Prosthetic Heart Valves

Biomaterials 29 (2008) 385406
Leading Opinion
Prosthetic heart valves: Catering for the few
$
Peter Zilla
, Johan Brink, Paul Human, Deon Bezuidenhout

Christian Barnard Department of Cardiothoracic Surgery, University of Cape Town Medical School and Groote Schuur Hospital,
Anzio Road, 7925 Observatory, Cape Town, South Africa
Received 2 August 2007; accepted 23 September 2007
Available online 24 October 2007
Abstract
Prosthetic heart valves epitomize both the triumphant advance of cardiac surgery in its early days and its stagnation into a
retrospective, exclusive rst world discipline of late. Fifty-two years after the rst diseased heart valve was replaced in a patient,
prostheses largely represent the concepts of the 1960s with many of their design-inherent complications. While the sophisticated medical
systems of the developed world may be able to cope with sub-optimal replacements, these valves are poorly suited to the developing
world (where the overwhelming majority of potential valve recipients reside), due to differences in age proles and socio-economic
circumstances. Therefore, it is the latter group which suffered most from the sluggish pace of developments. While it previously took less
than 7 years for mechanical heart valves to develop from the rst commercially available ball-in-cage valve to the tilting pyrolytic-carbon
disc valve, and another 10 years to arrive at the all-carbon bi-leaet design, only small incremental improvements have been achieved
since 1977. Similarly, bioprosthetic valves saw their last major break-through development in the late 1960s when formalin xation was
replaced by glutaraldehyde cross linking. Since then, poorly understood so-called anti-calcication treatments were added and the
homograft concept rediscovered under the catch-phrase stentless. Still, tissue valves continue to degenerate fast in younger patients,
making them unsuitable for developing countries. Yet, catheter-delivered prostheses almost exclusively use bioprosthetic tissue, thereby
reducing one of the most promising developments for patients of the developing world into a fringe product for the few rst world
recipients. With tissue-engineered valves aiming at the narrow niche of congenital malformations and synthetic exible leaet valves
being in their fth decade of low-key development, heart valve prostheses seem to be destined to remain an unsatisfying and exclusive
rst world solution for a long time to come.
r 2007 Elsevier Ltd. All rights reserved.
Keywords: Heart valve; Bioprosthesis; Calcication; Immune response; Degradation; Thrombogenicity
1. Introduction
The emergence of heart surgery was closely linked to the
technological advances of the post-second world war
period. Pioneering spirit and innovative academic minds
broke new ground on an almost daily basis. Once the
heartlung machine was invented, it did not take long until
prosthetic heart valves were implanted into patients [1,2].
By the second half of the 1970s, these crude initial
prototypes had already evolved into the valve prostheses
we know today: bioprosthetic tissue (BPT) valves had long
undergone the quantum leap from unstable formalin
treatment [3] to the far superior glutaraldehyde xation
[4] and mechanical prostheses had moved from the original
ball-and-cage valve [5] to tilting disc [6] and even bi-leaet
designs [7]. Against this background it is disappointing
that, more than three decades later, commercial products
are still based on the largely unchanged concepts of the
1970s. Glutaraldehyde-xed tissue valves have been only
marginally improved by eliminating design aws and
adding so-called anti-calcication treatments. Mechanical
valves are still mostly of the bi-leaet design and
improvements were restricted to better-polished pyrolytic
ARTICLE IN PRESS
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0142-9612/$ - see front matter r 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.biomaterials.2007.09.033
$
Editors Note: Leading Opinion: This paper is one of a newly
instituted series of scientic articles that provide evidence-based scientic
opinions on topical and important issues in biomaterials science. They
have some features of an invited editorial but are based on scientic
facts, and some features of a review paper, without attempting to be
comprehensive. These papers have been commissioned by Editor-in-Chief
and reviewed for factual, scientic content by referees.
Corresponding author. Tel.: +27 21 406 64 76; fax: +27 21 448 59 35.
E-mail address: peter.zilla@uct.ac.za (P. Zilla).
carbon coatings or some minor reductions in turbulences in
the crucial hinge area. In contrast to the pioneering years,
courage and incentive towards a new developmental
quantum leap have been mostly absent from commercial
product strategies.
2. Population needs and obstacles
Unfortunately, socioeconomic circumstances still limit
access to valve surgery to a fraction of the patients who
actually need it. While the bulk of the estimated 275,000 [8]
to 370,000 [9] annual valve replacements benet predomi-
nantly the older patients of the First World, developing
countries with their much higher incidence of rheumatic
fever [10] often have no access to heart surgery. Related to
European service levels, for instance, cardiac surgery is
only available to 8.1% of the Chinese and 6.9% of the
Indian population [11]. However, given the fast growing
economies of some of these countries, it is predictable that
they will soon have a high demand for prosthetic heart
valves that are affordable and that address the specic
needs of their mainly young patients. Since performance
demands, complications and degeneration distinctly differ
between age groups, the largely geriatric experience prole
from developed regions [12] does not allow generalized
conclusions as to what is the best replacement heart
valve? for recipients in threshold countries. The often-
deadly complications associated with mechanical valve
prostheses accumulate over patient years. In developing
countries these complications are multiplied by a lack of
compliance with anti-coagulation due to infrastructural
and educational decits [13,14]. Together with the younger
age of patients (Fig. 1) the individual likelihood of
experiencing a thrombotic or thromboembolic disaster in
the course of a life-time is therefore distinctly higher than
in rst-world patients [13,14]. Unfortunately, the alter-
native use of contemporary tissue valves is equally over-
shadowed in these patients due to the fast degeneration of
bioprostheses in young recipients.
Taking all these factors into account, it is obvious that:
The overwhelming majority of potential recipients of
prosthetic heart valves reside in developing countries.
The fact that 85% of all open-heart procedures are
performed in countries representing 11% of the
world population emphasizes how unrepresentative the
current heart valve recipients are with regard to global
needs [15].
The fact that the economies of many of these threshold
countries are growing fast makes it predictable that
cardiac surgery will be increasingly accessible to those
millions who are in need of a valve replacement. Since
improved socio-economic circumstance will only have a
delayed impact on reducing the incidence of rheumatic
fever, a huge demand for valve replacements will exist in
these newly developed countries for a relatively long
time.
The unattractive prot margins for rst-world-pros-
theses in developing countries as well as the relatively
ARTICLE IN PRESS
Fig. 1. Typical age-distribution of patients undergoing heart valve replacement in the First World and in a Developing Country. While prosthetic valve
recipients in a First World population are predominantly in the age group of 6069 years (red line) they are broadly disseminated over an age-spectrum
from 20 to 70 years in a Developing Country such as South Africa (blue line). As the age distribution of 2000 consecutive heart valve recipients at the
Groote Schuur Hospital (University of Cape Town) shows, a signicant proportion of patients is even younger than 20 years.
P. Zilla et al. / Biomaterials 29 (2008) 385406 386
small market in developed countries, together with the
exceptionally long bench-to-prot delays for heart
valve prostheses have hampered major research invest-
ments in this eld during the past three decades.
Inasmuch as locally manufactured prosthetic heart
valves will help to partially overcome the affordability
factor for threshold countries, they will be replicas of
valves which were designed to address the specic
circumstances of rst world patients.
Therefore, the discrepancy between the worlds needs
and industrys commitment will continue to widen for
many more years: an ever increasing number of young
patients from threshold countries in need of a new
concept of a truly long-lasting valve prosthesis on the
one side as opposed to the regardless pursuit of
continuously stepped-up sale-efforts of non-innovative,
long-established products of yesterday on the other.
A good example of the latter is the sales-speak of
actual freedom from structural valve failure as opposed
to actuarial. While the actuarial median failure time of
bioprosthetic valves in elderly rst-world patients is
approximately 14 years [16], the actual failure-rate
after the same period of time as reported by industry-
supported research is 8% in AVRs and 11% in MVRs
[17]! As a damage-control measure, the Journal of Heart
Valve Disease announced in an Editorial its intention to
reject any manuscripts in the future that report actual
rather than actuarial data [18].
For the time being, we need to accept that the limited
market for valve prostheses in todays world of high prots
with mass-selling low-tech products such as coronary stents
will continue to perpetuate a situation whereby heart valve
research is too cumbersome and unattractive for the main
players to sufciently invest in truly disruptive technologies.
This is opposed by a urry of innovative ideas by
University-based entrepreneurs and start-up companies.
However, the particularly long and costly lead-time between
product development and marketing as well as the moderate
prot margins will unfortunately prevent many of these
innovations from becoming a mainstream product. Until
then, the hype around the endovascular delivery of yester-
days concepts may ironically and unintentionally turn into
a success story for the huge number of potential recipients of
heart valve prostheses in threshold countries: In contrast to
the heavily calcied heart valve pathology in the rst world,
young patients with rheumatic valves almost naturally offer
themselves as ideal recipients of endovascularly or transa-
pically placed prostheses as their diseased native valves are
mostly delicate and non-calcied. With the incentive of a
potential mass market, durability issues in young patients
may eventually be confronted.
