shown by thick arrow. Note the central supporting
structure (fibrosa) inserted in the fibrous ring (Ann. Fibr.) and the
presence of shock-absorbing layers (spongiosa), which are structural extensions of the cardiac endocardium.
properties are also found in each heart valve, which include matrix-producing cells known as fibroblasts, active
valvular interstitial cells known as myofibroblasts, and
endothelium and resident macrophages (Fig. 3). Valvular
cells exhibit high metabolic activities related to matrix
homeostasis (synthesis and degradation of collagen and
proteoglycans) as well as reactivity toward vasoactive
compounds such as epinephrine and angiotensins. Therefore, this multivariate cell design clearly indicates that
specific cellular activities characterize the form and function of each valve, which permits continuous adaptation to
subtle hemodynamic modifications (6). In conclusion,
heart valves are unique, specialized components of the
cardiac connective tissue network that rely on delicately
balanced homeostatic activities for their mechanical and
biological functions.
3. HEART VALVE DISEASES ARE ‘‘CURED’’ BY SURGICAL
REPLACEMENT
Valvular pathology is an important aspect of cardiovascular diseases. Mechanically speaking, valve dysfunction
can be expressed as either imperfect closure (insufficiency)
or incomplete opening (stenosis). In the majority of pathological cases, valvular tissue appears either excessively
deformed (floppy) or very thick and rigid, characterized by
leaflet calcification (Fig. 4). The importance of the structural/functional connection of the heart muscle and the
valves is clearly demonstrated by known pathologic situations. For example, in aortic stenosis, the heart muscle
attempts to compensate for deficiencies in blood flow by
growing in mass (hypertrophy). Consequently, regression
of myocardial mass after valve replacement is one of the
major clinical indicators of effective treatment of valvular
pathology (7).
Valvular diseases associate with cell activation and alterations in metabolism of collagen and proteoglycans.
These structural changes induce functional modifications
that eventually lead to malfunction. The causes of valvular diseases are typically associated with congenital defects, atherosclerosis, infections, or postrheumatic
episodes (6). However, the mechanisms of onset and progression of valvular diseases are largely unknown, specifically because of the lack of adequate experimental
models.
Heart valve diseases progress rapidly and may become
fatal. As the majority of heart valve disease is irreversible,
its progression cannot be prevented by pharmacological
treatments. Moreover, damaged heart valves lack the ability to spontaneously regenerate (8). The only treatment
option presently available is open-heart surgery, in which
the diseased valve is removed and replaced with an artificial device. Although effective, this procedure is quite
traumatic for the patient. For a fortunate few, however,
small areas of the valve can be reconstructed or repaired
using biomaterials, obviating the need for major surgery
to install new artificial heart valves. Pathological heart
valves exhibit significantly altered mechanical and biological properties that eventually require surgical replacement with artificial devices. For an excellent update on
ARTIFICIAL HEART VALVES
3
Atrium
Legend
Myocytes
Ventricle
Smooth
muscle cells
Endothelium
Valvular
int. cells
Aorta
Fibroblasts
Macrophages
Ventricle
(a)
Figure 3. Cell types and distribution in heart
valves. Representative schematic depicting a simplified cross section through an atrioventricular
valve (top) and a semilunar valve (bottom); direction of blood flow is shown by arrow. Myocytes and
smooth muscle cells populate the base of the valve
indicating a ‘‘transition area’’ from a muscular
structure to a specialized fibrous connective tissue. Fibroblasts and interstitial cells mainly populate the load-bearing valve structures; valves are
fully covered by a continuous layer of endothelial
cells.
(b)
Figure 4. Pathology of human mitral valves
(viewed from the atrial side). Photo depicting
(a) an apparently normal valve, with some signs
of leaflet thickening (o); (b) stenotic valve with
signs of thickening (o); and extensive calcium
deposits (m) in both (c) and (d) with signs of
chordae thickening.
(c)
(d)
heart valve pathology, please refer to the work of F. J.
