ISO 5840:1996

INTERNATIONAL
STANDARD
Third edition
1996-l I-01
Cardiovascular implants -
Cardiac valve prostheses
Implants cardiovasculaires - Pro theses valvulaires
Reference number
IS0 5840:1996(E)
IS0 5840: 1996(E)
Page
Contents
........................................................................................
1 Scope
...............................................................
2 Normative references
3 Definitions .
......................................................................
4 Valve description
.................. 5
5 Material, component and valve assembly testing.
..............................................................
6 Hydrodynamic testing
.......................................................................
7 Durability testing
.....................................................
8 Preclinical in vivo evaluation
9 Clinical evaluation .
........................................ 19
IO Packaging, labelling and instructions
Annexes
A Rationale for the provisions of this International Standard.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
B Materials related to heart valve substitutes
C Physical and material properties of heart valve substitutes and
their components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
D Standards applicable to testing of materials and components
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
of heart valve substitutes
E Definitions of components of a heart valve substitute . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
F Valve description
0 IS0 1996
All rights reserved. Unless otherwise specified, no part of this publication may be
reproduced or utilized in any form or by any means, electronic or mechanical, including
photocopying and microfilm, without permission in writing from the publisher.
International Organization for Standardization
Case Postale 56 l CH-1211 Geneve 20 l Switzerland
Printed in Switzerland
II
IS0 5840: 1996(E)
0 IS0
Foreword
IS0 (the lnternational Organization for Standardization) is a worldwide
federation of national standards bodies (IS0 member bodies). The work of
preparing International Standards is normally carried out through IS0
technical committees. Each member body interested in a subject for
which a technical committee has been established has the right to be
represented on that committee. International organizations, governmental
and non-governmental, in liaison with ISO, also take part in the work. IS0
collaborates closely with the International Electrotechnical Commission
(IEC) on all matters of electrotechnical standardization.
Draft International Standards adopted by the technical committees are
circulated to the member bodies for voting. Publication as an International
Standard requires approval by at least 75 % of the member bodies casting
a vote.
International Standard IS0 5840 was prepared by Technical Committee
ISO/TC 150, implants for surgery, Subcommitte SC 2, Cardiovascular
implants.
This third edition cancels and replaces the second edition (IS0 5840:1989),
which has been technically revised. Additions include testing of materials
and components and a scheme for classification of heart valve substitutes
and their components.
Annexes A to F of this International Standard are for information only.

0 IS0
IS0 5840: 1996(E)
Introduction
There is, as yet, no heart valve substitute which can be regarded as ideal.
This International Standard has been prepared by a group well aware of
the problems associated with heart valve substitutes and their develop-
ment. In several areas, the provisions of this International Standard have
been deliberately left open as there has been no wish to inhibit
development and innovation. For these reasons, this International
Standard intentionally does not attempt to specify performance require-
ments for finished products. It does specify types of tests, test methods
and/or requirements for test apparatus, and requires disclosure of test
methods and results. The areas with which this International Standard is
concerned are those which will facilitate quality assurance, aid the surgeon
in choosing a heart valve substitute, and ensure that the device will be
presented at the operating table in a convenient form. Emphasis has been
placed on specifying types of in vitro testing, on preclinical in viva and
clinical evaluations, on reporting of all in vitro, preclinical in viva and clinical
evaluations and on the labelling and packaging of the device. Such a
process involving in vitro, preclinical in viva and clinical evaluations is
intended to clarify the required procedures prior to market release and to
enable prompt identification and management of subsequent problems.
With regard to in vitro testing and reporting, apart from basic material
testing for mechanical, physical, chemical and biocompatibility character-
istics, this International Standard also covers important hydrodynamic and
accelerated fatigue characteristics of heart valve substitutes. The exact
test methods for hydrodynamic and accelerated fatigue testing have not
been specified, but requirements for the test apparatus are given.
This International Standard is incomplete in several areas. It is intended to
be revised, updated, and/or amended, as knowledge and techniques in
heart valve substitute technology improve.
IV
IS0 5840:1996(E)
INTERNATIONAL STANDARD @ IS0
- Cardiac valve prostheses
Cardiovascular implants
1 Scope
1.1 This International Standard specifies tests to be performed and requirements for test apparatus to be used in
determining the physical, biological and mechanical properties of heart valve substitutes of all types, and of the
materials and components of which they are made.
1.2 Requirements are provided for preclinical in viva evaluation, for clinical evaluation, and for reporting the results
of all types of testing and evaluation covered in this International Standard. These requirements do not purport to
comprise a complete test programme.
1.3 Specifications are also given for packaging and labelling of heart valve substitutes.
1.4 This International Standard is not applicable to heart valve substitutes comprised in whole or in part of human
tissue.
A rationale for the provisions of this International Standard is given in annex A.