3. Mechanical heart valves
The groundbreaking initial years in the development of
prosthetic heart valves are tightly linked to mechanical
prostheses. A mechanical problem such as a leaking valve
of a pump naturally seemed amenable to an engineering
solution. Without this ability to exploit concomitant
developments in engineering and material sciences, pre-
vious pioneers were doomed to fail. Ten years after the rst
known operation on a heart valve by Harvey Cushing at
the Peter Bent Brigham hospital in Boston in 1913, Elliott
Carr Cutler and the cardiologist Samuel A. Levine
attempted a surgical valvotomy in a young female patient
with mitral valve stenosis. This operation, hailed as a
milestone by the British Medical Journal, had a subsequent
mortality of 90% and was soon abandoned.
In stark contrast to this rather gloomy era, the heady era
of replacement valves was the decade from the early 1950s
to the early 1960s, when break-through developments in
science and engineering were vigorously applied to clinical
needs. Insight into the physiology of hypothermia allowed
Floyd Lewis of Minnesota to gain open access to an atrium
in 1952 followed by Charles Hufnagels implantation of a
caged-ball heart valve into the descending aorta of ten
patients (six survived the operation) in the same year. By
1953, electrical engineering had provided the pacemaker,
and the miniaturization of industrial technologies had
allowed John Gibbon Jr. of Philadelphia to introduce the
heart lung machine, thereby for the rst time allowing
unlimited open access for the surgical replacement of a
heart valve on July 22, 1955 in Shefeld, UK. The epitomes
of this pioneering spirit were the use of synthetic materials
for the rst mitral valve replacement by Nina Braunwald in
1960 and the joint effort of the surgeon Albert Starr and
the electrical engineer Miles Lowell Edwardsfounder
of the medical device company American Edwards
Laboratories in 1950to improve the ball-and-cage valve
to a level where it could reliably be used as a replacement
heart valve (Fig. 2). The rst human implant of this valve
on September 21, 1960 concluded the most vibrant decade
of development in this eld. During the subsequent 15
years major insights into uid dynamics, material sciences
and engineering were still carried over into the improve-
ment of replacement heart valves, but they were no match
for the quantum leap of the preceeding era. The two crucial
elements of these post-pioneer years were the adaptation of
technologies that allowed the production of tilting discs or
semi-discs (Fig. 2) as occluders and the utilization of
materials developed in the course of atomic energy
research. The scientist J.C. Bokros from the General
Atomic Company had previously investigated pyrolytic
carbon materials for the coating of nuclear fuel particles.
Since this materials atomic microstructure was found to
increase resistance to cracking and distinctly lowered
thrombogenicity, it was introduced into heart valve
prostheses. For more than three decades all commercial
mechanical heart valves have either been using it for
surface coating (by depositing gaseous hydrocarbons
usually methaneonto a heated graphite substrate at
temperatures of between 1800 and 2300 1C) or for entire
leaets and housings of the valves (made from 100%
ARTICLE IN PRESS
pyrolytic carbon using uidized bed processes). Overall,
mechanical heart valve developments were largely con-
cluded in 1977 with the introduction of an all-pyrolytic
carbon bileaet valve (St. Jude Medical/SJM). What
followed was attention to engineering detail rather than
grand new concepts. Not surprisingly, the one aspect of
engineering which represented the monopoly component
of production, pyrolytic carbon, became the centre of
corporate interest and merry-go-round acquisitions: rst,
Dr. Bokros of the General Atomic Company helped to set
up their medical division under the name Carbomedics.
At one stage, Carbomedics manufactured 17 heart
valves for 16 different companies! Subsequently, Dr.
Bokros split off Carbon Implants. When Medtronic
bought it in 1992 to obtain their Parallel Valve, Bokros
split off the Medical Carbon Research Institute (MCRI)
in 1994, which designed the On-X valve and later changed
the name MCRI to On-X. At the same time, Carbome-
dics (Austin, TX) itself was bought by Sulzer Medica of
Switzerland in the late 1980s, and then in turn by Sorin,
the medical division of Fiat (the Italian automobile
manufacturer), which eventually transferred the produc-
tion from Austin to an FDA approved site in Milan, Italy.
The incestuous nature of corporate acquisitions in this
eld is further highlighted by another pioneer ending in
Italy: After Pzer took over Shiley, the very durable
Bjork-Shiley tilting disc valve was re-designed, leading to
one of the biggest disasters in the history of medical
implants when many of the convexo-concave Bjork-Shiley
valves developed mechanical failure [1921]. Eventually
Pzer sold Shiley to Sorin, but Sorin chose to exclude the
rights to the failing convexo-concave valve from this
purchase.
3.1. Mechanical durability
Out of 86,000 convexo-concave Bjork-Shiley tilting-disc
valves, 619 experienced a fracture of the outow strut,
which led to the patients death in two-thirds of the cases.
On a smaller scale, 46 leaet escapes were reported out of
200,000 implants of the EdwardsDuromedics bileaet
valve [22]. As unsettling as these failures were, and still are,
for the many patients living with one of these prostheses
(e.g. 23,000 Bjork-Shiley valves in North America alone),
they provided crucial insight into key elements of the three
major challenges of engineering, namely closing load,
material fatigue and cavitation.
As far as the rst is concerned, the major load on
mechanical heart valves generally arises from transvalvular
pressure generated at and after valve closure leading to
both impact wear and friction wear. Impact wear usually
occurs between occluder and ring in tilting discs and the
hinge regions in bileaets. At the same time, friction wear
occurs between occluder and struts in tilting discs and
between leaet pivots and hinge cavities in bileaets. In the
case of the Bjork-Shiley valve, the damage occurred on the
outlet strut, causing bewilderment as to how the closing
load could damage the outlet strut. In 1984, Shiley itself
provided the answer by calling the discovery of a transient
(o0.5 ms) occlusion impact on the outlet strut tip due to
over-rotation of the disc bimodal closure phenomenon.
This force was ten times higher than the actual opening
impact, causing bending stresses that exceeded the strut
wires fatigue endurance limit. In Duromedics case, where
the leaets seat was created through a lip or shelf on the
housing (rather than a cavity in the housing like in all other
models), erosion contributed to the breakages. All these
insights were addressed by modern strut- and hinge-
designs, some of them (Bjork-Shiley) by slightly increasing
the outlet strut clearance, some of them (On-X) by even
claiming a two-point landing system that reduces the load
impact.
The second most important cause of failure, material
fatigue as a consequence of the polycrystalline character-
istics of metals, was successfully addressed by a gradual
shift from metal alloys to pyrolytic carbon, a material that
belongs to the turbostatic carbons and thus has a similar
structure to graphite. Initially, strength and wear resistance
of pyrolytic carbon were increased by adding up to 8% of
its weight as silicon, co-deposited from silicon carbides, but
recent improvements by the same group, which has been
driving pyrolytic carbon development for the past 40 years,
led to what they call pure carbon. Allegedly, the
elimination of the silicon component resulted in a 50%
stronger material. The switch to carbon was rst pioneered
in the occluder discs when pyrolytic carbon-coated graphite
replaced the original Delrin disc in Bjork-Shiley valves in
1968 (rst implanted in 1971). Since then, all manufac-
turers have been using this carbon-combination for the
production of their mono/bileaet discs except for MCRI
(On-X) which introduced leaets made of solid, silicon-free
ARTICLE IN PRESS
Fig. 2. The development of mechanical heart valves experienced an
exponential slow-down over its more than 50-year history: while it took
only 7 years from the rst commercially available ball-in-cage valve to the
era of pyrolytic carbon-coated tilting disc valves and 10 years from the
latter to the rst all-carbon bileaet design, progress of the past 30 years
was incremental at most with leaets being either more parallel aligned or
mildly curved and hinge mechanisms slightly less thrombogenic.
pyrolytic carbon in 1996. In contrast to leaets, the
housings and struts were made out of metals until well
into the 1980s. Initial attempts at overcoming the fatigue of
metals involved either using alloys or particularly strong
pure metals such as titanium. Starr-Edwards ball-and-
cage valves were the rst to replace the original stainless
steel by a cobaltchromiummolybdeniumnickel-alloy, a
material that was later also used for the Bjork-Shiley
valves. The introduction of titanium to mechanical heart
valves also took place during the days of ball-in-cage valves
when pure titanium was used for the Smeloff-Cutter valve
as early as in 1965 [23]. Later, tilting-disc designs such as
the Medtronic Hall (1977), Sorin Monoleaet (1977),
Lilleihei-Kastner (1978) and Omniscience (1978) valve
machined their housings out of a solid block of titanium.