Schoen (6).
4. ARTIFICIAL HEART VALVES ARE EXCELLENT MECHANOMIMETIC DEVICES
Heart valve replacement, pioneered in the early 1970s, is
now a routine surgical procedure that employs devices
made of nonliving, nonresorbable biomaterials for substi-
tution of the valvular mechanical functions (9). Replacement of heart valves offers an excellent improvement in
the quality of life for thousands of patients and can be
considered one of the major accomplishments of biomedical engineering. It is estimated that more than 275,000
replacement heart valves are implanted annually worldwide; thus the social and economic impact of heart valves
research and development is considerable (10).
4
ARTIFICIAL HEART VALVES
position, contraction of the left ventricle will create sufficient blood pressure to thrust the ball toward the opposite
end of the cage, thus allowing blood to flow around the
ball. Immediately after systole (ventricular contraction),
the ventricular pressure decreases and the ball is pushed
toward the circular valve base, closing the orifice completely. However, imperfect blood flow through some of
these devices can create nonphysiological patterns that
may induce the formation of blood clots. Furthermore, the
surfaces exposed directly to blood flow are not entirely
antithrombogenic. For these reasons, in order to avoid
complications caused by thrombus formation, patients
with mechanical heart valves are required to take anticoagulation medications for the rest of their lives (13). As
such, because patients may have possible episodic internal
bleeding, mechanical valves are of limited use for pregnant women or women considering pregnancy and patients with coagulation diseases.
Biological heart valves (bioprostheses) are made of
porcine aortic valves or bovine pericardial sheets that
are mounted on adequate supports (stents) to mimic the
Engineered devices, or mechanical valves, are used to
replace diseased human heart valves in approximately
50% of the cases. Valves made of processed biological tissues are used in an additional 45% of cases. Pulmonary
autograft valves (whereby the patient’s own pulmonary
valve is transplanted into the aortic position) and human
cryopreserved allograft valves represent the remainder of
implanted valves. Autografts and allografts exhibit excellent durability after implantation, but are not readily
available for all patients (11).
Mechanical heart valves are constructed from rigid
supporting materials and mobile components whose designs range from that of a ‘‘caged ball’’ device to designs
encompassing free-moving tilting discs or flaps with restricted movement (Fig. 5). The components ensuring
proper opening and closing of valvular orifices are made
of inert, biocompatible materials such as pyrolitic carbon,
polyester (Dacron)-covered polymers, or metals (12). Blood
pressure differences within the chambers of the heart enable these mechanical valves to properly function. For example, for a caged ball valve inserted in the aortic
(c)
(a)
(b)
(d)
(e)
(f)
Figure 5. Artificial heart valves. Photo showing mechanical valves including devices that employ
a caged ball (a) or two hinged leaflets (b) for functioning. Tissue valves are either made from bovine
pericardium (c), porcine heart valves mounted on stents (d), or left unmounted (e and f). Valves in
(a), (c)–(e) are shown in closed position, and valve (b) in a partially open position. Images (a), (c),
and (f) were provided courtesy of Edwards Lifesciences, Inc. Models depicted are: Starr-Edwardss
Ball Valves (a), Carpentier-Edwardss PERIMOUNT Magnas Pericardial Bioprosthesis (c), and
Edwards Prima Pluss Stentless Bioprosthesis (f). Copyright Edwards Lifesciences, Inc. 2005. All
rights reserved. Images (b), (d), and (e) were provided courtesy of St. Jude Medical, Inc. Models
depicted are: St Jude Medicals Regent Valve (b), Biocor Aortic (d), and Toronto SPV (e). Copyright
St. Jude Medical, Inc. 2005. All rights reserved.