NOTE -
2 Normative references
The following standards contain provisions which, through reference in this text, constitute provisions of this
International Standard. At the time of publication, the editions indicated were valid. All standards are subject to
revision, and parties to agreements based on this International Standard are encouraged to investigate the
possibility of applying the most recent editions of the standards indicated below. Members of IEC and IS0 maintain
registers of currently valid International Standards.
IS0 8601 :I 988, Data elements and interchange formats - Information interchange - Representation of dates and
times.
- Part 1: Evaluation and testing.
IS0 10993-I : ----I), Biological evaluation of medical devices
- Part 2: Animal welfare requirements.
IS0 10993-2: 1992, Biological evaluation of medical devices
IS0 10993-3:1992, Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and
reproductive toxicity.
IS0 10993-4: 1992, Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood.
IS0 10993-5: 1992, Biological evaluation of medical devices - Part 5: Tests for cytotoxicity: in vitro methods.
Part 6: Tests for local effects after implantation.
IS0 10993-6: 1994, Biological evaluation of medical devices -
IS0 10993-7: 1995, Biological evaluation of medical devices - Part 7: Ethylene oxide sterilization residuals.
lSO/rR 10993-g: 1994, Biological evaluation of medical devices - Part 9: Degradation of materials related to
biological testing.
1) To be published. (Revision of IS0 10993-I :I 992)

@ IS0
IS0 5840: 1996(E)
Part IO: Tests for irritation and sensitization.
IS0 10993-I 0: 1995, Biological evaluation of medical devices -
- Part I ’!: Tests for systemic toxicity.
IS0 10993-I 1 :I 993, Biological evaluation of medical devices
- Part 12: Sample preparation and reference materials.
2), Biological evaluation of medical devices
IS0 10993-I 2:-
Requirements for validation and routine control -
IS0 11134:1994, Sterilization of health care products -
Industrial moist heat sterilization.
Validation and routine control of ethylene oxide sterilization.
IS0 11135:1994, Medical devices -
IS0 11137:1995, Sterilization of health care products - Requirements for validation and routine control -
Radiation sterilization.
IS0 14155: 1996, Clinical investigation of medical devices.
3 Definitions
For the purposes of this International Standard, the following definitions apply.
3.1 anticoagulant-related haemorrhage: Internal or external bleeding that causes death or stroke, or that
requires transfusion, operation or hospitalization.
NOTE - This definition is restricted to patients who are receiving anticoagulants and/or antiplatelet drugs.
3.2 arterial diastolic pressure: Minimum value of the arterial pressure during diastole.
3.3 arterial peak systolic pressure: Maximum value of the arterial pressure during systole.
3.4 closing volume: Component of the regurgitant volume that is associated with the dynamics of valve closure
during a single cycle (see figure 1).
3.5 cycle: One complete sequence in the action of a test heart valve substitute under pulsatile flow conditions.
3.6 cycle rate: Number of complete cycles per unit of time, usually expressed as cycles per minute (cycles/min).
3.7 external sewing ring diameter: Maximum external diameter of a heart valve substitute, including the sewing
ring (see figure 2).
3.8 forward-flow phase: Portion of the cycle time during which forward flow occurs through a test heart valve
substitute.
3.9 heart valve substitute: Device used to replace or supplement a natural valve of the heart, categorized
according to the position in which it is intended to be used (valve type).
3.9.1 mechanical heart valve substitute: Heart valve substitute composed wholly of synthetic materials.
3.92 biological heart valve substitute: Heart valve substitute composed wholly or partly of animal tissue.
valve substitute, excluding
3.10 internal orifice area: Minimum projected area normal to the plane of the heart
the occluder(s).
eakage through the closed
3.11 leakage volume: Component of the regurgitant volume that is associated with
valve during a single cycle (see figure 1).
NOTE - The point of separation between the closing and leakage volumes is obtained according to a defined and stated
criterion (the linear extrapolation shown in figure 1 is just an example).
3.12
mean arterial pressure: Time-averaged arithmetic mean value of the arterial pressure during one cycle.
2) To be published.
@ IS0 IS0 5840: 1996(E)
3.13 mean pressure difference: Time-averaged arithmetic mean value of the pressure difference across a heart
valve substitute during the forward-flow phase of the cycle.
NOTE - The usage of “mean pressure gradient” for this term is deprecated.
3.14 mean volume flow: Time-averaged arithmetic mean value of the flow across a heart valve substitute during
the forward-flow phase of the cycle.
3.15 nonstructural dysfunction: Abnormality resulting in stenosis or regurgitation of the heart valve substitute
that is not intrinsic to the valve itself.
NOTE - This dysfunction is exclusive of valve thrombosis, systemic embolus or infection diagnosed by reoperation, autopsy
or in vivo investigation. Examples include entrapment by pannus or suture, paravalvular leak, inappropriate sizing, and
significant haemolytic anaemia.
3.16 occluder: Component(s) of a heart valve substitute that move(s) to inhibit reflux.
operative mortality: Death from any cause during operation or within 30 days after operation.