Eventually, the introduction of the bileaet design in 1977
coincided with the advent of the all carbon valves where
both leaets and housing were made of pyrolytic carbon.
This bileaet concept has continuously dominated the
market for the past 30 years: St. Jude Medical (SJM; since
1977; 800,000 sold); Duromedics (19821988; 200,000 sold
[24]; reintroduced in 1990); Carbomedics (introduced in
1986 in France, 1993 in USA; 500,000 sold by 2004);
Advanced Tissue Science (ATS; since 1992; 135,000 sold);
Medtronic (since 1999, after Parallel valve was bought
from Carbon Implants in 1992) and On-X (since 1996
outside USA, 2001 USA; 50,000 sold). Yet, Titanium is still
part of the housing in some designs (e.g. Lockring and
Lockwires in ATS and the housing body in Sorin Bicarbon
which later became the Edwards Mira in 1997). Overall
it appears as if material science at least has provided us
with hardly improvable, optimal materials for mechanical
heart valves.
The third most important mode of failure is cavitation.
This well-known phenomenon is dened by the rapid
formation of vaporous microbubbles in a uid due to a
local reduction of pressure below vapour pressuresimilar
to boiling [25]. When the pressure conditions for cavita-
tion are present, bubbles will start to form and grow.
When the pressure recovers, the formed bubbles will
implode, producing pressure and thermal shock waves
that can impinge on solid surfaces. Pressure oscillations,
ow decelerations, tip vortices and squeeze jets are all
capable of inducing cavitation, the last one being the most
contributive factor. Squeeze jets are formed when the valve
is closing and the blood between the occluder and the valve
housing is squeezed out to create a high-speed jet. This in
turn creates vortices that can lead to additional cavitation.
Damages found on failed Duromedics valves, for instance,
were associated with conned areas of erosion and pitting
on leaets and housing [26] caused by cavitation.
Overall, the disasters of the 1970s and 1980s seem to
have helped eliminate mechanical failure. The fact that not
a single failure was reported on later designs (e.g. after half
a million Carbomedics implants) indicates that combined
efforts were successful. Part of these efforts is the
requirements for much more extended animal tests and
clinical trials before obtaining the European CE Mark and
American FDA approval. Unfortunately, this rigorous pre-
market testing added signicantly to the research and
development costs of the prostheses. The resulting cost
increases of mechanical heart valves added another
obstacle to the widespread use of these prostheses in
developing countries.
3.2. Weighing life and death
The Bjork-Shilry convexo-concave debacle did not
only help to identify the weak points of mechanical heart
valve engineering but also taught us to deal calmly with
potential failure by balancing the risk of valve fracture
against the risk of surgery to replace the valve. The decision
of both the University of Alabama and the Mayo Clinic to
remove every concavoconvex valve may not hold retro-
spective scrutiny. An average re-operation mortality of 8%
may well outweigh the actually occurred 0.9% incidence of
strut breakage, even if risk-stratication takes the three
particularly prone groups into account which were retro-
spectively identied [27]: (a) 33 mm mitral valves, for
instance, were 23 times more likely to fracture than
2125 mm aortic valves as were (b) valves with more
exible outlet struts, as determined by hook deection and
load deection tests during manufacture and (c) valves
produced by one particular welder.
3.3. Biological limits of mechanical solutions
Given the fact that both the uid owing through the
valves and the pump into which these valves are
incorporated consist of living cells, problems are likely to
be augmented by cascades of biological events. Fluid shear
forces and turbulences, for instance, do not only lead to
energy losses but to an activation of the platelet and
coagulation system which has the potential to immobilize
the entire valve or embolize into vital organs. Similarly,
small valvular orices do not only lead to higher pressures
in the outlet chamber but to a remodelling process of the
contractile tissue that may eventually lead to irreversible
pump failure.
3.3.1. Effective orice area (EOA)
Overall, it appears as if minimizing the energy required
to eject the blood through the valve has been more
successful than eliminating the activation of the coagula-
tion cascade. The effective orice area (EOA) is a means
of expressing the degree to which a prosthesis impedes
blood ow through the valve and thus increases the energy
loss. In contrast to the energy efcient central ow of
natural heart valves, caged-ball valves completely blocked
the central ow. While the rst tilting disc valve (Melrose)
in 1964 introduced some degree of central ow, the major
break-through occurred in 1977 with the rst bi-leaet
valve. The magnitude of this development is best expressed
by the increase of EOA from 1.5 to 2.1 cm
2
in tilting disc
ARTICLE IN PRESS
valves to 2.43.2 cm
2
in bileaet designs of the same outer
diameter. Again, improvements after 1977 were incremen-
tal rather than disruptive. By moving the sewing ring supra
annularly, for instance, additional increases of the inner
diameter were possible (e.g. 17% On-X; Carbomedics; etc).
Furthermore, by successively aligning the leaets parallel
with the blood stream, unobstructed central ow became
almost a reality. Again, most of the progress was already
made before 1978 when the tilting disc opening-angle of 601
of the rst Bjork-Shiley valve was increased to 751 (in
aortic; 701 in mitral valves) in the Medtronic Hall in 1977
and to 801 in the Lilleihei-Kaster valve (later Omniscience)
in 1978. The introduction of the bileaet design only
increased this angle to 851 (SJM 1977), with some makes
even having a lower opening angle than tilting discs
(Duromedics 771/731 in aortic/mitral valves, respectively,
and Carbomedics 801/781). Even with a 901 opening angle
(Medtronic Parallel; On-X), however, the actual travel arc
through which the leaets swing is/was mostly less than 601
(e.g. 551/601 SJM; 531/551 Carbomedics; Duromedics
581/621 and 501 Medtronic Parallel), resulting in a steeper
closing angle and thus carrying the potential of a higher
regurgitation volume.
3.3.2. Thromboembolic risks
Mechanical heart valves remain vulnerable to thrombus
formation due to high shear stress (one of the strongest
platelet activators), ow separation/stagnation (since
Virchows days the dreaded cause of coagulation) and
blood damage (through the release of pro-coagulant
substances). As a consequence, anti-coagulation therapy
has been a hitherto sine qua non. In general, thromboem-
bolism (e.g. stroke) is more pronounced in mitral valve
replacements, and within this group, more so in patients
with large left atria and in those in atrial brillation and/or
cardiac failure [28,29].
In tilting-discs, ow separation occurs behind the valve
struts and distal to the leaet edge as a result of a
combination of high velocity and stagnant ows. Of all
designs, the largest turbulent stresses of about 150 Pa were
found behind tilting disc valves in the minor ow region
parallel to the tilt axis [30]. The bileaet models have high
stress during forward ow and leakage regurgitation as
well as adjacent stagnant ow in the hinge area. As it turns
out, the hinge area is the most critical part of bileaets and
is where the thrombus formation usually commences.
Prosthetic valve-induced clot formation-triggered by
tissue factor exposure, platelet activation and contact
activation by foreign materialsoccurs in three steps:
initiation, amplication and propagation. Tissue factor
(TF) release usually occurs through cell rupture with blood
trauma playing a central role. High stresses during leakage
ow in aortic valves and forward ow in mitral valves lead
to blood damage releasing both TF and the platelet-
activating ADP. Plasma factor VII binds to TF, setting off
a chain reaction which activates factor Xa and Va which
bind to each other to produce thrombin which in turn
activates platelets and factor VIII. In parallel, platelet
activation is triggered when shear stresses reach a level
higher than 6080 dyn/cm
2
, followed by von Willebrand
factor binding to the platelet receptor GPIb and calcium
release. GP IIbIIIa facilitates plateletplatelet adhesion.
Last, but not least, contact activation begins when factor
XII binds to the non-endothelialized articial surfaces of
prostheses. This in turn activates prekallikrein and high-
molecular weight kininogen. Although back-wash designs
have aimed at reducing the thrombus formation in the
hinge area [3135], mechanical prostheses still require anti-
coagulation and the promise of freedom from thromboem-
bolism is still elusive and remains the Achilles heel of all
mechanical prostheses, even in the rst world. Although
the incidence of thromboembolism has changed from the
4.5% per patient year [3641] in the days of the ball-in-cage
valves, it is still 0.62.5% in Omnicarbon tilting disc
valves [42,43]; 1.34.2% in Medtronic Hall valves
[13,32,33,37,4447]; 1.13.7% in SJM valves [14,4854];
0.64.3% in Carbomedics valves [55,56]; 0.03.3% in ATS
valves [57,58] and 1.8% in On-X valves [59]. The most
lethal and debilitating forms of thromboembolism, how-
ever, is thrombotic prosthetic obstruction. While the
previously reported estimates for the tilting disc valves
were between 0.1% and 1.2% per patient year in the rst
world, there is general recognition that this became an
extremely rare complication in the era of bileaet valves
unless anti-coagulation had been stopped. Therefore, given
the unreliable degree of anti-coagulation in developing
countries, it is not surprising that thrombotic valve
obstruction is still a feared occurrence outside the
developed world. Unfortunately, the true number of
patients dying as a consequence of valve clotting will often
remain unrecognized in these geographic regions due to the
lack of centralized death registries and cultural resistances
to autopsies.