ARTIFICIAL HEART VALVES
and sterilizes the tissue for implantation. Interestingly,
the use of glutaraldehyde was inspired from its use in microscopy (as a fixative) and as a hospital sterilant (in the
form of Cidex, a commonly used bactericidal liquid sterilization medium for heat-sensitive materials) (16). Tissuederived heart valves are less thrombogenic than their mechanical counterparts and do not require long-term anticoagulation. For an excellent overview of different models
and properties of heart valves, please refer to the work of
J. Butany et al. (14).
Overall, mechanical and tissue-derived heart valves
perform exceptionally well as devices intended to open
and close valvular orifices, and thus could be considered as
admirable mechano-mimetic replacements.
valvular architecture, or they are left unmounted (stentless) (Fig. 5) (14). To understand how these devices are
created, a typical procedure for creating a pericardiumderived heart valve is shown in Fig. 6. Bovine pericardium
(the external fibrous sac that encloses the heart) is collected at the slaughterhouse, chemically stabilized, cut
into three leaflets, and mounted on a three-legged (stented) ring using surgical sutures. The final product is
adapted with a circular ring at the base that allows the
surgeon to secure the device to the human fibrous ring.
Similar to natural valves, the function of bioprostheses is
pressure-driven. When the blood pressure below the valve
is greater than the pressure above, the leaflets are forced
toward the outside, thus reversing curvature and causing
the valve to open. When the blood pressure above the
valve is greater than the pressure below, the valve closes
by pushing the leaflets toward the center. As the total
surface of the leaflets exceeds that of the orifice, the leaflets overlap in the center (coaptation) and allow for complete closure of the orifice, without backflow
(regurgitation).
Cross-species implantation of animal tissues is clearly
prone to severe immune rejection and rapid tissue degeneration. For this reason, bovine or porcine tissues are
treated with glutaraldehyde, a water-soluble cross-linker,
which almost completely reduces tissue antigenicity (15).
In addition, glutaraldehyde devitalizes tissues and kills
all resident cells, prevents degradation by host enzymes,
(a)
(b)
5
5. ARTIFICIAL HEART VALVES HAVE A LIMITED
BIOLOGICAL DURABILITY
Artificial heart valves function quite effectively for many
years after implantation, but their long-term durability is
quite limited. Clinical follow-ups indicate that more than
50% of patients with artificial valve implants develop complications within 10 years (6). This disturbing trend suggests that the majority of implanted valves would have to
be explanted after 20 years. From the perspective of the
valvular patients, a second open-heart surgery to retrieve
and replace the defective device is prone to high clinical
risks, and therefore undesirable. The lack of long-term
(c)
(d)
(e)
(f)
Figure 6. Artificial heart valve from bovine pericardium.
Diagram showing the steps involved in creating a heart
valve device. Bovine pericardium is collected (a) then crosslinked in glutaraldehyde (b), fashioned into three leaflets
(c), mounted on a stent (d), and fitted with a sewing ring.
While opening, blood flow (arrow) pushes leaflets toward
the outside (e) and creates an almost circular orifice (insert). Upon closure, leaflets are pushed toward the center of
the valve (f) and complete closure is ensured by central
coaptation of leaflets (insert).
6
ARTIFICIAL HEART VALVES
valve durability is especially important in the case of pediatric patients, where supplemental surgical procedures
are required to accommodate the natural growth of the
patients. The choice between bioprosthetic and mechanical valves depends on specific patient characteristics. Mechanical valves are more durable but require life-long
anticoagulant therapy, whereas bioprostheses tend to deteriorate more rapidly because of degenerative processes
but do not require anticoagulation therapy. In general,
tissue valves are implanted in elderly patients (60–65
years or older), which have a lower tendency to calcify tissue implants and a mean life expectancy of 10 to 15 years
(17). Conversely, more mechanical valves are implanted in
younger patients and children.
Analysis of explanted valves revealed that the principal
causes of device failure are thrombosis, degeneration, and
lack of full integration into host tissue, perivalvular leaks,
host tissue overgrowth, and susceptibility to infections.
Complications related to thrombogenicity are the major
problems of mechanical valves, whereas tissue-derived
valves are mainly affected by the degeneration and calcification of the tissue components (18). For example, explanted pericardial valves reveal tissue abrasion and
erosion, tearing and perforations, deformations and loss
of bending stiffness, along with deposition of calcium minerals (Fig. 7).