3.17
3.18 profile height: Maximum axial dimension of a heart valve substitute in the open or closed position,
whichever is greater (see figure 2).
3.19 prosthetic valve endocarditis: Infection involving a heart valve substitute.
NOTE - Diagnosis is based on customary clinical criteria, including an appropriate combination of positive blood cultures,
clinical signs (fever, new or altered cardiac murmurs, splenomegaly, systemic embolus or immunopathologic lesions) and/or
histologic confirmation of endocarditis at reoperation or autopsy. Morbidity associated with active infection such as valve
thrombosis, embolus or paravalvular leak is included under this category and is not included in other categories of morbidity.
Closing volume
Leakagevolume
Figure 1 - Example of flow waveform and regurgitant volumes for one cycle
IS0 5840:1996(E)
Occluder
c ---
HHC --
..
/
,
/
\
/-
\
/
\
Sewing ring -
\
/I /
.-
:
aJ
--J
.-
\c
z
a.
Figure 2 - Designation of dimensions of heart valve substitutes
employed to
3.20 reference valve: Heart valve substitute used to assess the conditions established in the tests
evaluate the test heart valve substitute.
NOTE - The reference valve should approximate the test heart valve substitute in type, configuration and tissue annulus
diameter; it may be an earlier model of the same valve, if it fulfills the necessary conditions. The characteristics of the
reference valve should be well documented with both in vitro and clinical data available in the literature.
3.21 regurgitant fraction: Regurgitant volume expressed as a percentage of the stroke volume.
3.22 regurgitant volume: Volume of fluid that flows through a test heart valve substitute in the reverse direction
during one cycle; it is the sum of the closing volume and the leakage volume (see figure 1).
3.23 root mean square (r.m.s.) volume flow: Square root of the time-averaged arithmetic mean square value of
the volume flow through a test heart valve substitute during the forward-flow phase of the cycle.
3.24 simulated cardiac output: Net fluid volume flowing forward through a test heart valve substitute per
minute.
3.25 stroke volume: Volume of fluid moved through a test heart valve substitute in the forward direction during
one cycle.
3.26 structural deterioration: Change in the function of a heart valve substitute resulting from an intrinsic
abnormality that causes stenosis or regurgitation.
NOTE - This definition excludes infection or thrombosis of the heart valve substitute as determined by reoperation, autopsy
or in vivo investigation. It includes intrinsic changes such as wear, stress fracture, occluder escape, calcification, leaflet tear
and stent creep.
3.27 systemic embolism: Clot or other particulate matter, not associated with infection, originating on or near
the heart valve substitute and transported to another part of the body.
NOTE - Diagnosis may be indicated by a new, permanent or transient, focal or global neurologic deficit (exclusive of
haemorrhage) or by any peripheral arterial embolus unless proved to have resulted from another cause (e.g. atrial myxoma).
Patients who do not awaken post-operatively or who awaken with a stroke or myocardial infarction are excluded. Acute
myocardial infarction that occurs after operation is arbitrarily defined as an embolic event in patients with known normal
coronary arteries or who are less than 40 years of age.

@ IS0 IS0 5840:1996(E)
Isti tute including any covering where it is
3.28 tissue annulus diameter: External d ameter of a heart valve sub I
t diameter of host tis sue (see figure 2).
intended to mate with the smalles
The usage of “mounting diameter” for this term is deprecated.
NOTE -
3.29 valve size: Manufacturer ’s designation of the dimensions of the heart valve substitute.
3.30 valve thrombosis: Blood clot, not associated with infection, causing dysfunction of the heart valve
substitute.
NOTE - Diagnosis may be proved by operation, autopsy, or clinical investigation (e.g. echocardiography, angiocardiography
or magnetic resonance imaging).
4 Valve description
components, materials and processes of construction shall
A complete description of the heart valve substitute, its
be provided.
NOTES
1 See annex E for definitions of terms that can be used to identify the heart valve substitute components.
2 Relevant construction processes may include anticalcification treatment or carbon coating of sewing rings (see annex F).
5 Material, component and valve assembly testing (see A.1 for rationale)
5.1 Principle
Physical testing of the materials and components of heart valve substitutes is performed to assure that the valve or
components will withstand the rigors imposed by the host over the lifetime of the device. Test selection is based
on a matrix criterion that accounts for the materials and components used in the heart valve substitute and the site
of use.
5.2 General
for evaluation shall emulate, as closely as possible, the condition of the finished
he test spe cimen s c hosen
roduct as su pplied for clinical use.
P
5.3 Testing fluid and temperature
Where emulation of in viva conditions is applicable, testing shall be performed using a testing fluid of isotonic
saline, blood or a blood-equivalent fluid whose physical properties (e.g. specific gravity, viscosity at working
temperature) shall be stated. The tests shall be conducted at 37 OC unless an acceptable scientific/engineering
rationale allows for other conditions.