3.3.3. Coumadin-related haemorrhage
The necessity for anti-coagulation with Coumadin
(Warfarin) that minimizes, but never completely eliminates
the risk of thromboembolism also exposes patients to the
additional risk of major haemorrhagic complications. The
most lethal and debilitating of these is intracranial
haemorrhage, which occurs at a rate of between 0.8%
and 3.7% per year [60]. Although INR requirements have
come down from 3.54.5 in ball-in-cage-valves to 2.53.5,
and anti-coagulation-caused haemorrhages are signi-
cantly fewer being reported by various authors [61,62],
the numbers are still worrying. While they were reported to
be between 0.6% and 3.7% per patient year in Starr
Edwards valves [38,40], they were 0.02.7% in Omnicarbon
valves [6365], 1.43.2% in Medtronic Hall valves [47,66];
0.32.8% in SJM valves [53,54], 0.02.8% in Carbomedics
valves [53,67], 0.04.9% in ATS valves [53] and 0.0% in
On-X valves [59]. Naturally, these complications occur at a
distinctly higher rate in the developing world where the
ability to ensure good anti-coagulation control is very
ARTICLE IN PRESS
limited and often impossible due to poor socio-economic
circumstances [13,14,6870]. Typically, half of these
patients presenting with obstructive valve dysfunction have
an INR of 1.4 or less at the time of failure [71].
3.3.4. Pannus overgrowth
Excess tissue growth across the sewing ring can lead
either to a narrowing of the orice or to leaet
immobilization. Although widely underestimated, it is
likely the primary cause of obstructive prosthetic valve
failure in patients on correct anti-coagulation therapy.
Pure pannus overgrowth is estimated to be behind
obstructive valve failure in between 31% [72] and 53%
[73] of cases. Even in geographic regions where the INR
control is sub-optimal, the reason for obstructive valve
failure is still overwhelmingly pannus rather than thrombus
related [71]. In the aortic position, pannus formation is
mainly on the inow side [74] while in the mitral position it
occurs both on the atrial and the ventricular side [71].
In order to prevent tissue ingrowth into the clearance of
leaets, one contemporary valve design introduced a longer
housing cylinder with the goal of creating an ingrowth
barrier.
Although pannus formation is a complex event, inam-
mation certainly contributes to a sustained growth signal
for the hyperplastic tissue. One of the sources of growth
stimulation is the chronic foreign body reaction against the
sewing ring material. The dominant cells in this reaction
are macrophages and giant cells which are known to secrete
an extended range of powerful cytokines and growth
factors, including IL-1, PDGF, bFGF, etc. [75].
3.4. Way forward for mechanical valves
Modern investigative technologies (microvascular ow
visualization, computational uid dynamics modelling,
laser Doppler velocimetry and anemometry measurements)
have contributed to the latest bileaet hinge pocket design
with the goal of further reducing turbulences and pro-
coagulant pockets. The two most recent bileaet valves on
the market, the On-X and the Medtronic Advantage valve,
have been designed and evaluated using these modalities
[76]. This has already resulted in one study reporting
lowered rates of valve thrombosis and thromboembolism
in a third world population [77]. Whether attention to
detail such as lower turbulence levels and better polished
materials may eventually allow the safe implantation of
mechanical valves into the young patients of developing
countries, regardless of their poor anti-coagulation control,
will need to be elucidated in large, dedicated studies. One
such study pursued by SJM has just been approved.
Another reduced anti-coagulation trial by On-X, using
lowered anti-coagulation targets in the mitral position and
only Aspirin (without Coumadin) in the aortic position,
has also been approved. In the meantime, an incremental
lowering of the INR-bar may be on the cards for many
of the current prostheses. Most recent guidelines for the
anti-coagulation of mechanical heart valves for the rst
time ventured into the grey zone of INRsp2.2 [78].
4. Tissue valves
Bioprosthetic heart valves were the answer to the
thromboembolic complications of mechanical valves. Since
commercial tissue quantities could be only obtained from
animal sources, antigen masking through cross-linking was
an integral part of the concept from the beginning.
In general, few improvements have been added since the
introduction of glutaraldehyde xation in the late 1960s [4]
and its translation into commercial valves (Hancock 1972;
Carpentier Edwards Porcine 1970/1976). Other than the
elimination of design aws such as ill-placed suspension
stitches (Ionescu Shiley 1976) [79] or over-zealous efforts to
reduce the valve prole (BioImplant) [80], poorly under-
stood anti-calcication treatments were added [8183]. At
the same time, market-driven preferences for either bovine
pericardial or porcine aortic valves cultivated a pseudo-
sense of progress amongst surgeons while in fact they
merely reected the circumstances of the time rather than
scientic insight. While in previous eras clinical failures due
to design aws affected the surgeons preferences for
bovine or porcine products, prion and virus concerns as
well as tissue availabilities and production advantages
determine todays marketing thrusts towards bovine or
porcine valves. Last, but not least, the much-hailed new
concept of stentless-valves (SJM Toronto SPV 1991;
Edwards Prima 1991; Medtronic Freestyle 1991; BioCor
1994), which emulated the homograft concept of the 1960s
grossly overstated the biomechanic advantages. Slowly
emerging mid-term results conrm the largely unfullled
expectations [84]. The fact that stentless roots do not
calcify more than homograft roots [85] is less a reection of
the success of stentless valves than the degree of degenera-
tion occurring in homografts.
4.1. Insight into failure modes
The absence of living tissue, as well as the necessity to
mask antigenicity, represents the system-inherent problems
of contemporary tissue valves. Instead of recognizing these
core issues and addressing them from the beginning,
however, there was a widely prevailing perception that
immunogenicity non-vital tissue was acceptable as long as
the right anti-calcication treatment was found. On the
basis of these two assumptions, bioprosthetic heart valve
research focused almost exclusively on down-stream
problems such as the intrinsic potential of glutaraldehyde
to trigger calcication although it was well known
that calcication affects less than half of failed tissue
valves while tears, as a consequence of inammation,
collagen degradation and a lack of repair mechanisms were
the predominant modes of failure [86,87]. Eventually, the
role of inammation was revisited and a link between
remnant-immunogenicity and tissue degeneration was
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established [88], but recognition and implementation are
slow.
4.1.1. Remnant tissue immunogenicity
It has long been known that the low-dose glutaraldehyde
treatment used for the xation of bioprosthetic heart valves
reduces immunogenicity but does not abolish it (Fig. 3)
[89]. The low-grade xation used in commercial valve
preparations fails to signicantly alter membrane-bound
receptors or structural glycoproteins [4]. Therefore, the
tissue continues to elicit both cellular and humoral immune
responses [90]. By increasing crosslink density, tissue
antigenicity could be reduced [88,89,91] and the humoral
antibody-response mitigated. Most importantly, by de-
monstrating a link between immune response and calcic
degeneration, a key aspect of bioprosthetic degeneration
could be clearly traced to insufciently masked immuno-
genicity [88,9295] (Fig. 4). After identifying porcine
bronectin as a major persisting antigen (Fig. 3) [96], the
main challenge ahead will be to identify more tissue
antigens and elucidate the exact mechanisms through
which antibody binding facilitates degeneration.
4.1.2. Inammatory degradation
In the vast majority of explanted tissue valves, inam-
matory cells are either found to cover the surfaces [97] or
focally inltrate into the tissue [98]. Since the initial signs of
xenograft rejection in the form of polymorphnuclear
inltrates [99,100] give way to a more macrophage- and
foreign body giant cell-dominated phenomenon, a percep-
tion of harmlessness ensued. Given the destructive poten-
tial of giant cells to erode even synthetic materials,
however, it becomes obvious that these war-formations
of macrophages are serious culprits of destruction. In
bovine pericardial heart valve prostheses, for instance,
macrophages are regularly found invading and focally
degrading the prosthetic collagen [90,101] (Fig. 5). Simi-
larly, clinically implanted porcine valves also show
inammatory cells inside the BPT [97]. Conspicuously,
dense inltrates of inammatory cells are found in valves
which had failed due to tissue tearing [100,102]. Macro-
phage-mediated tissue degradation is further evidenced by
the direct proof of collagen phagocytosis [99,103]. In
clinical series, as many as 82% of failed valves showed
signs of collagen phagocytosis by macrophages in trans-
mission electron microscopy [104] (Fig. 6).