Tissue degeneration in artificial heart valves occurs as
a result of the interplay between host-related factors and
implant-related factors. As a response to the implant, the
host selects one or more defense mechanisms that correspond to the degree of activation induced by the implant.
Implantation of tissue heart valves induces a chronic foreign-body response, a low degree of immune reaction, activation of the coagulation cascade, and inflammatory
response. These reactions are translated into deposition
of fibrin immunoglobulins and complement infiltration of
activated macrophages and lymphocytes and growth of
host fibrous tissue over nonmoving parts of the implant
(18).
The main pathways of bioprosthetic heart valve failure
are structural damage and calcification of the tissue component. Analysis of explanted (failed) bioprosthetic heart
valves typically reveals the coexistence of structural damage and calcification. Structural damage may be pure
(noncalcific), stress-induced disruption of fiber architecture (19), or mediated by enzymatic degradation (20). Me5
1
2
3
4
Figure 7. Pathology of tissue heart valves. Diagram showing
typical aspects observed in explanted devices, including (1) tissue
ruptures, (2) abrasions, (3) thickening of the tissue, (4) calcification, and (5) host tissue overgrowth.
chanical deformation was shown to accelerate calcification
and, conversely, calcific deposits significantly alter mechanical properties (21). These processes may be synergistic, but convincing evidence also exists that each may
occur independently. Many improvements in design and
geometry of the leaflets have reduced, but not fully eliminated, the incidence of mechanical damage. For an excellent overview of heart valve design issues, please refer to
the work of I. Vesely (22).
Calcium deposition in tissue-derived artificial heart
valves is one of the major causes of their clinical failure.
For this reason, noteworthy efforts have been made to
elucidate the mechanisms of valve calcification and to implement treatments that would prevent this unwarranted
side effect (23). Calcification typically appears as granular,
fibrillar, or lamellar deposits, which greatly reduce tissue
mechanical properties and can effectively contribute to
erosion, abrasions, tearing, and perforations. The major
factors involved in calcification are young age, hypercholesterolemia, and flexural stress, implant composition, and chemical pretreatments of the biological
tissues. Calcification may occur through passive mechanisms (direct deposition of calcium and phosphate) but
host cells, via remodeling mechanisms involving proteasemediated degeneration of matrix components and deposition of bone proteins, can mediate it (24). Mechanisms underlying calcification of tissue-derived artificial heart
valves in patients are still not fully understood, although
tissue composition and the use of glutaraldehyde appear
to be two essential factors. In most cases analyzed thus
far, the mineral phase is composed of bone-like hydroxyapatite associated with collagen, elastin, and chemically
devitalized cells. Ongoing research focuses on prevention
of calcification in tissue-derived artificial heart valves by
attempts to remove or extract cells, by structural modification of collagen and elastin, and by stabilization or addition of natural calcification inhibitors (25,26).
Glutaraldehyde induces adequate preservation of collagenous structures, but also triggers severe cell alterations, which result in the formation of cell debris that
resemble matrix vesicles formed by bone cells. For this
reason, treatments are under study to extract all cellular
components before implantation (23). Residual loosely
bound or unreacted aldehyde groups may also be involved
in tissue calcification. Neutralization of free aldehyde
groups with compounds that possess reactive amines
such as glutamine, glycine, homocysteic acid, and lysine
has been shown to reduce calcification in animal models.
In addition to simple aldehyde neutralization, amino-oleic
acid, a treatment recently implemented in clinical use,
may also hinder calcification by mechanisms related to
reduction of calcium diffusion through tissues (27). Additionally, amino-biphosphonates (28) may also act as crystal growth inhibitors to hinder calcification. A different
approach involving the use of stabilization chemistries,
which do not employ glutaraldehyde, is also under investigation. These chemistries include carbodiimides, dyemediated photo fixation, and epoxy-based crosslinkers
(29). Tissues cross-linked with nonglutaraldehyde agents
do not calcify in experimental models to the same extent
as glutaraldehyde-fixed tissues, thus directly linking the
ARTIFICIAL HEART VALVES
presence of glutaraldehyde as one direct cause of tissue
calcification. Extensive research on alternative cross-linking methods is currently being pursued, but none have yet
reached clinical use.