NOTE - Mechanical properties and degradation properties can vary with temperature.
5.4 Biocompatibility
The biocompatibility of the materials and components used in heart valve substitutes shall be determined in
accordance with the appropriate part(s) of IS0 10993.
5.5 Physical and material testing
5.5.1 Materials and component testing
Properties of heart valve substitutes and their components shall be evaluated, where applicable to the design of
the valve, according to tables 1 and 2. A rationale for the selection of properties evaluated shall be provided.
C, D, E and F for references and a description
NOTE - See annexes of possible ma teria Is and component testing of heart
valve substitutes. These annexes are provided to guide the reader in the use of tables 1 and 2.

@ IS0
IS0 5840: 1996(E)
- Physical and chemical properties for evaluation of heart valve substitute components
Table 1
Componentl)
Clause
Physical and chemical
reference
Synthetic
properties
Biological Metal Ceramic
Textile
(annex C)
polymer
c.2. 1 Bulk physical properties
1 ABCDEHJ 1 ABDJ
2.1 [ Chemical composition ABCDEFGHIJ 1 J 1 FGI
2.2 1 Densitv ABCDEFGHIJ 1 t ABCDEHJ IABDJ I
Liquid diffusivity ABCDEFGHI 1 m-ppmm I ABD I
2.3
ABCDEFGHJ 1 IABCDEHJ IABDJ I
2.4 Hardness
1 ABCDEFGHI I ABCDEHJ IABDJ I
2.5 1 Microstructure/morphology
2.6 1 Tear strenath Dl ABCDEFGHI
2.7 Young ’s modulus ABCDEH ABCDEH ABD
Poisson ’s ratio ABCDEFGHI 1 I ABCDEH ~__
2.8 hD 1
1 Dynamic moduli BDE 1 ABCDEFGHI I I I
2.9
ABCDE ABDH ABD
2.10 Ic oe ff’ tcient of thermal expansion
2.11 1 Glass transition temperature ABCDEFI FGI
2.12 1 Melt index ABCDEHI 1
T- I- I
ABCDEFI I I 1 FGi
2.13 1 Melting point I
ABCDEFHIJ 1 IJ
2.14 1 Hydraulic expansion IJ I
2.15 1 Biostability ABCDEFGHI
2.16 Film thickness J J J
2.17 % Elemental composition of a film
Surface physical properties
c.3.
ABDEJ I ABCDJ IABDJ 1
3.2 Critical surface tension
IJ
~ABCDJ TGDJ- I
3.3 Surface roughness ABDEJ
IJ
3.4 Surface chemical composition ABDEJ I ABCDJ IABDJ 1
IJ
t ARCD.1 I ARD.J I
Surface charge and charge density ABDEJ IJ
3.5
3.6 Surface resistance
i
c.4. Mechanical and chemical propertic
ABCDJ I ABDHJ IABDJ I
4.2 Wear resistance I
ABDE ABDH ABD
4.3 Coefficient of friction
4.4 Peel strength DE
4.5 Flexural strength BDE E ABD
ABCE
4.6 Compressive strength I IABD 1
I
4.7 Tensile strength DEI I ABCDE I ABCDEH IABD I
I ARCDFHJ I ARM I
4.8 Tensile strain to failure (elongation) DEIJ I ABCDE
4.9 Strain energy to failure
ABCDEH
4.10 Residual stress ABCDEFGH ABD
4.11 Stress relaxation ABCDEFGH ABCDE
4.12 ABCDEH
Creep
ABCDEH
4.13 Fracture toughness ABD
I
4.14 Crack growth velocity IABCDEH IABD I
I
4.15 Fatigue life ~ ABCDEHI I I ABCDEH IABD I
4.16
Stress corrosion potential I ABDH
4.17 Galvanic corrosion potential ABCDH
4.18 Fretting corrosion potential ABDH
4.19 Void concentration J J J
NOTE - See figure E.l and annex E for description of components A to J.
1) A Orifice ring (housing) D Occluder/leaflet G Sewing ring filler J Coating
B Occluder retention mechanism E Stent H Sewing ring retaining material
C Stiffening element F Covering I Component joining material
0 IS0 IS0 5840: 1996(E)
Table 2 - Physical and chemical properties for application to design of heart valve substitutes
and their components
Appropriate for current
Physical and chemical properties tests
Calcification (in viva model)
5.52 Valve assembly testing
The physical and chemical properties relating to valve design, listed in table 2, shall be evaluated on heart valve
substitutes, subassemblies or components as applicable.
5.6 Test report
Each test report shall include:
rationale for the test;
a)
b) identity of the material tested (e.g. generic chemical name or biological source) or a description of the item(s)
tested;
identification of the sample tested (e.g. batch number);
c)
d) number of specimens tested;
e) test method used and, where a test method other than a test specified in an International Standard is used, full
details of the test procedure;
f) test results.