4.1.3. Mechanical damage/lack of repair
The consequences of BPT being crosslinked and non-
vitaland thus deprived of repair mechanismsare most
obvious when it comes to mechanical wear and tear: in the
mechanically more stressed mitral position, as many as
75% of failed porcine prostheses show a rupture of a free
cusp edge and 43% of the cusp belly [105]. In vital, native
valves both a macromechanical and a micromechanical
principle reduce the impact of mechanical load. Macro-
mechanically, the distinct dilatation of the annulus during
systole results in the triangular stretching of cusp tissue,
thereby avoiding acute bending at the commissures beyond
601 [106]. Micromechanically, a sophisticated tri-layered
ultrastructural architecture ascertains optimal stress reduc-
tion whereby the lamina spongiosa provides a sliding gap
between the relatively smooth lamina ventricularis on the
outow side and a folded lamina brosa on the inow side.
Bioprosthetic heart valvesstented or stentlessdefy
both these principles of valve mechanics: by either
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Fig. 3. Demonstration of the need for increased crosslink density to
mitigate residual immunogenicity of glutaraldehyde xed porcine aortic
wall tissue. Commercially applied concentrations of the dialdehyde (up to
1.0%) failed to avoid an IgG response to porcine bioprosthetic tissuein
particular the glycoprotein bronectinin a rabbit subdermal implant
model. Only glutaraldehyde concentrations in excess of 1.0% (here 3.0%
ideally with L-lysine extension) were able to quench the response
(Densitometry plot of a porcine Fibronectin Western blot using 1:100
dilutions of rabbit sera) Ref. [91] with permission.
Fig. 4. Support for a possible role of graft-specic IgG in the calcication
of bioprosthetic tissue provided by atomic absorption spectroscopy
analysis of calcium levels in subdermally implanted glutaraldehyde-xed
porcine aortic wall tissue in the rabbit. An almost three-times higher level
of calcication was found in bioprosthetic tissue that was exposed to
serum containing graft-specic antibodies Ref. [91] with permission.
stent-mounting, or through glutaraldehyde xation, annu-
lar dilatation during systole is either eliminated or
dramatically diminished. As a consequence, the bending
angle becomes acute and reverse curvature and buckling
ensues. By eliminating the sliding gap between the
ventricularis and the brosa as a result of crosslinking,
a major means of stress distribution is lost.
4.1.4. Pannus overgrowth
Inasmuch as similar triggers initiate the tissue over-
growth of the sewing ring as in mechanical valves, the
process is augmented by the inammatory potential of the
BPT. Amongst other factors, the extent of this inamma-
tion is a reection of the degree of insufcient immune
masking of the BPT. A clear correlation between pannus
overgrowth onto leaet tissue and cross-link density has
been shown [96].
4.2. Scope for improvements
4.2.1. Anti-calcication treatments
Although the unifocal attention to intrinsic tissue
calcication was disproportionate, it remains an integral
component of bioprosthetic degeneration and as such
needs to be part of improvement strategies. Tissue
calcication is a multifactorial process, of which insuf-
cient immune masking is only one component. Glutar-
aldehyde is another factor, as this dialdehyde is known to
intrinsically elicit calcication. Initially, the glutaralde-
hyde-based crosslinks themselves were suspected of being
pro-calcic [107]. However, when extraction methods for
the unbound derivates of glutaraldehyde were developed, it
became clear that the intrinsic potential of glutaraldehyde
to contribute to the calcication process rests in the free
dialdehydes and their polymerization products rather than
the crosslinks. By extracting unbound glutaraldehyde, two
major improvements were achieved: tissue became non-
toxic allowing even endothelial cells to grow on it [108] and
calcication could be distinctly mitigated, even if much
higher concentrations of glutaraldehyde were used for
xation [109111]. The urry of approaches marketably
termed anti calcication treatments often represented
variations on glutaraldehyde detoxication. Substances
such as diphosphonates, for instance, are believed to act
twofold: aldehyde stabilization occurs through binding via
Schiffs bases and subsequent reduction by NaBH
4
, while
restriction of crystal growth is thought to occur through
direct diphosphonate binding to developing hydroxyapa-
tite nucleation sites [109]. The precise mechanism of the
anticalcication effect of a-amino-oleic-acid (AOA
s
)the
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Fig. 5. Torn leaet of a pericardial prosthesis leading to acute mitral
regurgitation 56 months after implantation. All retrieved tissue samples
showed signicant inammatory inltration into the depth of the leaet.
Although the inammation was macrophage-dominated [(a) CD 68/Ham
56; 40 ] there was also signicant involvement of granulocytes
dominated [(b) neutrophil elastase; 20 ].
Fig. 6. Typical transmission electron micrograph of a macrophage
inltrating into the depth of a porcine bioprosthetic heart valve. The
phagocytotic vesicles containing remnants of collagen are evidence that
these macrophages are no innocent bystanders but rather active players
in the degeneration of bioprosthetic tissue.
anticalcication substance incorporated into Medtronics
Mosaic and Freestyle valvesis not fully understood
either, but it is thought that it also binds with its two
amino groups to free aldehyde groups. Residual aldehyde
is pivotal for the binding of AOA [112].
4.2.2. Inuence of crosslinking on degeneration
Cross-linking appears to have a direct and an indirect
effect on tissue calcication: while the density of cross-links
indirectly acts through different degrees of immune
masking [88,89,91], there is an additional direct effect
through the chemistry of the cross-linking process itself.
One empirical approach was therefore to experiment with
alternative crosslinking procedures such as Photox
[113,114] or alternative crosslinking agents such as Epoxy
compounds [115], Carbodiimide [116], Diglycidyl [117],
Reuterin [118], Genipin [119] and many others. An
alternative approach to this empirical permutation of
crosslinking agents emerged in the wake of tissue- and
bio-engineered valves. The realization that engineering
principles can be applied to hitherto empirical processes
[120] led to a more fundamental and mechanistic analysis
of the engineerable elements of cross-linking. After
anchoring the cross-links to the carboxyl rather than the
amino groups, for instance, it could be demonstrated that
unblocked amino groups in the tissue have a strong pro-
calcic effect [121] and vice versa, the length and
hydrophobicity of the blocking agent determine the degree
of suppression. Once such rational engineering
approaches allowed the almost complete elimination of
tissue calcication [122], other consequences of tissue
xation, such as stiffness, became amenable to a similar
approach [123].
4.2.3. Cellular antigen removal (decellularization processes)
Cell extraction has been tried since the 1950s [124]. From
the beginning, the primary goal was to extract cellular
immunogenicity and thereby eventually manage to avoid
crosslinking. The misconception of this approach was that
it exclusively targeted cell surface molecules (MHC-II in
the case of allografts and the Gal-a1,4-Gal xenoantigen in
heterografts), implying that the extracellular matrix is non-
immunogenic. Apart from the fact that extracellular matrix
has been shown to be immunogenic [96], the decellulariza-
tion process itself holds a pro-inammatory potential.
Apart from the uncertainty with which solubilized antigens
and remnant detergents are eluded from the tissue, the
decellularization process itself may even liberate pro-
inammatory substances. Arachidonic acid, for instance,
a major component of the membranes of cellular orga-
nelles, may potentially not be removed by aqueous buffers
and thereby play a role in neutrophil chemotaxis through
leukotriene B
4
, a product of the arachidonic acid pathway.
The latter may partly explain the massive polymorph-
nuclear response to the clinically implanted Syner-
Graft
TM
valves [125,126] that were used as right
ventricular outow tract replacement in Ross procedures.
However, regardless of whether the inammatory response
is co-triggered by matrix immunogenicity and byproducts
of the extraction process or only by matrix immunogeni-
city: the latter will need to be addressed. The most obvious
way of dealing with it is an additional cross-linking step.
Interpreting contemporary research programs, however, it
seems unlikely that the cross-linking of decellularized BPT
will be eagerly embraced. The reason for this reluctance lies
in the fact that xation would conict with one of the
unfullled hopes behind decellularization. This unfullled
hope is the misconception thatonce implantedan
ideal, natural scaffold such as a decellularized matrix
would be eagerly populated by host cells. Whereas some
evidence appears to support the ingrowth potential of
acellular xenogenic matrices, at least in the sheep [127129]
and rat [130], the debate is skewed by the multitude of
decellularization methodologies in use, the wide range of
extraction times employed and the questionable animal
models used to validate the process. Our own experiences
(unpublished) with exhaustively washed decellularized
porcine aortic valves have conrmed a failure to repopulate
in rat, rabbit and primate models, with any ingrowth
potential confounded by a massive granulocytic response.