These results indicate that mechanical and biological
factors contribute significantly to failure of artificial heart
valves. Although they perform well mechanically, artificial
heart valves do not possess sufficient biological assets to
fulfill the requirements of true biomimetic devices. Their
lack of biologic properties may account for their limited
durability after implantation. As artificial heart valves
lack live cells, they are deficient in their ability to maintain and adapt the valvular matrix composition or to
maintain an adequate calcium homeostasis. In the absence of live cells, degenerative processes induced by mechanical fatigue, proteolytic enzymes, and calcium
deposition slowly erode the structural components and
lead to progressive valve deterioration. In addition, the
lack of an intact layer of endothelial cells may allow free
influx of blood components and could also contribute to
device-related thrombogenicity. Finally, the majority of
current artificial heart valves, except newer stentless
valves, do not maintain their cardiac skeleton-valve continuity and thus may progressively impair heart function.
In conclusion, pathological artificial valves exhibit altered mechanical properties, similar to human pathological valves. However, exciting research is currently
ongoing to improve these devices and increase their biological durability. It is expected that efforts targeted toward understanding the pathology of artificial heart
valves will facilitate greater insights into human valvular pathology.
6. THE ‘‘IDEAL’’ ARTIFICIAL HEART VALVE
One of the greatest biomedical engineering challenges today is to develop an implantable device that resists the
natural conditions to which heart valves are subjected,
without eliciting host reactions that would impair their
function. This research field is very exciting and poses
abundant questions whose answers will positively impact
the lives millions of patients. Specifically, these natural
conditions affecting the lifespan of an artificial heart valve
include their durability to 40 million beats per year for
about 80 years (summing up to about 3.2 billion cycles in a
lifetime) under a cyclical pressure of about 200 g/cm2 in a
very aggressive, corrosive fluid of high viscosity. Other research endeavors include testing valves within elevated
concentrations of calcium and phosphate, proteins, lipids,
enzymes, and cells, in the presence of potentially destructive defense mechanisms such as the immune system, coagulation cascade, inflammation, encapsulation, and
calcification (30). This ongoing research has initially concluded that the ideal artificial heart valve should fulfill the
following specific clinical, mechanical, and biological prerequisites. These prerequisites include, but are not limited
to:
1. Full valve closure and release, and an internal orifice area close to the natural valve;
7
2. Limited resistance to blood flow while moving, and
laminar flow through valve;
3. Mechanically durable, resistant to wear, maintain
properties throughout lifetime;
4. Perfect integration into host tissue with minimal
healing responses;
5. Chemically stable, nonleachable, noncytotoxic components;
6. Nonhemolytic, nonthrombogenic, substrate not supportive of infections;
7. Nonimmunogenic, noninflammatory, noncalcifying;
8. Long-term shelf life without changes in properties
and sterility;
9. Continuity with the cardiac skeleton;
10. Ease of implantation, preferably using minimally
invasive surgery;
11. Available in all sizes and reasonably priced.
To assess these properties, artificial heart valves are
rigorously tested in vitro and in vivo, before being approved for human use. In vitro testing includes analysis of
flow patterns by computer modeling and evaluation of
hydrodynamic functions using ventricle simulators (31).
In addition, valve components are routinely tested for mechanical properties such as elasticity, tensile strength,
and wear resistance. For long-term durability evaluation,
valves are subjected to fatigue testing at accelerated rates
(up to 20 times faster that normal heart rate) (32). In vivo
tests include subdermal implantation of tissue valve components for calcification studies (33) and valve replacement in sheep (34).