6 Hydrodynamic testing (see A.2 for rationale)
6.1 Principle
Hydrodynamic testing provides in vitro information on the fluid mechanical performance of the heart valve
substitute under steady and pulsatile flow conditions.
6.2 General
All heart valve substitutes to be tested shall be of quality suitable for human implantation. Before testing, each
heart valve substitute shall have been sterilized by the process used or intended to be used by the manufacturer
during production. If a heart valve substitute can be resterilized prior to implantation, it shall also be subjected to
the recommended maximum number of resterilization cycles, using the method stated by the manufacturer.
IS0 5840:1996( E)
6.3 Steady forward-flow testing
6.3.1 Measuring equipment accuracy and testing fluid
6.3.1.1 The pressure measurement system shall have a measurement accuracy of at least k 0,13 kPa
(+ 1 mmHg).
6.3.1.2 All measuring equipment shall have a measurement accuracy of at least + 5 % of the full-scale reading.
6.3.1.3 The fluid used for the test shall be isotonic saline, blood or a blood-equivalent fluid whose physical
properties (e.g. specific gravity, viscosity at working temperature) shall be stated.
6.3.2 Test apparatus requirements
6.3.2.1 Steady-flow testing for aortic and mitral heart valve substitutes shall be conducted in a straight tube
having an internal diameter of 35 mm.
6.3.2.2 The test system shall be capable of generating flowrates of at least 30 I/min.
6.3.2.3 Flow entering the test chamber shall be relatively nondisturbed, which can be achieved with a flow
straightener upstream of the heart valve substitute.
6.3.2.4 Pressure taps shall be located one tube-diameter upstream and three tube-diameters downstream from
the midplane of the heart valve substitute sewing ring. If sufficient data can be provided to demonstrate
comparable results, other pressure tap configurations may be used.
6.3.2.5 The pressure taps shall be flush with the inner wall of the tube.
6.3.2.6 A standard nozzle in accordance with figure 3 a) shall be used to characterize the forward-flow pressure
and flow-measuring equipment.
6.3.3 Test procedure
6.3.3.1 Carry out the test on at least three heart valve substitutes of each tissue annulus diameter.
6.3.3.2 Measure the pressure difference across the test valve and the standard nozzle over a flowrate range of
5 I/min to 30 I/min, in 5 I/min increments.
6.3.4 Test report
The steady-flow test report shall include:
a description of the fl ui d used for the test, ncluding its biolog ical origin or chemical components, temperature,
a)
specific ravity under the test conditions;
viscosity and
g
a description of the steady-flow apparatus, as specified in 6.3.2.
b)
range and standard d eviation of th e followi rfo rmance test va ria ble simulated
Details of the mean, s, at each
Kl Pe
condition for each tes t heart valve substitut e and standar *d nozzle, shall be presented in ta bular or graphic form:
steady flowrate, expressed in litres per minute;
d
d) pressure differences, expressed in kilopascals and in millimetres mercury;
effective orif ice area, expressed in square centi metres, calculated taking into account the pressure recovery
e)
downstream fro m the test heart val ve subs titute
IS0 5840: 1996(E)
Dimensions in millimetres
Surface roughners values in micrometres
8 +0,05
t
-=@--I
--m-------w----
In
d
tl
v3
-
In
Ftow
A
-
d
+I Flow
-_~- P _~_-
Ln m
Lh
L
0,s +0,05
I
---------------
Watt of vessel model
Watt of vessel model
a) Forward flow
b) Back flow
Standard nozzle
Figure 3 -
IS0 5840: 1996(E)
EXAMPLE, based on the Carnot equation:
EOA= A-.
I+ 2AP
PV
d
where
EOA is the effective orifice area;
A is the cross-sectional area of the tube;
AP is the mean pressure difference across heart valve substitute;
V is the cross-sectional average velocity in the tube;
is the density of testing fluid.
P
6.4 Steady back-flow leakage testing
6.4.1 Measuring equipment accuracy and testing fluid
6.4.1.1 Regurgitant volume measurements shall have a measurement accuracy of at least rt 1 ml.
6.4.1.2 All measuring equipment shall have a measurement accuracy of at least & 5 % of the full-scale reading.
be isotonic saline, blood or a blood -equivalent fluid whose physical
6.4.1.3 The fluid used for the test shall
properties (e. g. specific gravity, v iscosity at wo rking tern perature) shall be s tated.
6.4.2 Test apparatus requirements
6.4.2.1 The steady back-flow leakage testing shall be conducted in an apparatus that is capable of generating
constant back-pressures in the range of 5,2 kPa to 26 kPa (40 mmHg to 200 mmHg).
6.4.2.2 The heart valve substitute shall be mounted in a manner to prevent leakage around and through the
sewing ring.