This is supported by the ndings of others conrming the
ability of decellularized tissue to attract mononuclear cells
and granulocytes [131,132]. The last blow to the concept of
tissue vitalization came with the clinical implantation
of SynerGraft
TM
Valves, where no evidence of matrix
repopulation was seen even after a year of implantation.
Stock et al. [133] even suggested that, in an inert acellular
matrix devoid of MMPs and their inhibitors (TIMPs),
repopulation by cells from adjacent tissue is biologically
unlikely [133].
4.3. Way forward for tissue valves
The mantra of bioprosthetic research must be the
recognition of its system-inherent limitations such as
matrix immunogenicity and perpetual non-vitality. Inas-
much as the removal of the xenogenic cells reduces the
immune burden, the continual immunogenicity of the
extracellular matrix will always require masking. Similarly,
believing that the extraction of cells will leave voids behind
which are inviting spaces for ingrowing host cells means to
ignore the decades-old knowledge that even the best of
decellularized heart valves do not get repopulated:
Although homografts are non-crosslinked they remain
largely acellular even after years of implantation [134].
However, if our goal is less ambitious and we just want to
signicantly extend the longevity of a non-vital bio-
prosthesis, engineered crosslinking already offers a solu-
tion, potentially augmented by combining the process with
a preceeding immune burden reduction such as decellular-
ization. A more recent discovery may even allow one to
achieve immune masking without cross-linking: by lling
non-crosslinked tissue with a hydrogel, antigens and
proteins seem to have been spatially rendered inaccessible
ARTICLE IN PRESS
by cells, enzymes or immune molecules. It was hypothe-
sized that it was this inaccessibility that prevented the
in vivo degradation, inammatory inltration and calcica-
tion of hydrogel-inltrated tissue (Fig. 7) [135].
5. Polymeric exible-leaet valves
The promise of synthetic heart valves was to have
prostheses available that have the durability of mechanical
valves and the haemocompatibility of tissue valves. In
reality, most of the polymeric valves were the opposite,
combining the durability of tissue valves with the
thrombogenicity of mechanical valves. Therefore, years
after the rst exible leaet polymeric heart valves were
implanted into patients [2,136], they have yet to reach a
performance level which makes them clinically acceptable
beyond the short-term use in articial hearts (e.g.
Abiomed, Berlin-Heart, Medos [137]).
5.1. Valve design
Similar to synthetic vascular grafts, material and design
aspects stood in the foreground during the 1960s and 1970s
while biocompatibility was added as a third pillar from the
1980s onwards. Initially, most researchers used the basic
trileaet (Fig. 8a) aortic design for their prototype valves
[138141]. Advances in uid-dynamic measurements and
numerical modelling subsequently allowed for optimiza-
tion of ow dynamics and leaet stress. Variations ranged
from hemi-cylindrical cusps [142] to leaets in half-open
position [143,144]; from variable-curvatures [145] to
elliptical and hyperbolic shapes [146] and from a conical
base with spherical upper part [147] to high prole cusps
(Fig. 8b) [137,148]. Notable exceptions to the tricuspid
design include the very rst bileaet mitral valve implanted
by Braunwald [2], the single-leaet silicone-covered Dacron
cusps implanted by Hufnagel in the 1970s [149] and an
asymmetric bileaet mitral valve [137,150] comprising a
kidney-shaped stent-ring containing a large anterior and
small posterior cusp, thereby mimicking mitral ow
conditions [148] (Fig. 8c). Overall, design and material
improvements led to a gradually increased durability
(up to 900 million cycles) and fatigue resistance now
equals that of bioprostheses [151]. There still seems to be
high variability in cycle life not only between different
valve designs and different studies [137,146,148,150]
but also between similar valves within one and the same
study [151].
5.2. Leaet materials
Since 1959 [137,138], the overwhelming majority of
polymer valves were made of polyurethanes (PUs). These
user-friendly materials have continuously been favoured
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Fig. 7. A novel approach to abrogate bioprosthetic tissue calcication and degradation involves the lling of the tissue with hydrogel rather than cross-
linking the amino or carboxyl groups of the tissue as conventionally done in tissue xation. The ramied blue lattice of the hydrogel lling the space
between two yellow collagen strands schematically shows how a space ller has replaced cross-links. The tissue structure is well preserved after lling with
20% acrylamide (+ bis-acrylamide crosslinker; UV initiation) (top left; Goldner; original magnication: 40 ) and calcication (60 days rat
subcutaneous) is well below that seen after standard glutaraldehyde xation (bottom right) [135].
for blood contacting applications in spite of their initially
poor long-term chemical stability [152]. However, new-
generation materials such as Elasteon [153] seem to have
largely overcome the problem of bio-degradation. Simi-
larly, improved fabrication technologies [145,154] resulted
in even and constant leaet thickness thereby improving
fatigue resistance and durability [151,154,155]. Segmented
PUs are generally exible and durable at approx 100 mm
leaet thickness, although there was some concern that a
leaet thickness of less than 150 mm may not be sufcient
[156]. Overall, the choice of thickness and material
modulus is a trade-off between tensile strength and
imparted bending stresses. The difculty of this choice is
reected in the broad range of leaet thicknesses
(60400 mm) reported [137,147,148,150,151,155].
The second most widely used polymer family was
Silicone rubbers [140]. Both the ball of the rst successful
mechanical valve and the leaets of one of the rst
clinically implanted polymeric heart valves [141] were
made from this material. Disappointing results [136,157],
however, led to silicones eventually being abandoned.
In general, most of the biomaterials of the 1960s and
1970s were either tried for vascular grafts or synthetic heart
valves. Expanded Teon was one of the materials which
was used for both applications [139,158,159]. Most
recently, a novel polyolen, poly(styrene-b-isobutylene-
b-styrene) (SIBS), with excellent chemical stability, has
been proposed as alternative to the traditional polymers
[160,161]. The material was found to match PU in platelet
deposition tests, and was comparable with PU in terms of
tensile and fatigue properties, albeit only after reinforce-
ment with polypropylene bres [160,161]. Altogether, the
promising result with both the latest generation of
biostable urethanes [162] and innovative new materials
such as bre-reinforced SIBS [160] for the rst time
indicate that after 50 years of failure a new door may
eventually have opened a small gap.
5.3. In vivo performance
Initial results of the 1960s with synthetic exible leaet
valves were catastrophic [136,163]. During the subsequent
decade improvements were only moderate [149] or short-
lived. An example of the latter was the re-discovery of
ePTFE for a tricuspid heart valve prosthesis [139]. After
promising initial results, its leaets were soon found to be
prone to stiffening, free-edge inversion and calcication
[159] conrming a previous clinical trial that had led to a
high mortality rate, associated with leaet rupture and
thickening almost 15 years earlier [158].
Until the mid to late 1980s, calcication [142,164,165]
had almost inevitably led to leaet immobilization, rupture
and perforation [166]. This seemingly insurmountable
limitation briey resulted in an almost complete disconti-
nuation of polymer valve programs. Subsequent material
improvements during the 1990s [146,151,167] allowed the
re-commencement of some of these programs culminating
in a mitral implant study [162] where no valve related
deaths occurred. Furthermore, bioprosthetic anticalcica-
tion treatments of the 1980s and early 1990s were
incorporated in an attempt to modify the leaet surfaces
towards more biocompatibility. Covalently bound bipho-
sphonate [168,169], the extraction of low molecular weight
components [167] from methanol-extracted polyether
urethane (PEU) and the modication of a polyurethane
valve with polyethylene oxide and sulfonate groups
(PU-PEO-SO
3
) all showed reduced polymer calcication.
The latter also showed a decrease in thrombogenicity and
crack formation [170]. Similarly, heparin, taurine and
aminosilane modications equally resulted in extended
durability [171]. Yet, even the latest generations of polymer
valves continue to experience some degree of extrinsic
calcication [137,148,150] indicating that the goal of a
long-lasting synthetic heart valve may remain elusive as
long as no cellular components such as endothelial cells are
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Fig. 8. Polymeric heart valves: (a) a frame machined from polyetheretherketone (PEEK) and coated with a thin layer of leaet polyurethane. Leaets of a
commercially available polyetherurethane suitable for animal implantation (Estane 58315, BF Goodrich, Westerlo-Oevel, Belgium) were dip-coated onto
the frame. This valve design has achieved durabilities in excess of 400 million cycles (10.5 years) during in vitro fatigue testing [162]; (b) and (c):
polycarbonate urethane (PCU) tri-leaet and bi-leaet valves intended for the aortic and mitral positions. These particular designs achieved in vitro
durabilities of up to 600 million (15.8 years) and 1 billion (26 years) cycles, respectively [137].
an integral part of the concept. The rst successful attempts
to grow endothelial cells on polyurethanes and PU-silicone
rubber co-polymers were made in the 1980s [172174].