Currently, no artificial heart valve device, either mechanical or tissue-derived, fulfills all those previously described prerequisites. No material produced by the human
imagination or through cutting-edge technology available
can fully reproduce the complexity of the natural heart
valve. However, the possibilities for creating such a naturally complex construct are endless if biomaterials or approaches can be developed that, instead of waging war
with biology, will promote perfect integration within local
and systemic physiologic systems. One such promising avenue is the regenerative medicine/tissue engineering approach.
7. REGENERATIVE MEDICINE APPROACHES TO HEART
VALVE REPLACEMENT
The field of regenerative medicine is based on the innovative and visionary principle of using the patient’s own cells
and extracellular matrix components to restore or replace
tissues and organs that have failed. This regenerative approach is a derivative of reconstructive surgery, where
surgeons use the patient’s tissues to rebuild injured or
aging body parts. Modern approaches to heart valve regenerative medicine include several research methodologies, collectively known as tissue engineering. The most
intensely researched approaches are (1) the use of decellularized tissues as scaffolds for in situ regeneration, (2)
8
ARTIFICIAL HEART VALVES
construction of tissue equivalents in the laboratory before
implantation, and (3) use of scaffolds preseeded with stem
cells.
A widespread approach is to use native (uncrosslinked)
decellularized valves obtained from processed human or
animal tissues. Once implanted, decellularized tissues are
expected to provide proper environment and sufficient
stimuli for host cells to infiltrate, remodel, and eventually
regenerate the valvular tissue. As antigenic determinants
are mainly concentrated on the surface of cells, removal of
the original cells (decellularization) is necessary for avoiding complications related to immune rejection, which can
be satisfactorily attained using combinations of detergents
and enzymes, leaving behind 3-D scaffolds comprising apparently intact matrix molecules. Experimental data obtained with decellularized porcine valves yielded
spectacular results (35). In vitro hydrodynamic performance was excellent, and valves performed well after implantation in sheep for 5 months as replacement of
pulmonary valves. Explanted valves showed good repopulation of porcine scaffolds with fibroblast-like cells as well
as an almost complete re-endothelialization of valve surfaces. These encouraging studies prompted several smallscale studies in humans using a commercially available
decellularized porcine heart valve. However, despite the
initial enthusiasm, the results of a small study in children
were catastrophic.
In a breakthrough and intrepid study, a group of cardiac surgeons from Austria reported that three out of four
children implanted with decellularized porcine heart
valves had died within 1 year after implantation because
of tissue rupture, degeneration, and calcification of the
implant (36). Analysis of explanted decellularized porcine
heart valves revealed lack of cell repopulation or endothelialization. The collagen matrix induced a severe inflammatory response and encapsulation of the graft and also
served as a substrate for development of numerous calcification sites. The same group of researchers also recently
identified the presence of the porcine cell-specific
disaccharide galactose-alpha-1-3-galactose (alpha-Gal epitope) in decellularized porcine heart valves as the possible
source of immunogenicity (37). Similarly, decellularized
blood vessels also elicited inflammatory responses (38)
and failed to maintain patency (39). Evidently, more basic studies are required for further development of these
products as well as to reevaluate the relevance of animal
models. Several academic groups, as well as a group of
medical device companies, continue to pursue research
and development of decellularized cardiovascular tissues
(40–42).
A second approach involves construction of tissue
equivalents in the laboratory prior to implantation, with
the expectation that assembling the tissue-engineered valvular constructs from appropriate cells, and synthetic or
natural matrix components, would create mechanically
competent, nonthrombogenic, living tissues capable of adaptation and growth. Compared with decellularized tissues, this approach provides better control of the device
properties before implantation. However, because of the
enormity of this task, and because of possible early clinical
failures of decellularized tissues, researchers in the field of
heart valve tissue regeneration have taken a cautious,
stepwise approach.
The in vitro assembly of heart valve tissue from its individual components was pioneered by I. Vesely et al.