6.4.2.3 A standard nozzle in accordance with figure 3 b) shall be used to characterize the back-pressure, leakage
#ment.
volume flowrate and pressure-measunng
6.4.3 Test procedure
6.4.3.1 Carry out the test on at least three heart valve substitutes of each tissue annulus diameter.
6.4.3.2 Measure the static leakage across the test valve and the standard nozzle at five equidistant back-
pressures in the range of 5,2 kPa (40 mmHg) to 26 kPa (200 mmHg). Collect at least five measurements at each
condition.
6.4.4 Test report
The steady back-flow test report shall include:
a descriptio n of the flui d use d for the test, i ncluding its biological origin or chemical components, temperature,
VI under the test conditions;
scosity an d specific g ravity
a description of the steady flow apparatus, as specified in 6.42;
b)
c) details of the mean, range and standard deviation of the performance test variables, at each simulated
condition for each test heart valve substitute and standard nozzle, presented in tabular or graphic form; i.e.
static leakage volume flowrate, expressed in litres per minute, as a function of back-pressure, expressed in
kilopascals.
@ IS0 IS0 5840: 1996(E)
6.5 Pulsatile-flow testing
Measuring equipment accuracy and testing fluids
6.5.1
6.5.1.1 The pressure measurement system shall have a natural frequency of at least 20 Hz and a measurement
accuracy of at least & 0,26 kPa (+ 2 mmHg).
6.5.1.2 Regurgitant volume measurements shall have a measurement accuracy of at least + 2 ml.
6.5.1.3 All measuring equipment other than that specified in 6.5.1 .I and 6.5.1.2 shall have a measurement
accuracy of at least + 5 % of the full-scale reading.
6.5.1.4 The fluid used for the test shall be isotonic saline, blood or a blood-equivalent fluid whose physical
properties (e.g. specific gravity, viscosity at working temperature) shall be stated.
6.5.2 Test apparatus requirements
6.5.2.1 The pulsatile-flow testing shall be conducted in a pulse duplicator which produces pressure and flow
waveforms that approximate physiological conditions (see figure 4).
6.5.2.2 The pulse duplicator shall have had its properties and performance established by means of testing
reference valve(s).
6.5.2.3 The pulse duplicator shall have a variable stroke volume in the range of 30 ml to 100 ml or greater.
The pulse duplicator shall have a cycle rate range of 40 cycIes/min to 120 cycles/min or greater.
6.5.2.4
6.5.2.5 The pulse duplicator shall be an equivalent hydrodynamic model of the systemic circulation, incorporating
components that are analogous to systemic vascular resistance and to systemic vascular compliance.
Diastote
Systote
c-
P ! I ‘\ ’ Ad- Arterial
‘.
-w
-I
I
-\
Ventricular
Atriat
\\
#--
,/
-l
.’
.5-e
O-
Time
Outflow
sl
Inf tow
s
s
>
k
\
I
U
.-
L
\
c
/
I \
/
i.i ---
I
n -
O>
IS
Figure 4 - Diagrams of haemodynamic waveforms simulating those of healthy humans
@ IS0
IS0 5840: 1996(E)
6.5.2.6 The pulse duplicator shall permit measurement of time-dependent pressures and flows.
6.5.2.7 The system shall simulate a mean arterial pressure of at least 13 kPa + 0,65 kPa (I 00 mmHg 2 5 mmHg),
with an arterial peak systolic pressure of between 14,3 kPa and 19,5 kPa (110 mmHg and 150 mmHg) and an
arterial diastolic pressure between 7,8 kPa and II,7 kPa (60 mmHg and 90 mmHg), depending on valve size and
cardiac output.
6.5.2.8 The systolic forward flow shall account for 35 % + 5 % of the total cycle time at a cycle rate of
70 cycIes/min + 10 cycles/min.
6.5.2.9 Relevant dimensions of the cardiac chambers and vessels shall be simulated. The relevant compliance
should also be simulated when testing nonstented biological heart valve substitutes.
6.5.2.10 The chamber shall allow the observer to view and photograph the test heart valve substitute at all stages
of the cycle.
6.5.3 Test procedure
6.5.3.1 Carry out the test on at least three heart valve substitutes of each tissue annulus diameter and one
reference valve in the position in which they are intended to be used.
6.5.3.2 Include qualitative assessments over a flow volume range corresponding to simulated cardiac outputs
from 2 I/min to at least 7 I/min.
6.5.3.3 Examine at least four simulated cardiac outputs.
either consecutive or randomly-selected
6.5.3.4 Make at least ten measurements of each variable obtained from
cycles.
Qualitatively assess the opening and closing action of each heart valve substitute.
6.5.3.5
6.5.3.6 If appropriate, qualitatively assess the flow field in the immediate vicinity of the heart valve substitute.
6.5.3.7
Record or measure:
mean pressure difference across the test heart valve substitute;
a)
b) mean and r.m.s. flowrates through the test heart valve substitute;
c) stroke volume;
d) cycle rate;
e) mean arterial pressure over the whole cycle;
f) duration of forward flow through the test heart valve substitute, as a percentage of cycle time;
g) regurgitant volume at three cycle rates, including the closing volume, the leakage volume (see figure 1) and the
corresponding mean pressure difference across the closed valve.