A promising current approach to endothelialization in-
volved the pre-seeding of ECs onto cholesterol-modied
polyurethane cusps. This modication resulted in increased
collagen synthesis and cell retention in vitro and
in vivo [175,176].
5.4. Way forward for polymer valves
Over the course of half a century, polymeric valve
designs have been improved regarding ow characteristics
and stress reduction. During the same period of time,
degradation-resistant materials were developed, processing
methods evolved that allow reproducible high-quality
manufacturing, and thrombogenicity and calcication have
been partly addressed through surface modications. Yet,
without the integration of living cells into these con-
structseither through blood borne fallout healing [177] or
active incorporation through seedingit seems unlikely
that the full potential of polymeric valves will ever come to
fruition.
6. Tissue-engineered valves
Tissue-engineering technologies providing living auto-
logous heart valves with the capacity of regeneration and
growth have shown promising experimental results and
initial human applications have been reported [178181].
Resorption of the porous leaet scaffold initially led to
overshooting brosis [182,183] but ne-tuning of the
resorption process through the use of poly-glycolic-acid
(PGA)/poly-4-hydroxybutyrate (P4HB) instead of poly-
lactic acid (PLA) co-polymers led to living heart valves
with a tri-layered structure and many features of a native
leaet [181]. The ability to visualize the vitality and cellular
activity of heart valve cells in vivo is a backbone of follow-
up requirements of future clinical trials with tissue-
engineered valves (Fig. 9).
While the majority of researchers pursue a concept
whereby a scaffold is seeded in vitro with autologous cells,
an alternative approach aims at the in vivo recruitment of
cells [184] through the incorporation of biological signals
into a degradable scaffold. The latter is supported by the
observation that circulating endothelial progenitor cells
(ECP) led to the spontaneous endothelialization of the
blood surface of clinically implanted ventricular assist
devices [185,186]. Similarly, ECPs have been shown to
home to stents coated with CD 34 antibodies (CD34 being
cell surface molecules of ECPs) [187].
Although scientically representing a quantum-leap
improvement to todays heart valve prostheses, tissue-
engineered heart valves still have a long way to go towards
competing with contemporary heart valve prostheses
regarding safety, functionality, logistic feasibility and
nancial viability. A clearly unmet medical need and
indication, however, is in paediatric applications due to the
inherent growth-potential of tissue-engineered valves.
Furthermore, recent studies have demonstrated the feasi-
bility of using prenatal foetal cellswhich can be obtained
during pregnancy and used for the tissue-engineering
procedure prior to birthto provide living, autologous
heart valves for early correction of congenital heart defects
[178,188] (Fig. 10). Therefore, should tissue-engineering
technologies become an accepted clinical tool, it will
most likely happen through the niche of paediatric
applications.
7. Catheter-based valves
As attractive as the concept of a catheter-delivered heart
valve is, the emperors new clothes syndrome remains:
while it potentially reduces the implantation trauma, it
perpetuates the unsatisfying situation regarding available
prostheses. By using mainly conventional bioprosthetic
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Fig. 9. Novel multimodality molecular imaging techniques enable the monitoring of cell activation and remodelling enzymes during valve development
and disease. The long-axis view (a) shows the aortic root and arch, followed by a short axis view (b) which shows negative signal enhancement (darkening)
caused by the uptake of nanoparticles by activated cells. Colour-coded signal intensities (c) show focused uptake of the nanoparticles in the commissures
(modied from [217] with permission/mouse model/VCAM-1).
material, delivery-associated hype is not matched by
prognostic expectations. This is particularly true for the
largely young patients in developing countries, whose non-
calcied rheumatic valves would theoretically make them
ideal recipients for endovascularly placed prostheses.
Given the rapid degeneration of all contemporary exible
leaet valves in young recipients, however, the very patient
group that would dramatically benet from transcatheter
delivery is the one that hardly qualies for it.
7.1. Principle
The concept behind catheter-based valve delivery is
simple: a valved stent is collapsed into a catheter, the
catheter tip is positioned at the site of the valve to be
replaced, and the stent is balloon-expanded to unfurl the
new valve. The execution of the concept, however, is very
complex. In addition to the strenuous demands already
placed on surgically implanted valves, and to the ingenious
stent and catheter designs required to deliver them,
catheter-based valves must withstand being forced into a
tube at a fraction (approximately a third) of their expanded
diameter, and then be able to unfold into the precise
geometries required for function and durability. Although
ball-and-cage [189] and tilting disk concepts [190] were
proposed and evaluated, exible-leaet designs are prob-
ably the most suitable candidates to fulll the required
criteria, and it follows that transcatheter valve leaets are
preferentially fabricated from BPT or exible polymers
used in more conventional designs. Although the rst type
(BPT) suffers from degenerative exural failure, 50 years of
research have yet to produce a valve of the second type
(polymeric) that approximates its success (as seen in
sections above). Hyperelastic metal leaets comprise a
third option, but relatively little is currently known about
the suitability of this emerging technology for valve
applications.
7.2. For few of the few?
If there was ever a development that was tailor-made for
the millions of patients in threshold countries who need a
valve replacement, it was the catheter-based delivery of
heart valve prostheses. By offering patients with early
regurgitation who have no access to open heart surgery but
access to a modern C-arm visualization system a tool for
the placement of a functioning valve and thereby prevent-
ing ventricular dilatation, morbidity patterns of entire
populations could change. Yet, the available bio-materials
are so unsuitable for these patients that catheter-based
heart valves turned from a promise for millions into the
most exclusive rst world prostheses of all. Even worse,
contemporary catheter-based concepts cater for two rst-
world fringe-indications: severely diseased patients who are
inoperable due to co-morbidities [191] and pulmonary
placements in patients with congenital heart disease in
order to obviate or delay the comorbidity associated with
re-operation [192,193]. Even if indications may eventually
be extended to the majority of rst world patients, the
market is small. Given this small potential market, it is
astonishing how all the major players rushed to the scene.
Since the rst transcatheter implants in animals occurred in
1992, with Andersen et al. and Pavcnik et al. delivering a
stented porcine valve and a ball-and-cage valve (with
inatable ball), respectively [189,194], there are reported to
be more than 20 companies currently working on this
technology [192]. A Pubmed search for percutaneous
heart valve receives over 1500 hits, which include more
than 150 reviews!
Since the rst human catheter-based replacement of a
pulmonary valve in pediatric patients by Bonhoeffer et al.
[195] and an aortic valve by Cribier et al. [196], events
follow hot on the heels of one another. Bonhoeffer has
since treated more than 120 patients with pulmonary
insufciencies using a porcine jugular vein valve in a
platinum stent [197] (now the Medtronic Melody
s
valve)
(Fig. 11), while the Edwards Sapien
s
(equine pericardial
tricuspid valve in a stainless steel stent) [198] (Fig. 11), and
ARTICLE IN PRESS
Fig. 10. Ideally, an autologous cardiovascular substitute would be used
for the repair of congenital cardiovascular malformations which has the
potential to grow and regenerate, thereby avoiding secondary damage to
the immature heart and re-operations with their associated mortality and
morbidity over a life-time. If used at or shortly after birth, the process of
engineering such an autologous construct would need to be initiated
prenatally. Conceptually, foetal stem cells could be harvested from extra-
embryonic foetal tissues such as chorionic villi, the umbilical cord or
amniotic uid. After differentiation and proliferation in vitro, cells could
be seeded onto a biodegradable scaffold and conditioned in a bioreactor,
mimicking physiological conditions. The feasibility to fabricate foetal
tissues according to this concept has been recently demonstrated by the
in vitro fabrication of autologous living heart valve tissues based on
prenatal progenitor cells derived from umbilical cord [218], chorionic villi
[188] and amniotic uid [219].
Corvalve
s
(bovine pericardial valve in a Nitinol (NiTi)
self-expanding stent) [76,199,200] are arguably the most
commonly used aortic prostheses. Other valves include the
3F (Enable
s
and Entrata
s
) (bioprosthetic leaets in self-
expanding NiTi stents) and Sadra Medical Lotus
s
(pericardium/NiTi) aortic valves, the Shelhigh
s
(porcine
pulmonic/NiTi) pulmonary valve, the Aortex
s
valve, and
the Palmaz-Bailey
s
valve composed entirely of Nitinol
[76]. A rst assessment of the clinical experience with more
than 120 transvenous placements of pulmonary valves
years after correction of congenital malformations, was
favourable in comparison to surgical pulmonary valve
replacement in a historical cohort from the same institution
[201]. The median hospital stay was 2 days (compared to 7
in the surgical group). There was no mortality and the early
morbidity was 5.8% (vs. 8.5% in the surgical group).