(43,44). In this ingenious approach, a chemically crosslinked nonbiodegradable glycosaminoglycan gel was
seeded with vascular cells and cultured in vitro, which
resulted in the formation of a thin sheet of elastin at the
interface between cells and the glycosaminoglycan gel.
The collagen structural component was created by fibroblast-mediated compaction of soluble collagen, with the
expectation that in vitro assembly of these building blocks
would, at some point, create a valve-like structure. For
more details, please refer to the chapter on Tissue Engineering of Heart Valves in this Encyclopedia.
In an exemplary collaborative effort, clinicians, basic
scientists, polymer chemists, and biomedical engineers focused on creating functional tissue-engineered heart
valves in vitro using biodegradable scaffolds (45). These
efforts included scaffold design and characterization, optimization of cell sources, finding adequate mechanisms for
cell delivery, and optimizing in vitro culture of the seeded
scaffolds, culminating with the surgical replacement of
heart valves in sheep. A wide variety of scaffolding models
created from biodegradable polymers have been tested for
heart valve tissue engineering, including polyglycolic acid,
polylactic acid, polycaprolactone, and biodegradable elastomers, which are manufactured into nonwoven textiles
in shapes and conformations that mimic the natural architecture of the heart valve. These scaffolds are then
seeded with cells that can be obtained from (1) fully differentiated cells such as myofibroblasts and endothelial
cells derived from systemic arteries, or (2) pluripotent
stem cells derived from adipose tissue, bone marrow, or
peripheral blood (46). As mature cells have a limited lifespan, an attractive cell source was stem cells for heart
valve tissue engineering. Recently, in a landmark experiment, mesenchymal stem cells obtained from ovine bone
marrow were seeded onto biodegradable scaffolds and the
constructs were cultured in vitro before implantation as a
valve in the pulmonary position of sheep (47) for up to 8
months. Tissue-engineered valves performed well hemodynamically, with signs of slow degradation of the scaffolds, and concomitant deposition of new extracellular
matrix. Moreover, cell types resembled those present in
natural heart valves. Overall, these exciting results hold
great promise for truly effective regenerative approaches
to treatment of heart valve disease.
8. FUTURE AND PERSPECTIVES
By virtue of its clinical applications, biomedical engineering has matured into an interdisciplinary medical specialty, which necessitates intertwining expertise from
numerous fields, including surgery, pathology, cell and
molecular biology, matrix biochemistry, engineering, and
mechanics. In anticipation of major scientific breakthroughs in this field, surgeons will continue to treat
these diseases by first reestablishing the mechanical functions of the heart using artificial valves. The yellow brick
ARTIFICIAL HEART VALVES
road leading to effective treatments of valvular disease
continues to present multiple challenges. Three extremely
exciting lines of investigation are:
A. Finding causes and developing nonsurgical therapy
approaches for valvular disease. To achieve this
goal, more detailed molecular, biochemical, and cellular studies are needed on normal and diseased
human valves as well as development of more clinically relevant animal models for valve diseases.
B. Improvement of current artificial devices. Regarding mechanical valves, it would be a milestone of
success to drastically reduce the incidence of
thrombogenicity caused by valve replacement with
mechanical devices. For tissue valves, more effective
stabilization and anticalcification treatments are
required to reduce the incidence of tissue degeneration and extend device durability. More studies on
implant-host tissue interactions are needed to develop innovative materials that elicit minimal healing responses that are caused by surgically invasive
and inherently traumatic valve replacement techniques. Finally, a need to develop minimally invasive implantation approaches that would reduce the
need for open-heart surgery for valve replacement
exists.
C. Regenerative medicine approaches. Heart valve tissue engineering is only in the nascent stage of research. Therefore, to succeed, it is imperative that
we fully understand the structural-functional properties of normal heart valves and to determine how
the valvular cells remodel the tissue. As stem cell
research offers a marvelous potential for effective
regeneration of heart valve tissue by differentiation
into the ‘‘proper’’ cells, insights into embryological
development are also essential (8).
9
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