6.5.4 Test report
The pulsatile-flow test report shall include:
a) a description of the fluid used for the test, including its biological origin or chemical components, temperature,
viscosity and specific gravity under the test conditions;
b) a description of the pulse duplicator, as specified in 6.5.2, and its major components and associated apparatus,
including a schematic diagram of the system giving the relevant chamber dimensions, details of the location of
the pressure-measuring sites relative to the midplane of the heart valve substitute sewing ring, pressure
measurement instrumentation frequency response, and the appropriate representative pressure and flow
waveforms at approximately 70 cycIes/min, cardiac output of 5 I/min and mean arterial pressure of 13 kPa
(100 mmHg);
@ IS0 IS0 5840: 1996(E)
an assessment, including appropriate documentation, of the opening and closing action of a test heart valve
d
substitute and, if appropriate, its adjacent flow field under stated conditions;
a perma nent recording of at least ten consecutive cycles of t he time-depend ent simultaneous pressures,
d)
e heart valve substitute, and t he volume f low through it.
roximal and distal to th
P
tion of the following ulated cardiac
Details of mean, range and stan da rd devia perfo rmance test var ables at e ach sim
substitute and refere lnce valve shall be presented in tabular or graphic form:
output for each test heart valve
simulated cardiac output, expressed in litres per minute;
e)
cycle rate, expressed in cycles per minute;
f 1
duration of forward-flow phase, expressed as a percentage of the cycle time;
9)
stroke volume, expressed in cubic centimetres;
h)
mean and r.m.s. flowrates, expressed in litres per minute;
.
mean pressure difference, expressed in kilopascals and in millimetres mercury;
I)
effective orifice area (provide formula used), expressed in square centimetres;
k)
regurgitant volume, expressed in cubic centimetres, regurgitant fraction, expressed as a percentage, closing
1)
volume, leakage volume and the corresponding mean pressure difference across the closed valve, expressed
in kilopascals and in millimetres mercury;
mean arterial pressure over the whole cycle, expressed in kilopascals and in millimetres mercury.
ml
7 Durability testing (see A.2 for rationale)
7.1 Principle
ion on durability and failure modes experienced in vitro is provided which can be compared to a reference
lnformat
valve.
7.2 General
All heart valve substitutes to be tested shall be of quality suitable for human implantation. Before testing, each
heart valve substitute shall have been sterilized by the process used or intended to be used by the manufacturer
during production. If a heart valve substitute can be resterilized prior to implantation, it shall also be subjected to
the recommended maximum number of resterilization cycles using the method stated by the manufacturer.
7.3 Measuring equipment accuracy and testing fluid
7.3.1 The pressure-measuring system shall have a natural frequency of at least 1 000 Hz and a measurement
accuracy of at least + 0,65 kPa (?I 5 mmHg).
7.3.2 All other measuring equipment shall have a measurement accuracy of at least + 5 % of the full-scale
reading.
The fluid used for the test shall be appropriate for the purpose of the test.
7.3.3
7.3.4 Most mechanical and biological heart valve s u bstitu tes may be tested at room temperature, but ical
mechan
heart valve substitutes using flexible p olymer leaf let s or co ntaining coatings shall be tested at 37 ‘C.
7.4 Test apparatus requirements
7.4.1 The apparatus shall produce a minimum peak pressure difference of 1 I,7 kPa (90 mmHg) across closed
aortic valves, and a minimum peak pressure difference of 15,6 kPa (120 mmHg) across closed mitral valves. These
pressure differences shall be maintained for 95 % of all of the test cycles.
IS0 5840: 1996(E)
7.4.2 The apparatus shall produce full valve opening and closing during each cycle.
7.5 Test procedure
7.5.1 Conduct the test on at least three each of the largest, medium and smallest sizes of each type (aortic and
mitral) heart valve substitute. Test one equivalent-size reference valve under identical conditions, although it may
be tested in a separate testing machine. If the aortic and mitral heart valve substitutes are identical in configuration
except for the sewing ring, then test only in the mitral position.
7.5.2 During the test, examine each heart valve substitute at least every 50 x 106 cycles.
heart valve substitute
7.5.3 Continue the test until failure occurs or until at least 380 x 106 cycles (mechanical 1 of-
200 x 106 cycles (biological heart valve substitute) have been completed.
7.5.4 If failure occurs, describe and document the modes of failure and their most probable cause(s).
NOTE - Failures are characterized by structural damage and/or functional impairment Examples of structural deterioration
include holes, tears, gross delamination, fraying, incomplete coaptation, fracture, excessive deformation, failure of any
Examples of functional impairment include increased
individual component, other mechanical breakdown and/or wear.
regurgitation and/or increased forward pressure difference across the valve.