Percutaneous aortic valve replacement in humans was rst
performed as a femoral transvenous, transseptal procedure
with antegrade access to the aortic annulus [198]. In the
initial attempt in 26 high-risk patients (turned down for
conventional aortic valve surgery due to high risk), 22
deployments were successful and 4 failed (2 patients could
not tolerate the guidewire across the mitral valve and in 2
the valve migrated). Complications were high with 27%
early (o30days) and 41% late deaths. The survivors have
returned to a normal life with mean transvalvular gradients
being 11 mmHg and paravalvular leak grade 01 in seven
and grade 2 in four patients. Subsequently, Webb et al.
[202] from Vancouver reported a femoral transarterial
procedure with retrograde access to the aortic annulus.
Their initial results in 18 patients showed successful
deployment in 14 (the 2 failures were due to iliac arterial
injury in two and prosthetic valve embolization in another
two patients). There were 2 post-procedural deaths and one
surgical aortic valve replacement for failurein the 14
patients with successful deployment paravalvular leakage
varied from none to moderate. Because of the technical
difculty in deploying the device, Ye, Webb and colleagues
from Vancouver performed a hybrid procedure utilized a
transapical access to deploy the valve antegradely under
radiographic control [203]. There were no intraprocedural
mortalities or morbidities but one patient died on day 12 of
pneumonia and 2 died later on days 51 and 85, respectively
of non-cardiac causes; the remaining 4 have done well and
completed 6-month follow-uponly one has more than
trivial or mild aortic incompetence and none have had
valve-related complications. A larger series of 30 very high
risk patients (average age 8275.1 years) from Leipzig using
a similar method of transapically introduced valves was
more favourable with successful deployment of the device
in 29 of the 30 patients, experiencing 3 deaths [204].
Extracorporeal circulatory support was only used in the
initial 43% patients and thereafter the procedures were
successfully performed without circulatory support. Over-
all, this initial experience conrms transcatheter placement
of heart valves as a promising approach for fringe groups.
7.3. Design/procedural challenges
In addition to securing seatingin rst world patients
mostly on top of heavy calcium depositsand possible
interference with other cardiac structures, access and valve
placement are important considerations in valve develop-
ment [193]. In the pulmonary position, access is typically
gained via the femoral vein [195], although transventricular
pulmonary placement [205] has been advised in senescent
patients when the RVOT is large and the valve and catheter
size precludes traditional percutaneous placement.
In the aortic position, the initial antegrade transseptal
procedure via the femoral vein [206] was technically
demanding encountering difculties in accurately seating
and deploying the device via this tortuous route (via an
atrial septostomy, through the mitral valve and having to
negotiate an acute curvature in the left ventricle). There-
fore, the transseptal approach was subsequently aban-
doned for retrograde arterial placement [202,207]. This
procedure was also later extended to mitral valves
[208,209]. Although better tolerated by patients, it had its
own challengesespecially in older patientsin requiring
a large caliber femoral artery capable of receiving a 24F
(8 mm) catheter (commonly used for currently preferred
26 mm valves). Moreover, the long catheter route also
made accurate deployment of the device difcult. This led
Ye et al. [203] from Vancouver to utilize a similar catheter
mounted valve to implant an aortic valve via the apex of
the left ventricle antegradely via a small left anterior
thoracotomy and without the use of cardiopulmonary
bypass. Although not strictly complying with the conven-
tional interpretation of endovascular placement, transa-
pical placement via endoscopy or small thoracotomy
[203,210,211] allows the catheter-mounted valve conduit
to be introduced via the left ventricular apex more directly.
The shorter, more rigid and larger deployment system
allows more accurate and secure prosthetic valve deploy-
ment in the aortic annulus. This is done via radiographic
ARTICLE IN PRESS
Fig. 11. Two examples of percutaneously delivered heart valves, the
Edwards Lifesciences Sapien aortic valve prosthesis (left) and the
Medtronic Melody transcatheter pulmonary valve prosthesis (right).
Although both models use unconventional animal sources (equine
pericardial for the Edwards valve and bovine jugular for the Medtronic
valve), the debut of two major commercial players highlights how
conventional the actual valves areeven if the delivery is catheter
based. Reprinted from [76] with permission of Universal Medical Press,
Inc.
and echocardiographic control. It also allows a larger size
valve to be deployed.
7.4. What is in the pipeline?
An innovative way of accepting the shortcomings of
contemporary tissue valves while reducing the stress,
morbidity and eventually higher mortality of the re-
operations is the concept of the transapical renewal of a
degenerated, surgically implanted valve. One system
(ValveXchange, Inc.) consists of a two-piece valve and
the associated tools for replacing an exchangeable leaet
component without requiring cardiopulmonary bypass
(Fig. 12) [212]. Another one is a valve by Sadra Medical,
that also contains a re-positionable anchor, and allows for
valve replacement [213].
Other interesting developments include suture-less clo-
sure after transapical access [214], a low prole valve that
can be introduced with 1116F catheter (used in the rst
retrograde placement in humans) [207], and polymeric
valves by Sochman (folding silicone disk in a Nitinol) [215]
and Attmann (novel low prole PU valve in Nitinol stent
24 mm diameter that can be crimped down to 14F catheter)
[216]. Paniagua et al. [207] have developed a low prole,
metal-stented, tissue valve that can be introduced with a
1116F catheter).
8. Where to with replacement heart valves?
Contemporary heart valve prostheses are extremely ne-
tuned to a rst world situation. When using a mechanical
valve we replace one disease by another with turning young
to middle-aged patients into haemophiliacs with the
additional risk of clotting up their valve or having a
stroke. Only the sophisticated medical system of the
developed world can cope with this challenge without a
signicant level of morbidity and mortality. In the same
rst world population, tissue valves currently represent an
equally ne-tuned compromise for the aged, but are
otherwise almost as unsatisfying as in previous decades.
With no disruptive technology on the commercial horizon,
these valves will remain unacceptable for the young
patients of threshold countries while getting more trouble-
some for developed countries. The reason for the latter is
the increasing challenge for globally operating companies
to source internationally acceptable animal products in the
wake of prions and viruses. Moreover, if developmental
steps were particularly difcult to bring from bench to
marketing before, recently tightened European regulations
will not act as an encouragement for manufacturers, since
most of the tissue valves were previously developed in the
United States but clinically tested in Europe.
Tissue-engineered valves will undoubtedly eventually
represent the future. However, judging by the snail-pace
at which tissue engineering has developed since it became
vogue in the late 1970s, its clinical application in the eld of
replacement heart valveseven in the narrow paediatric
nichemay take at least another generation. In view of the
small market, it may yet remain in the domain of
Universities and start-up companies.
Given the current low incentive for the major companies
to develop a catheter-based heart valve that does not need
anticoagulation but nevertheless has a long durability in
young patients, one needs to ask where the niches may be
within existing technologies that may benet the huge
untapped number of potential recipients in threshold
countries. Judging by the technological abilities of coun-
tries such as India, China or Brazil, rst world develop-
ments could be (and already are!) easily and affordably
reproduced. One of the main obstacles, however, would
be licensing. Although hardly any of the developments
that have shown great promisefrom engineered cross-
linking to polymer lling, from heparin bonding to
ARTICLE IN PRESS
Fig. 12. Image of the ValveXchange transapically exchangeable
bioprosthetic heart valve. Rather than being a permanent valve, the
exchangeable valve is a two-piece device with leaets that can be replaced
after having worn out. In the main image, the exchange process is shown
through the apex of the heart. A special trocar locks onto the docking
station (the sewing cuff and valve stent) to stabilize the heart and valve,
and a valve removal tool is inserted. The stent posts are grasped, the valve
lifted from the docking station, collapsed and pulled out through the
trocar. A new valve is immediately inserted and the procedure is done
completely off-pump. The inset image shows a retrograde approach, in
which a similar valve holder is passed from the outow aspect to lock on
to the docking station. In this approach, the valve is passed over the shaft
of the valve holder during the exchange ([212], with permission).
decellularizationmay eventually be implemented in the
rst world, research was often nanced and patented by its
major commercial players. Therefore, generous licensing
programs could not only make valve replacements an
acceptable treatment for many times the numbers of
patients who currently benet from it, but also provide
the overdue feedback on performance patterns in young
recipients. With patients from threshold countries being
largely young and thus ideal for endovascularly placed
valves due to the lack of calcication, endovascularly
implanted tissue valves pioneering improvements already
lying in the drawers of companies, may create a winwin
situation which overcomes the 50 year long stalemate in the
development of commercially available heart valve pros-
theses.
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Prosthetic Heart Valves

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Biomaterials 29 (2008) 385406

, Johan Brink, Paul Human, Deon Bezuidenhout

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