7.6 Test report
The durability test report shall include:
a) a description of the fluid used for the test, including biological origin or chemical components, temperature,
viscosity and specific gravity under the test conditions;
a description and specification of the test and associated apparatus, including a schematic diagram of the
b)
system;
c) the cycle rate (cycles/min);
d) a validation of the test method, by documentation of the pressure difference, expressed in kilopascals and in
millimetres mercury, across the heart valve substitute and across a reference valve of a corresponding size, as
described by pressure/time waveforms, and appropriate visual recording of the opening and closing of at least
one heart valve substitute of each tissue annulus diameter studied and of at least one reference valve;
e) a detailed description of the appearance of the heart valve substitute at the completion of the test, or upon the
development of structural change and/or failure. Any damage shall be characterized using the appropriate
means, e.g. histology or surface characterization. It shall be indicated if the valves were intact for the length of
the evaluation.
8 Preclinical in viva evaluation (see A.3 for rationale)
8.1 Principle
Data are obtained pertaining to the claimed performance and unanticipated side effects of a heart valve substitute
in VIVO.
8.2 Method
8.2.1 General requirements
a) The test heart valve substitute shall be evaluated in at least one of the anatomical positions for which it is
intended;
rence valves shall
b) the heart valve substi tutes shall be of clinical quality, and of identical design and size; all refe
be of identical design and s ize;
0 IS0
IS0 5840: 1996(E)
c) the same surgical techniques shall be used for the implantation of all of the heart valve substitutes (e.g. suture
technique, anatomical location and orientation);
d) animal welfare shall be addressed in accordance with the principles given in IS0 10993-2.
8.2.2 Test procedure
species, and preferably of the same sex and age,
lmplan t animals of the same with test heart valve substitutes so
that at least six ani mals shall have survived a minimum of 20 weeks after impla ntation.
Implant at least two animals with a reference valve to serve as concurrent controls. Subject each animal in which a
heart valve substitute has been implanted to a post-mortem examination. Thus, the data shall include that obtained
from all animals; those that do and those that do not survive this 20-week period.
The assessment shall provide at least the following:
any pathological consequences to the major organs;
a)
b) the haematological consequences of implantation;
an evaluation of haemodynamic performance during or after the 20-week implantation period, including
cl
measurements of the pressure difference across the heart valve substitute at a cardiac index of approximately
3 I/(min. m2j1 the cardiac output and an assessment of regurgitation;
structural C hange in the heart valve substitute (e.g. macroscopic damage, degeneration of materials,
dj
any
defo rmation an d calcifi cation).
8.3 Test report
The test report shall contain:
a gross and microscopic pathology report on each animal in which a heart valve substitute was implanted,
a)
including any animal that did not survive for the minimum post-implantation period; this report shall include
visual records of the heart valve substitute in situ and the results of any thromboembolism of the major
organs; the cause of death shall be given if the animal was not sacrificed;
b) the description and results of all blood studies performed, including a statement of the time elapsed between
implantation and these studies; blood studies shall include at least an evaluation of haemolysis, haematology
and blood chemistry;
the post-operative haemodynamic performance of the heart valve substitute, including the pressure difference
d
across the heart valve substitute expressed in kilopascals and in millimetres mercury, cardiac output
measurements expressed in litres per minute, a quantitative assessment of regurgitation and visualization of
occluder or leaflet motion;
d) the appearance of the explanted heart valve substitute, including a visual record and an assessment of
structural changes (e.g. macroscopic damage, degeneration of the materials, deformation and calcification); if
appropriate, the functional status of the heart valve substitute shall be assessed by hydrodynamic testing as
described in clause 6;
e) a detailed description of the animal model used, the rationale for its use and the pretest health assessment of
each animal; this shall include documentation of the age of the animal at implantation;
f) the name and dose of medication(s) received by the animal during the survival period (e.g. antibiotics or drugs
which alter haemostasisj;
g) an assessment of the difficulty in surgical handling of the
va Ive and accessories, including any unusual or
unique characteristics;
h) operative procedure! including suture technique, test heart valve substitute orientation and operative
complications;
the names of the investigators and their institutions.
i)
IS0 5840: 1996(E)
9 Clinical evaluation (see A.4 for rationale)
9.1 Principle
Where a clinical evaluation is deemed appropriate, data are obtained on the safety and performance of heart valve
substitutes under normal conditions of use, and the side effects and related risks of heart valve substitute
implantation in humans are determined.
9.2 General
For new heart valve designs, a clinical evaluation shall be carried out. For modifications of an existing valve, the
need for a clinical evaluation shall be considered and the rationale for any decision documented.
A rationale shall be provided for deviation from any specified requirement of this section.
The clinical study shall be conducted in accordance with IS0 14155.
9.3 Number of institutions
The clinical evaluation shall be conducted at a minimum of five institutions. The minimum number of heart valve
substitutes implanted at any institution shall be 20 of each type being evaluated.
NOTE - Each valve type (e.g. aortic or mitral) should be implanted in as broad a distribution of tissue
...